Poster Presentations


POSTER SESSION 1 Sunday, June 17, 2012 12:30--14:00 Linear Park Marquee

Posters available for viewing 9:00--18:00

EPIDEMIOLOGY

1

The Parkinson's disease in Africa collaboration project in Ghana: The story so far

A. Akpalu, M. Cham, R. Cilia, G. Pezzoli (Accra, Ghana)

Objective: The socio-demographic, epidemiologic, clinical features and genetic causes of Parkinson's disease patients attending the Neurology out-patients clinic of the Korle Bu Teaching and Comboni hospitals are reviewed.

Background: Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease thought to be rare in Africa. A colloborative project with the Parkinson's Institute in Milan, Italy is ongoing in Ghana.

Methods: Consecutive patients clinically diagnosed with Parkinson's disease over the last year who were enrolled in the “Parkinson's disease in Africa collaboration project” were recruited. A detailed personal, family and social history was taken followed by a neurological examination, complete Unified Parkinson's Disease Rating Scale (UPDRS) assessment (part I to part IV), Hoehn and Yahr staging and initiation of treatment with Levodopa. Patients are reviewed at 3, 6 and 12 months. Brain imaging with a head CT scan is done were feasible. A saliva sample was collected after informed consent for analysis of the LRRK2-G2019S mutation amongst others.

Results: 35 subjects with parkinsonism have been identified so far: Mean age at onset 65.7±10.5 years; disease duration 7.45±3.1 years; Hoehn and Yahr stage 2. Mean daily levodopa dosage 520+187mg. The LRRK2 exon 41 screening did not reveal the presence of any G2019S mutation in the Parkinson's disease patients studied so far. Recruitment of more patients, follow up at 6 months and 12 months as well as completion of UPDRS data are the main thrust of the study now

Conclusions: A good response to Levedopa is seen and further genetic analysis is required

2

Association of cumulative some heavy metal exposure with Parkinson's disease

U. Dashdorj, B. Tserensodnom, B. Bold, U. Chimedregzen, F. Komatsu, Y. Kagawa (Ulaanbaatar, Mongolia)

Objective: We investigated the association between some heavy metal exposures(Al, Cd, Fe, Cu, Hg) and risk of PD.

Background: The association between PD and exposure to metals has been intensely investigated. Welders exposed to multiple types of metals appear to be at increased risk of developing PD, particularly at an earlier age (Racette et al. 2001).

Methods: The analysis was performed(Yasuda et al., 2010) in research laboratory the La Belle Vie Inc. Tokyo, Japan. As an indicator of chronic exposure heavy metal(Al, Cd, Hg, Cu, Fe), we measured concentrations of scalp hair using an inductively coupled plasma mass spectrometry method.

Results: We enrolled 11PD patients(3 men, 8 woman) and average age 57.3. The levels of Cd(29.87ppb) and Fe(14614ppb) in scalp hair in PD patients showed such as 3 times high than from healthy peoples Japanese. Alumenium accumulation showed the range from 907-11460ppb(6866±6651.0). Concentration it relatively very high from Japanese standart and healthy peoples of Ulaanbaatar. Mercury accumulation demonsrated very low and that range from 43.6-83.88ppb(58±24.7), whereas Japanese standart was 3830ppb.

Conclusions: Exposure to heavy metal was associated with increased risk of Parkinson's disease in Mongolian peoples.

3

Prevalence of neurodegenerative parkinsonism in the isolated population of South-Eastern Moravia, Czech Republic

K. Farníková, P. Kanovsky, L. Mikulicova, P. Jugas, J. Ovecka, M. Kaiserova (Olomouc, Czech Republic)

Objective: To assess the prevalence of neurodegenerative parkinsonism in the small, isolated, rural population of far South-Eastern Moravia.

Background: It has been recently described that the prevalence of neurodegenerative diseases in a small, isolated European communities might be higher than in the general population. We have observed this phenomenon also in the small village (population 1500) in the far south-east Moravia.

Methods: To assess precisely this increased prevalence, we have used the three-stage ascertainment method. All villagers received a validated screening mail questionnaire for parkinsonism. In the second stage of the ascertainment method, trained primary care neurologists identified all persons with positive signs of parkinsonism among those screened positive. In the third stage, all identified persons were admitted to the tertiary movement disorders center to exclude or confirm the diagnosis of parkinsonism.

Results: The response rate was 42%. There were 56 persons screened positive, and 19 of them were identified as manifesting signs of parkinsonism; the diagnosis has been confirmed in 16 of them.

Conclusions: The prevalence rate of 1% is surprisingly high; it substantially differs from the estimated prevalence in the common Central-European population. The next reserach will focus on the genetic background of the families in which has been parkinsonism identified.

4

Frequency and pattern of movement disorders in a Nigerian rural tertiary health care institution: A preliminary study

M.B. Fawale (Ile Ife, Nigeria)

Objective: To study the frequency and pattern of movement disorders with reference to other neurological disorders seen in the out-patients clinic of the Federal Medical Centre, Ido-Ekiti, Nigeria and to compare with observations from urban centres.

Background: There is a need to generate data, which are currently scarce, regarding the epidemiology of movement disorders in Nigeria.

Methods: A record of new patients presenting at the adult neurology out-patients clinic of the Federal Medical Centre, Ido-Ekiti was established in June 2009. Demographic and clinical data of all new patients were documented. The hospital frequency of movement disorders with reference to other neurological disorders was determined by comparing the total number of new movement disorder cases with the total number of new referrals to the neurology clinic over the same period (June 2009 to December 2011).

Results: In the two and a half year period, a total 164 new referrals were received in the clinic, 24 of which were movement disorder cases. Three cases were not eligible for the study). This gives a hospital frequency of 14.8%. The frequency of parkinsonism was 6.2% (10/161) while that of tremor, chorea and dystonia was 3.7% (6/161), 2.5% (4/161) and 1.9% (3/161) respectively. All the patients with parkinsonism met diagnostic criteria for Parkinson's disease (PD). The mean age ± SD of the PD patients was 71.2 ± 8.1 years and was significantly higher than that of the non-PD movement disorder patients (54.1 ± 17.7 years) (p=.014) and the other neurological conditions (47.3 ± 20.5 years) (p=.000). Male preponderance was the rule with ratios of 4:1, 1.8:1 and 1.7:1 for PD, other movement disorders and other neurologic conditions respectively. When compared with reports from earlier observations from an urban centre in the same region of the country, the frequency of Parkinson's disease in this study is much higher (6.2% vs 1.47%). The magnitude of male preponderance (4:1) is slightly different from those reported in past urban studies in the same region (4.5:1 and 3.3:1 respectively).

Conclusions: Although, these data may not be representative of the total population of persons with the disease, they suggest that movement disorders are common in this Nigerian rural center. Parkinson's disease may be more common in rural south-western Nigeria than in urban centers.

5

Pan-American consortium on multiple system atrophy

E. Gatto, C. Cosentino, P. Chana, J.L. Etcheverry, E. Gallin, M. Miranda, Y. Nuñez, V. Parisi, G. Persi, C. Vecchi, A. Sanguinetti, M. Rodriguez-Violante, J. Aparcana, L. Torres, I. Litvan (Buenos Aires, Argentina)

Objective: To describe the clinical and epidemiological characteristics of a series of patients diagnosed with MSA from 6 different centers from North America and Latin America.

Background: Multiple system atrophy (MSA) is an adult-onset and rapidly progressive, neurodegenerative condition that presents with autonomic dysfunction, parkinsonism, cerebellar ataxia and corticospinal deficit. Clinical, demographic and epidemiological data from different regions have provided valuable information concerning the natural history of MSA and have contributed to improved diagnostic criteria. Data of MSA in Latin American countries are limited.

Methods: We retrospectively analyzed the clinical data of 112 patients with MSA recruited from 6 referral movement disorders centers from Argentina, Chile, Perú, Mexico and the United States. Evaluations were performed according to the clinical and imagenologic criteria recently established.

Results: 59 women and 53 men compose the sample, with a mean age of 65 years. Mean disease duration at examination was 5.52 years MSA-P variant was reported in 71.88% of overall population. Interestingly, MSA-C variant was identified in ∼ 40% of cases from Mexico and Chile, two countries with greater “mestizo” populations (admixture between Europeans, Indians, and Africans). The occurrence and distribution of autonomic dysfunction was: 80.7% mictional urgency, 72.8% orthostatism, 57.8%, “cold hands”, 73.4% severe hypophonia and 58.8% dysphagia. REM behavior disorders were reported in 72.22% of cases. Response to levodopa was poor and transitory in 70.31% of patients. MR imaging showed putaminal atrophy in 26.4% of cases, hyperintense putaminal rims in 26.4% and the “hot cross bun” sign in 18.8%. The mean estimate survival was 5.52 years.

Conclusions: This is the first reported series of MSA patients from Latin America and North America. Although, the present series shows a great ancestry variability, the present data were similar to other previously reported international series.

6

The prognosis of psychogenic (functional) motor symptoms: A systematic review

J.M. Gelauff, A.J. Carson, J. Stone (Amsterdam, Netherlands)

Objective: We aimed to systematically review all follow-up studies of psychogenic motor symptoms to examine what is known about symptom outcome, disability and prognostic factors.

Background: Psychogenic (or functional) motor symptoms, refer to weakness or movement disorders that are genuine but do not relate to an underlying neurological disease. There is no systematic review of prognostic studies of these symptoms.

Methods: We used a broad search strategy on PubMed to search for all studies of ten or more patients with psychogenic motor symptoms (or synonyms) reporting follow up data of longer than six months (excluding studies reporting specific treatments). We recorded symptom duration, physical and psychiatric comorbidity, disability, occupational functioning at follow-up and prognostic factors. Diagnostic change has been systematically reviewed elsewhere. [1]

Results: The search strategy yielded 5874 articles; 24 were included. Heterogeneity was found regarding the number of included patients (n=10-491), follow-up duration (6 months-19 years), clinical setting, and data availability. Most studies (n=16) were retrospective, Reported symptom outcome was highly variable (10-90% improvement) but generally unfavorable. Levels of physical disability and psychological comorbidity at follow up were high when reported. Young age was a positive prognostic factor in only 3 of 11 studies when studied. Early diagnosis and satisfaction with care were positive factors in two studies. Gender had no apparent effect. Delayed diagnosis and personality disorder were negatively correlated with outcome. Prognostic factors that varied between studies included comorbid anxiety and depression, IQ, educational status, marital status and, pending litigation.

Conclusions: Existing follow up studies of psychogenic motor symptoms give us some insights regarding outcome and prognostic factors but are limited by their largely retrospective and selective nature. Overall, prognosis appears unfavorable. The severity and chronicity of psychogenic motor symptoms argues for the importance of larger prospective studies including multiple prognostic factors at baseline in order to better understand their natural history.

1. Stone J et al. Systematic review of the misdiagnosis of conversion symptoms/hysteria.. BMJ 2005; 331:989.

7

Plasma urate level associates the odds ration of Parkinson's disease (PD): Out-patient-clinic analysis in the neurology department

H. Iwaki, Y. Tamaki, T. Tsujii, N. Nishikawa, M. Nagai, M. Nomoto (Ehime, Japan)

Objective: To determine whether the serum urate level is associated with the odds ratio of Parkinson's disease (PD) on an out-patient clinic basis.

Background: Urate, the major antioxidant in serum, has been shown to correlate with a lower incidence and slower development of PD in several studies.

Methods: We conducted a trans-sectional analysis of serum urate and PD. All patients above the age of 40 visiting the out-patient clinic in the neurology department were included in the analysis. Other factors considered to be associated with serum urate levels such as sex, age, body weight and estimated glomerular filtration rate (eGFR) were recorded. The background data was compared between patients with and without PD using student t test. The odds ratio of PD was analyzed by logistic regression model.

Results: 373 patients were included in the study. The number of female patients was 211, including 112 patients with PD and the number of male patients was 142, including 71 patients with PD. In both sex groups, age, body weight and eGFR were not statistically different. The mean serum urate concentration of female patients with PD was 4.2 (SD 1.3) mg/dL, which was significantly lower than the female patients without PD, 4.9 (SD 1.4) mg/dL (p<0.0001). The mean serum concentration of male patients with PD was 5.4 (SD 1.2) mg/dL, which was not significantly different to that of patients without PD, 5.7 (SD 1.3) mg/dL (p=0.13). In the logistic regression model analysis, only the serum urate level significantly correlates with PD odds. The higher urate level was related to the lower PD odds ratio. The odds ratio of highest quantile group of serum urate against the lowest quantile is 0.23 (95% CI: 0.11-0.48). The inverse relationship between concentration and odds ratio was more pronounced in the female group than in the male group.

Conclusions: A higher serum urate level correlates with a lower PD odds ratio in the out-patients clinic basis analysis. Urate may have a protective effect on Parkinson's disease.

8

The incidence of Parkinson's disease in North East England

T.K. Khoo, G. Duncan, A.J. Yarnall, D.J. Brooks, R.A. Barker, D.J. Burn (Newcastle upon Tyne, United Kingdom)

Objective: To accurately define the incidence of Parkinson's disease (PD) in North East England using a representative cohort.

Background: Based on previous incidence studies in Cambridge and North East Scotland, the crude incidence of PD ranges from 13.6 to 16.0/ 100,000 population/ year [Brain 2004. Vol 127, pp. 550-560 & Journal of Neurology, Neurosurgery and Psychiatry 2010, vol 81, pp. e21]. The incidence of PD varies across many international studies and may be secondary to inherent methodological differences. This incident study was performed as part of the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation – Parkinson's Disease (ICICLE-PD) study.

Methods: This study was performed for a 24 month period (1st June 2009-31st May 2011). A geographical region comprising Newcastle and Gateshead (total area approximately 256 km2) which is representative of North East England was used. An accurate population denominator (488,576 people) was derived from the primary care patient list size that comprises 70 practices within the region. The National Institute of Clinical Excellence (NICE) guidelines state that all patients in primary care who are suspected to have a parkinsonian syndrome should be referred to specialist clinics for diagnostic evaluation. Specialist clinics were led by neurologists and geriatricians with experience in the diagnosis of PD. Diagnosis of Parkinson's disease was based on the UK Queen's Square Brain Bank Criteria. Subjects diagnosed with PD were referred into the ICICLE-PD study.

Results: A total of 173 cases of PD were identified. DaTSCAN was used as a diagnostic aid in 39/173 (22.5%) of cases. Incident cases comprised 94 males and 79 females (male: female = 1.2). The mean age [SD] was 72.5 years [9.9]. The crude incidence rate of PD in Newcastle-Gateshead was 17.7/100,000 persons/year (Mid-P Exact Test, 95% CI = 15.2-20.5). After age-standardisation to the European Standard Population, the incidence of PD in Newcastle-Gateshead was 13.2/100,000 persons/year (95% CI 11.1-15.2).

Conclusions: The incidence of PD in this study was similar to other well-designed local and international studies. Longitudinal assessment of this cohort will help us confirm diagnostic accuracy and further define risk factors for cognitive decline in PD.

9

Epidemiology and age at onset analysis of Parkinson's disease in the eastern region of Cuba (Holguín)

L. Laguna-Salvia, J.A. Valdevila-Figueira, J.M. Laffita-Mesa (Holguin, Cuba)

Objective: To estimate the prevalence of Parkinson's disease in Holguín.

Background: Parkinson's disease is the second most frequent neurodegenerative disorder, it affects 11% of the population aged >55 years and is the most common cause of parkinsonism. Little is known about the epidemiology of PD in Cuba, and is greatly underestimated the frequency of PD in the eastern region of the country.

Methods: We developed an active screening to estimate the frequency of PD in Holguín.

Results: We identified 358 subjects afflicted with PD in Holguín situated in the eastern region of Cuba. The picture suggest a prevalence of PD 34.5*105 people. All these individuals belong to the 14 municipalities in Holguín with conspicuous concentration in Holguín where more than half were found. Atypical forms of Parkinson's disease were ignored in the current study but are very frequent suggesting that parkinsonism in this region may reach comparable values to SCA2 (40.18 per 105) which reach the highest worldwide prevalence in the same region due to a founder effect. Age at onset averaged 58.05±10.74yrs and Disease duration 8.60±5.21yrs. Other regions in the eastern of Cuba with considerable frequency of PD were Camaguey, Tunas, Santiago de Cuba, Granma, and Guantánamo.

Conclusions: We found a considerable number of typical parkinsonian individuals in Holguín. This afflicted population need to be genetically delineated and other factors contributing to the PD etiology needs to be unveiled for improve treatment and diagnostic.

10

The progression markers in the premotor phase (PMPP) of Parkinson's disease study

I. Liepelt-Scarfone, K. Mueller, C. Bormann, K. Gauss, J. Streffer, D. Berg (Tuebingen, Germany)

Objective: To design and report baseline characteristics of a two year longitudinal study for the evaluation of disease progression in a highly enriched risk cohort for PD.

Background: Individuals with SN hyperechogenicity (SN+) have a 17 fold increased risk for PD. Although this method is sensitive for early detection its predictive value is low. Therefore a combination of SN+ and further markers indicating neurodegenerative decline seems promising.

Methods: The high risk (HR) cohort was defined by the presence of SN+ and additional occurrence of (i.) one motor sign of PD or (ii.) either two of the following markers: positive family history of PD, life time prevalence of depression, hyposmia and one sided reduced arm swing. The HR group was compared to patients with early PD (age>50 years, Hoehn&Yahr<2.5) and controls. Every 6 months motor, olfactory function and mood were assessed. Yearly, a comprehensive assessment referring to numerous markers and signs (e.g.123I-FP-CIT-SPECT, Magnetic-Resonance-Imaging, movement analysis, EEG) was performed.

Results: At baseline 40 HR persons, 16 PD patients and 40 controls were investigated. The control group was divided into 14 volunteers receiving the same comprehensive assessment as patients and 26 participants screened for blood analysis. First analyses of parameters referring to autonomic dysfunction, EEG and cognitive performance reveal that most of the calculated parameters in the HR group are between those of controls and PD.

Conclusions: Cognitive and autonomic parameters of individuals recruited as enriched risk persons for the development of PD reveal values between healthy controls and early PD indicating that the recruitment strategy may indeed indentify high risk individuals – a hypothesis that needs to be verified in follow up exams.

11

Prevalence and progression of mild parkinsonian signs in elderly men and women (Bruneck-study cohort): A population-based study

P. Mahlknecht, H. Stockner, S. Kiechl, J. Willeit, A. Gasperi, G. Rungger, W. Poewe, K. Seppi (Innsbruck, Austria)

Objective: To assess the prevalence and progression of mild parkinsonian signs (MPS) in the general population.

Background: MPS are common in the elderly population. However, the overall progression of these signs is not well defined.

Methods: Subjects of an ongoing prospective population-based study of carotid atherosclerosis and stroke risk (the Bruneck Study) underwent a baseline and 5-year follow up neurological assessment including the entire motor portion of the Unified Parkinson's disease rating scale (UPDRS III). Diagnosis of Parkinson's disease (PD) was based on UK Brain Bank Criteria, MPS were defined as follows: UPDRS III rating ≥ 2 points or presence of rest tremor (Louis et al. 2005).

Results: From the 574 baseline-subjects aged 55-94 years, 86 subjects (15.1%, 95%CI [12.3-18.3]) showed MPS. At follow-up 488 subjects aged 60-97 years were re-evaluated and 159 subjects (32.6% [28.6-36.9]) were found with MPS. Hence, there was a significant increase in the prevalence of MPS over the time course of 5 years (Chi-square test, p<0.001). Also mean UPDRS III ratings in the MPS group rose significantly from 3.8 (SD ±3.0) to 6.1 (SD±4.2) points (Wilcoxon signed-rank test, p<0.001). From the 86 subjects with MPS at baseline, 15 presented without MPS (17.4% [10.8-26.9]) at follow-up, 42 still showed MPS (48.8% [38.6-59.2]) and 5 had progressed to PD (5.8% [2.2-13.2]). There were 5 incident PD cases in the cohort without MPS at baseline (Chi-square test, p=0.011). Hence, the relative risk for incident PD was 5.3 [1.6-17.9] times higher in the MPS group compared to the non-MPS group.

Conclusions: In line with previous studies, we found a high prevalence of MPS in the general community. Prevalence as well as severity measured by the UPDRS III increased with age. The 5-year incidence of PD was higher in subjects with MPS compared to those without.

12

Tracking Parkinson's: The PRoBaND study (Parkinson's repository of biosamples and networked datasets)

N. Malek, N. Bajaj, R. Barker, Y. Ben-Shlomo, D. Burn, T. Foltynie, H. Morris, N. Williams, N. Wood, D. Grosset (Glasgow, United Kingdom)

Objective: To evaluate the clinical heterogeneity and variability in progression in Parkinson's disease in relation to genetic variation.

Background: PRoBaND is a large prospective multi-centre clinical study of Parkinson's disease patients in 35 centres in the United Kingdom, which commenced in January 2012. It is a natural history study of recently diagnosed and young onset Parkinson's disease patients and their relatives, with banking of DNA and serum. The study is funded by Parkinson's UK, initially for a 5-year period.

Methods: Data and blood samples for genetic analyses will be collected from 2000 PD patients diagnosed by UK Brain Bank Criteria within the preceding 3 years (recent onset cases) and 240 cases diagnosed at under 50 years of age (young onset cases). Data will also be collected from 750 first degree relatives (mainly siblings). The dataset includes demographics, medication, motor severity and non-motor symptoms. Recent onset PD patients will be reviewed every 6 months for an initial 3 years. First degree relatives will be reviewed at baseline and 3 years. Genetic testing will include LRRK2, PARKIN, DJ1, PINK1 and GBA.

Results: Data capture is by an online database (www.clinbase. co.uk). It is linked to other natural history studies, including the Oxford Discovery Award, the Non-motor Longitudinal Study (NILS), and the Parkinson's UK Tissue Bank. Data and biosamples will be accessible to study collaborators, and on application to other researchers to assist relevant studies.

Conclusions: Genetic diversity may account at least in part for phenotypic variability in PD. Large natural history studies are underway to explore these relationships and determine biomarkers predictive of disease course.

13

Frequency and clinical characteristics of movement disorders at the neurology clinic of the LAUTECH teaching hospital Osogbo Nigeria

A.F. Mustapha (Osogbo, Nigeria)

Objective: 1) To determine the frequency or prevalence of movement disorders at the neurology clinic of LAUTECH Teaching Hospital

2) To determine the frequency of the different movement disorders in terms of gender and age.

Background: Disorders of movement are relatively common in neurology practice. They range from benign to disabling and life threatening conditions. Parkinsonism is the most frequent and affects all races and both sexes. It is common in individuals older than 50 years and is a progressive debilitating condition which significantly affects the quality of life of the sufferers. Others include benign essential tremor, dystonia, chorea/athetosis and tics etc. Disorders of movement have not been well- studied in Nigeria and there are few hospital reports about it.

Methods: This study was a descriptive analysis of all cases of movement disorders seen at the neurology clinic of LAUTECH Teaching Hospital, Osogbo, Nigeria from June 2005 till December 2011. Demographic variables, clinical data and results of laboratory investigations were all collected. Statistical analysis was done using the SPSS 15 computer package.

Results: Out of the 450 patients seen during the study period at the neurology clinic, 95 (21.1%) patients had movement disorders with male patients being 72(75.8%) and females 23(24.2%). 65 patients (68.4%) were diagnosed to have parkinsonism which was the commonest followed by benign essential tremor in 17 patients (17.9%), dystonia 4 patients (4.2%), senile tremor 4 patients (4.2%), intention tremors 3 patients(3.2%); chorea/athetosis 2 patients (2.1%). The frequency of movement disorders was highest in the seventh decade for parkinsonism and overall.

Conclusions: Disorders of movement are prevalent among Nigerians in this study affecting one-fifth of the patients. Parkinsonism is the commonest movement disorder seen as in most centers in the world. A close differential was benign essential which followed closely in terms of frequency.

14

Risk factors and early non-motor features for Parkinson's disease: A systematic review and meta-analysis

A.J. Noyce, J. Bestwick, L. Silveira-Moriyama, C.H. Hawkes, G. Giovannoni, A.J. Lees, A. Schrag (London, United Kingdom)

Objective: To evaluate the strength of association between Parkinson's disease (PD) and factors that could be used for population-based screening through systematic review and meta-analysis.

Background: The clinical diagnosis of PD has been associated with a number of risk factors and early non-motor symptoms.

Methods: We conducted a systematic review using PRISMA guidelines. Factors reported to be associated with increased or decreased risk of future PD were identified from the Medline database. Studies were included in the systematic review if they assessed at least one factor preceding a diagnosis of PD, provided relative risks or odds ratios (OR) through a cohort or case-control design, and reported data that could be reasonably obtained in a primary care setting. Where a factor was reported by two or more studies in a consistent manner, a meta-analysis was performed to generate a pooled effect size and 95% confidence interval for each factor.

Results: 200 studies were included in the systematic review. Positive and significant associations with subsequent PD were having any relative with PD (OR 4.46), prior constipation (OR 2.34), anxiety or depression (OR 1.86), pesticide exposure (OR 1.81), head injury (OR 1.55), rural living (OR 1.43), exposure to beta-blockers (OR 1.28), farming occupation (OR 1.23) and well water drinking (OR 1.28). Negative and significant associations were found for smoking (OR 0.64), coffee drinking (OR 0.67), hypertension (OR 0.74), non-aspirin non-steroidal anti-inflammatory drugs (OR 0.83), calcium channel blockers (0.90), and alcohol (OR 0.91). There was no significant association of subsequent PD diagnosis and diabetes mellitus, cancer, oral contraceptive pill use, surgical menopause or hormone replacement therapy, statins, paracetamol or aspirin exposure, tea drinking, history of general anaesthesia or gastric ulcers. Other factors were reported to alter risk and could be included in the systematic review but not the meta-analysis. Examples were hyposmia, erectile dysfunction, excessive daytime sleepiness, physical activity and increased serum urate.

Conclusions: This systematic review and meta-analysis suggests risk factors amenable for screening, which can be used to identify subjects at increased risk of developing PD.

15

Peripheral biomarkers of inflammation and Parkinson's disease in women

E.J. O'Reilly, H. Chen, M. Schwarzschild, A. Ascherio (Boston, MA, USA)

Objective: Prospectively examine peripheral biomarkers of inflammation in relation to future Parkinson's disease among women

Background: Inflammation is present in Parkinson's disease. However, it is not clear whether inflammation is a part of the etiologic process.

Methods: The authors assessed levels of inflammatory biomarkers in plasma at baseline (1990) in relation to future risk of Parkinson's disease in a nested case-control study within the female-only Nurses' Health Study. Between 1990 and 2004, 101 women were diagnosed with Parkinson's disease. Cases were matched to 504 controls, and Parkinson's diagnosis was on average 7.1 years after blood draw.

Results: In analysis adjusted for age, pack-years of smoking, caffeine and alcohol intake, body mass index, and physical activity, the rate ratio (RR)for interleukin-6 was 0.59 (95% confidence interval: 0.29 to 1.19; p for trend: 0.07) comparing the highest (>1.39 pg/ml) to the lowest (<0.63) quartile, and corresponding RR for C-reactive protein was 0.53 (95% confidence interval: 0.25 to 1.44; p for trend: 0.06) comparing women in the highest (>4.24 mg/L) to lowest (<0.69) quartile. Concentrations of fibrinogen, and tumor necrosis factor-α receptors one and two were not related to disease risk.

Conclusions: These findings do not support the hypothesis that peripheral biomarkers of inflammation are elevated in the years prior to Parkinson's disease diagnosis among women.

16

Spectrum of movement disorders at the premier Lagos Movement Disorders Clinic in Nigeria: First year's experience

N.U. Okubadejo, O.O. Ojo, O.O. Oshinaike, I.A. Bankole, C.B. Aiyejusunle (Lagos, Nigeria)

Objective: To provide a report on spectrum of movement disorders in the first year of the Lagos Movement Disorders Clinic.

Background: Although diagnosis of neurological disorders has improved in subSaharan Africa, movement disorders remain under-recognised. Consequently, their management is suboptimal. Globally, management of MD by neurologists with special interest and training in the subspecialty is encouraged to improve quality of care and outcomes. We established the first MD clinic in west Africa in January 2011 to provide specialist care, encourage early referrals, provide a platform for training, and ultimately establish a centre of excellence for MD in west Africa.

Methods: The Lagos Movement Disorders Clinic runs at the Lagos University Teaching Hospital, serving a population of 30 million. At inception, we established a Clinic Database that documents personal data, baseline demographics, and diagnosis. Standardized diagnostic criteria are used. Cases with insufficient data are classified by movement disorder type (hypokinetic or hyperkinetic) and specific movement abnormality.

Results: Between January and December 2011, we registered 184 MD patients. Hyperkinetic MD comprised 82 (44.6%), and hypokinetic MD 102 (55.4%). Frequency by specific MD was: parkinsonism 101 (54.9%), tremor 44 (23.9%), dystonia 27 (14.7%), cerebellar ataxia 2.7%, choreoathetosis 1.6%, myoclonus 1.1%, hemifacial spasms and primary freezing gait (0.5% each). There was a male preponderance of parkinsonism (72:29), dystonia (20:7), and tremors (34:10). Parkinson's disease comprised 84.2% of all parkinsonism. Young onset parkinsonism (≤ 50) occurred in 17.8%. Essential tremor was the commonest non-parkinsonian, non-cerebellar tremor (41/44). 81.5% of dystonias were focal, 11.1% generalized, and 7.4% segmental. The most common dystonias were focal hand dystonia (29.6%) and blepharospasm with orofacial dystonia (18.5%).

Conclusions: The predominance of parkinsonism, tremors and dystonia is similar to other MD clinic reports. This may represent relative population prevalence, degree of disability warranting medical care, or recognition by primary carers driving referral. Improved education and public awareness of movement disorders and availability of specialist care may expand the spectrum of referrals.

17

Physical precipitating factors in functional movement disorders

I. Pareés, M. Kojovic, M. Pires, I. Rubio Agustí, T.A. Saifee, A. Sadnicka, P. Kassavetis, K.P. Bhatia, J. Stone, M.J. Edwards (London, United Kingdom)

Objective: To describe physical events which precede the onset of functional movement disorders (FMD).

Background: Functional disorders are common and disabling but their pathophysiology is still unclear. An historical explanation is that psychological stressors lead to unconsciously produced physical symptoms. However, psychological stressors can be identified in only a proportion of patients, and these may occur years prior to onset of symptoms. Patients commonly report a physical event at the onset of functional symptoms that appears phenomenologically related to subsequent symptomatology. However, this has not been systematically studied in the subgroup of FMD.

Methods: We assessed 50 new consecutive patients with FMD seen in a movement disorders clinic at the National Hospital for Neurology and Neurosurgery, London, UK. Face to face semi-structured interviews were carried out in the outpatient clinic. Physical events such as neurological disease, infection, drug reaction, physical injury or surgery, with clear temporal relationship with the onset of the movement disorder were recorded. Mode of onset was classified as sudden (in minutes), sub-acute (in hours-days) or gradual progression. Presence of additional symptoms from a list of panic-associated symptoms at the onset of FMD was assessed.

Results: A total of 39 females and 11 males (mean age of 39.8 years) were assessed. Main type of FMD was dystonia (34%) followed by tremor (16%) and myoclonus (8%). 30% of patients displayed a combination of two or more functional symptoms. 54% of patients reported sudden onset of FMD, 36% reported a sub-acute onset and the remaining 10% reported a gradual progression. 44 patients reported a physical triggering factor. Physical injury (28%), infection (18%), and neurological disease (18%) were among the most commonly reported triggers. In the 75% of the patients, these occurred within a month prior to the onset of FMD. Physical rather than emotional symptoms of panic were commonly present at the onset of the FMD.

Conclusions: We found that physical events precede the onset of the abnormal movement in most patients with FMD in this series. Physical precipitating factors may provide the initial sensory information necessary to drive subsequent functional symptoms.

18

Baseline characteristics for the first Mexican multicentric cohort study: The Parkinson's disease national registry

M. Rodríguez-Violante, C. Zuñiga, M. López, I. Estrada-Bellman, R. Mathieu, C. Ramírez, A. Cervantes-Arriaga (Mexico City, Mexico)

Objective: To describe demographic and clinical characteristics of patients with Parkinson's disease (PD) attending to five centres participating in the Parkinson's disease national registry (RENAEP).

Background: According to the National Instiute of Statistics and Geography 8.1% of Mexico's population is in the age group of 60 or more years; assuming an approximate PD prevalence of 1% to 2% the expected population with the disease would be 83,000 to 166,600 in our country. Currently there are no studies on PD epidemiology in Mexico, most data avaliable comes from single hospital population. This is the first study designed to create a Mexican PD cohort with yearly follow-up visits.

Methods: We included PD patients attending to the following centres during 2011: Insituto Nacional de Neurología y Neurocirugía, Instituto Nacional de Ciencias Médicas and Hospital General de México (all three in Mexico City), Hospital Civil (Guadalajara) and Hospital Universitario (Monterrey). For this first phase data collected included: Age, gender, familiy history, smoking habits, schooling, age at motor onset, age at diagnosis, motor phenotype, side of onset, current treatment, dosage, time from diagnosis to levodopa (LD) use, motor complications including dyskinesia, wearing off and freezing. Clinimetric instruments for this phase only included Hoehn & Yahr staging and Schwabb & England.

Results: A total of 773 patients were included (56.4% male). The mean age of the sample was 65.3 ± 13 years, while mean age at diagnosis was 58.7 ± 12.9 years. Time from motor onset to diagnosis was 2.4 ± 0.3 years. 14% of the sample had a familiy history of PD. 44.5% had mild disease (HY 1-2), 26.6% moderate (HY 2.5-3) and 9.1% had severe disease (HY 4-5). 78.7% were on levodopa, 22% on MAOi and 52.8% were on DA. Dyskinesia was present in 23.4%, wearing off in 22.4% and freezing of gait in 15.8%.1 (18)

Table 1 (18). Description of the dopaminergic replacement therapy
MedicationFrequencyDaily mean dose
Levodopa78.7%628.8 ± 320.3
Rasagilne10.7%1
Selegiline10.3%10
Pramipexole IR36.4%1.6 ± 1.2
Pramipexole ER6.9%1.4 ± 1.1
Rotigotine1.6%5.8 ± 1.9
Bromocriptine7.1%8.5 ± 4
Entacapone8%NA

Conclusions: With the exception of age of onset, the other features of the studied population were similar to those of international studies. It is estimated the use of levodopa in 80% of patients with PD, while 75% receive DA either, in our study 78.7% were on LD and only 52.8% on a DA. Second phase will include more centres and clinimetric data.

19

Head injury and risk of Parkinson's disease: A systematic review and meta-analysis

A. Samii, M. Etminan, F. Aminzadeh, S. Jafari (Seattle, WA, USA)

Objective: We performed a meta-analysis to investigate the association between head trauma and the risk of developing PD.

Background: Head trauma has been implicated in the etiopathogenesis of Parkinson's disease (PD).

Methods: We included observational studies if they 1) clearly defined PD; 2) defined head trauma leading to concussion; 3) presented odds ratios (ORs) and 95% confidence intervals (95% CI) or provided data to compute these parameters. Random effect model was used to estimate the pooled adjusted OR. Heterogeneity between studies was evaluated with the Q test and the I2 statistics. We did sensitivity analysis to assess the influence of each study and repeated the analysis by excluding the studies with the largest weights. We used funnel plot and Egger's test to assess the presence of publication bias.

