MORNING SESSION: 8:15 AM–NOON
The morning session consists of a keynote speaker and 11 presentations by the following individuals with allotted time for questions and answers after each presenter.
KEYNOTE ADDRESS: Genetics of Parkinson's disease
Mayo Clinic Jacksonville, Jacksonville, FL, USA.
A Clinic-Based Study of the LRRK2 Gene in Parkinson's Disease Yields New Mutations
C.P. Zabetian,1,2 A. Samii,1,3 A.D. Mosley,4 J.W. Roberts,5 B.C. Leis,4 D. Yearout,1,2 W.H. Raskind,6–8 A. Griffith.41Department of Neurology, University of Washington, Seattle, WA; 2Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA; 3Northwest Parkinson's Disease Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA; 4Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, WA; 5Section of Neurology, Virginia Mason Medical Center, Seattle, WA; 6Department of Medicine, University of Washington, Seattle, WA; 7Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA; 8Mental Illness Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
Background: Recent studies of referral-based samples indicate that a single mutation (G2019S) in exon 41 of the LRRK2 gene accounts for an unexpectedly large proportion of both familial and sporadic cases of Parkinson's disease (PD). If these data are representative of PD in the general population, then genetic testing for LRRK2 mutations might be useful in clinical settings. Methods: We resequenced exons 31, 35, and 41 of the LRRK2 gene in 371 PD patients consecutively recruited through five movement disorder clinics, and in 281 controls. Results: We found mutations in 6 (1.6%) PD patients, including two heterozygous for new putative pathogenic variants (R1441H, IVS31+3A→G). None of these mutations were observed in the control group. R1441H replaces a highly conserved amino acid, whereas IVS31+3A→G is predicted to disrupt splicing. We also found evidence of substantially reduced penetrance in a family with a previously reported pathogenic mutation (R1441C). Conclusions: Our findings in a clinic-based PD sample suggest that LRRK2 mutations are sufficiently common to justify testing in neurological practice. More data are needed, however, on the spectrum, frequency, and penetrance of pathogenic variants in the gene before such testing is implemented.
LRRK2Mutations in a Population-Based Study of Parkinson's Disease
L.M. Nelson,1 J.W. Langston,2 C.M. Tanner,2 R.M. Myers,1 A. Southwick,3 J. Doostzadeh,2 B. Topol,1 H.K. Tabor,3 M.J. Farrar,4 V. McGuire,1 R. Popat,1 A. Bernstein,5 A.D. Leimpeter,5 S.K. Van Den Eeden.51Stanford University School of Medicine, Stanford, CA; 2The Parkinson's Institute, Sunnyvale, CA; 3Stanford Human Genome Center, Stanford, CA; 4Mayo Clinic, Jacksonville, FL; 5Kaiser Permanente Division of Research, Oakland, CA, USA.
We investigated the frequency of seven mutations in the gene that codes for leucine-rich repeat protein kinase 2 (LRRK2) in a large community-based population of 400 unrelated Parkinson's disease (PD) patients and 453 age- and gender-matched control subjects. The frequency of heterozygosity for the most common LRRK2 mutation, a glycine-to-serine amino acid substitution at codon 2019 (Gly2019Ser, G2019S), was 6 of 399 cases (1.5%, only one of whom had a positive family history), compared to 1 of 453 controls (0.6%). The risk of parkinsonism was increased sevenfold among subjects with the G2019S mutation (odds ratio 6.9; 95% CI 0.8–318.1; P = 0.06). Another LRRK2 mutation (2378G>T, R793M) was present in three control subjects and no cases. No other LRRK2 mutations were found. The frequency of G2019S heterozygotes was higher among cases who reported one or more first-degree family members affected with PD (2.3%; 1/43) than among cases without familial PD (1.4%; 5/356). The clinical features of parkinsonism in cases with G2019S mutations were largely typical of idiopathic Parkinson's disease, but one or more unusual features were observed in almost all cases. The wide range of age of onset (57–90 years) among cases with the G2019S mutation, and its occurrence in an 82-year-old unaffected control subject, suggests that other modifying genes or environmental factors influence the penetrance of this LRRK2 mutation.