Results: After reviewing more than 631 article titles, 29 articles were selected for full review. A total of 19 studies (17 case control, one nested case control, and one cohort study) with 17,898 cases and 77,945 controls were included in the meta-analysis. The pooled OR for the association of PD and head trauma was 1.55 (95% CI: 1.31-1.84). Six studies were found to be the source of heterogeneity in this study. After removing these six studies, the pooled OR 95% CI was 1.41 (1.28- 1.55), and the association of head trauma and risk of development of PD remained statistically significant.

Conclusions: The results of our meta-analysis indicate that a history of head trauma that results in concussion is associated with a higher risk of developing PD.

20

Trends in initiation of antiparkinsonian drug treatment among patients with Parkinson's disease in the UK between 1997 and 2010: A population-based analysis

R. Schade, M. Sturkenboom (Rotterdam, Netherlands)

Objective: To describe trends in initiation of antiparkinsonian drug treatment in PD in the UK between the years 1997 and 2010.

Background: Between the years 2002 and 2006, a number of treatment recommendations for PD have been published. Data on real-life prescribing behaviour for treatment initiation in PD using longitudinal patient level data are scarce.

Methods: Data came from the THIN database which comprises longitudinal medical records of more than 8 million patients from more than 300 general practices in the UK. The database is representative for the UK population by age, gender, medical conditions and death rates. We identified a cohort of PD patients who were 50-89 years of age and received at least two antiparkinsonian drug prescriptions between 1997 and 2010. Percentages of patients receiving treatment regimes were calculated per sex, age, and calender year.

Results: The cohort involved 6261 newly treated PD patients (41% female) with a mean age of 73.3 (SD 8.5) years at first antiparkinsonian drug prescription. Dopamine agonist monotherapy increased from 13-18% before 2000 to 41-58% after 2001 for age category 50-64, while it increased from below 5% before 2000 to 11-16% after 2001 for age category 65-89. MAO inhibitor monotherapy increased to 10-14% after 2006 for age category 50-64, while it increased to around 8% in 2010 for age category 65-89. Monotherapy with anticholinergics decreased from 8-16% before 2003 to 2-3% after 2006 for age category 50-64, and decreased from 3-5% before 2003 to 0.4-0.7% after 2006 for age category 65-89. Levodopa monotherapy decreased decreased from 48-68% before 2002 to 22-38% after 2006 for age category 50-64, and decreased from 83-88% before 2003 to 76-79% after 2006 for age category 65-89.

Conclusions: There were substantial changes in prescribing behaviour for treatment initiation between 1997 and 2011. Critical evaluation and further investigation may be advised. Most patterns do not conflict with published recommendations, eg, to opt for delay of levodopa therapy in younger patients and to avoid use of anticholinergics in the elderly.

21

Incidence and prevalence of primary dystonia in Buenos Aires

C.V. Stefani, J.P. Tartari, A.M. Toral, A.L. Bisonni, D.H. Giunta, D.J. Bauso, E. Cristiano (Buenos Aires, Argentina)

Objective: To determinate the incidence of primary dystonia and the prevalence of different types of primary dystonia in an adult population from Buenos Aires City, Argentina.

Background: Primary dystonias are classified according to its distribution in focal, multifocal, segmental and generalized. To date there are no epidemiological data from Argentina.

Methods: The population was all members older than 18 years of the “Plan de Salud, Hospital Italiano de Buenos Aires”, a large prepaid health medical organization (HMO) in Buenos Aires City. Retrospective surveillance of the HMO's computer based-medical record system for “dystonia” or related disorders using the International Classification of Diseases system (ICD9) was conducted by 3 movement disorders specialists. A review of database of Movement Disorders section was also performed. Incidence Density (ID) was calculated with 95% confidence interval between January 2004 and December 2008. The day selected for prevalence calculation was December 31, 2008 and the denominator was the total of 123.238 members older than 18 years old. This study was conducted in parallel with other epidemiological studies of movement disorders with similar methodology.

Results: Fifty-two cases of primary dystonia were found. Forty (76.9%) were female. Average age at onset was 59.6 ± 17.6 years (10 – 79 years). The prevalence was 42.2/100,000. Focal dystonia had the highest prevalence 32.4/100,000; the prevalence of segmental dystonia was 9/100,000 and the prevalence of generalized dystonia was 0.8/100,000. Regarding focal dystonias the most frequent was cervical dystonia 14.6/100,000; the prevalence of blepharospasm was 8.1/100,000. Laryngeal dystonia was as prevalent as limb focal dystonia 4.9/100,000. A total of 35 incident cases of dystonia were identified. ID was 4.5/100,000 person-years.

Conclusions: We report the first epidemiological data of primary dystonia from Buenos Aires City, Argentina. The prevalence of primary dystonia was similar of some European countries.

22

Clinical and epidemiological features of hemifacial spasm in Buenos Aires, Argentina

J.P. Tartari, C.V. Stefani, D.H. Giunta, E. Cristiano, D.J. Bauso (Buenos Aires, Aruba)

Objective: 1) To describe clinical and demographic features of hemifacial spasm in an adult population of Buenos Aires City, Argentina. 2) To determinate its prevalence.

Background: Hemifacial spasm is characterized by clonic movements of the facial muscles of one side of the face. There are few epidemiological studies worldwide regarding hemifacial spasm.

Methods: The population was all members older than 18 years of the “Plan de Salud, Hospital Italiano de Buenos Aires”, a large prepaid health medical organization (HMO) in Buenos Aires City. Retrospective surveillance of the HMO's computer based-medical record system for “hemifacial spasm” or related disorders using the International Classification of Diseases system (ICD9) was conducted by 3 movement disorders specialists between January 2004 and December 2008. A review of database of Movement Disorders section was also performed. Prevalence was calculated on 31/12/2008 the denominator was the total of 123.238 members older than 18 years old. This study was conducted in parallel with other epidemiological studies of movement disorders with similar methodology.

Results: We found 47 patients with hemifacial spasm, 72.3% were female. The age at onset was 62.5 years ± 13.6 (33-80 years). The left side was involved in the 60.5% of the patients. Primary etiology was the most frequent (76.6%) followed by postparalitic hemispasm (23.4%). In 27% of primary cases that MRI was performed we found neurovascular compression. Prevalence was 34/100,000.

Conclusions: We report the first epidemiological data of hemifacial spasm from Buenos Aires City, Argentina. Our prevalence is higher than reported in other series. Primary etiology was the most frequent.

23

Prevalence of Parkinson's disease in Ukraine

Y.O. Trufanov (Lugansk, Ukraine)

Objective: To compare the prevalence of Parkinson's disease (PD) in Ukraine with other countries.

Background: According to different researchers' data, the number of the registered cases of PD in the USA, Canada, the countries of the European Union (Italy, Spain, Bulgaria, the UK, Estonia, Sweden), Australia and the countries of Asia (South Korea, Japan, China) ranges from 104 to 374 per 100,000 of population.

Methods: Statistical data of the Ministry of Health Protection of Ukraine was obtained to determine prevalence of PD. Ukraine is divided into 25 regions (oblasts), with separate data for the cities of Kiev and Sevastopol.

Results: Table 1 presents systematized data of reported cases of PD in all Ukrainian regions.1 (23)

Table 1 (23). The number of registered patients with PD per 100,000 of population all over Ukraine and in different regions of Ukraine (modified from Hobzei M.K., Zinchenko O.M., Golubchikov M.V., Mishenko T.S. The state of neurological service of Ukraine in 2010. Parkinson Disease)
Oblast (Region)The number of PD patients per 100,000 of population (2010)
Ukraine59.6
100 and more patients per 100,000 of population
Vinnytsya122.5
Kyiv city111.3
50-100 patients per 100,000 of population
Lviv91.9
Cherkasy90.9
Kyiv region85.8
Khmelnytskyi81.8
Kharkiv71.3
Zaporizhia69.3
Poltava68.7
Zakarpattia65.8
Volhynia64.8
Chernihiv63.2
Sevastopol city61.1
Zhytomyr52.2
30-50 patients per 100,000 of population
Luhansk47.0
Mykolaiv46.2
Ivano-Frankivsk46.1
Rivne45.0
Ternopil43.5
Kirovohrad42.8
Kherson39.2
Chernivtsi38.8
Sumy38.8
Autonomous Republic of Crimea38.7
Dnipropetrovsk31.8
Odesa31.1
Donetsk30.6

As seen in table 1, the number of the registered patients with PD in Ukraine makes 59.6 per 100,000 of population. The largest number of the patients with PD per 100,000 of population in 2010 was registered in the Vinnytsya region (122.5) and in the city of Kyiv (111.3). In 11 regions of Ukraine and in the city of Sevastopol, the number of the registered patients was 50-100 per 100,000 of population. In 13 regions of Ukraine, only 30-50 per 100,000 of population was seen.

Conclusions: The prevalence of PD in Ukraine appears to be lower than in other countries. As well, the number of the registered cases of PD varies significantly among regions. Whether these are true differences, or the variation is due to lack of awareness of the disease, misdiagnosis, and lack of subspecialty training in Movement Disorders requires further study.

24

Establishing a population-based cohort to investigate Parkinson's disease

S. Tunc, J. Graf, A. Schmidt, V. Tadic, S. Wolff, A. Lorwin, E.J. Vollstedt, J. Hampf, L. Piskol, C. Klein, M. Kasten, J. Hagenah (Lübeck, Germany)

Objective: To study mild parkinsonian signs (MPS) and substantia nigra (SN) hyperechogenicity by transcranial sonography (TCS).

Background: MPS (defined as mild or isolated cardinal signs) are present in 30-40% of the elderly and may progress to Parkinson's disease (PD). Hyperechogenicity of the SN can be detected by TCS in 15% of healthy adults and almost 90% of PD cases. A possible relation between SN hyperechogenicity and MPS is elusive.

Methods: We screened a population-based sample of 10,000 inhabitants of Lübeck/Germany, aged 50-79, including questions on PD symptoms, comorbidity, and demographic data. We classified four groups: 1) no symptoms; 2) comorbidities explain symptoms; 3) symptoms resemble PD; 4) reported PD-diagnosis. Subjects were administered the UPDRS and TCS of the SN. Likely presence of MPS was defined as a score of ≥ 1 for one of the UPDRSIII items ‘bradykinesia’ ‘rest tremor’ ‘rigidity’ ‘postural instability’ ‘gait disturbance’ or for the UPDRSII item ‘handwriting’. TCS data was averaged across groups using the side with the larger SN hyperechogenicity. An area ≥0,25 cm2 was defined as enlarged.

Results: We examined 617 people, 316 men aged 66±7 years, and 301 women aged 65±7 years. MPS were present in 300 (49%) participants, their frequency differed by motor feature: Rigidity (9%) tremor (6%), bradykinesia (17%), gait disturbance (20%), postural instability (31%), and altered handwriting (23%). Frequency of MPS differed by group status with increasing prevalence of each MPS from Group 1-4. Similarly, the size of SN hyperechogenicity increased from Group 1 (0.16±0,1cm2; p=0.004) to Group 4 (0.27±0.11cm2; p=0.002), as did the percentage of enlarged SN: Group 1(10%), Group 2 (14%) Group 3 (35%) and Group 4 (65%). Participants with MPS had larger hyperechogenic areas in the SN than those without MPS (p=0.022).

Conclusions: None of the MPS was present in all PD patients and none is absent in all controls, underlining the complexity of diagnosing PD. An enlarged SN is more frequent in subjects with symptoms resembling PD than in controls, and its size associated with the occurrence of MPS, suggesting SN hyperechogenicity as a possible pre-motor marker.

25

Stimulant use associated with risk of Parkinson's disease

S.K. Van Den Eeden, K.S. Albers, C.M. Tanner, A.D. Leimpeter, C.P. Quesenberry, L.M. Nelson (Oakland, CA, USA)

Objective: To examine the risk of Parkinson's disease (PD) associated with stimulant use.

Background: Recent studies have reported that amphetamine use was associated with an increased risk of Parkinson's disease.

Methods: Our study population was the participants in the Parkinsonism Epidemiology in Kaiser 3 (PEAK3) case-control study. Cases were individuals under the age of 60 years who were newly diagnosed individuals with idiopathic Parkinson's disease while a member of Kaiser Permanente Northern California between 2000 and 2005. Cases (n=174) were determined by confirmed by expert review of KPNC electronic clinical records. Controls (n=191) were matched to cases based on age and sex. Exposure to amphetamines was determined by questionnaire regarding the use of legal and illegal drugs, including stimulants. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI) associated with stimulant use, after adjusting for confounders.

Results: Mean age on onset for cases was 53.3 years. Cases were, on average, less likely to smoke, and drink more coffee compared to controls. Cases and controls had similar body mass index distribution. Nine cases and five controls reported stimulant use. The OR for use of stimulants was 2.01 (0.63-6.45).

Conclusions: While the association between stimulants and an increased risk of Parkinson's disease was similar to recent studies, we cannot rule out chance in this study.

26

Withdrawn by Author

27

Prevalence of restless legs syndrome in Ankara, Turkey

A. Oto, O. Aykac, N. Yilmaz, M.C. Akbostanci (Ankara, Turkey)

Objective: To determine the prevalence of restless legs syndrome (RLS) in Ankara, Turkey.

Background: RLS is a common disorder with prevalence rates between 5 to 30 percent. Prevalence is highest in the western world, and gets less frequent as one goes to east, down to 0,1% in some eastern Asian countries.

Methods: Number of people, above 15 years of age, living in Ankara was 2420973 at the time of the study. We made contact with 815 persons from randomly selected 600 addresses from eight administrative districts of the city. This number was calculated taking confidence 95%; power 90%; and estimated prevalence of RLS 10%. Four experienced pollsters visited the addresses and helped to complete a four-item screening questionnaire. Anyone who gave a positive response to any of the four questions were invited to hospital by telephone and evaluated by two neurologists based on the standard diagnostic criteria suggested by the International Restless Legs Syndrome Study Group (IRLSSG).

Results: Among 429 persons answered yes to any one of the screening questions, 109 of them were unavailable to our telephone calls, and among 320 persons who could be reached by telephone, 39 were diagnosed to have RLS (32 females, 7 males). So the prevalence of RLS was 5.5% (7.4% among females, 2.5% among males).

Conclusions: The prevalence of RLS in Ankara was found 5.5%. This rate is quite similar to other studies from Turkey (3.2% from Mersin, 3.4% from Kandira). The prevalence rate is somewhere between western and eastern world as is the geographical location of Turkey.

28

Prevalence of Parkinson's disease and agricultural employment in Austria

H. Zach, H. Cetin, G. Fülöp, W. Pirker, E. Auff, F. Zimprich (Vienna, Austria)

Objective: To evaluate the association of farming and the incidence of Parkinson's disease (PD) in Austria.

Background: Rural living has long been debated as a risk factor for PD. A few epidemiological studies have implicated the use of pesticides in farming with the incidence of idiopathic PD, however these data are considered incomplete and are therefore regarded controversially.

Methods: We used the national hospital discharge register to identify all patients discharged with a main or secondary diagnosis of PD (ICD-10 G20) in Austria in 2007. These figures were correlated with the agricultural index in each district, which expresses the share of agricultural employment. Both figures were provided by the OEBIG (Austrian Health Institute).

Results: For the investigated year 2007, we identified 14.771 individual patients hospitalized with a main or secondary diagnosis of PD (ICD-10 G20) in Austria. This yielded a hospitalized patients prevalence of 177 per 100.000 residential population. We correlated the standardized hospitalized patients prevalence rates for all Austrian districts (n = 100) with the agricultural index of these districts. We found a highly significant positive correlation between these parameters, i.e. a higher hospitalized-prevalence of PD with an increasing employment in the agricultural sector (linear correlation, p= 0.001). The agricultural index would explain about 9% (R2) of the total variance of the hospitalized PD-patients' prevalence.

Conclusions: The significant association between the prevalence of PD and the agricultural employment in Austria supports the view that agricultural toxins or other factors associated with an agricultural lifestyle might be involved in the pathogenesis of this disease.

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29

Cognitive dysfunction in early Parkinson's disease: Neuropsychological analysis

C. Adams, R. Fulbright, M. Thomas (Bedford, TX, USA)

Objective: To determine whether there are cognitive deficits in early Parkinson's disease (PD) patients and whether there are deficits other that executive dysfunction.

Background: Executive dysfunction has been shown to be associated with PD later in the disease process. However, few studies have looked at other cognitive deficits in PD patients, such as parietal and temporal lobe dysfunction. Further few studies have analyzed cognitive deficits early in the disease process.

Methods: Neuropsychological evaluations were retrospectively analyzed for 102 genetic and idiopathic PD patients. ANOVAs were run on the data after separating the patients into those with 0-5, 5-10, and greater than 10 years disease duration.

Results: Integrated Visual and Auditory Continuous Performance tests of Auditory Stamina, and Auditory Vigilance and Controlled oral Word Association tests showed a trend for a significant difference between the groups [table 1]. Wechsler Memory Scale Logical Memory Percent Retention was the only score that showed a significant difference between groups [table 1]. The groups were not significantly different in mean age (0-5: 70.72, 5-10: 69, >10: 69.65). Executive function appeared to be compromised even from 0-5 years of disease as shown by the pie chart below [figure 1]. Specifically, performance on the COWA and the trail-making tests A and B were below average. Consistency, Vigilance, Focus, and speed were also below average. Further, patients showed deficits in the Wechsler Adult Intelligence Scale III block design test and Wechsler Memory Scale Visual Reproduction I test compared to average. 1 (29)1 (29)

Figure 1 (29).
Table 1 (29). 
TestAbbreviation0-5 years5-10 years>10 yearsANOVA
IVA Stamina AuditoryStamAud100.708333389.7142857192.94117647F=3.06, p=0.054
IVA Vigilance AuditoryVigAud91.2469.8260869671F=2.80, p=0.0687
Stroop Color Word Raw ScoreStroopCW64.8611111157.6086956564.75F=0.68, p=0.51
WMS-III Logical Memory % Retention Scaled ScoreLMRetSS11.6538461510.333333339.473684211F=3.73, p=0.03
WMS-III Visual Reproduction II Scaled ScoreVR2SS9.438.9210.15F=0.63, p=0.54
Controlled Oral Word Association TestCOWAraw35.9640.6432.64F=2.68, p=0.08
WAIS-III SimilaritiesSimil10.0606060610.3076923111.65384615F=2.61, p=0.080

Conclusions: In addition to executive dysfunction, test results were consistent with dysfunction in the parietal lobe (block design) and temporal lobe (WMS-III Visual Reproduction I). Further, cognitive deficits can be seen even at 0-5 years of disease duration. Physicians should consider running more extensive cognitive testing batteries on PD patients earlier in the disease process.

30

Diurnal sleepiness and executive dysfunctions: A virtual and neuropsychological study in Parkinson's disease and sleep apnea syndrome

G. Albani, L. Priano, P. Cipresso, S. Raspelli, R. Pignatti, P. Ferronato, A. Liuzzi, G. Riva, A. Mauro (Piancavallo, Italy)

Objective: Aim of this study was to evaluate the impact of sleep disturbances on decision making in non demented Parkinson's disease (PD) patients compared with Sleep Apnea Syndrome patients (OSAS), by using a virtual immersion in a supermarket.

Background: In PD, sleep disturbances are one of the most relevant symptoms in the premotor phase and often occurs even in de-novo or early-middle stages, when, the daily amount of dopaminergic therapy is still low; in this clinical stage, executive functions may be mildly altered, and may appear normal by the neuropsychological tests. Also patients with OSAS may often complain attention and memory deficit, clinically correlated with diurnal sleepiness.

Methods: We used a Virtual Reality version of the Multiple Errand Test (VMET) in order to evaluate decision making ability in 12 PD not-demented patients, 12 OSAS patients and 14 controls. The MET is an assessment of executive functions in daily life and consists to perform tasks according predefined rules, so that there are items to be bought and informations to be obtained. (www.neurovr.org). All three groups of patients performed a videopolysonnographyc study within a week after the VMET evaluation and a dedicated neuropsychological battery including FAB, Corsi, MMSE, Panda, Digit span forward and backward, Raven, Rey, Trail making test Token test.

Results: In control subjects, neuropsychological tests resulted correlated with findings of VMET. By comparing with controls, while OSAS patients showed no significant differences, PD patients showed significant lower performances in the virtual strategies. Muchmore, the defective strategy in a virtual supermarket was significantly correlated with polysonnographyc abnormalities.

Conclusions: In our study patients with OSAS showed a normal decision making in the virtual test. On the other side, our data suggest that in PD, the alteration of some executive functions may be correlated much more with the abnormal microstructure of sleep, than the deprivation of sleep “per se”. Neurodegenerative process may involve common anatomofunctional pathways regulating REM and N-REM sleep structure and some executive functions.

31

Graded dual task benefits of cognitive tasks on cycling in Parkinson's disease: Effects of kinesia paradoxa

L.J.P. Altmann, E. Stegemöller, A.A. Hazamy, J.P. Wilson, D. Bowers, C.M. Sapienza, M.S. Okun, C.J. Hass (Gainesville, FL, USA)

Objective: To evaluate the effects of concomitant cognitive tasks of increasing difficulty on speed of cycling in people with Parkinson's disease (PD).

Background: Studies have demonstrated that compared to healthy older adults, people with PD show greater declines in motor performance (gait, balance) when simultaneously performing a second task, regardless of the domain of the second task (motor, cognitive, language). Cycling reduces fall risk and thus may better assess true dual task interactions. We predicted that there would be a direct and graded effect of cognitive task difficulty on cycling performance.

Methods: 25 people diagnosed with idiopathic PD (Hoehn & Yahr 1-3) by fellowship-trained movement disorders specialists completed a battery of 14 cognitive tasks while sitting in a quiet room (single task) and while riding a stationary bicycle (dual task). Cycling speed (RPMs) was recorded with no cognitive task (baseline) and during each cognitive task. Cognitive tasks were chosen from 5 domains of increasing difficulty: processing speed, controlled processing, memory, executive function, and language.

Results: Unexpectedly, in nearly all tasks, cycling performance (RPMs) improved in the dual task. Further, dual task benefits decreased as difficulty of the task increased (r= -.69, r2=.48, p<.01). Two speed tasks improved the most, showing a significant 19-20% dual task benefit to RPMs over single task cycling. Dual task benefits during controlled processing tasks were also significant, but those for memory and the most difficult executive and language tasks were not.

Conclusions: We posit two interacting processes. We suspect kinesia paradoxa led to the approximately 20% improvement in RPM during cycling. Kinesia paradoxa is a phenomenon in which motor performance in PD is facilitated by external stimuli (a line on the floor, a metronome). This may be the first report of kinesia paradoxa resulting from cognitive, rather than sensory, stimuli. The second process was a typical dual task effect (but from the improved dual task level rather than baseline), that showed a graded increase in dual task costs on motor performance as cognitive task difficulty increased across a broad range of cognitive domains.

32

Screening for cognitive impairment in Parkinson's disease and age-matched controls using MMSE and MOCA: Which visuospatial tests are most sensitive?

J.E. Alty, S.L. Smith, S. Jamieson (Leeds, United Kingdom)

Objective: To examine Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MOCA) performance in patients with Parkinson's disease (PD) and to assess which visuospatial tests are most sensitive to cognitive impairment.

Background: Cognitive impairment is an important issue in PD. The cumulative prevalence of dementia in PD patients (PDD) is 70-80%. Mild cognitive impairment (MCI) predicts the development of PDD and negatively impacts on quality of life. A brief screening instrument for global cognitive function is needed to aid comprehensive management of patients.

Methods: A cohort of 43 PD patients (28 male) and 38 age-matched controls (12 male) undertook MMSE and MOCA. In the PD group the mean age (SD) was 68.9 years (±8.2), Hoehn and Yahr stage 2.5 (±0.7) and disease duration 5.8 years (±4.0). The mean age of controls was 62.7 years (±9.2). A score of 26/30 was used as the cut-off for MCI in both assessments, as per previous studies. All patients were ‘on’ during the assessment.

Results: The mean scores for MMSE and MOCA were 28.9 and 26.3 in the PD group, and 29.7 and 28.3 in the control group. The range, and SD, of scores was larger for MOCA than MMSE in the PD (18-30, 2.5 vs 24-30, 1.3) and control groups (24-30, 1.4 vs 28-30, 0.6). Eleven PD patients scored <26 on MOCA with impairments seen most commonly in visuospatial, delayed recall and attention domains. There was a more pronounced ceiling effect with MMSE (37% PD and 79% controls scored 30) than MOCA (0% PD and 21% controls scored 30). All subjects who scored ≥26/30 on MOCA also scored ≥26/30 on MMSE but 26% of PD patients (and 5% of controls) who scored ≥26/30 on MMSE had a score <26/30 on MOCA. Cube copying was the most likely visuospatial task to be impaired in the PD group, followed by the trail-making, clock-drawing and interlocking pentagons. The mean MOCA score of subjects who were impaired on cube-drawing was 25.1, compared to 27.6 for those who were unimpaired.

Conclusions: MOCA classifies more subjects as having MCI and is less prone to ceiling effects than MMSE. The earliest stages of MCI may not be recognised if MMSE is solely used. All of the visuospatial assessments on MOCA are more sensitive to MCI than the interlocking pentagon task on MMSE, especially the cube-copying task.

33

Gait pattern and cognition in Parkinson's disease

M. Amboni, P. Barone, L. Iuppariello, I. Lista, R. Tranfaglia, A. Iavarone, A. Fasano, M. Picillo, G. Sorrentino (Naples, Italy)

Objective: To find an association between gait pattern and specific cognitive profiles in patients affected by Parkinson's disease (PD).

Background: Although recently the relationship between cognition and gait in PD has received increasing attention, the specific connections between gait pattern and cognitive features are not fully understood1.

Methods: Using a gait analysis system, we studied 43 PD patients during normal gait at on state. We evaluated the following gait variables based on their clinical relevance and their reported association with cognitive function2: 1) step length; 2) stance phase; 3) swing phase; 4) single support/double support time ratio; 5) cadence; 6) velocity; 7) step length variability; 8) swing time variability. In order to reduce the larger number of gait variables to a smaller number of factors, a factor analysis was performed. Furthermore, we assessed all patients with an extensive neuropsychological battery and correlated the composite scores of three main cognitive domains, namely episodic memory, executive and visuospatial domains with the gait factors scores. We also evaluated correlations between gait factors and clinical measures (disease duration, Hohen& Yahr stage, Gait Questionnaire, UPDRS III).

Results: Factor analysis revealed two independent factors, namely “pace” and “stability”. The “pace” factor was not correlated with cognitive or clinical variables. The “stability” factor was strongly and directly correlated with the visuospatial domain. Furthermore, the “stability” factor was also inversely correlated with almost all the main clinical measures of disease progression.

Conclusions: Visuospatial impairment was strongly associated with the development of instability and more generally with the progression of PD.

References:

1. Yogev-Seligmann G, Hausdorff JM, Giladi N. The role of executive function and attention in gait. Mov Disord 2008;23(3):329-342.

2. Verghese J, Wang C, Lipton RB, Holtzer R, Xue X. Quantitative Gait Dysfunction and Risk of Cognitive Decline and Dementia. J Neurol Neurosurg Psychiatry 2007; 78:929-935.

34

Changes of cognitive function in Parkinson's disease following bilateral subthalamic nucleus stimulation: Evaluation by test battery including repeatable battery for the assessment of neuropsychological status

T. Asahi, N. Nakamichi, H. Hamada, A. Takaiwa, M. Koh, M. Kigawa, N. Hayashi, N. Kuwayama, N. Dougu, S. Takashima, S. Endo (Toyama, Japan)

Objective: To investigate the cognitive function following subthalamic nucleus stimulation (STN-DBS) for Parkinson's disease (PD) by test battery including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

Background: RBANS is used for conveniently evaluating cognitive function and has been reported to possess greater sensitivity for evaluating the cognitive function in PD as compared to other tests, such as the mini-mental state examination (MMSE). Preoperative and 3–4-month postoperative RBANS STN-DBS data have been compared in a previous report; the visuospatial constructional ability was significantly improved, but no long-term follow-up evaluation was undertaken.

Methods: Eleven PD patients (6 male, 5 female) at Toyama University Hospital underwent the following examinations: Unified Parkinson's Disease Rating Scale (UPDRS), levodopa equivalent dose, MMSE/Japanese adult reading test (JART)/Wechsler adult intelligence scale-revised (WAIS-R)/RBANS for cognitive function, and frontal assessment battery (FAB)/word fluency test for frontal lobe function. These examinations were conducted preoperatively and 1 year postoperatively.

Results: Thus, the results suggest that temporary improvement in visuospatial constructional ability was reverted 1 year following STN-DBS. Moreover, lowering of the word fluency test score was detected, similar to previous reports.

Conclusions: Thus, the results suggest that temporary improvement in visuospatial constructional ability was reverted 1 year following STN-DBS. Moreover, lowering of the word fluency test score was detected, similar to previous reports.

35

Effect on cognitive functions of clinical autonomic dysfunction in Parkinson's disease

D. Aygun, K. Akpinar, S.K. Yön, M.K. Onar (Samsun, Turkey)

Objective: We assessed whether there is a negative effect on cognition of clinical autonomic dysfunction in PD patients.

Background: Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder characterized by tremor, rigidity, bradykinesia, and postural instability. PD also involves nonmotor manifestations such as autonomic failure, cognitive disorders, and sleep disorders. These clinical characteristics are not identical in severity, frequency, and onset time in all PD patients.

Methods: This prospective study includes 37 PD patients with autonomic failure. From each patient, a questionnaire (SCOPA-AUT) including symptoms associated with clinical autonomic dysfunction such as constipation, urinary incontinence, orthostatic hypotension, and hyperhydrosis was obtained and the patient's clinical condition was rated on the Hoehn and Yahr (H-Y) scale in the ON-medication state. The patients' cognitive function was assessed by the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Digid Span Test (DST) (forward, reverse). Cognitive test scores were compered with SCOPA-OUT scores.

Results: Mean age was 66,53±11.2 years. There was no correlation between cognitive test scores and SCOPA-OUT scores (p>0.05). However, H-Y scores were negatively correlated with the DSTf, DSTr, FAB, and MMSE scores (p=0.005, r:-0.451; p=0.025, r: -0.367; p=0.040, r: -0.340; p=0.044, r=-0.333, respectively).

Conclusions: According to our results, clinical autonomic dysfunction did not seem to have an effect on cognition. In addition, severity of cognitive dysfunction showed a strong negative correlation with the stage of disease.

36

DEMPARK: Parkinson's disease and dementia

M. Balzer-Geldsetzer, I.A. Heber, M. Kronenbürger, J.B. Schulz, S. Röske, A. Spottke, U. Wüllner, A. Storch, C. Schneider, O. Riedel, H.U. Wittchen, C. Seifried, R. Hilker, N. Schmidt, K. Witt, G. Deuschl, B. Mollenhauer, C. Trenkwalder, I. Liepelt-Scarfone, S. Gräber-Sultan, D. Berg, T. Gasser, E. Kalbe, A. Petrelli, W.H. Oertel, R. Dodel (Marburg, Germany)

Objective: DEMPARK is a large-scale prospective-longitudinal cohort project. Based on repeated clinical and neuropsychological assessments, the development and course of cognitive impairments is examined, coupled with serial MR-imaging, genetic, serum proteomic analysis to identify risk factors, early diagnostic biomarkers and predictors for the development of cognitive impairments.

Background: Cognitive impairment (CI) and dementia (D) are disabling non-motor complications of Parkinson's disease (PD). The question why patients develop CI or D, and the longitudinal course and trajectories are poorly understood. Thus, the DEMPARK study is to determine incidence and prevalence of cognitive impairment, dementia and their risk factors in a large cohort of PD patients and to examine their developmental pathways and trajectories.

Methods: DEMPARK is a multicentre (8 centres in Germany) observational study of about 700 PD patients with/without signs of (beginning) dementia (as determined by neuropsychological testing and clinical judgement). Follow-up examinations are at 12 and 24 months after baseline.

Results: Up to 10/2011, n=646 PD patients have been enrolled. Mean age of the participants (66.9% males) was 67.9±7.8y with males being significantly older than females (68.4±7.8 vs. 66.9±7.7, p<.05). Disease duration at enrolment was 7.1±5.7y, with a preponderance of Hoehn&Yahr stages I-III (88.7%). At baseline, 55.8% of PD patients showed no signs of dementia, 31.0% met criteria for mild cognitive impairment (PD-MCI), and 13.2% for dementia (PDD).

Conclusions: Preliminary DEMPARK baseline findings indicate that the study program is feasible and should allow to identify putative trajectories of cognitive decline over the total observation period of 24 months.

37

Comparison of The Movement Disorder Society criteria for Parkinson's disease dementia with routine clinical neuropsychological testing

B.R. Barton, B. Bernard, G.T. Stebbins, J. Goldman, B. Dubois, C.G. Goetz (Chicago, IL, USA)

Objective: To compare diagnostic classification differences for Parkinson's disease dementia (PDD) patients between the new Movement Disorder Society (MDS) criteria for detecting PDD and routine neuropsychological testing.

Background: Diagnostic criteria for PDD have been proposed by a MDS Task Force. MDS PDD diagnosis includes criteria based on a checklist (Level 1) and additional specific criteria based on more complete neuropsychological tests (Level II). Few studies have compared outcomes of these MDS criteria to the diagnosis of PDD based on routine neuropsychological testing that does not utilize the MDS criteria.

Methods: Parkinson's disease (PD) subjects were recruited from those scheduled for neuropsychological testing at two specialty PD centers. All subjects were categorized as having PDD or no PDD based on routine neuropsychological test results and clinical judgment of the neuropsychologist. In addition, Level 1 and Level II MDS diagnostic criteria for PDD were applied to each subject based on the same test results by a blinded neurologist.

Results: We tested 91 PD subjects, with mean age 66.3 (SD=9.7) and mean disease duration 8.8 years (SD=6.1). All subjects classified as PDD by the neuropsychologists (n = 9) were also classified as having PDD using the MDS checklist criteria (Level 1). However, there were an additional 6 subjects diagnosed with PDD using the MDS Level II Criteria who were classified as having no dementia by the neuropsychologists. These 6 cases had more significantly more education (10.6 vs 15.5), better MMSE scores (20.4 vs 26.33), and less impairment on several cognitive tests compared to the group concordant for PDD by both MDS criteria and the neuropsychologist designation.

Conclusions: MDS Level II criteria diagnoses PDD more frequently compared to routine neuropsychological testing and may be more sensitive to impairment in cases with higher education levels and where the cognitive function is not as severely impaired.

38

Gait training associated with executive functions tasks in subjects with Parkinson's disease: Improvement of performance and effects in motor learning

C. Bedeschi Ferrari, L. Rodrigues, D. Bauer, A. Manfredi, M.E. Pimentel Piemonte (Barueri, Brazil)

Objective: The aim of this study was to compare the effectiveness of gait training associated with executive function (EF) tasks versus gait training alone, for improving gait, motor learning and transfer in PD patients.

Background: The dependence of the gait control of cognitive processes has been demonstrated by studies involving the performance of more than one task at a time (dual-task). The PD patients have both gait and cognitive disorders, so the development of a gait training which involving these domains should be interesting in attenuate these deficiencies, and enhance performance in this group of patients.

Methods: A blinded, randomized, controlled, longitudinal clinical trial was conducted. Patients (mean age 67,2 years) were randomly assigned into an experimental group (n=12), which underwent a total of 10 (2 per week) executive function gait training sessions (EFGT), or a control group (n=8), which underwent 10 (2 per week) gait training sessions (GT). Both types of training session were preceded by 30 minutes of general mobility exercises. In the EFGT, gait was trained in association with six different tasks simulating daily living situation and requiring divided attention, working memory, perceptual judgment, decision-making, response inhibition, response monitoring and planning. In the GT, gait was trained in the same manner and for the same period but with no associated tasks. Patients from both groups were instructed to walk as quickly as possible. The sessions 1, 5 and 10 were included for statistical analysis.

Results: It was found that PD patients of EFGT showed improvements in motor learning and retention after training (p < 0,005), by increasing the gait speed (p < 0,005) and accuracy (p < 0,005) on EF trained in each condition. Additionally, PD patients were able to transfer the improvements in performance in only some tasks, for some cognitive and motor tests. This appears to be associated with deficiency in EF, such as divided attention, working memory and decision making.

Conclusions: The EFGT promoted improvement in gait and in some of EF tasks trained, showing that despite automatic motor control and cognitive deficiencies, the patients with PD can learn and retain some tasks after gait training in dual-task.

39

Cognitive characterization of mild cognitive impairment subtypes in Parkinson's disease

R. Biundo, S. Facchini, P. Formento-Dojot, M. Pilleri, A. Antonini (Venice, Italy)

Objective: To identify specific cognitive deficit profiles in an incident cohort of PD patients.

Background: The most common MCI categorization (amnesic, non-amnesic/multidomains impairments) does not clarify how specific MCI subtypes affect the rate of dementia development. Based on recent studies it may be better to focus on discrete profiles namely posterior, frontal-striatal and global cognitive impairment to predict their contribution to dementia progression.

Methods: We tested a total of 124 patients with idiopathic PD who completed an extensive neurological assessment including a full neuropsychological battery as part of their diagnostic work-up.

We categorized our PD population as follows: PD without cognitive deficits (PD-CNTR), PD with mainly fronto-striatal cognitive deficits (PD-MCI-FT), PD with mainly posterior cognitive deficits (PD-MCI-PT) and PD with global impairments (PD-MCI-MD) and PD dementia (PDD). We compared the groups in terms of age, education, gender, disease duration and motor characteristics (e.g. H&Y). We utilized parametric statistic (ANOVA) to compare groups on continuos variables when the data were normal distributed and nonparametric statistics (Kruskal Wallis) when the data followed a non-parametric distribution.. Chi-square tests were used to compare categorical variables.

Results: Within the whole PD cohort [age: 63.77 +/- 9.96, education: 11.09 +/- 4.64 and disease duration: 9.68 +/- 6.19] 32.26% were PD-CNTR, 51.61% PD MCI (16.13% PD MCI-FT, 18.48% PD MCI-PT, 25.00% were PD MCI-MD) and 16.13% PDD. There was a linear trend between clinical (Y&H) and demographic variables (age) and cognitive deficits (PDD>PD-MCI>PD-CNT). Among the three MCI subgroups MCI-P had a trende for younger age and shorter disease duration. MCI-P had a significantly better performance (p = 0.000) in the TMTB and TMTB-A compared to both the other groups (MCI-FT and MCI-MD). Moreover MCI-FT profile had a significantly better performance on Rey figure copy and delayed compared to both MCI-P and MCI-MD (p = 0.000).

Conclusions: Our results suggest that specific cognitive profiles canbe identified in PD and they may help predicting the emergence of cognitive changes.

40

Impaired judgment of harmful intent in Parkinson's disease: Examining the role of dopamine

E. Gleichgerrcht, G. Gómez Arévalo, S. García, G. Mizraji, F. Manes, O. Gershanik, A. Chade (Buenos Aires, Argentina)

Objective: To examine the role of dopamine among patients with Parkinson's disease (PD) in their ability to judge harmful intent actions as morally inappropriate.

Background: Judging an action as morally right or wrong demands that we infer the feelings, beliefs, and intentions of the actor. This ability, usually referred to as Theory of Mind, has been shown – albeit not uncontentiously – to be impaired even in the earlier stages of non-demented PD patients, highlighting the potential role of dopamine in Theory of Mind.

Methods: We recruited 15 PD patients undergoing either Apomorphine or Levodopa tests. Both during OFF and ON phases of the test, patients were (a) assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) and (b) presented with a series of 12 moral vignettes. Each vignette introduced an actor executing an action with either neutral intent (e.g. Sally added sugar to Kelly's coffee) or harmful intent (e.g. Sally added poison to Kelly's coffee) and either a neutral outcome (e.g. Kelly was fine) or a negative outcome (e.g. Kelly died). For each vignette, participants were asked to determine 1) how morally appropriate or inappropriate the actor's action was; and 2) how severely the actor deserved to be punished. Vignettes were presented in counterbalanced order.

Results: We initially compared UPDRS scores and moral vignette responses of patients who had undergone Apomorphine vs. Levodopa test to ensure that results were independent of the dopaminergic agonist administered. We then analyze the way in which responses to moral vignettes were modulated by the action of dopamine in an OFF vs. ON analysis. We especially focus in the way PD patients' ability to detect harmful intent actions as morally wrong changes during the ON phase relative to the OFF phase.

Conclusions: Decreased dopamine levels in PD appear to be associated with a diminished ability to infer other people's beliefs and intentions. This, in turn, influences the way in which PD patients judge immoral actions as inappropriate. The present study highlights not only the potential role of dopamine in higher cognitive functions, but also the wide array of social cognitive functions that may be disrupted in patients with PD.

41

Motor impulsivity in Parkinson's disease subtypes: Postural instability with gait difficulty versus tremor predominant

D.O. Claassen, S.A. Wylie (Nashville, TN, USA)

Objective: To determine if the Parkinson's disease (PD) subtypes, Postural Instability with Gait Difficulties (PIGD) and Tremor Predominant (TD) are differentiated by motor inhibitory control.

Background: PIGD patients experience unique cognitive difficulties as compared to patients with TD. These differences may have important consequences on motor performance and motor control. For instance, PIGD patients are characterized by propensity for falls, and patients seem to react impulsively to their environment. In the current investigation, we tested the hypothesis that PIGD patients show reduced cognitive control over motor impulses compared to TD patients.

Methods: On the basis of UPDRS III motor scores, 34 non-demented PD patients were equally divided into PIGD and TD subtypes. All patients performed the Simon task, which requires speeded manual reactions to stimuli presented on a computer screen. More specifically, the task involves trials that produce either conflict or congruence between goal-directed responses and spontaneous response impulses. A dual-process activation-suppression model provides a theoretical and analytical framework for quantifying measures of the strength of motor impulsivity and the proficiency of inhibiting these impulses as an act of cognitive control.

Results: All PD patients had similar mean UPDRS scores(PIGD vs TD: 21.2 (+/-7.4) vs 17.6 (+/- 7.6)). Patients were considered to have mild to early moderate symptom profiles. Both groups showed similar mean reaction times, but compared to TD patients, PIGD patients made significantly more impulsive motor errors. Notably, when the initial impulsive response was avoided, PIGD and TD groups were similar in their ability to suppress the incorrect motor impulse from interfering with the selection of a correct action.

Conclusions: These results show that the PIGD subtype of PD features a specific deficit in motor impulsivity. This finding may have direct implications for fall risk and point to dissociable neurocognitive phenotypes in TD and PIGD subtypes. Clinically, the use of specific cognitive instruments to assess the expression and inhibition of motor impulses may help identify PD patients at a high risk of falling.

42

β-amyloid and τ burden in the midbrain across the Lewy body spectrum

Y. Compta, M.J. Marti, E. Gelpi (Barcelona, Spain)

Objective: To assess midbrain involvement by τ and β-amyloid aggregates in Lewy body disorders (LBD).

Background: Both in published reports and in our own experience with PET amyloid-imaging there is an increased midbrain uptake in part of LBD cases. This is a rather unexpected finding, since presence of β-amyloid in the midbrain corresponds to an advanced phase of brain amyloidosis in Alzheimer's disease (AD). Despite growing interest in recent years in β-amyloid involvement of the striatum (which precedes midbrain in amyloid deposition) in LBD in the setting of dementia (Parkinson's disease [PD] with dementia and dementia with Lewy bodies [DLB]), there is little information about the deposition of β-amyloid in the midbrain in these disorders and the relation this might hold with increased midbrain uptake in some PET studies.

Methods: Semiquantitative assessment of α-synuclein, τ and β-amyloid aggregates using standardized immunohistochemistry of midbrain sections from healthy controls (n= 9), PD with no dementia (PDND; n= 11), PD with dementia (PDD; n= 10), dementia with Lewy bodies (DLB; n= 10), and AD cases (n= 10) collected at our Brain Bank. Non-parametric statistics were used.

Results: In tectum/tegmentum there was a gradation for β-amyloid (global p<0.0001) with significantly greater burden in LBD cases with dementia (PDD + DLB) than in both controls and LBD cases without dementia (PDND) (pair-wise p<0.01), but lesser, albeit non-significantly, than in AD (p>0.1). Similarly, in the substantia nigra β-amyloid ranged from controls (almost absent), to PDND and DLB (mild), PDD (moderate) and AD (severe involvement) (global p=0.009). For τ a similar gradation from controls (almost absent) to LBD (mild to moderate, peaking in PDD cases) and then AD (severe) was seen in both tectum/tegmentum and substantia nigra (global p<0.0001). For α-synuclein, both controls and AD cases mostly ranged from none to mild involvement, whereas the most severe involvement was seen in the substantia nigra of DLB followed by PDD.

Conclusions: Our findings support the notion that there is an advanced phase of brain amyloid deposition and also τ midbrain-involvement in LBD mostly in the setting of dementia. Still, it remains uncertain how the density and distribution of these aggregates relate to increased midbrain uptake in some PET amyloid-imaging studies.

43

Is the PFAQ a valid instrument for defining disability due to cognitive impairment in Parkinson's disease?

C.P. Souza, G. Nascimento, G.G.R. Rodrigues, D. Sabino, V. Tumas, J.F. de Oliveira (Ribeirão Preto, Brazil)

Objective: The objective of this study is to verify if PFAQ can be applied in patients with PD.

Background: One of the major issues for the diagnosis of dementia in PD is to establish that the cognitive impairment caused significant disability, because it can be difficult to distinguish between the functional restriction due to motor signs and the disabilities due to cognitive impairment. The PFAQ is an instrument used to grade functional loss in patients with dementia.

Methods: It has been examined 58 of 104 patients with PD consecutively seen at a movement disorders outpatient clinic, as they were followed by a close caregiver which could inform accurately about the cognitive abilities of the patients. The patients were evaluated with UPDRS simplified motor score, Hoehn and Yahr scale (H&Y), Schwab and England state (S&E), MMSE, FAB, clock drawing test (Sunderland score), CDR scale, PFAQ, DSM IV, and the data were analysed with Mann-Whitney test (MWt), Spearmann test (St) and ROC curve.

Results: There were 23 females and 35 males, with 0-19 (median 4) years of education, motor score of the simplified scale of 4-36 (median = 14) points, H&Y 1-4 (median = 2), S&E between 40-100% (median = 80%). Twenty three of 58 patients were diagnosed with dementia according to DSM-IV. The MWt showed a significant difference between the scores on PFAQ obtained by patients with and without dementia (p = 0.0001). The ROC curve showed an AUC = 0.775 (p = 0.0001), the 2/3 score to differentiate between the two groups showed 69% sensitivity and specificity of 78%. The St showed that the score in PFAQ did not correlate significantly with motor score (cc = 0.194, p = 0.14), with the disability level measured by the S&E (cc = 0.218, p = 0.10) and correlated with stage of H&Y (cc = 0.324, p = 0.015), with MMSE score (cc =- 0.519, p = 0.0001), with the clock drawing test (cc =- 0,435, p = 0.001) and the FAB score (cc =- 0.488, p = 0.001).

Conclusions: Defining disability due to cognitive impairment is a difficult assignment in PD patients, however, the PFAQ seems to be a good tool for such task.

44

Elevated homocysteine levels predict cognitive dysfunction in an incident cohort of non-demented Parkinson's disease patients

G.W. Duncan, T.K. Khoo, A.J. Yarnall, J.T. O'Brien, D.J. Brooks, R.A. Barker, D.J. Burn (Newcastle upon Tyne, United Kingdom)

Objective: To determine whether elevated plasma homocysteine (Hcy) levels impact upon cognition in early Parkinson's disease (PD).

Background: Elevated plasma Hcy is a risk factor for cognitive dysfunction and dementia in the general population. Levodopa (L-dopa) therapy is a cause of elevated Hcy levels. Elevated homocysteine levels have been associated with motor and cognitive decline in established PD and predict a poorer response to rivastigmine in those with PD dementia.

Methods: Participants were drawn from a sample of consecutive incident PD patients (n=80) and age-matched healthy control subjects (n=62) recruited as part of the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation – Parkinson's Disease Study. Motor severity was assessed with MDS-UPDRS part 3. Cognitive function testing comprised Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Depression was rated with the Geriatric Depression Screen (GDS-15). Plasma levels of Hcy, vitamin B12 and folate were analysed. Linear regression was used to examine the relationship between Hcy and cognition with age, education, folate and vitamin B12 as covariates.

Results: Hcy was significantly higher in PD (11.12) than controls (9.22) P = 0.001. The results are shown in table 1.1. (44)

Table 1. (44). Demographic, clinical and biochemical characteristics of the PD and control participants
 Control (N = 62)PD (N = 80)L-Dopa -ve (N = 56)L-Dopa +ve (N = 24)
  1. Values represent means with (standard deviations), except where percentages are shown. *P < 0.05 PD vs control.†P < 0.05 PD patients taking L-dopa vs those not taking L-dopa. ‡ P < 0.05 for Pearson correlation coefficient associated with homocysteine level.

Age (years)66.03 (8.08)68.35 (9.71)‡65.71 (9.12)74.50 (8.11)†
Sex M/F n (%)33/29 (53.2/46.8)53/27 (66.3/33.7)37/19 (66.1/33.9)16/8 (66.3/33.7)
Education (years)13.67 (3.64)13.36 (4.02)13.63 (4.08)12.73 (3.91)
Disease Duration (months)NA5.2 (3.9)4.83 (3.88)6.03 (3.90)
L-dopa dose (mg)NA268.75 (80.50)NA268.75 (80.50)
Vitamin B12 (ng/L)490 (179)383 (175)*‡404 (186)336 (137)
Folate (µg/L)317 (148)258 (135)*‡265 (151)242 (89)
Homocysteine (µmol/L)9.22 (3.17)11.12 (3.55)*10.54 (3.68)12.47 (2.88)†
Homocysteine > 14 µmol/L n (%)4 (6.45)14 (17.5)7 (12.5)7 (29.2)
MDS-UPDRS IIINA25.51 (11.97)24.30 (11.20)28.33 (13.41)
GDS-151.18 (1.82)2.61 (2.54)*‡2.32 (2.32)3.29 (2.95)
MMSE29.03 (1.24)28.68 (1.34)28.93 (1.14)28.08 (1.61)†
MoCA26.84 (2.43)25.30 (3.82)*‡26.16 (3.51)23.29 (3.83)†

Patients on L-dopa were older with higher Hcy and worse cognitive function. Homocysteine levels were positively correlated with age (r = 0.275, P = 0.014) and inversely correlated with levels of Vitamin B12 (r = -0.403, P < 0.001) and folate (r = -0.244, P = 0.032) but not L-dopa dose or PD duration. MoCA score was significantly lower in the PD group than in the controls and a worse MoCA score was associated with higher Hcy in the PD group (r = -0.386, P <0.001). Elevated homocysteine levels predicted lower MoCA scores in a model adjusting for variables known to affect homocysteine and cognition (R2= 0.294, F=5.920, P = 0.005).

Conclusions: Our findings indicate that homocysteine is elevated even in the earliest stages of PD and predicts worse cognitive function. This cohort will be followed up over the next 3 years to determine the significance of Hcy in predicting cognitive decline. Further work is needed to establish whether Hcy is a potentially modifiable risk factor for PDD.

45

Mechanisms of psychomotor slowing in Parkinson's disease

C. Duru, T. Lelard, M. Roussel, Y. Yerro, O. Godefroy, P. Krystkowiak (Amiens, France)

Objective: (1) To highlight psychomotor slowing in Parkinson's disease (PD) patients, (2) to determine the underlying mechanisms and (3) to determine whether levodopa medication influences reaction time.

Background: Although psychomotor slowing is well documented in Parkinson's disease, few studies have focused on its pathophysiological mechanisms. Determine its mechanisms is now possible with a validated and reliable battery assessing the speed of the four components of reaction time (perceptual, motor, decision and attention processes).

Methods: We recruited 20 patients with PD and 20 controls matched for education and age. First of all, we examined the performance of both groups on psychomotor speed with simple reaction time (SRT) (simple and dual task), digital tapping, choice reaction time (CRT) and visual inspection time (VIT) tasks. Afterwards, we compared the effects of dopaminergic medication on reaction time performance: PD patients were tested both in “worst OFF” and in “best ON” conditions when an acute dopaminergic challenge. Between-group comparisons were performed with a one-way analysis of variance (ANOVA) using the group (PD and controls) as a between-subjects factor. When necessary, ANOVA for repeated measures on the condition factor was performed.

Results: PD patients were not different from controls. Decision time (p=0.013) and tapping (p=0.026) were impaired in PD patients as compared to controls. VIT, SRT (simple and dual task) and CRT were similar to controls. No significant improvement in reaction time performance was seen after administration of dopaminergic medication. Only tapping frequency became increasingly impaired in OFF condition as compared to ON condition (p=0.037).

Conclusions: Psychomotor slowing of PD is due to slower motor and decision processes. This psychomotor slowing profile could constitute a diagnostic marker in PD.

46

Neuropsychological profile in LRRK2-R1441G associated Parkinson's disease

A. Estanga, J. Ruiz-Martínez, A. Gorostidi, M.aC. Rodríguez-Oroz, J.F. Marti-Masso (San Sebastian, Spain)

Objective: To assess cognitive function in LRRK2-R1441G associated PD patients, and to compare it with idiopathic PD patients.

Background: LRRK2 mutations are the most common known genetic causes of autosomal dominant PD. The most frequent LRRK2 mutation, G2019S, has been observed throughout the world. The LRRK2-R1441G mutation is responsible for 46% of familial PD and for 2.5% of sporadic PD patients with Basque origin, with a penetrance of 80% at age 80. Clinically, the motor features of LRRK2 related PD and idiopathic PD are indistinguishable. However the cognitive profile is less well characterized. Previous studies have found that cognitive function is similarly affected in PD patients with and without LRRK2-G2019S, but little is known about the cognitive status in LRRK2-R1441G mutation carrier patients.

Methods: A total of 24 LRRK2-R1441G PD patients were evaluated and 44 idiopathic PD patients were selected with comparable age, disease duration and age of disease onset. A comprehensive neuropsychological battery of neuropsychological test was administered for assessing general cognition, attention, executive function, memory, language, visuoperceptive and visuospatial skills, and emotion recognition.

Results: There was not any significant difference in demographic variables and education level in the two groups. There weren't significant differences on cognitive test performance between idiopathic patients and LRRK2-R1441G patients.

Conclusions: Our data suggest that the cognitive profile is similar in PD patients with R1441G mutations in LRRK2 gene and idiopathic PD with comparable clinical features.

47

Neuropsychological performance in asymptomatic LRRK2 mutation carriers (R1441G and G2019S)

A. Estanga, A. Bergareche, J. Ruiz-Martínez, A. Gorostidi, M.aC. Rodríguez-Oroz, J.F. Marti-Masso (San Sebastian, Spain)

Objective: To evaluate neuropsychological performance and neuropsychiatric and personality traits in non-manifesting LRRK2 mutation carriers.

Background: LRRK2 mutations are the most common known genetic causes of autosomal dominant Parkinson's disease (PD). The most frequent LRRK2 mutation, G2019S, has been observed throughout the world. The LRRK2-R1441G mutation is responsible for 46% of familial PD and for 2.5% of sporadic PD patients with Basque origin. Neuropsychiatric abnormalities are considered as pre-motor manifestations of idiopathic PD. It is not known if carriers of LRRK2 mutations, non-manifesting any motor signs of parkinsonism, have some neuropsychiatric or personality alterations that can be considered as a premotor marker of PD.

Methods: A total of 74 relatives of PD-LRRK2 patients were enrolled in the study. Thirty-nine were asymptomatic mutation carriers (32 with R1441G mutation and 7 with the G2019S) and thirty-five were non-carriers. Neuropsychological assessment included general cognition evaluation, attention, working memory and executive function, memory, visuospatial function, and emotion recognition. Neuropsychiatric assessment included depression, anxiety, personality characteristics and novelty-sensation seeking evaluation.

Results: There was not any statistically significant difference between carriers and non-carriers in age, sex and years of education. Between-group comparison revealed that the mean scores of the carriers were higher than the non-carriers in the attention subscale of Scopa-Cog (p=0.02), Verbal Fluency-FAS (p=0.02) and Stroop-Word part (p= 0.03). Correlation analysis between age and the scores of these three tests showed a poorer performance in the older non-carriers than in the older carriers, indicating a different impact of age in the two groups. We didn't found any significant difference in neuropsychiatric scales between groups.

Conclusions: Our data suggests that LRRK2 mutation carriers, in higher risk to develop Parkinson's disease than non-carriers, could have higher performance on some neuropsychological test related to attention and processing speed abilities. Longitudinal data are needed to confirm these results and to unravel their meaning.

48

The influence of reward and punishment on probability learning in patients with Parkinson's disease as compared to healthy controls

M. Fritz, D. Weiss, R. Krueger, A. Lindner, T. Waechter (Tuebingen, Germany)

Objective: To evaluate the effect of reward and punishment on probability learning in patients with Parkinson's disease as compared to healthy controls.

Background: Impairment in implicit learning has been demonstrated in patients with Parkinson's disease. Yet it remains unclear, if this impairment is due to a disability in acquisition of content or a difficulty in processing of feedback. If processing of feedback is impaired it remains to be elucidated, whether positive as well as negative feedback is affected.

Methods: 12 non-demented, non-depressed patients (59,8 ± 8,1 years) with Parkinson's disease on dopaminergic medication were tested using a feedback-based probabilistic classification task and compared to 12 age- matched (62,7 ± 7,9 years) healthy controls.

Results: Parkinson's patients with dopaminergic medication were not impaired as compared to healthy controls in learning from negative feedback. However in trials with positive feedback patients showed a significant impairment in learning.

Conclusions: Our data show an impairment of reward learning in patients with Parkinson's disease even when dopamine is substituted orally. However, this does not seem to reflect a general impairment of content acquisition or processing of feedback in general, but rather seems to be specific for learning from positive feedback. This effect may be explained by the PD-associated loss of dopaminergic neurons in the midbrain leading to an impaired processing of the reward prediction error generated in the midbrain, which cannot be compensated by a pharmacologically increased dopamine level.

49

Evolution of cognitive state in advanced Parkinson's disease

C. Gasca, A. Estanga, I. Lamet, P. Clavero, J. Obeso, M.C. Rodriguez-Oroz (Pamplona, Spain)

Objective: To study the progression of cognitive deficits in PD patients with MCI and with normal cognition and to identify risk factors for cognitive decline.

Background: Dementia is frequent in Parkinson's disease (PD). Mild cognitive impairment (MCI) is a risk factor for dementia but little is known about the progression of cognitive deficits in this population of PD patients.

Methods: We performed a longitudinal study at 30 months of follow-up in 48 non-demented PD patients classified as cognitively normal (CN-PD) (n=24), and with MIC (PD-MCI) (n=24). Patients were older than 60 years and the disease duration was of at least 10 years. An extensive neuropsychological evaluation was undertaken. Univariate analysis was done to study the evolution of cognitive test scores and cognitive domains. Afterwards a logistic regression matched by age, sex and educational level, was applied to determine associated risk factors for progression of cognitive deficits.

Results: Eight patients progressed from CN to MCI and 1 to dementia, and 10 from MCI to dementia. Attention, executive function and memory were the cognitive domains with a significant worsening in PD-CN patients who developed MCI or dementia over the time. Patients with PD-MCI with four or five affected domains at baseline had a higher risk of dementia. Visuospatial function was the only cognitive domain with significant impairment in PD-MCI patients who developed dementia. Postural instability in PD-CN patients was associated to progression to MCI or dementia. A trend towards significance was also observed for low scores in the copy of intersecting pentagons. A worse score in attention and visuospatial function were associated to progression to dementia in PD-MCI patients.

Conclusions: After 2.5 years of follow-up, PD patients with more than 60 years of age and 10 or more years of evolution of the disease, have a high rate (33% for PD-CN and 41% for PD-MCI) of conversion to a more severe cognitive diagnostic category. Postural instability and poor attention and visuospatial function seem to be risk factor for the progression of cognitive decline.

50

Baseline-dependent effects of levodopa on cognitive performance and rCBF in Parkinson's disease: A PET study

I.K. Goerendt, A.D. Lawrence, M.A. Mehta, D.J. Brooks (Hamburg, Germany)

Objective: In this study, we report how pharmacological treatment in Parkinson's disease (PD) affects neural circuitry involved in spatial working memory processing and how it affects spatial working memory performance.

Background: An important feature of PD is the emergence of cognitive deficits. However, findings of previous cognitive studies have not been consistent and the specific effects of levodopa on cognition remain unclear.

Methods: We combined two studies. In the behavioural study we assessed whether treatment in PD has a beneficial effect on spatial working memory performance outside the scanner in a within-subject counterbalanced cross-over design. In the imaging study we scanned PD patients withdrawn from medication for 12 hours and after taking levodopa in a counterbalanced, cross-over design. To assess the interaction effects of task and medication a between-subject fixed-effect analysis was carried out with patients data from the first scanning session only. To assess possible relationships between performance change and neural activity changes following treatment a within-subject random-effects analysis was carried out using the behavioural data obtained outside the scanner.

Results: We found that mean parkinsonian performance on this task was unimpaired in both the treated and the untreated state, though this was accompanied by modulatory changes in a task-relevant neuronal network - decreases were observed in dorsolateral and orbitolateral prefrontal blood flow associated with treatment. Levodopa had a differential effect on task performance in that it was dependent on working memory performance in the untreated state. Those patients with low working memory performance when off improved after levodopa, and those with high working memory performance when off deteriorated after levodopa. Levodopa may, therefore, enhance spatial working memory in some and impair it in other patients. This baseline-dependency was linked to caudate activation which was highest when performance deteriorated after levodopa.

Conclusions: These data suggest that withdrawal from levodopa medication disrupts fronto-striatal activity in PD and suggest that the PFC changes observed in treated PD reflect downstream changes resulting from alterations in striatal dopamine function rather than intrinsic PFC dysfunction per se.

51

Sleep quality indices and cognitive impairment in Parkinson's disease

R. Ghode, G.T. Stebbins, B. Bernard, B. Ouyang, C. Comella, J.G. Goldman (Chicago, IL, USA)

Objective: To investigate the relationship between Pittsburgh Sleep Quality Index (PSQI) global and component scores and Parkinson's disease (PD) cognitive impairment.

Background: Sleep disturbances are common in PD and contribute to worse cognitive performance. While many studies focus on global PSQI scores, evaluation of sleep quality components may elucidate contributors to poor sleep quality in PD and their relationship to cognition.

Methods: Non-depressed PD subjects (n=93) underwent clinical/neuropsychiatric evaluations including PSQI. Subjects were classified as cognitively normal (PD-NC), mild cognitive impairment (PD-MCI), or demented (PDD) by consensus conference using clinical/neuropsychiatric data, MDS-PDD criteria, and Petersen's MCI criteria. Demographic, disease-related, and cognitive/neuropsychiatric variables were analyzed using univariate and multivariate methods. Differences in PSQI component scores across cognitive groups wereanalyzed with Kruskal-Wallis tests, followed by Mann-Whitney U comparisons with Bonferroni corrections. Relationships between sleep and cognitive measures were examined with Spearman correlations.

Results: PD-NC (n=26), PD-MCI (n=42), and PDD (n=25) subjects differed significantly regarding PD duration (p=0.0001) and motor severity (p<0.0001) but not age, gender, education, or levodopa equivalents. In the entire PD cohort, 59% had poor sleep (PSQI global score > 5). Global PSQI scores did not differ significantly among cognitive groups. There were significant group differences for PSQI components of sleep duration (p=0.01) and a trend for daytime dysfunction (p=0.06). Sleep duration was significantly longer in PDD, compared to PD-NC subjects. Only sleep duration and daytime dysfunction significantly correlated with cognitive deficits, specifically with memory, attention/executive function, and visuospatial domains.

Conclusions: PD subjects with greater cognitive impairment exhibit a profile of longer sleep duration and possible greater daytime dysfunction. These PSQI components also are associated with memory, attention/executive function and visuospatial deficits. Global sleep quality, however, is impaired in most PD subjects, regardless of cognitive status. Thus, component score analysis may enhance our understanding of PD sleep-wake problems and their relationship to cognition.

52

The neural basis of coordination in social decision-making: Evidence from Lewy body spectrum disorder

R.G. Gross, C.T. McMillan, J. Kitain, K. Rascovsky, R. Clark, M. Grossman (Philadelphia, PA, USA)

Objective: To demonstrate that patients with Lewy body spectrum disorder (LBSD), including Parkinson's disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB), have impaired decision-making related to frontal/executive dysfunction.

Background: Individuals often must coordinate with others when making decisions. For example, we provide a less typical boy's name in a random list (John=9%) than when asked to coordinate responses with another participant (John=50%; Mehta, 1994). Coordination is supported by executive and theory of mind resources mediated by prefrontal cortex (PFC; McMillan et al., in press).

Methods: LBSD patients (PD=9; PDD/DLB=12) and healthy elderly controls (N=22) answered 10 questions probing various semantic categories (e.g., a boy's name). In the Survey condition, participants could provide any response. In the Coordination condition, participants were asked to respond with the same answer they think an anonymous partner would give. Responses were quantified using a measure of semantic representativeness, the focal index (FI; e.g., FIAlfred < FIJohn). Cognitive testing and volumetric MRI analysis were related to coordination performance.

Results: An FI difference score (Coordination-Survey) confirmed that while PD patients coordinate similarly to controls, PDD/DLB patients are significantly impaired when asked to coordinate their responses [t(32)=2.54, p<0.05]. 1 (52)

Figure 1 (52).

The FI difference score was correlated with a test of mental flexibility (Trails B; r=0.72, p=0.001). Regression analysis related coordination deficits to atrophy in left rostral PFC (BA 10), as well as the right insula and right occipital lobe.2 (52)

Figure 2 (52).

Conclusions: PDD/DLB patients show impairment of coordinated decision-making, related to frontal/executive dysfunction. We propose that impaired coordination in PDD/DLB relates to disrupted hierarchical control mechanisms located in rostral PFC that model a partner's response.

Mehta et al. Focal points in pure coordination games: An experimental investigation. Theory and Decision 1994; 36: 163-185.

McMillan et al. The neural basis of establishing a focal point in pure coordination games. Soc Cogn Affect Neurosci, in press.

53

Long term follow-up of executive functions after brain stimulation (DBS) in Parkinson's disease (PD) patients: Preliminary results

N. Schlede, U. Gschwandtner, F. Hatz, R. Zimmermann, E. Taub, M.M. Ehrensperger, A.U. Monsch, P. Fuhr (Basel, Switzerland)

Objective: To analyze the course of performance in semantic and phonemic fluency tasks in PD patients after DBS.

Background: A wide range of cognitive functions seem to remain stable after DBS in the STN, however performance in verbal fluency tasks have been shown to decrease 6 to 36 months after surgery (Witt et al. 2008, Zangaglia et al. 2009).

Methods: 8 PD patients with DBS treatment (age 28-76 years, education 5-16 years, MMSE 27-29/30 points and follow up time 8-19 months) took part in the study. As part of the pre-DBS check-up, extensive neuropsychological testing was carried out pre- and post DBS surgery. The courses of the performance in semantic fluency- (animals) and phonemic fluency (s-words) were analyzed.

Results: All but one patient had normal findings (age-, gender- and education corrected z-values >-1.28) in both fluency tasks before surgery and remained (with fluctuations) within the normal limits after surgery. One patient showed abnormal performance (semantic fluency z-value = -1.6, phonemic fluency z-value = -1.8) in both fluency tasks before surgery, which did not change after surgery (z-values: -1.6 and -1.8).

Conclusions: No clinically significant worsening could be observed in both fluency tasks. These preliminary results suggest DBS to be relatively safe regarding dysfunctions in vulnerable executive functions.

54

Survey of cognitive screening in Parkinson's disease across UK centres

S. Hanumantha Reddy, B. Elliott, D. MacMahon, Delegates at the 16th BGS Parkinson's Academy (London, United Kingdom)

Objective: To look at the common practice in Movement Disorders clinics across the country regarding cognitive screening and tools used in patients with Parkinson's disease.

Background: 20% to 30% of patients with Parkinson's disease (PD) have been reported to have Mild cognitive impairment (MCI) 1. MCI in PD predicts future cognitive decline including development of PD dementia (PDD)1 and deterioration of health-related quality of life. Impairments in executive function, attention, visuospatial skills, and memory characterize the “typical” cognitive profile in PD, whereas language and praxis are thought to be relatively spared. The Mini-Mental State Examination (MMSE) which is the most commonly used screening instrument for global cognition, primarily assesses memory and language skills and may not be sensitive to detect many cases of MCI2.

Methods: Data was collected by participants on the 16th BGS Parkinson's Academy from 12 centres across the UK. Patients with PD for greater than one year, attending the Movement Disorders clinic was included. Their medical records were surveyed for cognitive screening and the tool used.

Results: 101 of 237 patients (42.6%) were screened for cognitive impairment. 88 patients (87.1%) had MMSE; 4 of whom had another test of executive function. Other tools included; Addenbrooke's Cognitive Exam-Revised (ACE-R):6, Abbreviated Mental Test:4, Royal College of Physicians Mental State Exam:1, Neuro-psychiatric testing:2.

Conclusions: Cognitive screening was done only in 42.6% of PD patients; MMSE being the most commonly used screening tool. Due to the high prevalence of MCI in PD and its association with future development of dementia, we recommend routine cognitive screening with a sensitive tool like Montreal Cognitive Assessment or ACE-R to aid in the comprehensive management of all PD patients.

References:

1: Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA. Evolution of cognitive dysfunction in an incident Parkinson's disease cohort. Brain. 2007 Jul;130(Pt 7):1787-98. Epub 2007 May 29. Review. PubMed PMID: 17535834.

2: Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. PubMed PMID: 15817019.

55

A substantial investigation on psychiatric symptoms in patients with Parkinson's disease-(PD) from our own out-patients survey

K. Hasegawa, T. Yokoyama, E. Horiuchi, E. Kaneko, A. Kumon, N. Kawashima (Kanagawa, Japan)

Objective: To investigate a situation of psychiatric conditions in patients with PD.