Clinical and Pathological Characterizations of Families With LRRK2 Gene on PARK8 Locus
A. Imamura,1 R.J. Uitti,1 D.W. Dickson,1 D.B. Calne,2 J. Stoessl,2 A. Zimprich,3 M.J. Farrer,1 T. Gasser,4 Z.K. Wszolek.11Mayo Clinic, Jacksonville, FL, USA; 2Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC, Canada; 3Medical University of Vienna, Vienna, Austria; 4Hertie Institute for Clinical Brain Research, University of Tubingen, Tubingen, Germany.
Mutations in six genes (SNCA, PRKN, PINK1, DJ-1, MAPT, and UCH-L1) have been identified in familial parkinsonism in the last 8 years. The PARK8 locus on chromosome 12p11.2-q13.1 was first found in a large Japanese family known as the Sagamihara kindred in 2002. In 2004, we found the first two mutations in the leucine-rich repeat kinase 2 (LRRK2) gene in Family D (Western Nebraska; R1441C) and Family A (German-Canadian; Y1699C). We have followed these families for 15 years. Seven autopsies are complete: four in Family D and three in Family A. We report here additional clinicopathological findings in these two families. The clinical presentation of affected Family D members resembles those seen in sporadic Parkinson's disease patients. The late age of symptomatic disease onset, lack of atypical clinical features and good response to carbidopa/levodopa therapy are uniformly seen in affected family members. On autopsies, pleomorphic findings have been noted. The clinical presentation of Family A is more heterogeneous and includes parkinsonism, dementia, amyotrophy, earlier age of onset, and good response to carbidopa/levodopa therapy. Autopsies showed neuronal loss and gliosis in pigmented brainstem nuclei and a number of inclusions, some of them awaiting further characterization. We hypothesize that distinct mutation localization in the LRRK2 gene domain is most likely responsible for differences in clinical feature, but pathological presentations are pleomorphic even in same family.
Arkansas Family: Autosomal Dominant Parkinsonism, Essential Tremor and Restless Legs Syndrome
A. Imamura,1 R.F. Pfeiffer,2 L. Brown,1 M.J. Farrer,1 D.W. Dickson,1 Z.K. Wszolek.11Mayo Clinic, Jacksonville, FL; 2University of Tennessee, Memphis, TN, USA.
The cause of Parkinson's disease (PD) remains unknown, but one major risk factor includes positive family history. In the last 8 years, mutations in seven genes have been identified in familial parkinsonism. We have just identified a new Caucasian family predominantly residing in Arkansas (thus the name). This kindred contains 117 family members spanning five generations including 15 affected: 1 with definite PD, 8 with probable PD, and 1 with possible PD alone, 4 with essential tremor (ET) alone, and 1 with restless legs syndrome (RLS) alone. Mode of inheritance is autosomal dominant. The average age at onset of PD symptoms is 58 years ranging from 39 to 77 years. Parkinsonism is carbidopa/levodopa responsive. There is no ataxia, dementia, muscle weakness, or other neurodegenerative symptoms. The molecular genetic analysis revealed no known PD loci/mutations. Autopsy carried out on 1 affected parkinsonian family member (57-year-old female with bradykinesia, rigidity and postural tremor of about 1-year duration but no rest tremor and with unknown response to levodopa/carbidopa therapy who died of stomach carcinoma with metastasis to the liver) demonstrated large megaloencephalon (brain weight of 1,440 g) and enlarged lateral ventricles without distinguishable histopathology suggestive of congenital communicating hydrocephalus. Further longitudinal studies of Arkansas Family are planned and hopefully they will lead to better understanding of this kindred phenotype, pathological abnormalities, and molecular genetics.
Gene Therapy for Parkinson's Disease With AAV-GAD: An Open-Label, Dose Escalation, Safety-Tolerability Trial
A. Feigin,1 M. Kaplitt,2 M. During,2 K. Strybing,2 M. Cox,1 V. Dhawan,1 D. Eidelberg.11Institute for Medical Research, North Shore–LIJ Health System, Manhasset, NY; 2Weill Cornell Medical College, New York, NY, USA.