Background: It is generally accepted that manifestations of non-motor symptoms in PD is one of the factors negatively influence QOL. Psychiatric symptoms in PD are the biggest factor in impaired QOL as well as motor impairment. We have a chance to investigate psychiatric symptoms in PD. Our aim of this study is to develop strategy for making an improvement or for maintaining the psychiatric conditions in PD.

Methods: Our survey was carried out after our Hospital Ethics Committee approved our clinical research program. We conducted 351 patients with PD in our out-patient clinic who assented to our clinical research program. We used the methods of questionnaire and interview technique for psychological examination by skillful clinical psychotherapists. Used test butteries were bellows; for cognition were MMSE and WAIS-III, for frontal lobe function were FAB, word fluency test and apathy test, for depression were HAM-D, BDI and SDS, for memory function was RBMT, for hallucination was NPI, for sleep function was ESS. At the same time, we checked their motor function (UPDRS), their QOL (PDQ-39) and imaging studies (MRI, ECD-SPECT, MIBG cardiac spectroscopy). These data were analyzed by adequate statistical methods.

Results: 1. Patients background; M:F=160:191, examined age: 69.6±7.7 y-o, age of onset: 63.0±4.5 y-o, duration of illness: 4.5±6.6 years. H-Y stage; Y-2; 36%, Y-3; 44%, Y-4; 19%.

2. Results of score in the first year were follows; PDQ-39:30.1, MMSE:26.1, FAB:12.9, WAIS-III(FIQ;87.8, VIQ;94.0, PIQ;82.1), BDI:16.9, HAM-D:2.1, SDS:45.1, FAB:12.7, RBMT(SPS):16.8, ESS:7.12. In MMSE score < 23 points; 30.3%, in RBMT score <15 points; 32.3%, detected depression state by BDI; 48% (however, no one in depression state in HAM-D).

3. From the results of RBMT, verbal memory is well preserved compared with spatial and prospective memory.

4. Concerned with cognition, score of FAB was wrong compared with score of MMSE.

5. Frontal lobe function is impaired in proportion to other lobes from our results.

Conclusions: In this investigation, characteristics of psychiatric symptoms in PD become identified. It is important to continue with such investigations for the purpose of improve QOL in PD patients.

56

Dual task dissociations in cognitive performance in Parkinson's disease

A.A. Hazamy, L.J.P. Altmann, J.P. Wilson, E. Stegemöller, D. Bowers, C.M. Sapienza, M.S. Okun, C.J. Hass (Gainesville, FL, USA)

Objective: To examine the effects of performing simultaneous cognitive and motor tasks on cognitive performance (executive function, processing speed, and working memory (WM)) in Parkinson's disease (PD).

Background: While the effects of cognitive tasks on motor performance have been explored, the effects of concurrent motor tasks on cognitive performance in PD are not fully understood.

Methods: Twenty-six persons diagnosed with idiopathic PD (Hoehn & Yahr 1-3) by fellowship-trained movement disorders specialists completed cognitive tasks while sitting in a quiet room (single task) and during stationary cycling (dual task). Cognitive tasks included: a nonverbal 2-back, requiring participants to decide if a current figure matched that shown two trials previously; a Digit Symbol Substitution task requiring identification of the digit associated with a featured symbol; an Operation Span task requiring recall of a series of letters after an intervening mathematical equation verification task; and a visual WM task requiring participants to recognize a series of 1-4 figures.

Results: Accuracy on the 2-back showed typical dual task effects: participants were more accurate during the single task. Response times on the Digit Symbol Substitution task exhibited a reverse dual task effect: faster response times during the dual task. Accuracy on the Operation Span also showed a reverse dual task effect, with better recall during the dual task. However, the visual WM task showed no dual task effects. Indeed, in both the single and dual tasks, participants performed at chance for the most difficult level of the visual WM task. There was no evidence that cognitive tasks were prioritized over cycling.

Conclusions: In contrast to a robust literature on healthy older adults that largely documents declines in cognitive performance during a simultaneous motor task, our findings in PD demonstrate that some motor dual tasks may differentially improve some but not all aspects of cognitive performance. We suspect that these findings may be specific to cycling as a dual task in PD, due to low demands on motor coordination and balance and its rhythmicity, which may normalize patterns of neuronal activity in striatal-thalamo-cortical circuits supporting motor and cognitive function (Ridgel et al., 2009).

57

Do the sub-types of Parkinson's disease patients respond differently to challenging walking conditions?

T. Herman, A. Weiss, M. Brozgol, S. Shema, N. Giladi, J. Hausdorff (Tel Aviv, Israel)

Objective: To test whether challenging walking conditions have a greater impact on Postural Instability Gait Difficulty (PIGD) sub-type of Parkinson's disease (PD) compared to the Tremor Dominant (TD) sub-type.

Background: PIGD generally exhibit more severe deficits in balance and gait, compared to TD patients. However, the effects of challenging walking conditions on those 2 sub-types have never been studied. We hypothesized that dual task (DT) walking and obstacle negotiation (ObN) will be more difficult in PIGD.

Methods: We examined 19 PIGD (mean age: 65.9±7.1ys) & 19 TD patients (mean age: 61.8±11.3ys). Subjects walked under 4 conditions: usual walking (UW), walking while subtracting 3 (DT) & walking in an ObN course with & without DT, while wearing an accelerometer on lower back. Derived measures included average stride duration (strav) & variability (strcv), step & stride regularity (strreg) & frequency-based measures which reflect the strav (peak frequency), strcv (width) and consistency (amplitude). We compared gait measures of PIGD vs. TD including their DT & obstacle cost (DTC, OC), defined as the difference between the DT or ObN measures vs. the UW, normalized by UW. Cognitive (Cog) function was evaluated using a computerized neuropsychological battery that generated indices for several Cog domains.

Results: The PIGD group walked significantly slower in UW & DT (DT gait speed: 1.04±0.21m/s; vs. 1.24±0.21m/s; p=0.01). PIGD had higher strcv (0.002), lower strreg (0.03) & higher DTC and OC, which was reflected by the frequency measures (Obstacle DTC amplitude: 0.33±0.15 vs. 0.19±0.11; p=0.006). The PIGD scored lower on MMSE & MoCa (0.04). Higher amplitude DTC was related to poorer computerized catch game score (r=-0.55, p=0.001) & lower global Cog score (r=-0.36, p=0.03). DT strcv effect was correlated with MoCa (r=-0.42, p=0.01) & EF (r=-0.42; p=0.01).

Conclusions: Acceleration-derived measures of gait confirm that PIGD have worse walking performance than TD. Moreover, these results demonstrate for the first time that PIGD apparently have less coping abilities during challenging walking conditions. Associations with Cog measures suggest that the exaggerated response to DT and ObN may represent Cog deterioration and points to the importance of motor-Cog interactions in these patients.

58

Naming dynamic actions in Parkinson's disease

E. Herrera, E. Poliakoff, J. Holler, K. McDonald, F. Cuetos (Oviedo, Spain)

Objective: The aim of this study was to test the performance of PD patients in naming static versus dynamic actions compared to controls.

Background: Parkinson's disease (PD) is a neurodegenerative disorder associated with dopamine deficiency in the fronto-striatal networks. Recent findings have demonstrated a specific impairment in the processing of verbs in PD patients assessed by naming actions from pictures. This effect could be explained according to the notion that the same prefrontal areas related to planning and execution of movements are involved in verb processing. Several studies have been conducted with static action pictures, but only a few comparing both static and dynamic actions; better naming performance has been found for static than dynamic actions in brain damaged people.

Methods: A group of 14 non-demented PD patients (mean age 62,07; UPDRS mean 25,21) and 12 healthy controls (mean age 63,05) matched for IQ participated in the experiment. A set of 48 videoclips (4s duration) and 48 real static photographs were selected. The psycholinguistic variables of the verbs associated with the presented actions were matched.

Results: We found that naming times tended to be slower for PD patients than controls for both, dynamic and static actions. However, these differences were significant only for naming dynamic actions.

Conclusions: Our PD patients were significantly poorer at naming dynamic actions compared to healthy controls. This result suggests that PD patients may need more time to understand dynamic actions, which probably require extensive cognitive and premotor mechanisms.

59

Subcortical white matter hyperintensities within the cholinergic pathways of Parkinson's disease patients according to cognitive status

J. Shin, S. Choi, J.Y. Hong, J.E. Lee, Y.H. Sohn, P.H. Lee (Seoul, Korea)

Objective: We evaluate whether the CHIPS burden differs according to cognitive status in patients with PD and we analyze the correlation between the CHIPS score and performance on individual tests of different cognitive subdomains.

Background: White matter hyperintensities (WMH) in the cholinergic pathways show a stronger correlation with cognitive performance than general WMH in Alzheimer's disease. However, the role of WMH within the cholinergic pathways in cognitive dysfunction has not been investigated in Parkinson's disease (PD).

Methods: We compared the severity of WMH within the cholinergic pathways of PD subgroups with intact cognition (PD-IC, n = 44), mild cognitive impairment (PD-MCI, n = 87), and dementia (PDD, n = 40) using the Cholinergic Pathways Hyperintensities Scale (CHIPS), and analyzed the correlation between the CHIPS score and performance on individual tests of cognitive subdomains.

Results: The mean CHIPS score was significantly higher in patients with PDD compared with those with PD-IC (p = 0.03) or PD-MCI (p = 0.015). The CHIPS score in patients with PD was negatively correlated with general cognition assessed using the Mini-Mental State Examination (r = -0.28, p < 0.001) and positively with the Unified PD Rating Scale motor score (r = 0.24, p = 0.002). The CHIPS score showed a significant correlation with cognitive performance on individual cognitive subdomains and had the highest independent correlations with contrasting program (β = -0.33, p < 0.001) and forward digit span (β = -0.17, p = 0.04).

Conclusions: This study demonstrated that the burden of WMH within cholinergic pathways was significantly higher in patients with PDD relative to other groups and that cholinergic WMH was significantly correlated with a decline in frontal executive function and attention.

60

Neurocognitive and atrophic patterns in Parkinson's disease based on subjective memory complaints

J.Y. Hong, J.E. Lee, Y.H. Sohn, P.H. Lee (Seoul, Korea)

Objective: we investigated whether cognitive profiles and gray matter (GM) density differed in cognitively normal patients with PD based on the presence of SMC using standardized neuropsychological tests and voxel-based morphometry (VBM).

Background: Ample evidence has suggested that individuals with subjective memory complaints are at a higher risk for cognitive decline. Nevertheless, the significance of subjective memory complaints in Parkinson's disease has not been studied until now.

Methods: We investigated whether the patterns of cognitive profiles and gray matter density differed in cognitively normal patients with Parkinson's disease based on the presence of subjective memory complaints. Using a single question with a Yes or No answer, cognitively normal patients with Parkinson's disease were classified as with (n = 20) or without subjective memory complaints (n = 15). Cognitive profiles and gray matter density were examined using standardized neuropsychological tests and voxel-based morphometry.

Results: No significant differences in demographic characteristics were observed between groups. The detailed neuropsychological tests demonstrated that Parkinson's disease patients with subjective memory complaints had significantly decreased verbal fluency and slightly lower scores on the backward digit-span test compared with those without subjective memory complaints. A voxel-based morphometry analysis revealed that Parkinson's disease patients with subjective memory complaints had significantly decreased gray matter density in the anterior cingulate gyrus and right inferior parietal lobule compared with those without subjective memory complaints.

Conclusions: Our data demonstrated that Parkinson's disease patients with subjective memory complaints showed a poorer performance on tasks related to verbal fluency and attention with more severe cortical atrophy compared to those without subjective memory complaints, suggesting that subjective memory complaints in patients with Parkinson's disease may represent an early manifestation of underlying Parkinson's disease -related pathological changes

61

Quantitative assessment of clock drawing test combined with Minimental Status Exam in screening of cognitive impairment in PD

H.Y. Jeong, J.Y. Lee, S.Y. Seo, H.J. Kim, H.K. Park (Seoul, Korea)

Objective: To assess the usefulness of Clock drawing test (CDT) combined with Mini-mental status exam (MMSE) in comparison with Montreal Cognitive Assessment (MoCA) in detection of cognitive impairment in Parkinson's disease (PD) under low educational backgrounds.

Background: The MMSE and MoCA have been used in screening of cognitive impairment in PD. MoCA may be more sensitive than MMSE, but its positive predictive value relatively low in populations of low edication. The validated cut-off value of MoCA(22/23) in elderly of our country (Lee, 2008) is lower than that of countries with higher educational status (26/27). CDT is quick to administer (<2 min.), well tolerated in elderly and independent of culture, language and education. Quantitative assessment of it by command and by copy condition is reported to be sensitive for temporal and frontal, and parietal dysfunction, respectively.

Methods: A representative sample of 91 patients with PD at 2 movement disorders clinic was administered MMSE, MoCA and CDT. CDT was quantitatively assessed by both command and copy conditions according to the methods of Rouleau (1992). The cognitive impairment was defined by diagnostic criteria of dementia in PD blinded to the results of the 3 screening tools. The discriminative validity of MMSE, MoCA and MMSE+CDT was ascertained by receiver operating characteristic (ROC) analysis.

Results: The mean age and the duration of PD was 69 and 4.3 years. The mean educational year was 7.2. The ROC areas under the curves (AUCs) (95% confidence interval) were 0.79 for the MMSE (0.69-0.89), 0.81 for the MoCA (0.72-0.91), and 0.81 for the MMSE+CDT (0.71-0.90). The best screening cut-off points of MMSE, MoCA, and MMSE+CDT were 25/26 (sensitivity 89.7, specificity 56.9), 21/22 (sensitivity 82.8, specificity 53.4) and 41/42 (sensitivity 82.8, specificity 67.2). In a group of patients ≤ 6 years of education, the sensitivity and specificity of MoCA were 83.3 and 35.5 with AUC 0.77 (0.64-0.91) whereas those of MMSE 94.4 and 45.2 with AUC 0.77 (0.64-0.90) and MMSE+CDT 94.4 and 54.8 with AUC 0.81 (0.69-0.93).

Conclusions: In the country where elderly population has low educational backgrounds, quantitative assessment of CDT combined with MMSE would be a better screening tool for cognitive impairment in PD than MoCA.

62

Clinical and neuropsycological profile of patients with Parkinson's disease

D. Joshi, A. Zafar (Varanasi, India)

Objective: To study the clinical and neuropsycological profile in Parkinson's disease patients at a tertiary care referral centre.

Background: The cognitive impairments in Parkinson's disease produce s significant disability, and affects normal physi-cal, social, intellectual, and occupational activities, thereby producing significant distress.

Methods: Forty one patients with a clinical diagnosis of PD who were of 20 years of age and above, had completed their primary education, were enrolled. Thev were evaluated with MMSE and the eight lobar scales for the right and left hemispheres of the AIIMS comprehensive neuropsycological battery in Hindi (adult form). The results were compared with age & gender matched control subjects.

Results: Out of a total of 41 patients included in our study 30 were male it included 11 females. Majority of the patients 20 (48.8%) presented with less than 2 year duration of symptoms, while 13 (31.7%) of patient presented within 3-5 years, 6 patients (14.6%) of patient presented within 6-10 years and 2 (4.9%) presented > 10 years of duration of first symptom. Twenty two patients were in H&Y stage 2 and below while 19 patients were in stage 2.5 and above. The mean Mini Mental Status Examination (MMSE) score in the patient's group came out to be 21.70 ±2.87 and in the control group it was 26.46± 1.07. Neuropsychological testing revealed that the mean T scores of the lobar scales (both right and left hemispheres) in patient group (LF – 77.33; LSM – 76.57; LPO – 79.26; LT- 82.74; RF – 95.14; RSM – 92.05; RPO – 73.86; RT- 74.45) are remarkably significant as compared to the controls (p<0.0005). in addition involvement of right hemisphere, and mainly right frontal region was distinctly significant in patients with disease stages of 2 and above.

Conclusions: Thus our study revealed significant impairment of lobar functions in patients with PD with predominantly right hemispheric dysfunction in patient's stage 2 and above.

63

Longitudinal course of cognition in elderly women with Parkinson's disease

G.A. Kang, L. Lui, H. Fink, B. Miller, K. Yaffe (San Francisco, CA, USA)

Objective: To assess the longitudinal course of cognition in elderly women diagnosed with Parkinson's disease (PD).

Background: Cognitive deficits are a common non-motor manifestation of PD with as many as 80% of patients developing cognitive impairment. However, few studies have investigated the longitudinal course of cognition in PD, especially among older women.

Methods: We studied 7393 older women (mean age 71 years at baseline) who were followed for up to 18 years as part of the ongoing study. Cognition was measured at a baseline exam and then every 2 to 4 years with the Trails B test and a modified Mini Mental State Exam (mMMSE). In addition, participants completed an expanded cognitive battery at a final visit 18 years after baseline. At each visit, women self-reported if they had been diagnosed by a physician with PD since their last study visit. Cognitive trajectory slopes were modeled with an inflection for report of PD if made after baseline. Repeated measures regression analyses were used to calculate cognitive trajectory slope on Trails B or MMSE over 18 years; models were adjusted for age, education, and depression.

Results: Of the 7393 women, 259 (3.5%) reported a diagnosis of PD during the course of the study. Compared to women without PD, those with PD had a greater decline on Trails B (PD slope: 6.1+3.2; non-PD slope: 5.3+3.1, p =0.0001), but not on mMMSE (PD slope: -0.14 +0.14; non-PD slope: -0.13 +0.12; p =0.23). 51 of the women with PD and 1289 of the women without PD attended the final visit and were evaluated with a more extensive cognitive battery, At that time, subjects with PD performed worse than non-PD subjects on verbal fluency (PD: 8.8+3.5; non-PD: 10.7+4.1, p <0.005) and Trails B (PD: 199.8+90.6 seconds; non-PD: 172.0+85.6 seconds, p = 0.05) but not on any other of the cognitive tests (3MMSE, digit span, CVLT).

Conclusions: In comparison to age-matched females without PD, elderly women reporting a diagnosis of PD have an increased rate of decline in executive function but not in other cognitive domains. These results may have implications for the underlying longitudinal neuropathological characteristics in this population.

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Brain derived neurotrophic factor G196A polymorphism and cognitive impairment in Parkinson's disease

C. Karakasis, K. Kallinderi, G. Kourtesi, D. Milioni, L. Fidani, Z. Katsarou, S. Bostantjopoulou (Thessaloniki, Greece)

Objective: The purpose of this study was to determine the distribution of Brain-derived neurotrophic factor (BDNF) G196A (Val66Met) polymorphism in a sample of Greek patients with Parkinson's disease (PD) and to explore its possible association with cognitive impairment.

Background: BDNF is widely expressed in the central nervous system and enhances the survival of dopaminergic neurons in the substantia nigra, whereas BDNF mRNA expression is decreased in PD. BDNF Val66Met polymorphism has been associated with the risk of developing cognitive impairment in patients with PD.

Methods: The BDNF G196A polymorphism was evaluated in 124 consecutive Greek patients with PD .There were 78 men and 46 women with a mean age of 66.9±8.8 years and a mean age at disease onset 54.3±8.9 years. PD patients were genotyped by means of a PCR-restriction fragmentation length polymorphism (PCR-RFLP) method. Cognitive function assessment was based on the Dementia Rating Scale (DRS) total score.

Results: The frequency of the BDNF Val/Val genotype in our patients was 65.38% (group I), while the Met allele (Val/Met and Met/Met genotypes combined) was present in 34.62% (group II). Performance in the DRS test was equal in both groups (133.1±7.3 vs 134.2±6, p=.394).

Conclusions: Our results do not support the hypothesis that Brain Derived Neurotrophic Factor Val196Met polymorphism plays a major role in cognitive function in PD patients.

65

Pill questionnaire for detecting cognitive dysfunction and its impact on daily living in Parkinson's disease

J.S. Kim, J.H. Kang, B.S. Jeon (Cheongju-si, Korea)

Objective: To investigate the correlation of pill questionnaire on cognitive function and activities of daily living (ADL) in patients with Parkinson's disease (PD).

Background: Pill questionnaire has been proposed as a simple questionnaire for assessing decline in cognitive function and its impact on daily live in PD. This item can be assessed by asking the patient or caregiver whether the patient can manage his/her pills. This is very easy to administer, however there is little evidence on the correlation of other screening instruments. In this paper, we evaluated the correlation between the pill questionnaire score and cognitive deficit and impaired ADL.

Methods: All were evaluated on the Hoehn and Yahr scale, and the Unified Parkinson's Disease Rating Scale (UPDRS). Two brief cognitive tests (Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA)) and Clinical Dementia Rating (CDR) were assessed for detecting of cognitive changes, and determined the characteristics of cognitive profile in PD. Pill questionnaire score was estimated by asking the patient to describe verbally his/her treatment and its time schedule. According to each severity score, patients were divided into two groups: ‘absent of cognitive functional impact on daily live’ and ‘impact on daily living’ group. The statistical analysis was performed for comparison of the variables' mean between them. Correlations of pill questionnaire scores, cognitive impairment variables, ADL, and PD severities were determined using logistic regression models.

Results: A total 208 participants (93 men) were included. The average score of the MoCA was 22.3±5.1, while the MMSE was 26.6±3.0. The groups differed significantly for all cognitive measures and motor severities. Correlation analysis showed that pill questionnaire appeared to represent ADL. Moreover, pill questionnaire were significantly correlated with an MMSE, MoCA, CDR and the UPDRS III scores.

Conclusions: Pill questionnaire is a sensitive and useful test for detecting cognitive impairment and its impact on daily living in PD.

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The relationship between dysphagia and cognitive impairment including frontal lobe function in Parkinson's disease

J.Y. Kim, H.Y. Shin, J.E. Shin, H.R. Na (Seongnam-si, Korea)

Objective: To investigate (1) the clinical factors affecting dysphagia and (2) the relationship between cognitive impairment including dysexecutive function and dysphagia in Parkinson's disease (PD).

Background: Swallowing difficulty is frequently observed in PD patients and the risk of aspiration pneumonia in patients affects the quality of life. Multiple clinical factors associated with PD including cognitive function are supposed to influence dyphagia. More pronounced frontal dysexecutive function in PD may play a significant role in swallowing function.

Methods: Thirty-nine patients with PD (Hoehn and Yahr stage 2-5) were recruited. Their clinical motor symptoms were evaluated by Unified Parkinson's Disease Rating Scale part III (UPDRS III). Mini-Mental State Examination (MMSE) and a frontal assessment battery at bedside (FAB) were checked. To estimate the severity of dysphagia, we applied American speech-language-hearing association national outcome measurement system (ASHA NOMS) swallowing level scale supported by modified barium study (MBS).

Results: The severity of dyphagia strongly correlates with motor disturbances as seen in HY stages and UPDRS motor scores. (r = -.594, p = .000 and r = -.473 p=.002, respectively) MMSE and FAB scores are also positively related with swallowing ability. (r=.409, p=.010 and r=.350, p=.029 respectively). Motor series (programming) and prehension behavior (environmental autonomy) subscores of FAB are correlated with the severity of dysphagia.

Conclusions: Swallowing difficulty occurs more frequently in the patients with severe motor symptom and cognitive impairment. Frontal dysexecutive symptom is shown to disturb the proper eating process from oral to pharyngeal stage. Early detection of dysphagia in patients with silent aspiration seems to be necessary and the rehabilitating therapeutic strategy enhancing motor and cognitive function together may help the swallowing ability in PD.

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Cognitive impairment in Parkinson's disease: A pilot study with minimental Parkinson's, the clock drawing test and the generation of words by category and code

A.P. Kleinert, E. Rodríguez, L. Romero, H. Juárez (Mexico City, Mexico)

Objective: To evaluate the presence of cognitive impairment in Parkinson's disease (PD) using the minimental Parkinson's scale, the clock drawing test and the generation of words by category and code.

Background: Cognitive impairment is frequent in Parkinson's disease, and could be present up to 70% of patients. The prevalence of dementia in PD is 30-40%.

Methods: Observational, descriptive and transversal pilot study, involving 8 patients, with more than 3 years of PD diagnosis, 40 years old or more, excluding those with incapacitating tremor and peak-dose diskinesias. The patients were dated early in the morning and at the same time they took their medication. After 30 minutes of the intake of treatment it was performed the minimental Parkinson's scale, The clock drawing test (CDT) by copy and order, and finally the generation of words in 1 minute by category (semantic) and by code (phonologic). We performed univariate and bivariate statistical analysis data in SPSS 15.0.

Results: From all patients, 50% were male and 50% female, mean age 68 (SD 6.4), mean time of PD evolution of 9 years (SD 5.2), mean time of onset of motor fluctuations of 41 months (45), mean education years of 7(SD 5). The mean Minimental Parkinson's Scale score was of 22 (SD 4), with 50% of patients with cognitive impairment (< 24). The Clock Drawing Test's mean total score (copy and order) was of 17 (SD 3.8). The mean words/min by code was 8 (SD 3.4) and by category was 12 (SD 3.4) (minimal 15). Bivariate analysis r (Spearman): schooling-minimental Parkinson's (r=0.3, p= 0.4), schooling-words/min by code (r=.72, p<0.05), schooling-CDT (r=0.43, p=0.2), age-minimental Parkinson's (r= -.643, p=0.08), age-words/min by code (r= -.576, p=0.135), age-CDT (r=.43, p=0.2).

Conclusions: Patients with PD do have cognitive impairment as we found in this pilot study, having a relationship with age and schooling years, as we saw specially when performing the generation of words by code in 1 minute, which talks about frontosubcortical impairment, as seen in PD. It is important to perform the tests in “On” phase, in order to eliminate the skewness of a cognitive non-motor fluctuation.

68

COMTval158Met genotype and executive function in Parkinson's disease

G. Kourtesi, L. Fidani, Z. Katsarou, K. Kallinderi, T. Katopodi, V. Tsipropoulou, S. Bostantjopoulou (Thessaloniki, Greece)

Objective: The purpose of this study was to address the question whether COMTval158Met genotype would be associated with performance in Executive function tests in Parkinson's disease (PD).

Background: The functional polymorphism (COMT Val108/158Met) affects COMT activity, with the valine (Val/Val) variant associated with higher, the Val/Met variant with intermediate and the methionine (Met/Met) variant with lower COMT activity. This polymorphism has been associated with frontal lobe function in normal subjects and in a variety of disorders including PD, but the literature data on this relationship are contradictory and inconsistent.

Methods: The study population consisted of 130 PD patients (77 men and 53 women) with a mean age of 60.58±9.51 years. The Val158Met COMT polymorphism was assessed using a PCR-restriction fragmentation length polymorphism (PCR-RFLP) method. Furthemore PD patients' general cognitive ability was assessed by means the Test of Non Verbal Intelligence (TONI-2),while executive functions were evaluated by the Wisconcin Card Sorting Test (WCST),a Word Fluency (WF) task and the Trail Making test, part A&B.

Results: The frequencies of the three COMT genotypes in PD patients were: Val/Val= 45.7%; Val/Met =37.2%; and Met/Met =17.05%. Performance in TONI-2 test was equal in the three genotype groups. There was no difference in WCST pertinent outcome measures between the three groups. There was a slight difference in favor of the Val/Val phenotype carriers regarding the total correct answers measure of the WCST .However this subtle difference did not affect the whole WCST performance. There was also no difference in the performance on the WF task or the Trail Making test.

Conclusions: Our results does not support the hypothesis that genetic variation in the catechol-O-methyltransferase (COMT) Val158Met polymorphism can influence executive functions in PD patients.

69

The pattern of cortical atrophy in Parkinson's disease with mild cognitive impairment according to the timing of cognitive dysfunction

J.E. Lee, J.S. Kim, K.H. Cho, Y.H. Sohn, P.H. Lee (Seoul, Korea)

Objective: We analyzed whether the pattern of cortical atrophy in PD-MCI differed depending on disease duration prior to cognitive impairment.

Background: The density of Lewy bodies or the concurrent β-amyloid pathology would act as acting as modulators in the relative timing of dementia during the course of Parkinson's disease.

Methods: Depending on the temporal relationship between the onset of parkinsonism and that of cognitive impairment, patients with Parkinson's disease with mild cognitive impairment were divided into two groups of earlier (<1yr) and later (≥1yr) cognitive decline, and cortical atrophy patterns and correlation of gray matter and timing of cognitive decline was analyzed using voxel-based morphometry.

Results: The morphometric analysis showed that patients with earlier cognitive decline demonstrated greater cortical atrophy in the inferior parietal and orbitofrontal areas than did those with later cognitive decline. Additionally, the anatomical bases of the timing of their cognitive declines differed in terms of correlation patterns.

Conclusions: These data suggest that the pathological burden in Parkinson's disease with mild cognitive impairment may be more severe in patients with earlier cognitive decline than in those with later cognitive decline and that the neural basis corresponding to the timing of cognitive decline may differ in these patients.

70

Changes on the mini-mental status examination and Montreal cognitive assessment over time in Parkinson's disease

S.L. Lessig, D. Nie, S. Edland, R. Xu, J.P. Corey-Bloom (La Jolla, CA, USA)

Objective: To compare change over time in cognition on the Mini Mental Status Examination (MMSE) with the Montreal Cognitive Assessment (MoCA) in Parkinson's disease (PD).

Background: Both the MMSE and MoCA have been proposed as brief screening measures for cognition in PD. Few studies have examined changes on the MMSE over time and no studies, to our knowledge, have examined changes on the MoCA.

Methods: 221 subjects with PD were examined using the MMSE and MoCA, with a subset examined on repeat testing up to 3 years. Individual items on the MMSE and MoCA were divided into four cognitive-specific domains. A linear mixed-effects model was used to assess change in the MMSE and MoCA over time.

Results: The MoCA was more sensitive in identifying cognitive deficit, specifically in the domains of visuospatial abilities, language, and memory. On longitudinal study, the MMSE significantly changed over time, particularly in patients with disease duration of >10 years. The MoCA, however, did not change significantly, regardless of disease duration, even when subjects were stratified by age, MMSE score, and time in the study.

Conclusions: This suggests the MoCA warrants further study in assessing its value for longitudinal study, such as for use in clinical trials.

71

Parkinson's disease patients with “normal” MMSE score have a broad range of cognitive performance

D. Burdick, S. Watson, J. Trojanowski, A. Siderowf, B. Ritz, S. Rhodes, C. Wood-Siverio, S. Factor, J. Quinn, K. Chung, S. Srivatsal, K. Edwards, T. Montine, C. Zabetian, J. Leverenz (Seattle, WA, USA)

Objective: To characterize the range of cognitive performance in patients with Parkinson's disease (PD) with normal MMSE scores and to evaluate the role of MMSE in predicting cognitive impairment in PD.

Background: Cognitive impairment is common in patients with PD, and up to 80% of PD patients fulfill criteria for dementia by 15 years of disease onset. The MMSE has been recommended by the MDS task force on dementia in PD as a reliable screening tool for PD dementia with values of 26 or higher considered to be in the normal range. We characterized detailed neuropsychological testing in a large sample of PD patients with MMSE ≥26 in order to evaluate the range of cognitive function in this group.

Methods: In this multi-center study, 928 patients with PD were screened, and 788 patients had an MMSE score ≥26. They underwent a battery of cognitive tests including MoCA, Mattis Dementia Rating Scale, Trails A&B, Digit Span, Letter Number Sequencing, Digit Symbol, Judgement of Line Orientation, Boston Naming, animal and letter fluency, Hopkins Verbal Learning Test – Revised, and Logical Memory. A subset of 290 patients underwent a review of the above tests and assessment of level of functional impairment from cognitive dysfunction, by a consensus panel of at least two neurologists and a neuropsychologist, and received a diagnosis of no cognitive impairment, dementia, or cognitive impairment with no dementia.

Results: Of the 788 patients with MMSE scores within normal range, more than 20% showed impairment of 1.5 or more standard deviation below the mean in the neuropsychological battery, strongly suggesting cognitive impairment. The greatest impairments were found on Trails B and Digit Symbol. In the subset of participants who received a cognitive diagnosis by a consensus panel, the sensitivity of the MMSE for diagnosing dementia was 45%.

Conclusions: In PD patients with a normal MMSE, a wide range of cognitive impairments can be noted suggesting that the MMSE has limited utility as a screening tool for cognitive impairment in PD.

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Neuropsychological assessment in collaborative PD research: A proposal from the National Institute of Neurological Disorders and Stroke Morris K. Udall Centers of Excellence for Parkinson's Disease Research at the University of Pennsylvania and the University of Washington

G.S. Watson, B. Cholerton, R.G. Gross, D. Weintraub, C.P. Zabetian, J.Q. Trojanowski, T.J. Montine, A.D. Siderowf, J.B. Leverenz (Seattle, WA, USA)

Objective: To develop a neuropsychological test battery that promotes and assists in collaborative studies of cognition in Parkinson's disease (PD).

Background: Cognitive impairment and behavioral disturbances can be the earliest symptoms of PD and afflict the vast majority of patients as disease progresses. Together, cognitive impairment and behavioral disturbances account for increased disability for patients and greater burden for caregivers. Despite their prevalence and significance in PD, cognitive impairment and behavioral disturbances are only recently a focus of investigators. In addition, large-scale collaborative studies have been hindered by a lack of a standard approach to neuropsychological assessment.

Methods: Two Morris K. Udall Centers of Excellence for Parkinson's Disease Research, with a focus on these common and devastating features of PD, were supported by the National Institute of Neurological Disorders and Stroke (NINDS) in an effort to devise a comprehensive yet readily usable cognitive and behavioral assessment battery to fuel collaborative research.

Results: We devised a tiered approach of four levels of evaluation that is based on the most recent scholarship and that is suitable for studies with varying emphasis on cognition and behavior. Our approach is intended to be flexible and not place undue burden on participants or research resources. We sought a high degree of compatibility with existing test batteries to promote collaboration not only across our Udall Centers but also other national research programs focused on PD as well as other neurodegenerative diseases.

Conclusions: We hope this approach will promote collaborative research across multiple institutions and centers, and thereby accelerate research progress into cognitive and behavior changes in PD and related disorders.

73

Parkinson's disease patients fulfilling level-I criteria for dementia differ in ADL functions and phenotype

I. Liepelt-Scarfone, D. Prakash, J.B.M. Christ, E. Riedl, I. Csoti, M. Fruhmann Berger, S. Graeber, D. Berg (Tuebingen, Germany)

Objective: To evaluate whether Parkinson's disease (PD) patients who meet the cognitive Level-I criteria for the diagnosis of dementia according to the consensus guidelines (MDS-Task-Force) differ with regard to activities of daily living (ADL) function. If so, whether patients fulfilling Level-I criteria with (ADL-Dys+) and without (ADL-Dys-) ADL impairment are present with different phenotypes.

Background: The use of the MDS-Task-Force Level-I criteria might lead to an overestimation of suggested PDD patients. However, crucial for the final diagnosis of PDD are both cognitive deterioration and ADL-Dys+. Impact on ADL function is often judged by caregivers. Besides cognitive impairment, motor worsening might influence patients ADL ability.

Methods: In 131 PD patients motor and neuropsychological assessments including the neuropsychiatric inventory (NPI) and the Parkinson's Disease Questionnaire (PDQ-39) were performed. Impact on instrumental ADL function was rated according to the standard scores (PR) of a proxy scale (NAB).

Results: Thirty patients (22.9%) met the Level-I criteria, 12 of them were rated to not have ADL Dysfunction (ADL-Dys-, NAB-PR>16). Nearly all patients (94.4% n=17) who met Level-I with ADL-Dys+ suffered from postural instability and gait problems (p=0.009) and were more often medicated with neuroleptics (p=0.049). Furthermore they performed worse on tests assessing visual-construction performance (p<0.05) and attention (p=0.03) than ADL-Dys-. Moreover ADL-Dys+ patients suffered from more severe anxiety (p=0.05, NPI-subscale-E), and stated more problems in communications (p=0.05, PD-Q-39-subscale-7).

Conclusions: PD patients who meet the Level-I criteria for dementia with and without ADL dysfunction seem to represent different phenotypes of cognitive impairment.

74

A survey of the management of psychosis in Parkinson's disease

J. Lonnen, L. McNeil, E. Capek, C. McCarthy, V. McGill, G. MacPhee, D. Stewart (Larbert, United Kingdom)

Objective: This survey aimed to investigate:

• The perceived prevalence of PD psychosis.

• Management strategies employed by specialist clinicians.

• Perceived barriers to achieving optimal management of PD psychosis.

Background: Psychosis related to Parkinson's disease (PD) has an estimated prevalence of 40% and is clinically challenging to manage. It can accompany the progression of motor disability and titration of dopaminergic therapy. Psychosis can be distressing to both patient and carer, whilst increasing the need for placement in nursing care. Limited evidence is available to guide management of psychosis in PD. Scottish Intercollegiate Guidelines Network (SIGN) recommends initially identifying and modifying any contributing factors, followed by reduction in dopaminergic therapy. If antipsychotic therapy is required, low dose clozapine with monitoring of white cell count is recommended as the first line. If blood monitoring is not possible, low dose quetiapine is recommended.

Methods: Recommendations from the SIGN guideline 113 (2010) were used as basis to an internet-based questionnaire constructed by the authors. This was distributed, via email, to consultants specialising in Movement Disorders, PD nurse specialists (PDNS) and trainees in Geriatric Medicine in Scotland. There were 47 responses (19 consultants, 14 PDNS, 15 trainees).

Results: Ninety three per cent of clinicians deal with hallucinations ‘frequently’ or ‘often’ and 67.4% respondents routinely screen for psychosis in the outpatient setting. The majority (75%) use quetiapine as first line antipsychotic treatment, with only 2.5% using clozapine first line. Only 42% clinicians routinely involve psychiatry in the management of PD psychosis due to perceived issues in access to service. Conversely 70.5% felt that psychiatry should be responsible for monitoring of antipsychotics in a multidisciplinary setting. Respondents reported clozapine is not used routinely due to concerns about the side effect profile, intensive monitoring and lack of drug familiarity.

Conclusions: Despite SIGN guidance, quetiapine remains first line for the majority of clinicians in the treatment of PD psychosis. This is due to service and clinical issues. Closer collaboration with old age psychiatry may improve the service for people with PD and their carers.

75

Olfactory dysfunction correlation to non-motor symptoms in Parkinson's disease patients

G.J. Lopez, K. Bayulkem, B. McElroy, M. Brooks, B. Bayulkem, M. Hallett (Bethesda, MD, USA)

Objective: To evaluate association of olfactory dysfunction to other specific non-motor manifestations in patients with PD.

Background: Non-motor symptoms in Parkinson's disease are major contributors to the progressive difficulty PD patients have in their activities of daily living and subsequent loss of independence. In particular, olfactory dysfunction appears to be one of the earliest signs of several neurodegenerative disorders such as Alzheimer's disease and PD. Olfactory dysfunction is present in the majority of PD patients and often precedes the onset of motor manifestations. However, olfactory dysfunction is usually seen as part of a constellation of non-motor symptoms.

Methods: 245 patients were evaluated at the Parkinson's Disease Clinic at the National Institutes of Health, National Institute of Neurological Disorders and Stroke with a detailed neurological evaluation. The University of Pennsylvania Smell Identification Test (40 items) was administered to all patients. Other non-motor measures included Mini Mental Status Exam, Montreal Cognitive Assessment, Restless legs syndrome questionnaire, Epsworth Sleep Scale, Fatigue Scale, and Geriatric Depression Scale. Correlations between measures used the Pearson correlation-coefficient and measures were compared by Independent samples t-test.

Results: Olfactory dysfunction correlated positively with PD duration, Hoehn & Yahr, UPDRS, Fatigue score, and age. It correlated negatively with MoCA and MMSE scores. Men had worse olfactory function than women.

Conclusions: Olfactory function is correlated with fatigue and cognitive function as well as age and motor function.

76

Visual sampling during walking in people with Parkinson's disease and the influence of task complexity

S. Lord, B. Galna, D. Daud, N. Archibald, D. Burn, L. Rochester (Newcastle upon Tyne, United Kingdom)

Objective: To examine (1) visual sampling during walking in PD under different levels of environmental complexity and (2) associations between saccadic outcomes and clinical measures.

Background: Gait disturbance is intrinsic to advanced Parkinson's disease (PD), but its aetiological basis is incompletely understood. Visuospatial dysfunction may play a crucial role, in particular how visual exploration of the environment is integrated into gait control.

Methods: Visual sampling (frequency and timing of saccades) and gait were measured concurrently for 21 people with PD and 12 age-matched controls during a series of walking tasks using electrooculography synchronised with 3D motion analysis (VICON). Participants walked under four environmental conditions during single and dual task. Saccade frequency and timing, and task duration were measured. The effect of environment and dual-tasks was determined using a mixed model ANOVA.

Results: PD participants took longer to complete all tasks than controls (p = .004) and made less frequent saccades (p = .009). Saccade frequency increased with increasing environmental difficulty in both groups (p < .001) however it was not affected by dual-tasking for either group. Saccadic timing prior to turning through a door was the same for PD and controls (p = .975) despite PD taking longer to complete the walk (p < .001).

Conclusions: People with PD explore their environment less frequently than controls and are unable to alter the timing of saccades in response to environmental features. Lack of visual adaptation may contribute to the gait disorder of PD.

77

Subthalamic deep brain stimulation alters cognitive flexibility and reward-based learning in Parkinson's disease: Preliminary results

U. Lueken, S. Rietzel, M. Wolz, A. Storch, T. Goschke (Dresden, Germany)

Objective: To investigate DBS effects on cognitive flexibility and reward-based learning in patients with Parkinson's disease that underwent DBS treatment.

Background: Although being an effective treatment option for advanced Parkinson's disease (PD), deep brain stimulation (DBS) of the subthalamic nucleus (STN) can alter cognitive and affective functions. Animal and computational models underline the importance of the hyperdirect prefrontal-subthalamic pathways for fast-forward inhibitory behavioural control.

Methods: Using a postoperative on/off design, DBS effects on cognitive flexibility and reward processing were assessed in n = 17 PD patients and n = 14 healthy controls employing a set switching task (ST) and the Iowa Gambling Task (IGT).

Results: Preliminary data from an ongoing trial are reported. Patients exhibited slower reaction times in the ST compared to controls. Higher switching costs during perseveration, but lower distractibility under stimulation-on conditions were observed. Patients also developed less adaptive gambling strategies in the IGT in the -on when compared to controls.

Conclusions: Results from this ongoing study indicate that DBS of the STN influences non-motor functions such as cognitive flexibility and reward processing. DBS appears to shift the balance between cognitive flexibility and stability in the direction of enhanced stability. Under DBS, patients were more impulsive and less sensitive to high-risk (e.g. punishment-related) choices. Findings could be interpreted within the functional profile of the STN for phasic behavioural inhibition. Due to the high inter-individual variability and limited sample size data should be interpreted with caution. Larger sample sizes are needed to analyze patient-related sources of influence that could explain additional variance.

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Olfactory dysfunction is associated with cognitive impairment in Parkinson's disease

C. Sáez-Zea, F. Escamilla-Sevilla, M.J. Pérez-Navarro, Á. Ortega-Moreno, C. Carnero-Pardo, A. Mínguez-Castellanos (Granada, Spain)

Objective: To estimate the prevalence of olfactory dysfunction (OD) in patients with Parkinson's disease (PD) attending a specialist clinic and to assess its relationship with motor, autonomic, and cognitive dysfunction.

Background: PD patients can exhibit OD in several modalities, especially in odor identification tests.

Methods: In this cross-sectional study, we selected 29 consecutive patients at different stages of PD, without family history and with disease onset at >50 yrs of age. Assessments included a 12-item odor identification test (BSIT), motor scales (UPDRS III, SCOPA), cardiovascular autonomic tests (photoplethysmography, tilt table), and a complete cognitive, behavioral, and functional evaluation.

Results: Patients were 18M/11F, aged 69±7 yrs, and at Hoehn-Yahr (HY) stages I-V (n= 7/11/6/2/3). According to sex/age normative data for BSIT scores, patients were classified as with or without OD (73% vs. 27%). Failure in any of four items (banana, gasoline, cinnamon, chocolate) perfectly discriminated the two groups. The presence of subjective complaints had a high positive predictive value (0.94) but a low negative predictive value (0.58). The main predictive factor for OD was HY stage > I (OR=15.83; p=0.003). The presence of OD was associated with a worse performance in motor and cognitive tests but not in autonomic tests. Thirteen patients (45%) were diagnosed with cognitive impairment by an independent researcher, and this diagnosis was significantly associated with OD (OR=1.88; p=0.007), especially in the patients without subjective complaints (OR=5; p=0.015).

Conclusions: Odor identification deficit is common in PD, especially from HY stage II, and is associated with cognitive impairment.

79

Screening for cognitive impairment and dementia in Parkinson's disease using multivariate predictive models

C. Sáez-Zea, F. Escamilla-Sevilla, M.J. Pérez-Navarro, Á. Ortega-Moreno, C. Carnero-Pardo, A. Mínguez-Castellanos (Granada, Spain)

Objective: To evaluate the use of multivariate predictive models to screen for cognitive impairment (CI) and dementia (DEM) in Parkinson's disease (PD).

Background: CI and DEM are common in PD and requesting subjective complaints has limited predictive value. Hence, there is a need for screening tests in this setting.

Methods: We selected 89 consecutive patients at different stages of PD with disease onset at ≥ 45 years of age, after excluding those with other diseases that could be associated with CI or interfere with the evaluation. After a complete cognitive, behavioral, and functional evaluation, they were classified by an independent researcher as: without CI (nCI); with CI without DEM (CInD); or with DEM. Multivariate logistic regression analysis was used to define predictive models for the presence of CI or DEM.

Results: Patients were 47M/42F, aged 72±7 yrs and at Hoehn-Yahr (HY) stages I-V (n= 3/37/31/11/7). CI was present in 63% of patients (38% CInD and 25% DEM). Subjective cognitive complaints were reported by 51% of patients, which was related to the final diagnosis (p=0.004) but with poor predictive values. The multivariate predictive model for DEM included the HY stage and the presence of complaints; the model for CI also included the educational level. Based on these models, ROC curve analysis of individual risks showed an optimal discriminative power (area=0.9), similar to other widespread cognitive tests such as Mini-mental or SCOPA.

Conclusions: Screening for CI and DEM in patients with PD can be effectively performed by using simple predictive models.

80

Identifying frequency of memory impairment in Parkinson's disease clinic

A. Malik, S. Ali, F.S. Khan (Karachi, Pakistan)

Objective: The aim of our study is to identify presenting symptoms in patients with Parkinson's disease and frequency of memory impairment among these patients.

Background: Dementia was the term first introduce over 300 years ago. The diagnosis of dementia requires the development of multiple cognitive deficits that are sufficiently severe to cause impairment in occupational or social functional. Patients with Parkinson's disease (PD) who, by definition, have parkinsonism are at high risk of developing dementia, at a rate of up to 10 per cent per year with a prevalence of 20–30 per cent in contemporary cross-sectional studies. Dementia is increasingly recognized as an important feature of PD in the elderly. Approx. a quarter of PD patients without dementia have mild cognitive impairment. Dementia and depression was observed in 10-17% and 21-31% patients respectively.

Methods: We enrolled 35 cases in a weekly base OPD in six months from July 2011 to December 2011. The demographic characteristic and clinical presentation of the disease pattern were recorded. Memory impairment (Dementia) was defined and identified on DSM-IV criteria. The data collected was analyzed on SPSS version 16.0.

Results: A sample of 35 cases (23 males and 12 females) with PD was included (graph-1). Age's b/w 40-85years (mean 57years). Out of 35 cases six (17.1%) had PD with dementia (PDD); while 29 (82.85%) out of 35 were non-demented (graph-2). Out of six demented patient's five (83%) were males and one (17%) was female (graph-3). We divided the sample into two groups on the basis of presence and absence of dementia features among the patients. Most having PDD started their Parkinson's symptoms of dementia after the 6 the decade. Four (64%) out of six having dementia age range from 61-75 years and remaining two (36%) range on 75 years so advance age of PD had more memory impairment as compared to young age. Duration of Parkinson's disease was less than 10 years in all non-demented patients as compared to the Parkinson's disease patients having dementia.

Conclusions: Dementia in Parkinson's disease was at the Department of Neurology Jinnah Postgraduate Medical Center Karachi not quite high in our study as compared to the western studies but having a significant percentage with the male predominance.

81

Brain dopaminergic (FluroDOPA PET) correlates of kinematic flexibility in Parkinson's disease

L. Marinelli, S. Morbelli, L. Mori, A. Piccardo, A. Brugnolo, A. Picco, G. Abbruzzese, F. Nobili (Genova, Italy)

Objective: To evaluate the correlation of kinematic parameters of upper limb motor performance with brain dopaminergic function in Parkinson's disease (PD).

Background: By means of 6-[18F]fluoro-l-dopa (FluoroDOPA) positron emission tomography (PET) both nigrostriatal and extra-nigrostriatal dopaminergic function can be imaged in PD. When compared to normal controls, PD patients present a reduced flexibility in selecting the time required to perform movements to predictable versus unpredictable targets. This has been related to a reduced kinematic flexibility and involvement of the direct pathway (Moisello C et al. Parkinsonism Relat Disord. 2011;17:642-4), however this peculiar phenomenon needs to be further investigated.

Methods: Fifteen drug-naïve, de novo PD patients were recruited (3 females, mean age 67 years, range 60-76). Patients underwent clinical staging with Hoehn&Yahr and UPDRS scales, brain MRI, extensive neuropsychological assessment, FluoroDOPA brain PET and kinematic study involving a digitized tablet where patients had to perform reaching movements to one of 8 radial targets displayed on a computer screen. Two different motor paradigms have been performed: 1) RAN - targets appeared in an unpredictable order and instructions were to reach the target as soon as possible, 2) CCW - targets appeared in a predictable order and patients had to reach them without specific constrains.

Results: Indexes of motor performance such as reaction time, movement time, spatial accuracy in reaching the target were computed. The difference between the time required to reach the target in the CCW and the RAN conditions was also computed (delta-MT; Moisello et al, 2011). No significant correlation was found between FluoroDOPA uptake and reaction time, movement time and spatial accuracy. A significant direct correlation (p<0.001 uncorrected at voxel level; p<0.05 FDR-corrected at cluster level by means of SPM8) was found between delta-MT and FluoroDOPA uptake in the lateral temporal cortex (Brodmann area 22) of the less affected hemisphere.

Conclusions: Our data try to contribute in understanding the novel concept of kinematic flexibility in PD and point to the involvement of lateral temporal cortex in this peculiar function in early PD.

82

Cerebellar activity increases along with striatal activity after levodopa administration in patients with PD

K. Martinu, M. Oury (Montreal, QC, Canada)

Objective: Our goal was to explore the effect of levodopa on the cortico-cerebellar loop and the cortico-striatal loop during self-initiated (SI) and externally triggered (ET) finger movements in Parkinson's disease (PD).

Background: The cortico-striatal loop is recruited to different extents during SI and ET movements. However, the differential response of the cerebellum and the cortico-cerebellar loop to these types of movements remains controversial. We have previously shown that cortico-striatal loop activity during SI and ET movements is disrupted in PD, and that levodopa leads to a non-task specific increase in striatal activity. How levodopa affects the cortico-cerebellar pathway in PD is still unclear.

Methods: Early idiopathic PD patients and a group of healthy volunteers were asked to perform SI, ET and control finger movements during functional MRI. PD patients performed the protocol after 12 to 18 hours of parkinsonian medication withdrawal on two occasions, before and after levodopa administration. We compared the blood-oxygen level dependent activity of structures involved in the cortico-striatal and cortico-cerebellar loops during SI and ET finger movements.

Results: Significant increases in activity in the cerebellum were observed for SI compared to ET movements for all groups of participants. Compared with healthy volunteers, PD patients off medication revealed decreased activity in the premotor cortex, the striatum and the cerebellum for SI and ET movements. PD patients' activity in the striatum and the cerebellum was significantly increased after levodopa administration.

Conclusions: Our results show that there is a significant increase in activity in structures implicated in both the cortico-striatal and the cortico-cerebellar loops for SI than ET movements. Levodopa has a strong effect not only on the basal ganglia, as expected, but also on the cerebellum. Our results support the hypothesis that the cerebello-cortical pathway might play a role in levodopa-induced dyskinesias.

83

GBA mutation carriers with Parkinson's disease are not at increased risk for cognitive impairment

I. Mata, J. Leverenz, J. Trojanowski, A. Chen-Plotkin, B. Ritz, S. Rhodes, S. Factor, C. Wood-Siverio, J. Quinn, K. Chung, A. Espay, F. Revilla, K. Edwards, T. Montine, C. Zabetian (Seattle, WA, USA)

Objective: To determine whether Parkinson's disease (PD) patients with mutations in the glucocerebrosidase (GBA) gene are at increased risk for cognitive impairment (CI).

Background: Mutations in the GBA gene confer a 5-6 fold increase in susceptibility for PD. Furthermore, among patients with PD several studies have reported a higher prevalence of CI in GBA mutation-carriers than in non-carriers.

Methods: Nine hundred ninety two patients with PD from six sites in the U.S. underwent detailed psychometric testing which included the Hopkins Verbal Learning Test (HVLT), Letter-Number sequencing (LNS), semantic (animals) and phonemic (FAS) verbal fluency, Trailmaking A and B, Judgment of Line Orientation, and the Montreal Cognitive Assessment. The entire GBA coding region was screened for mutations in all patients. Linear regression was used to test for association between mutation status and raw scores on all tests adjusting for sex, years of education, and disease duration. For HVLT immediate and delayed recall, LNS, animals, and FAS raw scores were transformed into z-scores using published age-adjusted normative data. Performance on each of these five tests was then categorized as “impaired” for z-scores < -1.0 or “normal” for z-scores ≥ -1.0 and compared between carriers and non-carriers using logistic regression. P values < 0.05 were considered significant.

Results: Pathogenic GBA mutations were identified in 42 of 992 (4.2%) PD patients. Mutation carriers and non-carriers did not significantly differ in mean raw scores for any of the psychometric tests, with or without adjustment for covariates. Furthermore, the proportion of patients with impaired performance on HVLT immediate and delayed recall, LNS, animals, and FAS was not significantly different between the carrier and non-carrier groups (p > 0.3 for all tests).

Conclusions: In contrast to previous reports using limited cognitive data, our findings based on detailed psychometric testing suggest that in PD patients GBA mutation status does not influence cognitive performance or risk for CI.

84

APOE and SNCA predict cognitive performance in Parkinson's disease

I. Mata, J. Leverenz, J. Trojanowski, A. Siderowf, B. Ritz, S. Rhodes, S. Factor, C. Wood-Siverio, J. Quinn, K. Chung, A. Espay, F. Revilla, K. Edwards, T. Montine, C. Zabetian (Seattle, WA, USA)

Objective: To determine if common variation in the MAPT, SNCA, APOE and COMT genes is associated with cognitive performance in patients with Parkinson's disease (PD).

Background: Cognitive impairment (CI) is an increasingly recognized problem in PD and approximately 80% of patients will develop dementia during the course of the disease. Though there are several well-established susceptibility genes for PD, whether common genetic variation influences risk for CI in PD has not yet been determined.

Methods: We recruited 937 PD patients from six academic centers in the U.S. All study participants underwent psychometric testing that assessed performance in four major cognitive domains: memory (HVLT), language (phonemic and semantic verbal fluency), visuospatial skills (Judgment of Line Orientation), and executive function (Letter-Number Sequencing and Trail Making Test Parts A and B). Subjects were genotyped for single nucleotide polymorphisms (SNPs) in four genes; two (MAPT and SNCA) known to alter risk for PD and two (APOE and COMT) reported to associate with cognitive function in PD. Linear regression was used to test for association between genotype and cognitive performance (at baseline) adjusting for sex, years of education, disease duration, and age at testing.

Results: The APOE ϵ4 allele was associated with lower performance on HVLT immediate (p=0.0002) and delayed recall (p=0.02), semantic verbal fluency (p=0.02), Letter-Number sequencing (p=0.006), and Trail Making B-A (p=0.007). The SNCA SNP rs356219 was correlated with performance on HVLT immediate (p=0.02) and delayed recall (p=0.02). COMT-Val158Met was marginally associated with HVLT delayed recall (p=0.04). The MAPT H1/H2 haplotype was not associated with scores on any tests.

Conclusions: Our data indicate that APOE ϵ4 is an important predictor of cognitive performance in PD across multiple domains, and SNCA exhibits an effect on memory-related tasks. The latter observation suggests that SNCA is both a susceptibility gene for PD and modifier of cognitive function in patients with an established diagnosis of PD. These results serve as proof of principle that common genetic variation influences cognition in PD and provide a rationale for expanding future studies to a genome-wide scale.

85

Capgras syndrome in Parkinson's disease: A case report

S. Medic, D. Kuljic Obradovic, D. Markovic Zigic (Belgrade, Serbia)

Objective: To indicate the possible association between Parkinson's disease (PD) and Capgras syndrome which could be a rare psychiatric manifestation of PD.

Background: Capgras syndrome is a delusional phenomenon in which the patient believes that a closely related person has been replaced by one or more impostors. This rare syndrome has initially been observed in psychiatric disorders and more recently has also been described in some neurological conditions especially in head trauma and neurodegenerative diseases such as Lewy body dementia.

Methods: We present the patient with PD and dementia who developed one of the delusional misidentification phenomena - Capgras syndrome.

Results: Our patient is 75 years old man with a 5-year history of idiopathic PD. Initially he exhibited unilateral rest tremor, bradykinesia and rigidity and had a good response to dopaminergic therapy. After two years he developed visual hallucinations (seeing little children), which responded to discontinuation of dopa agonist and its replacement with levodopa. His PD was well controlled with levodopa 125mg 5x/day, without motor fluctuations. One year ago the patient visited his son in USA and there he became confused believing that his family was replaced by impostors. After he returned home he continued to have delusional belief that his wife is replaced with several identical-looking women. The patient had a mild dementia. Neuropsychological testing demonstrated impaired visuospatial and visuomotor abilities, dysexecutive syndrome, attention and concentration difficulties and mild memory impairment. Brain MRI (2007, 2011) revealed mild brain atrophy and leukoencephalopathy of unclear origin (comprehensive clinical and laboratory investigations had been performed). Treatment with rivastigmine and quetiapine slightly improved his Capgras syndrome.

Conclusions: It is well known that patients with PD have a high incidence of psychiatric symptoms like hallucinations, depression, anxiety, sleep disturbances and repetitive behavior. To our knowledge, Capgras syndrome has been rarely reported in PD. Every patient with PD and Capgras syndrome should be thoroughly examined to rule out any other possible cause of this delusion.

86

MRI brain integrity and perfusion measures in Parkinson's disease: Prediction and progression

T.R. Melzer, D.J. Myall, R. Watts, M.R. MacAskill, T.L. Pitcher, R. Keenan, L. Livingston, J.C. Dalrymple-Alford, T.J. Anderson (Christchurch, New Zealand)

Objective: To predict Parkinson's disease (PD) patients at high and low risk of severe cognitive decline using serial MRI scanning across two years.

Background: We need to identify patients with PD at imminent risk of dementia so they can be appropriately targeted in forthcoming therapeutic trials. Recent developments in other disorders suggest that serial MRI may provide effective prediction of cognitive decline.

Methods: Serial diffusion tensor imaging (DTI) and arterial spin labeling (ASL) images were acquired at baseline and 2 years on a 3T GE scanner in 22 older PD patients (>59yrs, mean age(sd): 70.0(5.7), 5 females, all non-dementing at baseline). Participants also completed neuropsychological and motor assessment at both timepoints. DTI metrics (fractional anisotropy, FA; mean diffusivity, MD) were extracted from the major “skeletal” white matter tracts. Perfusion values were extracted from occipital and posterior parietal cortex. A Relevance Vector Machine (RVM) predictive model with leave-one-out cross validation assessed whether change in DTI and ASL measures predicted conversion across cognitive categories; patients were classified as either PD with normal cognition (PD-N), PD with mild cognitive impairment (PD-MCI), or PD with dementia (PD-D).

Results: 5/22 patients converted to either PD-MCI or PD-D. The RVM model provided an AUC of 0.94 for conversion/non-conversion at 2 years based on the prediction using change in both white matter microstructural integrity and posterior cortical blood flow.

Conclusions: Serial MRI of microstructural integrity of the major white matter tracts and perfusion of posterior cortex was able to predict a group (59%) with low risk of conversion and a group (41%) who had high risk of conversion, supporting the clinical utility of our approach.1 (86)

Figure 1 (86).

87

Motor learning, retention and transfer after virtual reality-based training in Parkinson's disease: Effect of motor and cognitive demands of games

F. Mendes, J.E. Pompeu, K. Guedes, A. Mondenesi, M.E.P. Piemonte (Sao Paulo, Brazil)

Objective: The aim of this study was to evaluate the learning, retention and transfer of patients with Parkinson's disease (PD) on 10 Nintendo Wii Fit (NWF) games, compared with healthy elderly (HE).

Background: We used the Nintendo Wii Fit Plus® to provide PD patients with training in a virtual environment in a bid to verify the potential to improve performance in this condition. We hypothesized that, according to the motor and cognitive demands of the games selected, patients with PD, after extensive training, would be able to learn, retain and transfer to a similar motor task, with or without impairments, compared to healthy elderly.

Methods: Sixteen idiopathic PD patients (mean age=66.4, SD=7.1), at stages 1 and 2 of disease evolution according to the Hoehn and Yahr Classification, asymptomatic for depression and dementia, and 12 healthy elderly (mean age=65.3, SD=6.4), took part in the study. A total of 10 games were selected on the Nintendo Wii Fit Plus® which elicited slow and fast movements from the center of gravity, associated or otherwise with upper limb movement, and step alternation under different conditions. The training was split into 14 sessions with two sessions given per week. Performance on each of the games during the 14 sessions was analyzed using repeated measures ANOVA.

Results: Patients with PD showed no deficit in learning or retention on 7 of the 10 games, despite showing poorer performance on 5 games in comparison to healthy elderly. Patients showed marked learning deficits on 3 other games, independently of poorer initial performance. This deficit appears to be associated to cognitive demands of the games which require decision making, response inhibition, divided attention and working memory. Finally, PD patients were able to transfer performance improvements on games to the functional reach test.

Conclusions: The ability of PD patients to learn, retain and transfer performance improvements after training on the NWF depends largely on the demands, particularly cognitive, of the games involved, reiterating the importance of selecting games for rehabilitation purposes.

88

Baseline data of the DeNoPa-Kassel cohort: Biomarkers and non-motor features of 160 drug naïve PD subjects and 115 matched healthy controls

B. Mollenhauer, E. Trautmann, T. Wicke, J. Ebentheuer, F. Sixel-Döring, C. Trenkwalder, DeNoPa Study Group (Kassel, Germany)

Objective: To conduct a long term follow-up study for an early diagnostic and prognostic marker for Parkinson's disease (PD). We hypothesized that (1) an algorithm out of several markers will improve the early differential diagnosis and reflect disease progression of PD when compared to healthy controls (HC) and (2) predict different clinical courses of non-motor symptoms in PD.

Background: Clinical diagnosis of PD still relies on expert opinion or years of clinical follow-up. No objective biomarker reflects disease progression. Different fluid and non-fluid markers have been shown to be useful in the early and differential diagnosis of PD.

Methods: Between 9/2009 and 1/2012 we enrolled 160 drug-naive PD patients and 115 HC (matched for age, gender and education). Clinical diagnosis was supported by DaT SPECT in most PD cases prior to enrolment. All subjects underwent neuropsychological testing, collection of biological fluids (blood, cerebrospinal fluid, urine, etc.), smell testing, electroencephalography, polysomnography, brainstem ultrasound, MRI as well as various scales and scores on non-motor symptoms. The cohort will be followed for several years with investigations every two years.

Results: We will report the entire baseline data. So far, data of 122 PD subjects, 74 male and 48 female (mean ±standard deviation: 64.8 years±9.68) and 107 HC, 63 male and 44 female (64.9 years±6.66, p=0.972) of the cohort are available. Hoehn and Yahr stage in PD subjects ranged between 1 and 3 (mean: 1.78±0.61). Neuropsychological testing, smell testing, midbrain ultrasound and polysomnography revealed significant differences between PD and HC subjects. Lumbar punctures were performed in 78% of patients and 54% of healthy controls. CSF α-synuclein was lower in PD subjects (1.48 pg/ul ±0.23) compared to controls (1.55 pg/ul ±0.36).

Conclusions: We present the baseline data from a newly established cohort of PD and HC subjects designed to evaluate early diagnostic and prognostic biomarkers for non-motor-features in PD. We conclude that an algorithm of different biomarkers will improve the early diagnosis of PD and for prognostic evaluation of non-motor symptoms in PD.

89

Prevalence and profile of neuropsychiatric symptoms in Parkinson's disease subjects with mild cognitive impairment

R. Monastero, P. Di Fiore, G.D. Ventimiglia, C.C. Ventimiglia, R.M. Camarda, C. Camarda (Palermo, Italy)

Objective: We describe the prevalence and profile of neuropsychiatric symptoms (NPS) in non-demented PD subjects with and without Mild Cognitive Impairment (MCI) selected from a large hospital-based dataset.

Background: NPS are common in PD, particularly in those subjects with dementia. However, NPS prevalence and profile in PD subjects with MCI has been scarcely investigated.

Methods: A total of 410 non-demented PD subjects were included. Of those, 164 were cognitively normal PD subjects (PD-cn), 142 PD with amnestic MCI (PD-aMCI), and 104 PD with non-amnestic MCI (PD-naMCI). For the purpose of the study, NPS - rated with the Neuropsychiatric Inventory (NPI) - were recorded as present (NPI score ≥1) or absent (NPI score = 0). Univariate and multivariate logistic regression analyses were carried out to evaluate the association between NPS and the status of PD-aMCI or PD-naMCI.

Results: Subjects with PD-cn were significantly younger than those with PD-MCI (p=< .0001 for both comparisons); further, the former group showed significantly lower UPDRS-ME and ADL/IADL scores compared to PD-aMCI and PD-naMCI (p= <.001 for all comparisons). Subjects with PD-aMCI showed the highest NPS prevalence, with depression (70.4%), anxiety (61%) and apathy (54.2%) being the most frequent symptoms detected. Multiple logistic regression models with PD-cn as reference groups showed PD-aMCI was significantly associated with hallucinations (OR=3.6, 95% CI =1.2-10.4) and with irritability (OR=3.1, 95% CI =1.7-5.8), while PD-naMCI was marginally associated with irritability (OR=2.0, 95% CI = 1.0-4.0).

Conclusions: NPS prevalence is higher in PD subjects with respect to those without MCI. In particular, the PD-aMCI status was independently associated with hallucinations and irritability. Further studies are needed to evaluate the meaning, clinical correlates and prognostic role of NPS in subject with PD-aMCI.

90

Effect of COMT and DAT1 polymorphisms on the cognitive profile and patterns of neural activity of patients with PD

O. Monchi, A. Noreau, C. Habak, B. Mejia, A. Nagano, A.L. Lafontaine, S. Chouinard, G.A. Rouleau (Montreal, QC, Canada)

Objective: To compare the effect of COMT and DAT1 polymorphysms on the cognitive profile and patterns of neural activation observed with fMRI in early PD.

Background: The COMT Val158Met polymorphysm has been reported to have an effect on cognition in early PD and it has been proposed that the Val-Val genotype, which is linked to a higher cortical dopaminergic tone, may be associated with worse performance on executive functions. However, the effect on cognitive functions in PD of the Variable Number Tandem Repeat (VNTR) of the DAT1 gene, which is linked to dopamine reuptake in the striatum has not been studied.

Methods: 36 early PD patients underwent a neuropsychological evaluation assessing multiple cognitive domains and an fMRI session while performing Wisconsin Card Sorting Task which we have shown to recruit the PFC, caudate nucleus and thalamus in controls when planning the set-shift. Participants were genotyped according to their profile on the VNTR for DAT1 (9 repeat and 10 repeat alleles), and the COMT val-158-met polymorphism.

Results: The genotype on the DAT1 polymorphism had a much stronger effect on the cognitive profile of PD patients than the COMT one. Indeed, patients with the 10R/10R genotype performed significantly better than those with the 9R-10R or 9R-9R genotype on most neurpsychological tasks, while the met-met genotype was only linked to better performance than the val-val one in two executive function tsaks. Furthermore, the 10R/10R polymorphysm was associated with reduced activity in the required fronto-striatal loop during set-shifting compared to the 9R/10R or 9R/9R ones. Interestingly, this was also the case for the val-val vs. the met-met group. However, for conditions not dependent on striatum, the met-met group exhibited over-activity in PFC regions not required for the task, while the val-val one had patterns of activity that resembles those of healthy individuals.

Conclusions: The imaging and behavioural data indicate that the effect of the COMT polymorphism may be dependent on specific components of cognition, while the DAT1 one may reflect a more global cognitive profile in PD. Longitudinal studies are ongoing to find out whether the 10R/10R genotype correlates with a higher rate of progression to dementia.

91

Attentional set-shifting deficits correlate with severity of freezing of gait in Parkinson's disease

S.T. Moore, J.M. Shine, S.L. Naismith, N.C. Palavra, V. Dilda, T.R. Morris, S.J.G. Lewis (New York, NY, USA)

Objective: To correlate set-shifting performance as measured by the Trail Making Test (TMT) with severity of freezing of gait (FOG) in patients with Parkinson's disease (PD).

Background: Although the pathophysiological basis of FOG is a poorly understood, several lines of evidence suggest that freezing is associated with impaired cognitive function, particularly set-shifting. However, no study to date has explored whether these attentional deficits are directly related to the severity of actual FOG episodes.

Methods: Eighteen patients with idiopathic PD and self-reported FOG were assessed in the ‘off’ state whilst performing a series of timed up-and-go tasks. Percent time frozen, previously demonstrated as a more robust FOG metric than number of events [Shine et al. Parkinsonism Relat Disord 2012 18:25-9], was defined as the total duration of FOG episodes divided by TUG duration (determined by two experienced raters from video recordings). Patients were also administered parts A and B of the Trail Making Test to assess baseline visuomotor speed and set-shifting ability.

Results: Poorer performance on the trail making test was significantly correlated with increased severity of freezing of gait during the locomotion task. There was a significant correlation between diminished performance on the trail making task (TMT part B - part A) with increased severity of freezing (percent time frozen) during the TUG tasks (r=0.56; p=0.01).1 (91)

Figure 1 (91).