Objective: To assess the safety/tolerability of adeno-associated-virus vector delivery of the glutamic acid decarboxylase gene (AAV-GAD) into the subthalamic nucleus (STN) in Parkinson's disease (PD). Background: Dopaminergic neuronal loss in PD leads to changes in basal ganglia circuitry, including decreased GABAergic input to the STN. In primates, STN AAV-GAD increases GABA and improves parkinsonism, and is safe and well tolerated. Design/Methods: An open-label, safety-tolerability trial of unilateral STN AAV-GAD in 12 PD patients (11 men, 1 woman; age 58.2 ± 5.7). The first 4 subjects received low-dose AAV-GAD, the next 4, middle dose, and the final 4, high dose. Inclusion criteria included HY stage ≥3, motor fluctuations with significant off time, and age ≤70. Subjects are evaluated at baseline and after 1, 3, 6, and 12 months with the UPDRS, timed tasks, videotaped exams, and neuropsychological testing. Results: There have been two serious AEs, both of which were unrelated to study treatment: (1) A subject experienced worsening in parkinsonism after discontinuing entecapone, resulting in a one-night hospitalization. After resuming entecapone, the subject returned to baseline; (2) A subject developed pneumonia requiring 3 days of IV antibiotics. No other AEs have occurred. Baseline off UPDRS was 59.4 ± 10.6 (n = 12). At 3, 6, and 12 months, UPDRS scores were 48.6 ± 16.7 (P = 0.11; n = 8), 53.7 ± 15.9 (P = 0.23; n = 7), and 54.8 ± 25.0 (P = 0.33; n = 4), respectively. Conclusion: Thus far, AAV-GAD gene therapy seems to be safe and well tolerated in PD. Efficacy data should be viewed with caution because this is an open-label study with a small sample size.
Subthalamic Nucleus Deep Brain Stimulation: A Meta-Analysis of Outcomes
G. Kleiner-Fisman,1 J. Herzog,2 G. Deuschl,2 A.E. Lang,3 K. Lyons,4 R. Pahwa,4 F. Tamma,5 D. Fisman.61Parkinson's Disease Education, Research and Clinical Center (PADRECC), Philadelphia VA Hospital, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Neurology, Christian-Albrechts-Universität Kiel, Kiel, Germany; 3Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada; 4Parkinson's Disease and Movement Disorder Center University of Kansas Medical Center, Kansas City, KS, USA; 5Clinica Neurologica Centro Parkinson Osp. San Paolo–Milano, Italy; 6Drexel School of Public Health, Drexel University, Philadelphia, PA, USA.
Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) is currently the most common therapeutic surgical procedure for patients with Parkinson's disease (PD) who have failed medical management. A summary of clinical evidence on the effectiveness and utilization of STN-DBS, however, has been lacking. We report the results of such a systematic review and meta-analysis. Methods: A comprehensive review of the literature using MEDLINE and OVID databases from 1965 until 2004 was conducted. Estimates of change in absolute UPDRS scores after surgery were generated using random-effects models. Sources of heterogeneity were explored with meta-regression models, and the possibility of publication bias was evaluated. Results: Twenty-two studies were included in the meta-analysis. The estimated changes in absolute UPDRS II and III scores after surgery were 13.35 (95% CI, 10.85–15.85) and 27.55 (95% CI, 24.23–30.87), respectively. Changes in UPDRS scores were significantly higher in studies with higher baseline UPDRS scores, increasing disease duration before surgery, earlier year of publication, and higher baseline levodopa responsiveness. Average baseline UPDRS scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. No evidence of publication bias was found in the available literature. Conclusion: Synthesis of the available literature indicates that STN-DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies probably reflect differences in patient populations, rather than surgical technique. Given the apparent effectiveness of this intervention, the wider application of surgery seen in more recent medical literature is likely appropriate.
Subthalamic DBS for the Treatment of “Runaway” Dyskinesias After Embryonic or Fetal Tissue Transplant
C. Cho,1 R. Alterman,1 J. Miravite,1 J. Shils,2 M. Tagliati.11Mount Sinai School of Medicine, New York, NY; 2Lahey Clinic, Boston, MA, USA.
Objective: To describe the use of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of “runaway” dyskinesias in Parkinson's disease (PD). Background: Uncontrollable dyskinesias have been reported as a complication of embryonic/fetal nigral tissue grafting for the treatment of PD. STN DBS improves parkinsonism and levodopa-induced dyskinesias. We report three cases of graft-induced dyskinesias (GID) that were ameliorated with bilateral STN DBS. Methods: We carried out bilateral STN DBS surgery in 3 advanced PD patients who developed disabling GID after embryonic/fetal nigral tissue engraftment. Disabling GIDs were defined as hyperkinetic movements that interfered with routine activities and persisted despite withholding levodopa. One patient responded well to left pallidal DBS for 2 years but subsequently developed generalized GID despite optimal stimulation settings. Stereotactic MRI and intraoperative microelectrode recording were used to target the STN bilaterally. Items 32 to 34 of Part IV of the Unified Parkinson's disease rating scale (UPDRS-IV) were used to evaluate the severity of GID before and after surgery. Patient follow-up was at least 4 months. Results: After STN DBS, all 3 patients were improved. Cumulative preoperative UPDRS-IV dyskinesias sub-scores of 8, 5, and 4 were reduced to 3, 0, and 0 respectively at last follow-up. In one case, improvement of dyskinesias was maintained despite an increased levodopa dose. Conclusions: STN DBS is effective in treating “runaway” dyskinesias after embryonic/fetal nigral transplantation for PD. These results suggest that the attenuation of dyskinesias after STN DBS surgery may not be explained solely by a postoperative reduction in levodopa requirements.