Conclusions: While a relationship between FOG and cognitive dysfunction has long been recognized in PD patients, this is the first study to show a significant correlation between impaired performance on a specific neuropsychological task assessing set-shifting and direct measures of FOG severity during walking. These findings provide further support for the hypothesis that freezing of gait in Parkinson's disease and attentional set-shifting impairments share similar underlying neural mechanisms.

92

Withdrawn by Author

93

Spatial planning ability in early stage Parkinson's disease patients (ICICLE-PD)

C. Nombela, J.B. Rowe, A. Hampshire, A.M. Owen, D.P. Breen, T.K. Khoo, M. Firbank, A. Yarnall, G. Duncan, J.T. O'Brien, D.J. Burn, D.J. Brooks, R.A. Barker (Cambridge, United Kingdom)

Objective: The ICICLE-PD study aims to better define factors that predict the transition in idiopathic Parkinson's disease (PD) to the dementia associated with PD (PDD). Here, we investigated cognitive performance on an executive task (Tower of London-TOL) and associated regional activations in patients in early stage disease, before dementia has developed, to see the extent to which this network is compromised.

Background: Executive deficits in PD are often attributed to deficits in fronto-striatal systems. TOL task of planning is associated with activation of including bilateral frontopolar, dosolateral prefrontal (DLPFC) and posterior parietal cortex.

Methods: 118 recently diagnosed PD patients (early PD, H&Y≤3) were assessed in two sites (70 in Newcastle and 48 in Cambridge) prior to fMRI scanning (3-Tesla, 10 minutes, TR=2s, 32 slices, isotropic 3 mm voxels). During fMRI they performed TOL task (‘Planning’ and a ‘Count’ control condition). Preprocessing and imaging analysis used Statistical Parametric Mapping 8.

Results: Reaction times were comparable for Planning trials at both sites in both patients and controls (RTcmb=10.91±4.6, RTnwc=12.09±7.07, RTControl=10.11±3.9) and Count trials (RTcmb=5.71±1.5, RTnwc=5.32±1.8, RTcontrol=4.43±1.39). The SPM{t} map confirmed that in PD patients, the main effect of Planning (versus Count) averaged over all difficulty levels was associated with activation of a bilateral network including dlPFC, medial parietal cortex, inferior parietal and temporoparietal cortex. 1 (93)

Figure 1 (93).

There were no significant differences between PD patients and controls in the activations associated with Planning (vs Count) trials.

Conclusions: PD patients in the earliest stages show normal activation of a frontoparietal network during planning on the TOL task. Behavioural and fMRI results were reproduced at two sites, with no significant differences. 2 (93)

Figure 2 (93).

These results represent an important baseline from which to assess the development of cognitive decline and dementia in PD. The investigation of individual differences, and their potential predictive value for dementia, is underway with follow up of this cohort in 2012-2013.

94

Levodopa-induced dyskinesia and neurocognitive function in Parkinson's disease

G.D. Oggioni, J. Devoto, R. Cantello, A.J. Espay (Novara, Italy)

Objective: To evaluate the relationship between levodopa induced dyskinesias (LID) and neurocognitive profiles among Parkinson's disease (PD) candidates for deep brain stimulation (DBS).

Background: Both neurocognitive changes and LIDs are common in demented and non-demented PD patients. The neurocognitive profile and LID vary widely in type and severity. We sought to determine whether LID correlate with neurocognitive function.

Methods: We evaluated demographic data (including functional status with UPDRS score and levodpa equivalent dose -LED), video recording of motor OFF-ON evaluation and an extensive neuropsychological battery of tests among PD candidates for DBS at the University of Cincinnati Movement Disorders Center from 2005 to 2010. Phenomenology (predominantly chorea vs. dystonia), timing (predominantly peak-dose vs. diphasic), distribution of LID (predominantly axial vs. appendicular) and severity of LID were assessed by two independent neurologists and correlated with the neuropsychological and demographical data.

Results: 119 patients were evaluated (77 M, 42 F; mean age,63.4 years (range, 43-84); disease duration 10 years (range 3.2-25)). LID were identified in 94 patients (exclusively ON in 56, both in the ON and OFF states in 38). They were predominantly axial in 72 patients; exclusively appendicular in 20. Chorea was the most common phenomenology (65%). There were no differences in age, disease duration, LED and neurocognitive profile between those with and without LID. Axial LID were more common among those with longer disease duration, younger age at disease onset and higher UPDRS score. Perseveration subscore of the ACT (Auditory Consonant Trigrams) test was lower in patients with axial-predominant LID, but no other frontal-lobe subscores were correlated with this or any other phenotype.

Conclusions: Correlation between distribution of LID and neurocognitive function is poor. The artificial context within the presurgical OFF-ON evaluations and the a-priori exclusion of overtly demented patients may have limited the true expression, severity, and distribution of LID, lowering the power to find tassociations with specific neurocognitive profiles.

95

Correlation of cognitive impairment evaluated by Montreal Cognitive Assessment with functional brain imaging of Parkinson's disease patients

K. Ohta, T. Osada, T. Tajima, M. Seki, Y. Shinohara (Tokyo, Japan)

Objective: This study aimed to demonstrate anatomical and quantitative cerebral functional map in patients with Parkinson's disease (PD), and to reveal its correlation with their cognitive impairment evaluated by Montreal Cognitive Assessment (MoCA).

Background: MoCA (Nasreddine ZS, J Am Geriatr Soc 53:695, 2005) covering 8 cognitive domains is recommended as the most suitable measure for screening of cognitive impairments of PD (Chou KL, Mov Disord 25:2501, 2010).

Methods: The subjects were 41 patients with PD (age 73±8, Hoehn-Yahr 3.0±0.8, mean±SD). Their cognitive function was assessed by MMSE and MoCA. IMP-SPECT data were collected for brain perfusion. Normalized brain activity of each patient was compared with normal controls by pixel-by-pixel Z-score = (control mean value – patient value)/control SD. Stereotactic extraction estimation (SEE) method (Mizumura S, Ann Nucl Med 17:289, 2003) classified anatomically the cerebral cortex into 31 segments for each hemisphere on the basis of gyrus, and estimated the extent of hypoperfusion of each segment (E(Z≥2)) by calculating the rate of pixels with Z-score ≥2 in each segment. As differences in E(Z≥2) were often found between the right and left sides of each segment, the larger E(Z≥2) of either side was employed for the statistical analyses.

Results: The subjects yielded MMSE score 25.0±4.8 (range 12-30) and MoCA score 19.1±5.8 (range 6-28). These scores showed a strong correlation (R2=0.76, p<0.0001) with each other. MoCA, compared to MMSE, was demonstrated to be a more sensitive measure for cognitive impairment of PD. Negative correlation was found between MoCA score and E(Z≥2) in the superior parietal lobule (R2=0.31) and angular gyrus (R2=0.36, p<0.0003). Compared to the total score, the score of visuospatial/executive domain was correlated with E(Z≥2) in these cortical segments more strongly (R2=0.45 & 0.39, respectively, p<0.0002). Correlation between the score of attention doamin and E(Z≥2) was the strongest in the middle temporal gyrus (R2=0.24, p<0.002).

Conclusions: The profile of cognitive impairment in PD evaluated by MoCA is correlated with hypofunction of particular cortical segments, providing physiological basis of MoCA in terms of cerebral cortical topography.

96

Assessment of the relationship between total plasma homocysteine and cognitive function in Parkinson's disease

O.O. Ojo, N.U. Okubadejo, O.O. Osinaike, O.O. Oladipo, F.I. Ojini, M.A. Danesi (Idi-araba, Nigeria)

Objective: Our aim was to determine the relationship between hyperhomocysteinemia and cognitive function in Parkinson's disease (PD) patients attending the Lagos University Teaching Hospital (LUTH).

Background: Hyperhomocysteinemia (HHcy) associated with levodopa utilization may cause cognitive decline and thus complicate the clinical course of PD. There is sparse information on the impact of HHcy on cognitive function in Africans with PD.

Methods: 40 PD attending the neurology clinic of LUTH were consecutively recruited between March and September 2006. 40 healthy age and sex-matched controls were also studied. Cognitive function was assessed in all subjects using a composite score (summation) of the mini-mental state examination (MMSE) and the category fluency scores. Fasting total plasma homocysteine (Hcy) levels were determined in all subjects. HHcy was defined as any level above the 90th percentile of Hcy values in controls. Consequently, HHcy was defined as total plasma Hcy level > 16.3umol/L. Cognitive impairment was defined as any score below 2 standard deviations of the mean composite score of MMSE and category fluency of controls i.e. below 38.

Results: PD cases and controls were matched for age, gender and level of education. The PD cases had a mean age at onset of 60.7 ± 9.1years, mean disease duration of 64.9 ± 49.6 months, mean UPDRS motor score of 41.1 ± 17.6, mean UPDRS ADL score of 13.6 ± 7.2 and a median Hoehn and Yahr score of 2. Mean Hcy level (umol/L) was 13.8 ± 5.4 in PD and 12.4 ± 3 in controls (P>0.05). HHcy occurred in 9 (22.5%) PD (all on levodopa) and 6 (15%) controls (P>0.05). Mean composite cognitive score was 35.9 ± 4.4 in PD and 46.1 ± 4.1 in controls (p < 0.0001). Cognitive impairment occurred in 60% of PD (24/40) and 5% of controls (2/40) (P< 0.001). Cognitive impairment occurred in 100% (9 of 9) of PD with HHcy and 0% (none of 6) controls with HHcy. 100% (9 of 9) of PD with HHcy had cognitive impairment compared to 48.4% (15 of 31) of PD with normal Hcy levels (c2 = 7.74, p = 0.006).

Conclusions: Hyperhomocysteinemia is associated with cognitive impairment in Nigerians with PD seen at the Lagos University Teaching Hospital as previously documented from other populations.

97

Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) as screening tools for cognitive impairment among patients with idiopathic Parkinson's disease: A descriptive study

L.A. Penaserada, L.K. Ledesma, R.E. Picar, D.E. Cid Czarina, C.E. Carcel (Makati City, Philippines)

Objective: To compare the scores of patients with idiopathic Parkinson's disease using the Montreal Cognitive Assessment and Mini-Mental State Examination in a tertiary hospital.

Background: Parkinson's disease (PD) is a neurodegenerative disorder diagnosed clinically based on the signs of resting tremor, bradykinesia, rigidity and loss of postural reflexes. According to Bassett et al, 20% to 40% of PD patients ultimately become demented with an incidence of 10% per year. Cognitive decline is an important predictor of dementia in PD. Almost all patients with PD suffer from selective cognitive impairments including difficulties with attention, concentration, planning, sequencing, concept formation, problem solving, set-shifting and memory which are thought to reflect dysfunction of cortical circuits subserving frontal brain regions. Identification of cognitive impairment in PD is crucial. It predicts future cognitive decline and may eventually be a target for pharmacologic intervention to prevent or delay the development of dementia.

Methods: A descriptive study. A convenience sampling of 95 patients with idiopathic Parkinson's disease were screened for cognitive impairment.

Results: Mean MMSE and MoCA scores were 26.1 (SD 2.9) and 19.8 (SD 4.28). Based on the published cutoff scores for cognitive impairment for Parkinson's Disease, 72% of the participants scored 26/30 and below on MoCA whereas only 42% scored 26/30 and below on the MMSE. Impairments were seen in numerous cognitive domains including executive function, language, recent semantic memory, visuo-spatial processing and constructional praxis. Predictors of cognitive impairment on the MoCA include low level of education and older age.

Conclusions: MoCA was able to detect more cognitive impairments in patients with Parkinson's disease than MMSE. Therefore, MoCA is a better screening tool to detect cognitive impairments in PD patients.

98

Mild cognitive impairment and dementia in Parkinson's disease: 5 year follow up

M. Petrovic, E. Stefanova, T. Stojkovic, V. Kostic (Kragujevac, Serbia)

Objective: The objective of this study was to examine the prevalence and demographic and clinical correlates of mild cognitive impairment and dementia in a clinical population-based sample of patients with Parkinson's disease.

Background: Parkinson's disease (PD) is often associates with mild cognitive impairment and dementia. The point-prevalence of dementia is 30% ant patient with PD have an almost sixfold incresed risk of developing dementia compared to healthy controls; and old age and severity of the disaese are predictive factors for cognitive impairment.

Methods: A series of 360 PD patients; the assessment included comprehensive neurological and psychiatric examinations and battery of neuropsychological test.

Results: A total of 172 were cognitively intact; whereas 114 (36%) were diagnosed with MCI (amnesic= 61; single non-memory domain= 15; and multiple domains, n= 18). Thirty patients (9.4%) were diagnosed with dementia. Age, phenotyp and severity of the disease, presence of behavioral disorders were shown to be significant predictive factors.

Conclusions: These data suggested that PD patients with more prominent axial signs and older age are in higher risk for developing cognitive impairment. Therefore, early detection of mild cognitive impairment is very important diagnostic step.

99

Self-awareness of dyskinesias in Parkinson's disease

S. Pietracupa, A. Fasano, M.C. Bloise, A. Latorre, G. Fabbrini, A. Berardelli (Rome, Italy)

Objective: To investigate the self-awareness of levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD).

Background: Preliminary data suggest that patients with LID have less awareness of their dyskinesias than caregivers and physicians.

Methods: Twenty-five PD patients with LID (13 women; age: 69.2±7.0; disease duration: 12.1±5.6; LID duration: 3.5 ± 3.7) were enrolled. Patients with cognitive impairment were excluded (MMSE: 27.9 ± 2.2). LID were rated by means of the Unified Dyskinesias Rating Scale (UDysRS). Patients were videotaped during their “on” phase while having LID, at rest and during the motor activities described in the UDysRS. At the end of this session patients were asked to rate the site of the body affected by LID and the severity of their LID according to a 5-points scale. Patients were then asked to rate again the site and severity of their LID while watching themselves on the videotape previously taken. Finally, the patients rated the site and severity of LID on a videotape showing a standard PD patients with LID.

Results: Intra-class coefficient (ICC) between patients' and neurologist's evaluation was very poor either during subjective self-evaluation (0.24±0.41) or while watching their own video (0.24±0.52). ICC between patients' and neurologist evaluation was poor while rating a standard patient with LID (0.41±0.32). Patients rated the severity of LID similarly to the neurologist's evaluation in all body sites except for trunk (p=0.0002 subjective vs. objective; p=0.0005 video evaluation vs. objective). ICC between patients' subjective self-evaluation and neurologist's evaluation did not correlate with any of the demographic and clinical features except for the severity of lower limb dyskinesias, where a significant positive correlation was found (ρ=0.56 and ρ=0.46 for right and left; p=0.004 and 0.02).

Conclusions: Our results confirm the poor awareness of patients when rating their own dyskinesias. Patients can better recognize the dyskinesias of other patients. Interestingly, trunk dyskinesias are less likely to be recognized while severe dyskinesias, mainly involving lower limb, are associated with a better recognition.

100

Vascular risk factors and dementia in Parkinson's disease

B. Lobb, S. O'Connor, A. Peterson, K. Chung, N. Carney, J. Mack, J.F. Quinn (Portland, OR, USA)

Objective: To test the hypothesis that vascular risk factors increase the likelihood of dementia in Parkinson's disease.

Background: Dementia is common and disabling late in the course of Parkinson's disease (PD). Established risk factors for dementia in PD include age, male gender, hallucinations, and more severe motor dysfunction, none of which are modifiable. Modifiable risk factors for dementia in the non-Parkinson's general population include hypertension, hypercholesterolemia, diabetes mellitus, smoking, and obesity. We examined the relationships between these risk factors and cognitive function in PD patients in an effort to identify modifiable risk factors as therapeutic targets in a dementia prevention trial.

Methods: All PD patients seen in the Portland VA Medical Center PADRECC clinic were invited to participate in an observational study evaluating cognitive function. All subjects had a screening Mini-mental state examination (MMSE), and those scoring > 24 had a neuropsychological evaluation including the Mattis Dementia Rating Scale (MDRS). Vascular risk factor data was extracted from the electronic medical record.

Results: Out of 90 PD patients consenting to participation, 18 scored <24 on MMSE and were classified as “dementia”. The remaining 72 patients were divided based on evidence of impairment on MDRS, with 18 categorized as “cognitive impairment” and 54 categorized as “not impaired.” Subjects with dementia were significantly older than subjects that were”not impaired”(p<0.001). Subjects with “cognitive impairment” had more severe disease on Hoehn and Yahr (p=0.047) and were more impaired on Schwab and England (p=0.015) compared to “not impaired”. Prevalence of obesity (BMI > 25) was significantly different across the 3 groups, lowest in “dementia” and highest in “not impaired” (p=0.009). There were non-significant trends to higher rates of smoking and diabetes mellitus in “dementia” and “cognitively impaired” compared to “not impaired”subjects. Prevalence and severity of hypertension did not vary across groups.

Conclusions: Age and PD severity were confirmed as risk factors for dementia in this PD population. Of the vascular risk factors evaluated, only the prevalence of obesity distinguished patients based on cognitive function, and the direction of difference was opposite that predicted by the hypothesis.

101

Long-term verbal memory disorders in Parkinson's disease (PD)

A. Saenz, A. Doe de Maindreville, J. Vaunaize, J.M. Visy, S. Bakchine, N. Ehrle (Reims, France)

Objective: The aim of this study was to investigate more ecological consolidation processes in PD by lengthening the delay of long term retrieval (several nights of sleep) with a classic clinical tool.

Background: For a long time, episodic memory impairment of PD patients was considered as executive (encoding and retrieval deficits), sparing storage processes. However, recent imaging studies suggest slight hippocampal atrophy in these patients and storage deficits were suggested in part of them (Camicioli et al., 2003 for review). The critical role of sleep in memory consolidation processes has been shown. Night sleep periods would be especially beneficial for an optimum stabilization of encoding informations (Stickgold& Walker, 2007 for review).

Methods: We added a phone procedure consisting in a words delayed recall seven days after the learning of a standard memory task (French version of the Grober and Buschke test). Usual and long-term memory performances were collected in 24 non-demented PD patients and 24 matched healthy participants.

Results: When no storage impairment was shown with the classical delayed recall (twenty minutes), a significant deficit was demonstrated one week later in comparison to healthy participants, for both free and total long-term delayed recalls (U=186, p<.04; U=129, p<.001, respectively). The selective production of intrusions after seven days by PD patients is an additional argument (U=493, p<.04).

Conclusions: If consolidation disorders are rarely reported in PD in common clinical practice, they seem emphasized while increasing the interval, means a week at least. We must consider this specific factor in order to set up adapted evaluations of long-term verbal memory and cognitive rehabilitation in PD. It remains to define the prevalency of storage deficits through further explorations, considering clinical characteristics as disease duration.

102

Screening utility of Montreal Cognitive Assessment (MoCA) for detecting cognitive impairment in patients with Parkinson's disease

M. Seki, M. Kobari, B. Mihara, K. Isozumi, K. Ohta, K. Muramatsu, T. Shirai, K. Takahashi, H. Nozaki, J. Gotoh, K. Yamaguchi, Y. Tomita, H. Sato, D. Yasutomi, Y. Nihei, S. Iwasawa, N. Suzuki (Tokyo, Japan)

Objective: We investigated screening utility of Montreal Cognitive Assessment (MoCA) to detect cognitive impairment in Parkinson's disease (PD) patients with normal Mini-Mental State Examination (MMSE) score.

Background: MDS Task Force (Dubois B et al. Mov Disord, 2007) proposed MMSE score <26 as one of the diagnostic criteria of PD with dementia. However, MMSE often fails to detect early cognitive decline in PD patients. MoCA is a brief tool developed to detect mild cognitive impairment that assesses a broader range of cognitive domains compared to MMSE.

Methods: The subjects were 267 PD patients registered at 13 participating hospitals. We examined their clinical/neurological features and cognitive functions evaluated by MMSE and MoCA-Japanese Version.

Results: 179 patients (67%, age 68.9 ± 8.1, disease duration 6.6 ± 4.9 years, mean ± SD) among 267 subjects showed normal MMSE score (≥26). Their mean MoCA score was 24.1 ± 3.3 (range 14-30). Among these 179 patients, 116 patients (65%) had cognitive impairment by MoCA score <26. We classified the 116 patients into 3 groups according to MoCA score. Comparison among the groups revealed that patients with less MoCA score had older age (p<0.05). There were no significant differences in Hoehn-Yahr stage, disease duration and L-dopa daily dose among the groups. On the other hand, if we divided the 116 patients into 3 groups according to their disease duration, no differences were observed in MoCA score and age among the groups.

Conclusions: Two thirds of PD patients with normal MMSE score showed cognitive impairment according to MoCA. This result suggests that MoCA is a more sensitive tool compared to MMSE for screening of cognitive impairment in PD patients. MoCA score is correlated with age rather than severity of motor symptoms or disease duration of PD patients, suggesting cognitive impairment in PD might proceed independently of motor impairment.

103

Prolonged finger tapping test in Parkinson's disease

V. Senanarong, A. Pisanpong, N. Aoonkaeew, S. Udomphanthurak (Bangkok, Thailand)

Objective: To compare cognitive and motor functioning in well-characterized subjects with Parkinson's disease (PD) with dementia or cognitive impairment(CI) with subjects with Alzheimer's disease (AD) or mild cognitive impairment (MCI).

Background: Motor function and cognitive function are associated. Previous evidence showed prolonged finger tapping (FT) test can differentiate parkinsonson disease (PD) and other ovement disorders. Quick assessmet of these 2 domains should be explored.

Methods: Subjects' conditions were evaluated clinically and psychometrically at entry into a longitudinal study of cognition and neuropsychiatric symptoms in Parkinson's clinic and memory clinic at Siriraj Hospital, Thailand. Measures included a Mattis dementia rating scale (DRS), logical memory, Rey visual memory test, digit span, spatial span, category and lexical verbal fluency, Boston Naming Test, clock drawing test, and 30 second finger tapping (FT). Neuropsychiatric inventory and Thai activity of daily living scale were assessed at baseline. Fourteen AD, 8 MCI, 8 PD dementia (Hoehn & Yahr stage 3-4), and 14 PD with cognitive impairment (Hoehn & Yahr stage 3-4) were included.

Results: Mean age (SD) of those with AD, MCI, PDD, and PD with CI was 75.57(6.19), 71.75(2.49), 53.88(10.13), and 57.71(12.52) accordingly (ANOVA, p<0.001). Means 30 second FT on right side in those with AD, MCI, PDD, and PD with CI were 23.79(7.84), 36.38(5.40), 40.27(12.30), and 37.02(14.28). Means 30 second FT on left side in those with AD, MCI, PDD, and PD with CI were 21.64(10.72), 33.63(4.10), 36.69(12.79), and 31.61(13.91). Men performed better on 30 second FT than women in this study (ANOVA, p<0.05). There are statistical significant and good correlation (r≥0.4, p<0.05) between right and left FT and between FT and age, activities of daily living, Mattis DRS, Rey visual memory test scores, immediate logical memory scores, Boston naming test scores, and animal verbal fluency. However, after being covariate by age, the correlations were lost.

Conclusions: Prolonged 30 second FT can be potential bedside cognitive assessment for PDD and AD. Further study to find normative data for each age group and gender should be done in the future.

104

Neural basis of memory impairment in Parkinson's disease: A longitudinal PET study

Y. Shoji, Y. Nishio, A. Takeda, M. Uchiyama, T. Kashinoura, Y. Hosokai, H. Fukuda, E. Mori (Sendai, Japan)

Objective: To delineate the neural basis of memory impairment in patients with Parkinson's disease (PD).

Background: Memory impairment is the most or second common cognitive symptom in PD. Although earlier studies stressed the role of frontal-subcortical dysfunction, several recent studies have indicated the relationship between medial temporal degeneration and memory impairment.

Methods: Memory and other cognitive status were assessed using the Clinical Dementia Rating (CDR). 39 PD patients with CDR 0 underwent FDG-PET twice with an interval of 3 years (mean duration 1130±95 days). On follow-up, 26 patients scored 0 on all domains (Non-converter, NC), 7 patients scored 0.5 only on memory domain (Memory-only, MO) and 6 patients scored 0.5 or more on memory and other domains (Memory-plus, MP). We compared longitudinal metabolic changes among the NC, MO and MP groups using voxel-based PET analysis. 14 healthy volunteers also underwent FDG-PET.

Results: In comparison with controls at baseline, discrete hypometabolic regions were observed in the frontal and occipital cortices in the NC and MO groups, whereas widespread parieto-occipital hypometabolism was observed in the MP group. Longitudinal comparisons revealed metabolic decline in the thalamus, parieto-occipital and frontal cortices in the NC group and metabolic decline in the medial temporal and frontal cortices in the MO group. There was no significant 3-year longitudinal change in the MP group. An ANOVA showed that 3-year metabolic decline in the medial temporal region was larger in the MO group than in the NC group.

Conclusions: The results suggest that memory impairment in PD is associated with medial temporal dysfunction and that extensive dysfunction in the posterior cortices predicts future decline in multiple cognitive domains.

105

Genetic influences on cognitive decline in Parkinson's disease

J.F. Morley, S.X. Xie, H.I. Hurtig, M.B. Stern, A. Colcher, S. Horn, N. Dahodwala, J.E. Duda, D. Weintraub, A.S. Chen-Plotkin, V. Van Deerlin, D. Falcone, A. Siderowf (Philadelphia, PA, USA)

Objective: To examine whether variations in apolipoprotein E, microtubule-associated protein tau or catechol-O-methytransferase genotypes are associated with cognitive decline in Parkinson's disease.

Background: Cognitive impairment is common in Parkinson's disease and is associated with increased morbidity and mortality. The role of genetic factors in cognitive decline associated with Parkinson's disease is unclear.

Methods: We performed a prospective cohort study of 212 patients 60 years of age or older with a clinical diagnosis of Parkinson's disease. The primary outcome was change in Mattis Dementia Rating Scale version 2 score. Linear mixed-effects models and survival analysis were used to test for associations between genotypes and rate of change in cognitive function over time.

Results: The ϵ4 allele of apoliporotein was associated with more rapid decline (loss of 2.9 (95% CI, 1.7-4.1) more points/year, p<0.001) in total score compared to all other genotypes. Apolipoprotein E ϵ4 carrier status was also associated with increased risk of a loss of at least 10 points in total score during the follow-up period (Hazard Ratio 2.8, 95% CI 1.4-5.4, p=0.003). Apolipoprotein E ϵ4 was associated with more rapid decline in subscales measuring initiation, construction, conceptualization and memory. Apolipoprotein E ϵ2 allele, microtubule-associated protein tau haplotype and catechol-O-methytransferase genotype were not associated with the rate of cognitive decline.

Conclusions: Carrying at least one apolipoprotein E ε4 allele is associated with more rapid cognitive decline in Parkinson's disease. This finding supports the idea of a component of shared etiology between Parkinson's disease dementia and Alzheimer's disease. Clinically, these results suggest genotyping can provide information about the risk of future cognitive decline for Parkinson's disease patients.

106

Association between olfactory dysfunction and cognition in the PPMI study

A. Siderowf, J.F. Morley, J.E. Duda, D. Weintraub, For the PPMI Investigators (Philadelphia, PA, USA)

Objective: To evaluate the association between olfactory function and cognition in early Parkinson's disease.

Background: Olfactory dysfunction has been associated with cognitive deficits in patients with Parkinson's disease. The Parkinson's Progression Marker Initiative (PPMI) cohort offers the opportunity to confirm these preliminary results.

Methods: The PPMI study is a multi-national cohort study in which biological and clinical data is collected in patients with early PD and controls frequency matched for age and gender. We used data from the PPMI study to investigate the association between olfactory deficits and cognitive performance in both cases and controls. Olfaction was measured by the University of Pennsylvania Smell Identification Test (UPSIT). Cognition was measured by the Montreal Cognitive Assessment (MoCA) and a battery of neuropsychological tests.

Results: This analysis included 152 PD patients and 126 controls. There was a moderately strong and statistically significant positive association between UPSIT score and cognition as measured by the (MoCA in PD patients (r= 0.25, p = 0.002), but not in controls (r=0.12, p=0.17). In PD patients, UPSIT scores were also correlated with striatal dopamine transporter (DAT) binding. However, the association between UPSIT and MoCA was only minimally affected by adjustment for average striatal DAT binding (adjusted r = 0.21; p = 0.015). Similarly, there was still a significant relationship between MoCA and UPSIT after adjustment for age, education and gender (adjusted r = 0.19, p = 0.020). Among neuropsychological tests, the strongest correlations were with measures of fluency (r = 0.21, p = 0.009) and processing speed (0.23, p = 0.004) and not with memory or visual-spatial function (p = 0.08 and 0.48 respectively).

Conclusions: Data from the PPMI study confirms the association between cognitive function and olfactory performance in PD patients, and extends this finding to untreated, de novo patients. The results of this analysis suggest that the association is not mediated through dopaminergic dysfunction.

107

Utilization of cognitive enhancers in patients with Parkinson's disease. National Parkinson Foundation (NPF) Quality Improvement Initiative

B. Stell, M. Kwansy, O.N. Oguh, T. Simuni, on behalf of the NPF QII Investigators (Chicago, IL, USA)

Objective: To evaluate correlates of the utilization of cognitive enhancers in PD patients.

Background: Dementia is the major cause of non-motor disability in PD. Cholinesterase inhibitors (CEI) are FDA approved for PD dementia. However, utilization and physicians prescribing of the “cognitive enhancers” in PD have not been systematically studied.

Methods: Data was obtained from the National Parkinson's Foundation (NPF) Quality Improvement Initiative database, which is an observational prospective longitudinal study, conducted at 18 NPF sites. All PD patients are eligible for enrollment into NPF-QII registry. Dataset includes demographics, disease severity, categorical medications utilization history including cognitive enhancers, PD quality of life (PDQ-39), multidimensional caregiver strain inventory (MSCI). A brief cognitive assessment includes verbal fluency and immediate/delayed word recall. Cognitive impairment was defined as <11 on the verbal fluency test, and ≤ 4 on the recall.

Results: 5,221 patients with PD were included in the data analysis. 453 (9%) utilized cognitive enhancers. Of the total sample 690 (13.2%) patients had cognitive impairment (based on <11 score on verbal fluency). Correlates of utilization of cognitive enhancers were worse cognitive ability (cognition battery), PDQc (cognition subscale) and disease severity (HY≥3). PDQc was a more significant predictor of use. Based on the multiple logistic regression models using stepwise selection, variables associated with significant predictors of new prescriptions of cognitive enhancers were immediate 5 word recall, verbal fluency and PDQc subscore.

Conclusions: Cognitive enhancers were, as expected, utilized in patients with worse cognitive ability and worse disease severity. The PDQc subscore was the most significant predictor of the utilization of cognitive enhancers. New prescriptions were most significantly predicted by the immediate 5 word recall. Longitudinal data is needed to determine the impact of cognitive enhancers on patient's cognitive performance and quality of life.

108

Mobility and falls in people with Parkinson's disease with and without cognitive impairment

E. Stack, C. Fitton, A. Ashburn, H. Roberts, K. Amar (Southampton, United Kingdom)

Objective: To compare indicators of postural instability in people with Parkinson's disease (PwPD) of similar disease severity but with and without cognitive impairment.

Background: PwPD with cognitive impairment have often been excluded from research into falls, so more is known about falls among the cognitively intact cohort than among their peers with cognitive co-morbidity. Thus, the frequency with which the latter fall and whether we can predict (or prevent) future falls is open to question. Understanding the pattern of falls among PwPD with cognitive co-morbidity enhance their inclusion in research, opening avenues to better management in future.

Methods: From a clinic sample of 318 PwPD, 101 (median age 76, years since diagnosis 6) agreed to participate in a face-to-face assessment at home (plus 68 carers). A Montreal Cognitive Assessment was administered (MOCA) and PD severity was recorded, alongside a 12-month retrospective fall history, ability to perform a simple turn test (the SS-180, scored 1 – 5 and steps counted).

Results: In Hoehn & Yahr stages I-II, 16 PwPD passed MOCA (4 fell, 1 repeatedly; median turn quality 4.5, 3.5 steps) and 15 scored abnormally (none fell; median turn quality 4, steps 4). In stage III, 20 passed MOCA (16 fell, 11 repeatedly; median turn quality 4.5, 5 steps) and 24 failed (all fell, 15 repeatedly; median turn quality 4, 5.5 steps). In stages IV-V, 4 passed (all fell repeatedly; median turn quality 2, 20.5 steps) and 22 failed MOCA (19 fell, 15 repeatedly; median turn quality 3, 12 steps).

Conclusions: Preliminary analyses suggest that only at Hoehn & Yahr stage III did the group of cognitively impaired PwPD fall more frequently and move less well than their cognitively intact peers. If further investigation around the circumstances in which the two groups fall continues to reveal few differences, these findings suggest that cognitively-impaired PwPD should no longer be excluded from inclusion in falls research.

109

Severe olfactory dysfunction is predictive of dementia associated with Parkinson's disease: A 3-year longitudinal study

T. Baba, A. Kikuchi, K. Hirayama, Y. Nishio, Y. Hosokai, S. Kanno, T. Hasegawa, N. Sugeno, M. Konno, E. Miura, E. Mori, A. Takeda (Sendai, Japan)

Objective: We investigated the possible associations between olfactory dysfunction and the risk of developing dementia within a 3-year observation period.

Background: Dementia is one of the most debilitating symptoms of Parkinson's disease. Despite its clinical importance, the development of dementia is still difficult to predict at early stages. On the other hand, we previously identified olfactory dysfunction as one of the most important indicators of cortical hypometabolism in Parkinson's disease.

Methods: Forty-four patients with Parkinson's disease without dementia underwent the odour stick identification test for Japanese, memory and visuoperceptual assessments, 18F-fluorodeoxyglucose positron emission tomography scans and magnetic resonance imaging scans at baseline and 3 years later.

Results: A subgroup of patients with Parkinson's disease who exhibited severe hyposmia at baseline showed more pronounced cognitive decline at the follow-up survey. By the end of the study, 10 of 44 patients with Parkinson's disease had developed dementia, all of whom had severe hyposmia at baseline. The multivariate logistic analysis identified severe hyposmia and visuoperceptual impairment as independent risk factors for subsequent dementia within 3 years. The patients with severe hyposmia had an 18.7-fold increase in their risk of dementia for each 1 SD (2.8) decrease in the score of odour stick identification test for Japanese. We also found an association between severe hyposmia and a characteristic distribution of cerebral metabolic decline, which was identical to that of dementia associated with Parkinson's disease. Furthermore, volumetric magnetic resonance imaging analyses demonstrated close relationships between olfactory dysfunction and the atrophy of focal brain structures, including the amygdala and other limbic structures.

Conclusions: Our findings suggest that brain regions related to olfactory function are closely associated with cognitive decline and that severe hyposmia is a prominent clinical feature that predicts the subsequent development of Parkinson's disease dementia.

110

A novel test for assessing gait under multiple-task conditions: Comparison of the performance among adults, elderly and patients with Parkinson's disease

E. Tardeli, N. Santo, R. Bovi, D. Bertolo, M.E.P. Piemonte (Sao Paulo, Brazil)

Objective: The aim of this study was to analyze results following the application of a novel test for assessing gait under multiple-task conditions, comparing performance of adults, healthy elderly, and Parkinson's disease (PD) patients.