A Randomized Controlled Trial of Etilevodopa in Parkinson's Disease Patients With Motor Fluctuations
Parkinson Study Group (Steven Schwid, presenter), University of Rochester, Rochester, NY, USA.
Background: Motor fluctuations are a common complication in Parkinson's disease (PD) patients on chronic levodopa therapy. Slowed gastric emptying and poor solubility of levodopa (LD) in the gastrointestinal tract may delay onset of drug benefit after dosing. Etilevodopa (EtiLD) is an ethyl-ester prodrug of LD that has greater gastric solubility, passes quickly into the small intestine, is rapidly hydrolyzed to LD, and has a shortened time to maximum LD concentration. Objective: To determine the efficacy, safety, and tolerability of EtiLD in PD patients with motor fluctuations in a multicenter, randomized, placebo-controlled, double-blind, parallel-groups study. Methods: PD patients (n = 327) with at least 90 minutes total daily time to on (TTON) after LD dosing were randomized to EtiLD/carbidopa (EtiLD/CD) or LD/carbidopa (LD/CD) for 18 weeks. The primary endpoint was the change from baseline in total daily TTON as measured by home diaries. Results: The reduction in mean total daily TTON from baseline to treatment was 0.58 hours in the EtiLD/CD group and 0.79 hours in the LD/CD group (P = 0.24). There was no significant difference between the EtiLD/CD group compared with the LD/CD group (−6.82% vs. −4.69%; P = 0.20) in the reduction of response failures. The total daily off time improved in both EtiLD/CD (−0.85 hours) and LD/CD (−0.87 hours) groups without an increase in on time with troublesome dyskinesias. Conclusions: Despite the theoretical pharmacokinetic advantage of EtiLD, there was no improvement in TTON, response failures, or off time compared with LD.
Prognostic Factors for Parkinson's Disease Progression Rate
L.W. Ferguson, M.L. Rajput, A.H. Rajput. University of Saskatchewan, Saskatoon, SK, Canada.
Background: Many studies have sought to identify PD prognostic factors with a variety of results. Tremor-dominant PD is associated with benign progression and akinetic–rigid PD is associated with rapid progression, as is older age at onset. Studies of gender and progression are contradictory and family history and smoking status have not been predictive. We report a retrospective analysis of a large clinical database. Methods: Idiopathic PD patients from 1985 to 2004 were included. Progression of PD was classified using all available Hoehn and Yahr (HY) scores as follows: <3.0 at 10 years after onset, benign; ≥3.0 between 3 and 10 years after onset, average; and ≥3.0 by 3 years after onset or ≥4.0 by Year 5, rapid. Data from first clinic visit was evaluated for association with progression. Results: Of 1,325 PD patients, 210 (16%) had benign progression, 234 (18%) rapid progression, and 344 (26%) average progression. We were unable to classify 165 (12%) patients and 372 (28%) could only be classified as “not rapid.” Benign progressors had younger age at onset (57.6 vs. 73.4 years for rapid; P < 0.0001), longer duration of disease at first visit (7.5 vs. 2.0 years; P < 0.0001), and were more likely to be male (68% vs. 52%; P < 0.0001), have a family history of movement disorders (28% vs. 15%; P = 0.012), and be current smokers (12% vs. 7%; P = 0.002). Of patients with a history of antiparkinsonian medications, benign progressors were more likely to report motor complications (43% vs. 13%; P < 0.001). Rapid progressors were more likely to present at first visit with mild or greater rigidity (69% vs. 59% for benign; P = 0.04) and/or bradykinesia (82% vs. 70% for benign; P = 0.02) and less likely to present with mild or greater resting tremor (40% vs. 57%; P < 0.0001). Rapid progressors were also more likely to have a Schwab and England ADL score <70 at first visit (27% vs. 4%; P < 0.0001). Conclusion: Disease characteristics measured at first clinic visit can be useful in predicting course of progression. Such information could assist physicians in planning a course of treatment and follow-up.