Background: The dependency on attention in gait control tends to increase during the aging process. Consequently, elderly experience greater difficulties in controlling gait under conditions which require divided attention. In PD, this deficit becomes marked owing to the combination of automatic motor control dysfunction and cognitive deficiencies. Tests for assessing the impact of aging and its increase in PD on gait performance during multiple tasks have not yet been standardized.

Methods: Fifty healthy young adults (mean age=28.5, SD= 4.2); 40 elderly (mean age=69.5 years, SD = 8.8), 60 patients with idiopathic PD (mean age= 68.5, SD=6.44) at stages 1,2 and 3 of disease evolution according to the Hoehn and Yahr Classification, were involved in the study.The functional gait test (FGT) consists of a 12-meter course along which participants are instructed to walk as quickly as possible while holding a cup of water in their hand, up to a table placed at the end of the 12-meter course, an d then through a doorway to fetch a glass flask from the flask of medicines and return to the start of the course. Which medicine flask is to be selected is decided by presentation of a clock displaying the time, 6 meters into the course. To compare performance under single-task (ST) and multiple-task (MT) conditions, participants performed the same route twice, without any associated tasks.

Results: The results revealed significant interaction between task type (ST and MT) and group (YG;EG;PD), (ANOVA, p=0.0001), confirmed by Tukey's post-hoc test which showed poorer performance by EG and PD patients under ST conditions compared to YG, and greater impairment among PD patients than EG under MT conditions, while both these groups performed worse than the YG.

Conclusions: The FGT was shown to be effective for assessing differences in performance among adults, elderly and PD patients, revealing differences between multiple-task and single-tasks, and proved sensitive to disease progression in patients with PD.

111

Association between CSF biomarkers and clinical phenotype of early Parkinson's disease in the Parkinson's Progression Marker Initiative (PPMI)

J.H. Kang, C. Caspell, C. Coffey, P. Taylor, M. Frasier, K. Marek, J.Q. Trojanowski, L.M. Shaw (Philadelphia, PA, USA)

Objective: The purpose of this study was to explore the association of CSF biomarkers with clinical features in de novo drug-naive PD patients enrolled in the PPMI study.

Background: There is substantial heterogeneity in the onset and progression of clinical phenotypes of Parkinson's disease (PD) such as cognitive impairment, a common non-motor complication that progresses to overt dementia in ∼80% of PD patients with long standing disease. The PPMI is an ongoing international multicenter study to assess progression of clinical features, imaging and biochemical biomarkers in PD compared to healthy controls (HC) and in PD subtypes.

Methods: Baseline CSF samples were obtained from 106 PPMI individuals (39 HC and 67 PD). CSF Aβ1-42, t-tau and p-tau181 were measured using the multiplex xMAP-Luminex platform with Alz-Bio3 immnoassay kits, and CSF α-synuclein (α-syn) was measured by ELISA. Demographics, H&Y stage, UPDRS, smell test (UPSIT) score, neuropsychological and cognitive assessments, CSF hemoglobin (Hb) level and dopamine transporter (DaT) scan were evaluated.

Results: Mean age (HC, 59±13 vs. PD, 62±10), gender distribution and CSF Hb level were not significantly different. Mean score of UPDRS motor function test in PD was significantly higher than in HC, and scores of cognitive assessments (MoCA, SDMT, semantic fluency, HVLT-R initial and delayed recall and WMS-III LNS) were significantly lower in PD than in HC. We found that CSF t-tau, p-tau181 and t-tau/Aβ1-42 ratio in PD were significantly lower than HC. PD patients showed significantly lower level of CSF α-syn compared with HC, which was not changed by adjustment of CSF Hb. CSF Aβ1-42 level in PD was lower than HC with marginal significance.1 (111)

Table 1 (111). Comparison of CSF biomarker levels between healthy control (HC) and PD patients
CSF biomarkersHC (N=39)PD (N=67)p value$
  1. $Mann-Whitney U test. *Mean±S.D. of α-syn levels after exclusion of samples with Hg > 200 ng/mL. The range of α-syn in HC (N=33) and PD (N=48) were 491.9-2025 and 227.4-2290, respectively. #Mean±S.D. of α-syn levels after exclusion of samples with CSF Hb >500 ng/mL. The range of α-syn in HC (N=37) and PD (N=55) were 419.9-2025 and 227.4-2295, respectively. †The mean±S.D. value was from 66 PD samples due to removal of 1 sample with CSF Hb level above upper limit of quantitation.

  2. CSF α-syn was significantly correlated with t-tau (r=0.7787, p<0.0001) or p-tau181 (r=0.4721, p<0.0001), but not with Aβ1-42 (r=0.1341, p=0.1704).

Aβ1-42 (pg/mL)242.8±49.95231.5±45.910.0968
t-tau (pg/mL)53.9±19.3346.6±24.650.0361
p-tau181 (pg/mL)24.9±8.4521.2±7.820.0109
α-syn (pg/mL)1264±425.71101±618.60.0194
α-syn (pg/mL)*1267±443.51041±487.20.0242
α-syn (pg/mL)#1269±435.21037±499.70.0104
t-tau/Aβ1-420.240±0.1410.214±0.1530.0494
p-tau181/Aβ1-420.113±0.0750.099±0.0610.1319
p-tau181/t-tau0.491±0.1600.540±0.2600.7064
α-syn/AB1-425.6±3.054.9±2.980.1159
α-syn/t-tau24.4±7.2325.0±8.610.9373
α-syn/p-tau18153.7±18.9452.4±21.940.5511
CSF Hb (ng/mL)121.7±324.6599.3±1837†0.1156

Conclusions: We found that the level of tau proteins (t-tau and p-tau181) and α-syn in CSF of these untreated PD patients were significantly lower than those of HC, and that CSF α-syn concentration was significantly correlated with the concentrations of CSF tau proteins. Further investigations are planned to test the predictive performance of the biomarkers for disease progression.

112

Predictors of cognitive impairment in Mongolian patients with Parkinson's disease

B. Tserensodnom, K. Baatar (Ulaanbaatar, Mongolia)

Objective: To evaluate the baseline predictors of the cognitive impairments valued by the using of the Mini Mental Status Examination (MMSE) in PD patients.

Background: It is estimated that the prevelance of dementia in PD is close to 30%. The main risk factors for cognitive impairment are older age, level of education, severe parkinsonism, depression, and mild cognitive impairment at baseline.

Methods: 117 patients with PD in according to criteria of the UKBBPD have been enrolled. The patients were assessed using HY stage, UPDRS II and III parts, MMSE, and Modified Beck Depression Inventory (BDI). Patients with dementia and non dementia were classified using cut-off MMSE scores 25 or below. Linear stepwise regression analyses were conducted to identify predictors of cognitive impairment in PD patients.

Results: Total 117 patients: 48 male (40.2%) and 69 female (59.8%) were included. The mean age was 61.9 years (range 33-88), the mean HY stage was 2.8 (range1.0-5.0) and the mean disease duration was 5.5 years (range1-16). The mean MMSE score was 25.7 (SD 4.0; range 16-30) with the following distribution for categories: non demented in 61.9% of patients (mean MMSE score 28.3 1.6), demented in 38.9% of patients (mean MMSE score 21.4 2.9). Nonparametric Mann-Whitney test revealed that patients with dementia had older aged (p<0.001), later onset (p<0.001), lower education (p<0.001), advanced HY stage (p<0.005), greater postural impairment on UPDRS III (p<0.001), and lower score of activity of daily living (ADL) on UPDRS II (p<0.001) than non demented patients. In contrast, there were no significant differences in disease duration and depressive disorder in BDI. When the predictors were entered into a linear stepwise regression analysis old age (p<0.001), education year (p<0.001), and reduced ADL (p<0.005) on UPDRS II were the most significant predictors (41.7% of the variables) of development of cognitive impairment in PD patients. This association was not seen between MMSE score and depressive disorder in BDI.

Conclusions: Our data supports that cognitive decline in PD patients is associated with old age, lower education, and greater impairment of daily living activity on UPDRS II. We suggest that accurate evaluation of impact of cognitive decline on ADL could be an important step for detecting dementia in PD patients.

113

Cognitive symptoms in a population-based cohort to study parkinsonism

E.J. Vollstedt, J. Graf, A. Lorwin, J. Hagenah, V. Tadic, N. Brüggemann, A. Schmidt, S. Tunc, J. Hampf, L. Piskol, C. Klein, M. Kasten (Lübeck, Germany)

Objective: To quantify and specify cognitive impairment (CI) in our cohort.

Background: In parkinsonism (PS) non-motor-symptoms (NMS) such as cognitive CI are frequent and often lead to care dependency. Systematic, population-based data on CI in PS is scarce.

Methods: We mailed a screening questionnaire to 10,000 inhabitants of Lübeck (Germany) aged 50-79 years. The questionnaire included a PS screening, a comorbidity list and basic demographic questions. We divided the respondents into 5 groups: (1) no symptoms of PS, (2) some symptoms but most likely due to another disease, (3) symptoms but most likely due to somatisation, (4) symptoms likely due to PS, (5) diagnosis of PS reported. In addition, 13 PS outpatients were included. For standardized in-person examination, we used the UPDRS (Unified Parkinson's Disease Rating Scale), Parkinson's Neuropsychometric Dementia Assessment (PANDA), Montreal Cognitive Assessment (MoCA) and Mini Mental Status Examination (MMSE). Group assignment was reevaluated after examination.

Results: We examined 621 subjects (49% female). MMSE scores were <24 in 4% (50% female), 24-26 in 16% (47% female) and >=27 in 80% (49% female, p=0.972). Older subjects had lower MMSE (p=0.005) and MoCA (p=0.009) scores, fewer years of education were associated with lower MMSE (p<0.001) and PANDA (p=0.002) scores, men had lower MoCA (p=0.006) and PANDA (p=0.046) scores and group 5 (PS) had lower MMSE (P<0.001) and MoCA (p<0.001) scores. Of these factors, education and diagnosis group remained significant in linear regression and explained 40% of variance in MMSE. The proportions of subjects receiving full scores differed by subtests of the MoCA: visuospatial/executive 44%, naming 96%, delayed recall 21%, attention 83%, language 62%, abstraction 72%, orientation 90%. PS patients scored lower in the visuospatial/executive domain than any other group.

Conclusions: We confirmed the known risk factors for CI, i.e. age and education. In addition, CI was associated with both male gender and PS diagnosis. Differences in MoCA subtests could be due to varying difficulty of individual test items or represent true differences in the cognitive profile.

114

Learning and memory deficits are dependent upon level of global cognitive impairment in Parkinson's disease

G.S. Watson, B.A. Cholerton, S.E. Thomas, C.P. Zabetian, J.F. Quinn, K.A. Chung, T.J. Montine, J.B. Leverenz (Seattle, WA, USA)

Objective: To examine patterns of learning and memory in patients with Parkinson's disease (PD).

Background: It is widely accepted that a majority of patients with PD will develop cognitive impairments during the course of their disease. Executive impairments are well-documented, but less attention has been devoted to the impact of PD on other cognitive abilities.

Methods: One hundred ninety-five subjects diagnosed with idiopathic PD completed the Hopkins Verbal Learning Test-Revised (HVLT-R) as a part of a larger neuropsychological battery. An expert panel of neurologists and neuropsychologists characterized the level of cognitive functioning of each subject.

Results: PD patients with normal cognitive functioning demonstrated poor initial encoding only, the mildly impaired group showed a pattern of impaired encoding and retrieval with substantial improvement on a recognition trial, and the group with diagnosed dementia showed severely compromised performance across all learning trials.

Conclusions: These results suggest that impaired learning and retrieval can occur even in subjects with subtle global cognitive impairments, a finding that has wider implications for the clinical management of non-motor symptoms in PD.

115

Computer-game based therapy for balance rehabilitation in individuals with Parkinson's disease

C.P. Whyatt, C.M. Craig (Belfast, United Kingdom)

Objective: To explore the potential of computer based games to improve levels of functional balance. The study was two-fold. (1) We aimed to see if benefits could be gained through playing commercially available movement based games. (2) To identify if these benefits are more pronounced using specifically designed rehabilitation-focused games.

Background: Research has begun to demonstrate that the use of external sensory stimuli (e.g. a moving object and/or sound) can dramatically reduce characteristic symptoms of Parkinson's disease such as Akinesia and Bradykinesia (e.g. Majsak et al.,1998), a phenomenon known as paradoxical kinesia. It is thought that this external sensory information acts as a movement cue or trigger that can help people with Parkinson's disease coordinate their movements better. Coupled with previous evidence for movement therapies as a method of balance rehabilitation (e.g. Horak et al., 1989), computer based games which are rich in sensory information and involve whole-body movements may provide a method of effective balance rehabilitation for individuals with Parkinson's disease.

Methods: A total of 35 participants took part in various stages of the study. Levels of functional balance were assessed prior to and following balance game training, using balance measures in the UPD-RS and objective balance tests. Participant's then completed a course of balance game training for 4 to 6 weeks. Training was either console based, using commercially available movement games, or tailored, using rehabilitation-focused games which were designed to interface with the commercial gaming hardware.

Results: Results indicate significant improvements on levels of functional static (p=0.007) and dynamic (p=0.01) balance following balance game training. Furthermore all participants to date have reported strong social benefits from the games based balance training.

Conclusions: Such results highlight how sometimes quite simple uses of existing or slightly modified technology can have a profound impact, often improving psychological well-being as well as alleviating some of the physical symptoms.

116

Dual task effects during sentence production in Parkinson's disease

J.P. Wilson, L.J.P. Altmann, A.A. Hazamy, E. Stegemöller, M.S. Okun, C.J. Hass (Gainesville, FL, USA)

Objective: To examine the effects of performing a concurrent motor task on language production in Parkinson's disease.

Background: While effects of a concurrent language task on motor performance have been occasionally reported, there are no studies examing the effects of a motor task on language produced in PD.

Methods: Twenty-six persons diagnosed with idiopathic PD (Hoehn & Yahr 1-3) by fellowship-trained movement disorders specialists completed a sentence generation task while sitting in a quiet room (single task) and during stationary cycling (dual task). Task order (single task 1st, dual task 1st) was counterbalanced. Participants described 20 randomized pictured events consisting of simple 2-actor and complex 3-actor pictures. Acceptable responses were required to be fluent, grammatical and complete.

Results: Dual task interacted with picture complexity: Participants showed typical dual task effects, producing fewer completely acceptable responses when describing complex but not simple pictures. In contrast, there was no evidence of slowed response times in the dual task, but picture complexity interacted with task order. Picture complexity slowed responses in the dual task regardless of task order but only affected response times in the single task when it was completed first. There was no evidence that the language task was prioritized over cycling.

Conclusions: Response times were unexpectedly fast and similar to typical sentence production times for healthy older adults. There was also a dissociation between response times and sentence quality during dual tasks. Compared to single task performance, dual tasks impaired the quality of sentences produced for complex pictures but did not slow responses. Also, complexity effects on response times were absent when the single task followed the dual task. Thus, it appears that strategies developed during the dual task transferred to the simpler single task, eliminating complexity effects. In contrast, strategies developed in the single task were insufficient to overcome complexity effects in the subsequent dual task. Findings suggest treatments requiring adaptation to difficult conditions (e.g., a dual task) may generalize well to a related simpler task, but initially training in simpler conditions may not help performance when performing the task under more difficult conditions.

117

Increasing the cognitive load of a familiar reach-to-grasp task impairs automatic control in patients with Parkinson's disease

P. Yanovich, R.W. Isenhower, E.B. Torres (Piscataway, NJ, USA)

Objective: To evaluate the extent to which increase in cognitive load of a familiar task specifically impairs automatic control in Parkinson's disease (PD) as the disease progresses.

Background: Cognitive processes are divided into conscious-slow-deliberate and unconscious-fast-automatic. Likewise we have introduced intended-deliberate and unintended-automatic movement classes along with various metrics to objectively assess the balance and differences between these modes of motor control. This balance is severely compromised in PD, yet we do not know if an increase in the deliberate cognitive load of a familiar task affects one motor-control mode more than the other.

Methods: 18 patients with PD in relation to normal controls (NCs) performed a reach-to-grasp task in a continuous forward-and-back loop. Patients held a rod in their dominant hand and matched the orientation of a virtual rod on a computer screen at two instructed speed levels (slow and fast). The intended-deliberate segment was aimed at the target. The unintended-automatic retracting segment was not aimed at any target and had no purpose. The experiment had two blocks: default and primed. A picture of the mug appeared next to the rod on the screen and required mental rotation to translate the orientation of the handle into the correct hand orientation. We asked if such increase in cognitive load would affect the kinematics of the automatic reach more than the kinematics of the deliberate reach.

Results: During the deliberate segments patients and controls maintained the instructed speed. However, during the automatic retractions in the primed case, 8/18 patients (PD1) did no longer distinguish the instructed speeds. Their hand's speed maxima were significantly lower than the rest (PD2). The distribution of the peak velocities in PD1 was Gaussian, but it was skewed in the PD2 patients as in NC. This marked differences were not entirely due to their timing during the retracting motions as this parameter was not significantly different between PD1 and PD2 in contrast to the NC. Most patients in the PD1 group had a diagnosis of at least 5 years.

Conclusions: Increase in cognitive load affects automatic more than deliberate control in patients with PD. Such negative effects seem to exacerbate as the disease progresses over time.

118

Comparison of the Montreal Cognitive Assessment and Mini-Mental State Examination in detecting cognitive impairment in South-East Asian patients with Parkinson's disease

L.L.L. Yeo, W.I. Koay, Y. Dong, W.Y. Lee, J.A. Catindig, S. Collinson, C. Chen, E.C.H. Lim (Singapore, Singapore)

Objective: We aim to establish the discriminant validity of the Montreal Cognitive Assessment (MoCA) and compare it with the Mini-Mental State Examination (MMSE) in detecting cognitive impairment (CI) in South-East Asian patients with Parkinson's disease (PD).

Background: CI is frequently observed in patient with PD, even early in the course of the disease. The 8-year cumulative prevalence of dementia in PD is high (78.2%). Hence, early detection of CI in PD patients is important.

Methods: 47 PD patients were recruited from a movement disorders clinic in Singapore. The Unified Parkinson's Disease Rating Scale (UPDRS) was used to measure the severity of PD. MoCA, MMSE and formal neuropsychological measures were performed. CI was defined as a score on the Clinical Dementia Rating scale of ≥0.5.

Results: The majority of patients were Chinese (78.7%) males (59.6%) with 8.5±4.9 years of education and a mean age of 65.2±11.1 years. The mean MMSE, MoCA and UPDRS scores were 24.0±4.2, 20.6±5.2 and 25.8±13.1 respectively. The MoCA and MMSE scores were significantly lower in PD patients with CI than those with no CI (NCI) (MoCA: 17.6±5.2 vs 23.7±2.8, p<0.001; MMSE: 22.1±4.8 vs 26.1±2.2, p=0.001). CI was also associated with PD severity, depressive symptoms and higher functional decline. Area under the receiver operator characteristics curve (ROC) analysis showed that the MoCA scores had trend towards a larger area under the curve (AUC) than that of the MMSE (0.84 (0.73-0.96) vs 0.74 (0.60-0.88), p=0.12). There was a similar trend in the AUCs of age and education adjusted MoCA and MMSE scores (p=0.13). However, the age and education adjusted MoCA had a borderline significantly larger AUC than the MMSE in detecting mild cognitive impairment (MCI) (CDR=0.5) (0.81 (0.66-0.96) vs 0.66 (0.48-0.83), p=0.07).

Conclusions: The MoCA may be superior to the MMSE in detecting MCI in PD patients. However, the statistically insignificant results could be attributed to a small sample size. An ongoing study aims to increase the sample size to 100.

119

Using ecological event-based acoustic guides to cue gait in Parkinson's disease patients

W.R. Young, M.W.M. Rodger, C.M. Craig (Belfast, United Kingdom)

Objective: Firstly, to design event-based, ecological acoustic guides that convey both spatial and temporal information relating to gait parameters. Secondly, to assess if both healthy adults and people with Parkinson's disease (PD) can adapt their gait patterns according to gait parameters perceived in the acoustic guide.

Background: It is widely accepted that PD patients can use various forms of sensory cueing to improve temporal and spatial parameters of their gait. However, when providing both spatial and temporal cues through separate modalities (e.g., lines on the floor in conjunction with a metronome), such benefits are compromised [1]. This is possibly due to patients' inability to simultaneously attend to multiple sensory stimuli. To avoid this problem, a novel method for combining both spatial and temporal parameters in a single auditory guide was implemented.

Methods: Sound recordings were taken of one young adult male walking on a gravel surface embedded in an 8m walkway at a range of stride amplitudes (specified by horizontal lines) at 50, 70 and 90cm, and at two different cadences (specified by a metronome) at 600 and 700ms. Twenty footsteps sound samples at each of the six possible gait parameters were concatenated together to create acoustic representations of steps on gravel at each gait parameter combination. Ten healthy adults and ten PD patients (scoring between 2 and 4 on the Hoehn and Yahr scale [2]) were asked to walk along a 10m walkway and imitate the successive stepping actions presented in the sound samples.

Results: Results showed an impressive ability of healthy adults and PD patients to adapt their gait patterns to relative changes (in stride amplitude and cadence) in the acoustic display.

Conclusions: Whereas traditional cueing methods for PD patients have been based on visual cues and intermittent auditory metronomes, the current study identifies the potential for using ecological event based sounds for cueing both spatial and temporal gait parameters in PD patients.

120

Prevalence of mild cognitive impairment subtypes in patients with Parkinson's disease– Comparison of two modes of MCI classification

H. Zach, G. Pusswald, D. Moser, A. Gleiß, E. Auff, W. Pirker, J. Lehrner (Vienna, Austria)

Objective: To establish the prevalence of PD-MCI subtypes in a movement disorder outpatient clinic cohort using two different modes of MCI determination.

Background: Early detection of dementia in PD is becoming more and more important due to the advent of pharmacologic treatment.

Methods: One-hundred twenty consecutive patients who came to the movement disorder outpatient clinic for assessment of their movement disorder and fulfilled the inclusion criteria participated in this study. All patients received a complete neurological examination, standard laboratory blood tests and psychometric testing.

Results: Categorizing MCI patients into MCI subtypes according to the minimum mode of MCI classification revealed the following results: Three patients (2.5%) were categorized as cognitively normal, whereas 117 patients (97.5%) met the criteria for MCI, subtyped as amnestic MCI single domain (0.8%), amnestic MCI multiple domain (50.0%), non-amnestic MCI single domain (13.3%), and non-amnestic MCI multiple domain (33.2%), respectively. When categorizing MCI patients according to the mean mode of MCI classification 41.7% patients were categorized as cognitively normal, whereas 58.3% met the criteria for MCI, subtyped as amnestic MCI single domain (2.5%), amnestic MCI multiple domain (15.8%), non-amnestic MCI single domain (15.0%), and non-amnestic MCI multiple domain (25.0%), respectively.

Conclusions: PD-MCI diagnosis frequencies are substantially affected by the criteria used for estimation of MCI, a single cognitive measure vs. the presence of impairment on a mean composite score of a certain domain differed considerably ranging from 58.3% to 97.5%, indicating the importance of the development of guidelines for operationalizing MCI in Parkinson's disease.

121

Cognitive training in patient's with Parkinson's disease

R. Zimmermann, U. Gschwandtner, N. Schlede, F. Hatz, P. Fuhr (Basel, Switzerland)

Objective: To test the efficacy of a computer based cognitive training in patients with Parkinson's disease and additional Mild Cognitive Impairment (PD-MCI).

Background: Many patients with Parkinson's disease are cognitively impaired, especially in the executive functions domain. Treatment options for cognitive impairment, particularly in early stages, are rare and rather ineffective up to now.

Methods: Patients with PD-MCI were trained with a computer program including tasks designed to enhance focused attention, working memory, inhibition and planning (N= 7). The control group (N = 8) was trained with a sports computer game. Differences between neuropsychological testing at baseline and after the training were compared between the two groups using Mann-Whitney tests.

Results: The groups were balanced for age and gender. No group differences were observed in a 2-back task, attention (reaction times), liability to interference (Stroop-test) and episodic memory (CVLT). Patients in the experimental group were significantly (p<0.05) ameliorated in tasks involving flexibility (Trail Making Test ratio (B/A) and Test of Attentional Performance (TAP): Flexibility) while patients in the control group showed a significant (p<0.05) enhancement in visuo-construction (Mosaik-test) and psycho-motor speed (Trail Making Test A) compared to the experimental group.

Conclusions: The proposed training might contribute to the amelioration of deficits of flexibility in Parkinson's disease. A larger sample is warranted to confirm these results.

POSTER SESSION 1 Sunday, June 17, 2012 12:30--14:00 Linear Park Marquee

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PARKINSON'S DISEASE: NEUROPHARMACOLOGY

122

To study the safety and efficacy of galanin on motor functions in parkinsonism induced rats

A. Amin, L.D. Iftimi, M. Figura, C. Ene (Srinagar, India)

Objective: 1) To study the effect of Galanin on Motor Dysfuntions. 2) To assess the Neuro-protective activity of Galanin in parkinsonism induced rats. 3)To study the Estimation of Rise or Fall in Neuronal Dopamine Levels by estimating HVA or DOPAC in Urine or Similar Blood Samples.

Background: The substance under test Galanin, is a neuropeptide discovered in the human brain, with several important roles among other neurotransmiters.The project will verify the influence of the neuropeptide on the cholinergic transmission, which is incriminated in the motor symptoms. Galanin has also been previously reported to show positive studies in other neurodegenrative dysfunctions, such as Alzheimer's disease.

Methods: An open Study will be conducted between the Experimental and Controlled group of Male albino rats of the Wistar strain previously induced with Parkinsinsonism as per ICH guidelines and the response will be obsereved as designed. We also aim to conduct neuroimaging studies and bold fMRI scans of the animal brain.

Results: Expectations from the study: 1)The effect of Galanin on Motor Dysfunctions; 2)Posibility of Further Research on Galanin; 3)Clinical Trials Studies may initiate. The Project Will Begin in January 2012.

Conclusions: Conclusions Expected after 6 from start of study.

123

Evaluation of oxidative/nitrosative stress markers in non-SN regions of post-mortem Parkinson's disease brain: Neuroprotection by natural antioxidant

M.R. Babu, H. Gangadharappa, C. Venkateshappa, S. Bharath (Bangalore, India)

Objective: 1) Evaluation of markers of oxidative and nitrosative stress, glutathione levels and astrocytic proliferation in non-SN regions of post mortem PD brain.

2) Evaluation of the neuroprotective efficacy of chronic dietary supplementation with turmeric in the MPTP models of PD.

Background: Parkinson's disease (PD) is an age associated neurodegenerative disease characterized as a movement disorder. Oxidative and nitrosative stress are important molecular determinants of PD pathogenesis. Glutathione (GSH) depletion and mitochondrial dysfunction are evident during PD. Oxidative stress and mitochondrial dysfunction, in the substantia nigra (SN) of the PD brain, have been well documented. However the status of such markers in the non-SN regions of the PD brain has not been studied extensively.

Methods: 1) Protein oxidation and nitration, mitochondrial complex I (CI) activity, antioxidant function and GSH levels were measured in human postmortem brain samples from frontal cortex and striatal regions.

2) Adult C57BL6 mice were subjected to chronic dietary supplementation with turmeric, the curry spice, followed by immunohistochemistry for tyrosine hydroxylase, GSH measurements and measurement of protein nitration.

Results: Results indicated that unlike SN, oxidative damage and mitochondrial dysfunction were not wide-spread in the frontal cortex and striatal regions of PD brain. While the antioxidant enzyme functions were not unchanged, the levels of GSH showed a 3-5 fold increase in PD when compared to controls. Further, chronic dietary turmeric offered significant protection from MPTP mediated SN neuron loss, protein nitration and CI inhibition in the midbrain.

Conclusions: Oxidative stress is not a widespread event in the non-SN regions of the PD brain, probably due to increased levels of the antioxidant GSH. Thus supplementation with a natural antioxidant, turmeric could protect from MPTP mediated damage in an animal model of PD.

124

Treatment in Parkinson's disease patients aged 65 and older: A hospital-based cohort

D. Barzola, M. Perez Akly, R. Diaz, F. Alvarez, M.M. Esnaola, C. Peralta (Buenos Aires, Argentina)

Objective: To describe a) treatment in old-age Parkinson's disease (PD) onset in an hospital-based cohort and b) the profile of adverse events (AE) in old-age Parkinson's disease (PD).

Background: Elderly PD patients are a growing population worldwide and in Argentina. However, the profile of dopaminergic adverse events (AE) learnt from clinical trials in younger PD patients are not well assessed in this group of PD patients (PDp).

Methods: Medical charts of PDp who attended the PD outpatient clinic from September to December 2011, aged 65 or older at Cesar Milstein Hospital, a hospital specialized in the care of elderly patients, were analyzed.

Results: There were 102 PDp, 54 male/48 female, mean age 74,8 years ± 8,51, mean disease duration 5,6 years ± 5.17, 62 (61%) tremor dominant and 40 (39%) rigid-akinetic. Seventy-one PDp were taking levodopa, as monotherapy n=30 (mean daily dose 611,66 mg), n=8 in combination with other drugs (mean daily dose 770,25 mg), n=4 on Amantadine (mean daily dose 270 mg) and n=4 on Rasagiline (mean daily dose 1 mg). On therapy with Dopamine Agonists (DA) there were 33 PDp, n= 20 on Pramipexole (mean daily dose 1,52 mg), n=3 on Ropinirole (mean daily dose 4,6mg) and n=10 on Piribedil (mean daily dose 130 mg). There were 22 PDp on DA, as monotherapy Pramipexole (n=18,mean daily dose 1,75mg), Ropinirole (n=3, mean daily dose 4,3mg) and Piribedil (n=1, mean daily dose 150mg). One PDp received Amantadine, 1 Rasagiline and 7 were untreated since they were recently diagnosed. As regards AE, hallucinations in DA monotherapy occurred in n=1 (5%), peripheral edema n=3 (14%), nausea n= 5 (22%), dizziness n=6 (27%) and excessive diurnal somnolence n=5 (23%). Impulse control disorders occurred in 4 patients, n=3 receiving DA and Levodopa (n= 2 compulsive sexuality and 1 pathologic gambling) and n=1 on DA monotherapy (compulsive eating).

Conclusions: Most patients were receiving levodopa alone or in combination with DA at low doses. Psychiatric AE on DA monotherapy were not relevant. Impulse control disorders occurred more frequently in PDp on combined therapy.

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Inpatient Parkinson's disease management – Call for immediate attention

P. Boovalingam, M. Ardron (Oxford, United Kingdom)

Objective: To explore whether there are problems administering Parkinson's medication to inpatients across the full range of hospital specialties and whether use is being made of self-medication.

Background: Idiopathic Parkinson's disease (PD) alone probably affects at least 1% of the population over 60 years of age in United Kingdom. Many affected people require hospital admission for other medical or surgical problems, and are often treated by staff unfamiliar with managing PD. Dose delays or omissions can cause serious decline in an individual's functional level. The Parkinson's UK encourages self-medication for hospital inpatients.

Methods: Prospective audit. All inpatients admitted with PD between 5th June 2011 and 30th Aug 2011 all inpatients with Parkinson's disease were identified in the tertiary teaching hospital. Medical notes and drug charts were analysed for medication delays, dose omissions, routes of administration and patient self-medication.

Results: 37 patients were studied, median age 85 (range 57 to 90), 63% female. 65% were A&E admissions, 21% emergency medical admissions, 10% surgery, 4% orthopaedic. For 5 patients usual medication timings were included in the initial clerking. 30 patients (81%) experienced a delay in receiving their first dose of Parkinson's medication. The delay was longer with dopamine agonists than with levodopa formulations (median delay 78 hours versus 30 hours). Subsequent dose omissions were common, with 88% of patients experiencing at least one omission. 4 patients received an alternative to oral medication (1subcutaneous apomorphine & 3 rotigotine patch). Only 8 patients (21.6%) self-medicated at any stage during admission.

Conclusions: 1. Parkinson's medication is poorly administered within the whole hospital setting, in particular in non- medical departments namely surgery & orthopaedics.

2. Majority being delayed first dose and frequent subsequent dose omissions as well.

3. Self medication is uncommon.

4. Staff education is mandatory and focusing education in particular areas (eg, orthopaedic wards, hospital pharmacists) may be the most effective strategy to raise the awareness.

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[123I] FP-CIT single photon emission computed tomography findings in drug-induced parkinsonism

M. Tinazzi, A. Cipriani, A. Matinella, A. Cannas, P. Solla, A. Nicoletti, M. Zappia, L. Morgante, F. Morgante, C. Pacchetti, M. Sciarretta, C. Dallocchio, S. Rossi, M. Malentacchi, R. Ceravolo, D. Frosini, S. Sestini, T. Bovi, C. Barbui, C. Barbui (Verona, Italy)

Objective: To estimate (1) the prevalence of DIP in an homogeneous cohort of patients with schizophrenia treated with antipsychotics (APs) and (2) the prevalence of SPECT abnormalities in patients with DIP, and (3) to describe socio-demographic and clinical variables associated with SPECT abnormalities.

Background: The prevalence and relevance of [123I]FP-CIT SPECT abnormalities (a marker of a dopamine nigrostriatal terminals defect) in patients with schizophrenia who develop drug-induced parkinsonism (DIP) is still unknown.

Methods: In a multi-centre, ambulatory setting, outpatients fulfilling DSM-IV criteria for schizophrenia, treated with AP drugs for at least six months, were enrolled in a multi-centre, ambulatory setting. A diagnosis of DIP was considered when at least two of the three basic parkinsonian signs (rest tremor, rigidity, bradykinesia) were present. In patients with a diagnosis of DIP, [123I]FP-CIT SPECT was employed to assess the integrity of the dopaminergic system.

Results: A diagnosis of DIP was formulated in 149 out of 448 patients with schizophrenia (33%). Age, utilization of long-acting APs and a positive family history of parkinsonism were the main risk factors for developing DIP. A total of 97 out of 149 DIP patients underwent [123I]FP-CIT SPECT, while the remaining 52 denied. Abnormal SPECT findings were found in 41 out of 97 DIP patients (42%). Age and clinical asymmetry differentiated this group of DIP patients from those with normal SPECT.

Conclusions: In DIP patients with abnormal SPECT, blockade of D2 receptors may coexist with a dopamine nigrostriatal terminals defect, possibly compatible with a neurodegenerative parkinsonism. This may have relevant prognostic and therapeutic implications.

127

Duodenal levodopa infusion in patients with advanced Parkinson's disease

M.T. Cáceres-Redondo, F. Carrillo, M.J. Lama, M. Carballo, P. Mir (Seville, Spain)

Objective: The objective of this study was to assess the efficacy and safety of duodenal levodopa infusion in patients with advanced Parkinson's disease (PD).

Background: Motor fluctuations are a common problem in the long-term management of PD, resulting in disability and impaired quality of life. Continuous infusion of levodopa/carbidopa directly into the small intestine of PD patients results in reduction of motor fluctuations by reducing plasma levodopa variability.

Methods: We included 21 patients (6 males, 15 females; mean age 67.9 ± 8.8 years) with advanced PD from October 2007 until September 2011. The mean disease duration time was 13.7 ± 6.1 years and the equivalent daily dose of levodopa was 1438 ± 851 mg/day. Clinical evaluation was performed with United Parkinson's Disease Rating Scale (UPDRS). Off daily time was assessed as percentage of the waking day in off and quality of life with the Parkinson's Disease Questionnaire-39 (PDQ-39). The adverse effects and complications of treatment were evaluated.