Pathophysiology of Levodopa-Induced Dyskinesia in Parkinson's Disease: A TMS Study
F. Morgante, A.J. Espay, C. Gunraj, A.E. Lang, R. Chen. Division of Neurology, University of Toronto, Toronto, ON, Canada.
We tested the hypothesis that levodopa-induced dyskinesia in Parkinson's disease (PD) is associated with aberrant plasticity in the motor cortex (M1). We employed paired associative stimulation protocol (PAS), an experimental paradigm that produces long-term potentiation (LTP) like changes in the sensorimotor system in humans. Sixteen patients (9 dyskinetic, 7 non-dyskinetic) with moderate PD and 9 age-matched healthy controls were studied. Patients were assessed in the practically defined off state (off) and after administration of the levodopa (on). Motor evoked potentials (MEPs) amplitudes and cortical silent period (CSP) were recorded from the contralateral abductor pollicis brevis (APB) in the more affected arm of the patients and on the dominant side of the controls. PAS was induced by delivering median nerve stimulation followed by transcranial magnetic stimulation to the contralateral M1 21.5 msec later at a rate of 0.1 Hz for 30 minutes. PAS significantly increased MEPs size in controls but not in dyskinetic and non-dyskinetic PD patients off medication (P = 0.02). Levodopa restored the increase in MEPs amplitudes by PAS in the non-dyskinetic group but not in the dyskinetic (P = 0.02) group. PAS prolonged CSP duration in controls and non-dyskinetic but not in the dyskinetic (P = 0.005) patients off medications. This was unchanged in the on medication state. Our results indicate that LTP-like plasticity was deficient in PD patients off medications and was restored by levodopa in non-dyskinetic but not in dyskinetic patients. Abnormal synaptic plasticity in the motor cortex may play a role in the development of LID.
A Novel PRKN Compound Heterozygous Mutation in a Caucasian Family With Early-Onset Parkinson's Disease
H. Deng,1 W.D. Le,1 C.B. Hunter,1 W. Ondo,1 Y. Guo,2 W.J. Xie,1 J. Jankovic11Baylor College of Medicine, Houston, TX, USA; 2Central South University, Changsha, Hunan, P.R. China.
Background: Mutations in the parkin gene (PRKN) cause autosomal recessive early-onset Parkinson's disease (EOPD). Objectives: To investigate the presence of mutation in the PRKN gene in a large Caucasian family with EOPD and the genotype-phenotype correlations. Design: Twenty members belonging to 3 generations of an EOPD Caucasian family with 4 affected subjects underwent genetic analysis. Direct genomic DNA sequencing, semi-quantitative PCR, real time quantitative PCR, and RT-PCR were performed to identify the PRKN mutation. Results: A novel compound heterozygous mutation (T240M and EX 5_6 del) in the PRKN gene was identified in 4 patients, mean age at onset: 34.5 (30–38) years. Although heterozygous T240M and homozygous EX 5_6 del mutations in the PRKN gene have been previously described, this is the first report of these mutations in compound heterozygotes. The phenotype of patients was that classic autosomal recessive EOPD, characterized by beneficial response to L-dopa, slow progression of the disease and diurnal fluctuations. Interestingly, all heterozygous mutation (T240M or EX 5_6 del) carriers and one 56-year woman, who was a compound heterozygous mutation (T240M and EX 5_6 del) carrier, were free of any neurological symptoms. Conclusions: A novel compound heterozygous mutation (T240M and EX 5_6 del) in the PRKN gene was identified to cause autosomal recessive EOPD in 4 members of a large Caucasian family. One additional member with the same mutation, who is more than 10 years older than the mean age of onset of the 4 affected individuals, had no clinical manifestation of the disease. This incomplete penetrance has implications for genetic counseling and it suggests that complex gene-environment interactions may play a role in the pathogenesis of PRKN EOPD.
AFTERNOON SESSION: 1:30–4:45 PM
The afternoon session consists of a keynote speaker and 8 presentations by the following individuals with allotted time for questions and answers after each presenter.
KEYNOTE ADDRESS: Advances on the Mechanisms Underlying Hereditary Ataxias
Henry L. Paulson, MD, PhD. University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
Proposed Criteria for Dementia in Patients With Huntington's Disease
G.M. Peavy,1 S.R. Wetter,2,3 J.M. Hamilton,1 M.W. Jacobson,2,3 J.L. Goldstein,1 A.C. Gamst,1,4 J. Corey-Bloom.1,31Department of Neurosciences, University of California, San Diego, CA; 2Department of Psychiatry, University of California, San Diego, CA; 3Veterans Administration Medical Center, San Diego, CA; 4Department of Family and Preventive Medicine, University of California, San Diego, CA, USA.
The study's objective was to define the construct of dementia in Huntington's disease (HD) by specifying criteria that can be reliably measured to predict functional capacity. Investigators have developed criteria for dementia in a number of neurodegenerative diseases, most notably Alzheimer's disease (AD). The term dementia is also used to describe cognitive deficits in HD patients, but no clear definition is available. The common practice of applying AD criteria for dementia to HD often results in misleading conclusions, since cognitive deficits in HD and AD differ. We administered tests of attention, executive functions, memory, fluency, and visuospatial ability, as well as a scale of functional independence to 39 subjects with or at risk for HD. Regression analyses determined the ability of selected neuropsychological variables to predict the FIS rating, and to classify subjects as functionally impaired or intact. Mean (SD) Mattis Dementia Rating Scale total was 123.9 (13.1) and FIS rating, 73.2 (12.9). The variance in the FIS rating accounted for by the Stroop Word Reading score (speed of processing; mean [SD] = 52.5 [18.6]) was 56%. The proportion accounted for by the DRS Conceptualization score (abstract reasoning; 35.1 [2.0]) was 9%, for a total of 65% (F = 32.4; P < 0.001). Ninety-four percent of subjects (χ2 = 19.2; P < 0.001) were classified correctly as either functionally impaired or intact. We propose a definition of HD dementia that includes demonstrable evidence of impairment in speed of processing and a deficit in one additional area of cognition (e.g., abstract reasoning, memory, visuospatial ability) in the context of impaired functional abilities and a deteriorating course.
Searching for Biomarkers in Huntington's Disease Using a Proteomic Analysis of Cerebrospinal Fluid and Plasma
B.R. Leavitt,1 R.A. Lindner,2 J. Decolongon,1 C. Remediakis,2 S. Prasad,2 L. Sebastian,2 R. Olsson,2 M. McKay,2 M. Wetterhall,2 S. Hunt,2 T. Goodall,2 N. Wilson,2 J. Harry.21The Centre for Molecular Medicine and Therapeutics, BC Research Institute for Children's and Women's Health, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; 2Proteome Systems Ltd., North Ryde, NSW, Australia.
Successful identification of biomarkers in Huntington's disease (HD) will have multiple applications in understanding the natural history of HD, in performing clinical drug trials, and in identifying pathogenic processes in this disease. Our hypothesis is that changes in protein expression in the plasma and cerebrospinal fluid (CSF) of HD patients occur during disease progression and differ from the protein expression in healthy control subjects. In the first phase of a rigorous study to identify biomarkers for HD, we have carried out comprehensive proteomic analyses of plasma and CSF from 14 subjects (4 gene negative controls, 5 early stage, and 5 mid-stage HD). This involved depletion of abundant proteins and fractionation to maximize the likelihood of detection of differentially expressed proteins using 2D SDS PAGE and mass spectrometry. Univariate statistical analysis of proteomic data for CSF and plasma identified a number of protein isoforms that showed strong trends of differential expression between non-HD controls and increasing severity of HD (P < 0.05). These protein isoform changes may represent useful biomarkers for HD disease progression. Validated biomarkers in HD will provide more specificity and sensitivity for early efficacy in therapeutic trials, thereby reducing the cost and time for drug development. In the clinical setting, presymptomatic biomarkers could enable early therapeutic intervention and will allow us to follow the progression of HD from its earliest stages. Ultimately, the identification of protein alterations in HD could lead to new insights into pathogenic mechanisms and to the identification of new drug targets.