Results: Daily off-time shortened significantly and there was an improvement in quality of life. There were no serious adverse effects apart from a sensory-motor axonal polyneuropathy.

Conclusions: Duodenal levodopa infusion improves motor conditions resulting in significant benefit in quality of life and it can be considered as a therapeutic option in advanced PD.

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Δ9-THC is protective in a cell culture model of Parkinson's disease through a PPARγ mediated mechanism resulting in increased expression of PGC1- α

M.L. Zeissler, O. Hanemann, J.P. Zajicek, C.B. Carroll (Plymouth, United Kingdom)

Objective: To investigate the downstream mechanisms by which activation of the nuclear receptor peroxisomal proliferator-activated receptor γ (PPARγ) by Δ9-THC results in neuroprotection in a cell culture model of Parkinson's disease (PD).

Background: We have recently demonstrated that the cannabinoid, Δ9-THC, is neuroprotective through activation of PPARγ in a PD cell culture model of PD. Activation of PPARγ by specific agonists such as the thiazolidinediones (TZDs), rosiglitazone and pioglitazone, has also been found to be neuroprotective by others. However due to the side-effect profile of TZDs, there is a need for alternative drugs that can target the same pathways.

Methods: SH-SY5Y neuroblastoma cells were differentiated with retinoic acid and exposed to the mitochondrial complex 1 inhibitor 1-methyl-4-phenylpyridine (MPP+) a neurotoxin known to induce a parkinsonian phenotype. Δ9-THC and the specific PPARγ antagonist T0070907 were co-administered for 48 hours after which the production of reactive oxygen species was measured and proteins were extracted for Western blotting.

Results: Although others have shown enhanced expression of IκBα to be involved in PPARγ mediated neuroprotection against MPP+, we found that the expression of this protein was not significantly changed by Δ9-THC. However, Δ9-THC resulted in significant inhibition of MPP+ induced oxidative stress which could be completely reversed with the PPARγ antagonist T0070907. Surprisingly, expression of the anti-oxidant enzymes catalase and superoxide dismutase 1 (SOD1) which are both known to have a PPARγ response element (PPRE) within their promoter region, remained unchanged. However, Δ9-THC was able to restore MPP+ induced downregulation of peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1-α), a protein involved in oxidative stress response and mitochondrial biogenesis, to the level of untreated control. This effect was inhibited by T0070907.

Conclusions: Here we demonstrated that Δ9-THC is able to protect against MPP+ induced oxidative stress and propose this to be mediated via PPARγ induced restoration of PGC1-α protein levels.

129

The role of norepinephrine in rat ultrasonic vocalizations

L.M. Grant, J.N. Basken, M.R. Ciucci (Madison, WI, USA)

Objective: To determine the role of norepinephrine in vocalization deficits in a rat model of Parkinson's disease.

Background: Voice deficits are common in Parkinson's disease (PD), but are not fully amenable to treatments aimed at modulating nigrostriatal dopamine (DA). Further exploration of the role(s) of non-DA mechanisms, such as norepinephrine (NE), is indicated. Unilateral 6-OHDA lesions to the medial forebrain bundle result in ultrasonic vocalization (USV) deficits analogous to those in PD.(Ciucci et al, 2009). However, these deficits may be related to the combined loss of DA and NE. To address this issue, we protected NE terminals with desipramine before neurotoxin infusion. We hypothesized that the USV deficits would be attenuated in animals with NE protection by desipramine.

Methods: Three month-old male Long-Evans rats (n=16) were used in this study; prior to unilateral 6-OHDA infusion, 8 were injected with desipramine, and 8 with saline. Complexity, bandwidth, intensity and duration were measured for USVs at 7, 14, and 21 days. Comparisons were made using a repeated measures ANOVA.

Results: Bandwidth and intensity were more vulnerable with the destruction of both DA and NE neurons. The bandwidth of frequency modulated calls was significantly increased at day 7 in the saline (DA and NE depletion) but not desipramine condition (DA depletion, NE spared) compared to all other time points. Moreover, initial declines in maximum intensity of simple calls in the desipramine condition returned to baseline by day 21, while in the saline condition there was a significant decrease at day 21 compared to baseline.

Conclusions: Nigrostriatal NE likely modulates some aspects of USV. Having an intact nigrostriatal NE system may have conferred an advantage, perhaps by protecting DA neurons from the neurotoxin or by modulating compensation or recovery. Furthermore, a complex interaction between the vulnerability of acoustic variables to the severity of nigrostriatal DA and NE depletion and time is suggested. Elucidating the role of NE in cranial sensorimotor functions such as vocalization may improve treatments for PD that are currently refractory to modulating dopamine signaling alone.

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Human microdyalisis during acute high frequency stimulation of internus globus pallidus increases dopamine release and improves parkinsonian symptoms

R.R.C. Martinez, M.C. Carvalho, M.L. Brandão, M.J. Teixeira, J. Navarro, E.T. Fonoff (São Paulo, Brazil)

Objective: The aim of this work was to employ intraoperative microdialysis technique during standard estereotactic procedure of microelectrode guided pallidotomy, in order to evaluate the time course of changes in extracellular levels of dopamine within Globus Pallidus pars interna (GPi) and its correlation to acute improvement in parkinsonian symptoms.

Background: Despite of clinical efficacy of high frequency stimulation in Parkinson's disease has been well established, its interaction with neurotransmitter release is still unknown.

Methods: In five patients, a microelectrode was inserted together with microdialysis probe (2mm apart) and the stimulating contact of microelectrode and the dialysis membrane (3 mm) were in the same dorso-ventral level in the GPi. After the insertion of the probe, samples were collected every 10 minutes for 70 min. First three samples corresponded to baseline levels of dopamine, followed by another 10 minute-stimulation-sample and the three remaining post-stimulation-sample.

Results: Our results showed that during the stimulation period, patients 1, 2, 3 and 4 showed a huge increase in dopamine levels while patient 5 had a small increase (Chi-square(1,6) = 15,09; p = 0,020). Another interesting data is that after the stimulation period (PS samples), there was another increase in dopamine levels observed in patients 1, 2 and 5. Additionally, during intraoperative physiologic testing, all patients exhibited suppression of their parkinsonian symptoms with electrical stimulation of the globus pallidus. The stimulation applied through GPi showed an improvement of contralateral lower and upper limb akinesia.

Conclusions: The present study provides an interesting information to understand how high frequency stimulation can be an efficient treatment for advanced Parkinson's patients.

131

Serum uric acid levels in Japanese Parkinson's disease: Their relationship to wearing-off fluctuation and levodopa induced dyskinesia

J. Fukae, K. Ishikawa, T. Hatano, Y. Shimo, N. Hattori (Tokyo, Japan)

Objective: The aim of our study was to estimate the association between uric acid levels and wearing-off fluctuation and levodopa induced dyskinesia in Japanese Parkinson's disease patients.

Background: The causes of Parkinson's disease are still unknown, oxidative stress could have a important role in the pathogenesis of Parkinson's disease. Several reports suggest that higher levels of serum uric acid reduce the risk of Parkinson's disease and slow the progression of the disease because uric acid have an anti-oxidative function. Treatment of advanced Parkinson's disease become difficult because advanced Parkinson's disease patients develop wearing-off fluctuation and levodopa induced dyskinesia.

Methods: We measured serum uric acid levels in 120 Parkinson's disease patients in Japan. Uric acid correlated with wearing-off fluctuation and levodopa induced dyskinesia.

Results: Age and Body mass index (BMI) did not affect serum uric acid concentrations while gender was found to contribute to the uric acid level. The uric acid level of Parkinson's disease without wearing-off fluctuation was higher than that of Parkinson's disease with wearing-off fluctuation (p<0.01). This association was especially significant for men. There was no association between uric acid level and the appearance of levodopa induced dyskinesia.

Conclusions: Our results suggest that serum uric acid levels may be the predictive factors of wearing-off fluctuation but not levodopa induced dyskinesia. Further research is required to confirm whether potential associations between uric acid level and wearing-off fluctuation exist.

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Implicit motor learning is impaired by levodopa, but restored by deep brain stimulation of the subthalamic nucleus

L.M. Hall, S.G. Brauer, P.W. Hodges (Brisbane, Australia)

Objective: To determine the effect of deep brain stimulation (DBS), levodopa and combined therapy on implicit motor learning of a postural task in people with moderate to severe Parkinson's disease (PD).

Background: Postural instability is a hallmark symptom of PD. The ability to refine postural strategies to changes in postural demands is essential for maintenance of postural equilibrium and relies, in part, on implicit motor learning. Implicit learning of postural tasks is unaffected in early PD but compromised by dopamine replacement therapy. The effect of DBS on the refinement of preparatory postural strategies is unknown. We hypothesised that DBS would not impair implicit motor learning due to a different mode of action on the basal ganglia and dopamine system.

Methods: Fourteen people with bilateral subthalamic nucleus DBS and 14 healthy controls performed 10 repetitions of a standing hip flexion task in four support conditions that presented novel and familiar postural constraints: unsupported standing, holding bilateral handgrips (familiar), biting on a bite plate that could provide postural support (novel) and a combined handgrip and bite plate condition. People with PD were tested in four experimental states with different levodopa and DBS combinations. Postural refinement was quantified by comparison of leg acceleration, vertical ground reaction forces and forces applied to support apparatus between the first and last repetitions of the 4 tasks.

Results: The ability to modify the postural strategy with presentation of new constraints and then refine this with practice was maintained when all treatment (levodopa and DBS) was withheld. Implicit motor learning (refinement) was impaired in the levodopa only state in all conditions (p>0.10) and reinstated when DBS was active with or without levodopa.

Conclusions: DBS does not have the same negative effect on postural refinement as levodopa therapy. This may be due to an effect of DBS on non-dopaminergic pathways or restoration of phasic dopamine release considered essential for learning.

133

A comparison of adverse events with monoamine oxidase inhibitors and catechol-o-methyl transferase inhibitors in combination with levodopa for patients with Parkinson's disease

R. Zhang, A.D. Hohler, M. Saint-Hilaire (Boston, MA, USA)

Objective: To investigate and compare adverse events (AEs) profiles of monoamine oxidase type B inhibitor (MAOBI) and catechol-O-methyltransferase inhibitor (COMTI).

Background: Medication is by far the most effective and important treatment for Parkinson's disease (PD). Combination therapy of MAOBI with levodopa and COMTI with levodopa were demonstrated to provide benefits to PD patients, such as regulating motor fluctuations and reducing levodopa dose, but are accompanied by increased frequency of dopaminergic AEs. Available data is too limited to directly compare the safety of these combination therapies (MAOBI vs. COMTI).

Methods: A retrospective cohort study was conducted. All the data used to analyze the AEs of different PD medications were retrieved from “The Boston University Medical Center's Parkinson's Disease and Movement Disorder Database”. Ten categories of AEs, i.e. compulsive behavior, dyskinesia, dementia, depression, freezing, hallucinations, motor fluctuations, orthostatic hypotension, other autonomic dysfunction and psychosis, were compared between MAOBI and COMTI groups. Fisher's exact test and multivariable logistic regression models were applied to analyze data.

Results: In total 87 subjects were included in the analysis who met criteria for combination therapy with levodopa and COMTI or levodopa and MAOBI. Out of ten AEs, presence of dementia was significantly different between the MAOBI and COMTI groups with an odds ratio of 6.9 (COMTI vs. MAOBI, 95%CI: 1.3-37.0). Motor fluctuations were also found to be differently distributed in the two medication groups with odds ratio of 3.1 (COMTI vs. MAOBI, 95%CI: 1.0-9.8).

Conclusions: COMTI combined with levodopa therapy was more likely to be associated with dementia and motor fluctuations than MAOBI combined with levodopa. These results may impact clinical care and should be further tested in other independent studies.

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Determination of plasma, brain and cerebrospinal fluid levels of L-DOPA in the MPTP-lesioned cynomolgus macaque model of Parkinson's disease

P. Huot, T.H. Johnston, J.B. Koprich, S.H. Fox, J.M. Brotchie (Toronto, ON, Canada)

Objective: To determine levels of L-3,4-dihydroxyphenylalanine (L-DOPA) in the plasma, brain and cerebrospinal fluid (CSF) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned cynomolgus macaques (Macaca fascicularis).

Background: Administration of the dopamine precursor L-DOPA is the mainstay of PD treatment, but its long-term administration is complicated by abnormal involuntary movements, i.e. dyskinesia. While dyskinesia can be reproduced experimentally by chronic administration of L-DOPA to MPTP-lesioned non-human primates (NHPs), concerns have been raised that the doses administered to NHPs are high on a mg/kg basis (typically in the range 20-40 mg/kg p.o.), and as such may not mimic the clinical reality. However, metabolism and bioavailability vary from species to species and what is most important in determining relevance of dosing is not dose administered per se but rather dose delivered, e.g. plasma and, ultimately, brain dosage. Here we determine levels of L-DOPA in the plasma, brain and CSF of MPTP-lesioned macaques and compare these levels to those obtained in clinical settings.

Methods: L-DOPA 30 mg/kg p.o. was administered to 3 MPTP-lesioned cynomolgus macaques. Blood samples were collected over a 24h period. In a terminal experiment, L-DOPA (30 mg/kg p.o.) was administered, blood, brain and CSF were collected 90 min later, corresponding to peak anti-parkinsonian effect. L-DOPA levels were determined by liquid chromatography–mass spectroscopy/mass spectroscopy.

Results: Peak L-DOPA plasma levels were 16.1±3.9 nM/mL. Peak L-DOPA CSF levels were 1.5±0.1nM/mL. Peak L-DOPA levels in the caudate nucleus were 1.2±0.3nM/mL. Time to maximal concentration was 1.7±1.3h and half-life was 1.0±0.4h. Elimination constant was 0.9±0.3 h-1.

Conclusions: In PD patients, L-DOPA plasma levels are typically in the 10–20 nM/mL range following administration of L-DOPA at therapeutic doses of 100–200 mg. Therefore, though L-DOPA doses administered to the MPTP-lesioned primate to elicit dyskinesia may seem high on a mg/kg basis, they lead to plasma levels comparable to those achieved in clinical settings. These data further validate the L-DOPA administration paradigms currently employed in NHP research in PD.

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L-745,870 reduces L-DOPA-induced dyskinesia in the MPTP-lesioned primate at doses at which it is a selective antagonist at D4 dopamine receptors

P. Huot, T.H. Johnston, J.B. Koprich, S.H. Fox, J.M. Brotchie (Toronto, ON, Canada)

Objective: To determine plasma, brain and cerebrospinal fluid (CSF) levels of the dopamine D4 antagonist L-745,870 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned cynomolgus macaque (Macaca fascicularis).

Background: L-745,870, administered at doses in the range 0.3–1.0 mg/kg p.o., alleviates L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in the MPTP-lesioned primate. Here we sought to establish whether the anti-dyskinetic effect of L-745,870 is achieved at doses at which it retains selectively for D4 receptors.

Methods: Three female cynomolgus macaques were rendered parkinsonian by MPTP administration. Animals were then administered L-745,870 (0.1, 0.3 and 1 mg/kg p.o. and 0.3 mg/kg i.v.) or vehicle once a week. Plasma levels of L-745,870 were determined over a 24h period. After the completion of the plasma sampling study, animals were administered an acute challenge of L-745,870 1 mg/kg and were killed 90 min after treatment administration, the time of maximal anti-dyskinetic effect. Plasma, CSF and brain samples were collected and levels of L-745,870 were determined by liquid chromatography/mass spectrometry-mass spectrometry.

Results: Maximal plasma levels of L-745,870 (1 mg/kg) were 181.3 nM/mL. After oral administration, L-745,870 bioavailability was 42.0%. At time of maximal anti-dyskinetic effect, CSF levels of L-745,870 were 12.7 nM/mL, motor cortex levels were 397.8 nM/mL and putamen levels were 342.5 nM/mL. At such brain levels, L-745,870 is highly selective for D4 receptors (Kramer et al. Arch Gen Psychiatry 1997;54:567).

Conclusions: These data confirm that the anti-dyskinetic effect of L-745,870 is achieved at brain concentrations at which the molecule selectively antagonises D4 receptors. These data highlight selective D4 antagonists as promising new anti-dyskinetic agents.

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The mGlu4 receptor positive allosteric modulator, Lu AF21934, displays anti-parkinsonian effects in the haloperidol-treated rat model of Parkinson's disease

T.H. Johnston, M.A. Uberti, M.D. Bacolod, D. Doller, J.M. Brotchie (Toronto, ON, Canada)

Objective: To evaluate the ability of the mGlu4 positive allosteric modulator (PAM) compound, Lu AF21934, to alleviate parkinsonism in the haloperidol-treated rat model of Parkinson's disease (PD).

Background: The value of current therapies for PD is limited by complications of long-term treatment, including dyskinesia. A novel therapy, with the ability to alleviate parkinsonism while producing fewer side effects would be of great value. One approach to this is to develop a non-dopaminergic treatment that has inherent anti-parkinsonian actions. It has previously been shown that mGlu4 PAMs may possess such potential.

Methods: Male SD rats were treated with vehicle (20% HPCD in water), Lu AF21934 (0.3-30 mg/kg, s.c.), Lu AF32615 (10-60 mg/kg, p.o.) or the delta-opioid agonist, SNC80 (10 mg/kg, i.p.). 30 min later animals also received haloperidol (1 mg/kg, i.p.) and behaviour evaluated by assessing catalepsy step test performance. Catalepsy score was assessed in triplicate once per h over a 3 h period commencing immediately following haloperidol administration. Independent animals were prepared for assessment of plasma and brain drug levels.

Results: SNC80 (10 mg/kg, i.p.) evoked a significant decrease in catalepsy, compared to vehicle-treated animals, at the 2- and 3 h time-points (by 90% and 74%).The mGlu4 PAM, Lu AF21934 (0.3-30 mg/kg, s.c.), also produced a dose-dependent decrease in catalepsy, compared to vehicle-treated animals, at the 2 h (3 mg/kg; by 71%, 10 mg/kg; by 46%, 30 mg/kg; by 65%) and 3 h (3 mg/kg; by 52%, 10 mg/kg; by 49%, 30 mg/kg; by 60%) time-points. Lu AF32615 (0.3, 10 and 30 mg/kg, s.c.) produced a similar decrease in catalepsy compared to Lu AF21934 at the 2 h (3 mg/kg; by 71%, 10 mg/kg; by 46%, 30 mg/kg; by 65% respectively) and 3 h (3 mg/kg; by 52%, 10 mg/kg; by 49%, 30 mg/kg; by 60%) time-points.

Conclusions: In the present study, the anti-cataleptic actions of Lu AF21934 were of similar magnitude to the effects of Lu AF32615 and SNC80. Given the profound anti-parkinsonian actions of SNC80 in MPTP-primates these findings support the continued development of mGlu4 PAMs as a therapeutic approach in PD.

137

PYM50028, an orally active neurotrophic factor modulator in development for Parkinson's disease, modulates axon guidance mechanisms related to semaphorin-plexin A-cofilin signaling pathways in the MPTP-lesioned macaque

T.H. Johnston, J.B. Koprich, M. Hill, S.H. Fox, P.A. Howson, J.M. Brotchie (Toronto, ON, Canada)

Objective: We sought to identify potential non-dopaminergic mechanisms of PYM50028 action by examining gene expression in brains of MPTP-macaques that displayed behavioural recovery following 18 wk treatment.

Background: PYM50028, an orally active GDNF and BDNF modulator, restores motor function in MPTP-macaques with established, stable, parkinsonism. Analyses suggest that restoration of dopaminergic function may only partially account for the efficacy of PYM50028. Restoration of dopaminergic function does not appear sufficient to fully explain the benefit of other neurotrophic factor-based approaches in MPTP-primates.

Methods: 14 female macaques received MPTP (0.2 mg/kg/d, s.c.) until marked, stable, parkinsonism developed. 4 months after final MPTP, animals were assigned to 2 groups (N=7) and received 1x-daily PYM50028 (20 mg/kg/d, p.o.) or vehicle for 18 wk. Additional non-lesioned, vehicle-treated macaques (N=5) were also prepared. After 18 weeks of treatment, animals were killed and prepared. Total RNA was extracted from caudate, putamen, cerebellum and visual cortex, and gene expression assessed (Agilent). Genes of interest were defined as those whose expression was either altered by MPTP and normalised by PYM50028 treatment or regulated by PYM50028, having been unaltered by MPTP. Genes of interest were identified in the caudate (331), putamen (71), cerebellum (10) and visual cortex (49). The majority of the genes of interest (87%) were from striatal tissue.

Results: Microarray analysis of striatal genes of interest identified a cluster of genes involved with axon guidance (9 gene products altered, 3.8-fold enrichment, p=0.0023), 6 of which, including dihydropyrimidinase-like 2 (DPYSL2), were of the semaphorin-related signaling pathway. MPTP decreased DPYSL2 by 2.2 fold and PYM50028 treatment increased DPYSL2 to a level not significantly different from control (P>0.05).

Conclusions: These data suggest that 18 wk administration of PYM50028 modulates cofilin/ DPYSL2 signaling. This should regulate axon guidance which potentially may reduce parkinsonism via re-organisation of basal ganglia circuits.

138

Medication reminder service for mobile phones; an open usability study in patients with Parkinson's disease

T. Keränen, S. Liikkanen (Kuopio, Finland)

Objective: To study the success of set up, usability and adoption of medication reminder service with mobile devices in patients with Parkinson's disease (PD).

Background: The progression of PD invariably results to the need of polypharmacy with several drug doses per day. This in turn may decrease the compliance with the medication. Mobile medication reminder could be one way to help in this problem. It is not yet fully known how the current generations of older people, such as PD patients consider mobile devices and services; however it is known that older people are a very challenging user group for these.

Methods: We conducted an open usability study to 50 patients with advanced PD (four or more doses of Levodopa per day). The success of an individually done set up process for reminder by web tool was measured (n = 50). After the set up phase, patients received SMS reminders to their mobile phones for about one month; first two weeks passively and next two weeks so that they were asked to reply every time they received SMS. Finally patients filled out a questionnaire about the usability and experience (n = 45). Logistic regression models were used for analysis of set up and willingness to continue the usage.

Results: Altogether 35/50 patients (70.0%) were able to set up the reminder without help. Men were more capable to set up the system at older age than women (p=0.028 for the interaction effect between age and gender). The mean age of patients responding to questionnaire (n =45) was 66.4 (SD 7.9). Almost 70% of responders rated the set up as “Very easy” or “Easy”. Subjects familiar with computers were more likely to consider the setup easy (p=0.041). Also age had a statistically significant effect (p=0.005); younger subjects were more likely to think that the setup was easy. Almost 80% of population (90% of men and 60% of women) wanted to continue the use of the system. Men were more willing than women (p=0.032) to continue the use of reminder system. Patient's age, mobile usage or computer background did not have a statistically significant effect on the response.

Conclusions: Our study suggests that mobile medication reminder is a feasible method to assist patients with advanced PD in medication compliance.

139

Anti-parkinsonian effects of Nurr1 activator in UPS impairment induced animal model of Parkinson's disease

Z. Zhang, W. Xie, S. Hintermann, J. Jankovic, W. Le (Houston, TX, USA)

Objective: The objective of this study is to determine whether Nurr1 gene activator compound 1 has anti-parkinsonian effects in animal model of PD.

Background: Nurr1 is a member of the nuclear receptor superfamily and is a potential susceptibility gene for Parkinson's disease (PD). Several lines of studies in vitro and in vivo reported that defects in the Nurr1 gene cause nigrostriatal neuronal deficiency as seen in PD. In the present study, a synthetic low molecular weight compound- 1 which remarkably increases the transcription of Nurr1 was used to investigate whether it has anti-parkinsonian effects against nigrostriatal neuronal degeneration induced by UPS impairment.

Methods: Adult C57BL/6 mice were treated with two compounds (compound 1 is a Nurr1 activator and compound 2 is an inactive form as control) at 10mg/kg per day. p.o starting 3 days before microinjection of proteasome inhibitor lactacystin into the medial forebrain bundle (MFB) and treatment continued for a total of 4 weeks. Animal behavior tests, pathological and biochemical examinations were performed to determine the anti-parkinsonian effects of the Nurr1 activator.

Results: We found that treatment with the Nurr1 activator significantly improved rotarod performance, attenuated dopamine (DA) neuron loss and nigrostriatal DA reduction, increased expression of Nurr1, DAT and VMAT2, and alleviated microglial activation in the substantia nigra of lactacystin-lesioned mice.

Conclusions: These results suggest that Nurr1 activator has potent anti-parkinsonian effect and the therapy using Nurr1 activator is an innovative strategy for the treatment of PD.

140

Maintenance of constant steady state therapeutic plasma concentrations of levodopa following its continuous subcutaneous administration with carbidopa

O. Yacoby-Zeevi, P.A. LeWitt (West Bloomfield, MI, USA)

Objective: To test the effect of continuous subcutaneous (SC) levodopa (LD) and carbidopa (CD) administration on LD pharmacokinetics (PK).

Background: The most common problems of advanced Parkinson's disease (PD) – wearing-off between doses and dyskinesias – are linked to the marked fluctuations of circulating LD that typically occur during oral administration. Improving the consistency of plasma LD concentrations has been a longstanding pharmacological challenge. Currently-available long-acting oral LD therapies generally fail at controlling variability in motor control. In contrast, dramatic clinical improvements (reduced dyskinesias and “off” periods) occur from treatment with LD by continuous intravenous or intraduodenal infusion. However, neither of these drug delivery options is convenient. For this reason, we investigated the effect of continuous subcutaneous delivery of LD/CD formulations on the pharmacokinetics (PK) of LD.

Methods: A novel method for solubilizing and stabilizing LD and CD was developed (a product termed ND0612) and used for the continuous SC administration of LD/CD solutions in pigs. Plasma LD and CD concentrations were measured repeatedly for PK analysis.

Results: Constant plasma LD concentrations were maintained following continuous subcutaneous administration of LD/CD formulations in pigs. The LD steady state plasma concentrations were LD- and CD-dose dependent. Continuous SC delivery of ND0612, 2-4 ml/d, was sufficient to obtain and maintain constant LD plasma concentrations in a range typically therapeutic for treating PD in man. The treatment was safe and well tolerated.1 (140), 2 (140)

Figure 1 (140).
Figure 2 (140).

Conclusions: Currently-available oral LD formulations are associated with marked PK fluctuations. SC delivery of solubilized LD and CD is a promising option for enhancing consistency of plasma LD concentrations. This approach offers improved control of motor fluctuations in PD as well as the opportunity to reduce the burden of frequent daily oral dosing with LD/CD. A Phase I single-centre, randomized, cross-over, double-blind, placebo-controlled study evaluating safety, tolerability and PK profile of LD following continuous SC administration of LD and CD is ongoing.

141

Is chronic levodopa therapy associated with distal symmetric polyneuropathy in Parkinson's disease?

N. Shahrizaila, U.A. Mahamad, A.C. Yap, Y.M. Choo, C. Marras, S.Y. Lim (Kuala Lumpur, Malaysia)

Objective: We aimed to compare the prevalence of DSP in levodopa-naive PD patients vs. PD patients on chronic levodopa treatment.

Background: It has been recently suggested that Parkinson's disease (PD) patients on chronic levodopa treatment may be at risk of developing a distal symmetric polyneuropathy (DSP).

Methods: In this prospective study, 51 PD patients were assessed for DSP using clinical and neurophysiological measures. 25 patients were levodopa-naive (Group 1) and 26 patients had taken at least 300 mg/day of levodopa for three or more years (Group 2). We investigated the prevalence of DSP as defined by the American Academy of Neurology and Electrodiagnostic Medicine (AANEM), and compared the mean electrodiagnostic values, and plasma levels of methylmalonic acid (MMA) and homocysteine between the two groups.

Results: The electrodiagnostic criteria for DSP were fulfilled in 24% of Group 1 and 23% of Group 2 patients. However, only one Group 1 patient and two Group 2 patients fulfilled the AANEM case definition for DSP, giving a prevalence of 5.9% in the overall PD cohort. There were no significant between-group differences in the mean electrodiagnostic values when adjusted for disease duration. We also failed to demonstrate a relationship between DSP or sural nerve parameters and plasma levels of MMA and homocysteine.

Conclusions: The current study demonstrated no difference in the prevalence of DSP between levodopa-naive patients and patients on chronic levodopa therapy. We also observed a lower prevalence of DSP in PD patients than previously reported.

142

Chronic transdermal rotigotine reduces levodopa-induced dyskinesias

G.J. Linazasoro, N. Van Blercom (San Sebastian, Spain)

Objective: To demonstrate that transdermal rotigotine (TR), by continuously stimulating dopamine receptors, reverts the pattern of response to a levodopa challenge in PD patients with motor complications.

Background: Motor complications in PD are related to changes in the pattern of response to a dose of levodopa: A short duration response (SDR) (shortening of the latency to reach the peak-effect and an increase in the magnitude of the response) accompanied by a simultaneous decrease in the threshold for dyskinesias, emerges. Strategies providing a continuous stimulation of the dopamine receptors improve them.

Methods: Prospective, open, single-blind, uni-center study including 17 patients (mean age 69.8 ± 6.7 yo, mean PD duration 9.3 ±5.7 years, mean Hoehn and Yahr 2.4 ±0.6) with motor complications on a stable dose of levodopa. A levodopa challenge consisting of the administration of the first levodopa dose in the morning was conducted at 2 and 6 months. Total UPDRS, latency, magnitude and duration of motor response and Obeso's dyskinesia rating scale were administered.

Results: Mean TR dose was 18 mg/24 h. The equivalents of levodopa remained unchanged during the study. Total UPDRS and the pattern of motor response remained unmodified. However, a significant reduction in dyskinesia scores (3.9 ± 2.4 vs 2.1±2.4 and daily time (3.6 ± 4.1 vs 1.6 ± 3.1) was obtained (p>0.05). This change appeared at 2 months and persisted at 6 months.

Conclusions: Reduction in dyskinesias without worsening the motor situation, indicates that TR may have a direct antidyskinetic effect, suggesting a different pathophysiological origin of motor fluctuations and dyskinesias.

143

Rotigotine treatment in Parkinson's disease: Evaluation of its characteristics in our movement disorders unit

L. Martinez, L.J. Lopez del Val, E. López, S. Santos (Zaragoza, Spain)

Objective: Rotigotine is a transdermal patch formulation of dopamine agonist indicated in early and in advanced Parkinson's disease. The aim of our study was to evaluate general characteristics of patients on rotigotine and corroborate its efficacy in some non-motor symptoms.

Background: None.

Methods: Data on outpatients of the Clinical Universitary Hospital of Zaragoza (Spain)Movement Disorders Unit were collected retrospectively. The total number of subjects with Parkinson's disease evaluated in this unit was 356. Of these, 182 were females and 174 males, with no significant differences in the age of the two groups. The 29% of this patients were on rotigotine (n=104).

Results: 56 rotigotine patients were in I to II Hoehn-Yahr clinical state and 48 were in III-IV clinical state. The medium daily dose was 8 mgr/24h. Rotigotine was well-tolerated in general. At the moment of this review 20 patients were on monotheraphy (excluding rasagiline). According with the UPDRS scale and, in most of the cases, with the PDSS and Hamilton scales rotigotine show benefit on reducing sleep disturbances, night-time and early-morning motor symptoms and subsequently improve quality of life. We couldńt demonstrate changes in mood disorders after rotigotine treatment. Although a few cases of impulse control disorders in rotigotine patients have been documented, none of our 104 patients developed this pathology.

Conclusions: Rotigotine is easy to administrate, well-tolerated and efficate in early and advanced Parkinson's disease. As seen in other previous studies it has shown benefit in controlling sleep disorders and early-morning motor symptoms. The 29% of our Parkinson's disease patients were on rotigotine but non impulse control disorders have been documented.

144

An audit of apomorphine in the management of complex idiopathic Parkinson's disease in Ireland

B. Magennis, A. Cashell, D. O'Brien, T. Lynch (Dublin, Ireland)

Objective: An audit was performed to evaluate the use of apomorphine in the control of complex Parkinson's disease.

Background: Idiopathic Parkinson's disease (IPD) is the second most common neurodegenerative disorder. Apomorphine, a dopamine agonist, is useful for treating “Off” periods and motor fluctuations, which are a common disabling complication of IPD resulting in increase dependence.

Methods: We audited our use of Apomorphine by a retrospective chart review of patients seen at a tertiary referral PD clinic from 2003-2011. We reviewed the records on all patients who underwent an Apomorphine challenge test prior to commencing Apomorphine as a part of their clinical treatment. We focused on the outcome of the challenge test, subsequent commencement of apomorphine and the impact it made on the overall management of the complex motor fluctuations and impulse control disorder (ICD).

Results: 41 patients (21M/20F) mean age 59.9 years old underwent the Apomorphine challenge test. Of the 41, 30 had a positive response and were successfully established on Apomorphine (25 infusion, 4 injection, 1 combination) and 11 were deemed unsuitable. Of these 11, 9 did not respond to the challenge, and 2 were unable to tolerate the challenge due to a vasovagal reaction. 30 were effectively started on Apomorphine resulting in reduction of UPDRS score and increased self-reported quality of life. Oral medications were reduced. Of the 9 non-responders, 6 went on to have a subsequent diagnosis of atypical parkinsonism The 3 remaining non-responders were levodopa responsive consistent with IPD; 2 had successful had deep brain stimulation. 13 patients had apomorphine discontinued (3 RIP, 5 had DBS, 5 with adverse effects). 2 of these 13 had sustained improvement in motor fluctuations and dyskinesia post discontinuation of apomorphine (1 self discontinuation and 1 due to leg oedema). We noted 5 patients with ICD on oral dopamine agonists had reduced ICD on subcutanous apomorphine infusion.

Conclusions: Apomorphine has a positive impact for patients in the complex stage of PD by reducing their tablet burden, reducing their UDPRS score, reducing ICD and creating a stable and predictable form of treatment with an increase in their quality of life.

145

Tardive tolerance to dopamine D1 agonists: A novel loss of response dependent upon continuous receptor occupation

R.B. Mailman, K.N. Boyd, K. Neitzel, E. Heinzen (Hershey, PA, USA)

Objective: To determine the nature of “tardive tolerance” seen with D1 dopamine agonists.

Background: It is oft assumed that activation of dopamine D2 receptors is the key to antiparkinson action, yet only D1 activators cause profound antiparkinson effects (e.g., dihydrexidine, ABT-431, A77636, apomorphine, levodopa). A77636, a promising D1 agonist, caused very rapid tolerance to its antiparkinson effects, and PK and tox issues have confronted other D1 drugs. Unless this tolerance issue can be overcome, the therapeutic potential of D1 agonists for PD will not be realized.

Methods: We used the unilateral rat 6-hydroxydopamine (6-OHDA) “model” of PD and experimental D1 agonists with varying duration of receptor occupancy administered by injection or minipump. Post-mortem studies included studies of receptor availability, and signaling properties.

Results: Regardless of route of administration, three structurally and pharmacokinetically dissimilar full D1 agonists (dinapsoline, dihydrexidine, A77636) and the low intrinsic activity partial D1 agonist SKF38393 caused near complete tolerance with continuous receptor occupancy for 24 h.