Neuronal Intranuclear Inclusions Do Not Cause Transcriptional Dysregulation in Huntington's Disease
G. Sadri-Vakili, G.J. Yohrling, A.S. Menon, L.A. Farrell, C.E. Keller-McGandy, D.G. Standaert, S.J. Augood, J.-H.J. Cha. MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
Neuronal intranuclear inclusions (NII) are protein aggregates consisting of ubiquitin, Htt, and other proteins and have been found in transgenic mice as well as in human HD brain. One possible mechanism by which mutant Htt disrupts transcription is by sequestering transcription factors into NII. Other studies have found inclusions to be protective against in vitro toxicity in cultured neurons transfected with mutant Htt. If NII are indeed pathogenic, one would predict that striatal neurons with NII would have more evidence of transcriptional dysregulation than would NII-negative neurons. To evaluate this possibility, we combined ubiquitin immunohistochemistry to identify NII-positive striatal neurons, along with radioactive in situ hybridization to measure mRNA. Using emulsion autoradiography, we saw that R6/2 striatal neurons had decreased expression of preproenkephalin (PPE) mRNA, irrespective of the presence of NII. We have also used laser capture microdissection (LCM) to harvest NII-positive and NII-negative neurons from R6/2 mouse striatum. In LCM-harvested neurons, there were no differences in mRNA levels encoding NMDA-NR1. In contrast, striatal neurons from R6/2 striatum had decreased mRNA levels of genes known to be downregulated in R6/2 striatum: PPE, dopamine D2 receptor (D2), and presomatostatin (PSS). There was no difference in D2, PPE, and PSS mRNA levels between NII-positive and NII-negative R6/2 neurons. These results suggest that there is no causal relationship between NII and transcriptional dysregulation. [Supported by the National Institutes of Health (NS045242, NS038106), the Huntington's Disease Society of America Coalition for the Cure, the Hereditary Disease Foundation, HighQ, and the Glendorn Foundation.]
Ropinirole Improves Sleep in Patients With RLS: Results From a Large Clinical Development Program
R. Bogan,1 D. Garcia-Borreguero,2 E. Monaghan.31SleepMed of South Carolina, Columbia, SC, USA; 2Sleep Disorders Center, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain; 3GlaxoSmithKline, Research Triangle Park, NC, USA.
The alleviation of restless legs syndrome (RLS) symptoms may reduce sleep problems and improve patients' ability to rest. The changes in subjective sleep quality and quantity during treatment with ropinirole in patients (18–79 years) with moderate-to-severe primary RLS were evaluated in a pooled analysis of four 12-week, double-blind phase-III trials (RESET PLM, TREAT RLS 1 and 2, and TREAT RLS US; protocols: 101468/191, 190, 194, and 249). Ropinirole or matched placebo, taken once daily 1 to 3 hours before bedtime, was titrated from 0.25 mg up to a maximum of 4.0 mg/day. Changes from Baseline to Week 12 (Last Observation Carried Forward) and adjusted mean treatment differences (AMTD) were derived for the Medical Outcomes Study Sleep Scale domains of Sleep Disturbance, Daytime Somnolence, Sleep Adequacy, Sleep Quantity, and a nine-item Sleep Problems Index. Baseline characteristics of the ropinirole (n = 466) and placebo (n = 470) groups were similar. There were significantly greater improvements with ropinirole compared with that for placebo in scores for sleep disturbance (−24.0 vs. −14.0; AMTD: −10.0; 95% CI: −12.9, −7.1; P < 0.001), daytime somnolence (−12.2 vs. −7.8; AMTD: −4.4; 95% CI: −6.7, −2.2; P < 0.001]), and the Sleep Problems Index (−18.2 vs. −9.9; AMTD: −8.3; 95% CI: −10.6, −6.0; P < 0.001). Additionally, sleep adequacy (18.4 vs. 6.7; AMTD: 11.8; 95% CI: 8.5, 15.1; P < 0.001) and sleep quantity (0.7 vs. 0.3 hours; AMTD: 0.5 hours; 95% CI: 0.3, 0.7; P < 0.001) were significantly increased with ropinirole compared with placebo. Ropinirole significantly improved all assessed sleep parameters in patients with RLS.
A11 Lesion and Iron Deprivation Induced Abnormal Behaviors Resembling Clinical Features of Restless Legs Syndrome
W.D. Le, S. Qu, X. Zhang, W. Ondo. Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
Restless legs syndrome (RLS) is a common neurological condition possibly precipitated by CNS iron deregulation and dopaminergic diencephalic spinal neurons (A11) dysfunction. We carried out stereotaxic bilateral 6-hydroxydopamine (6-OHDA) lesions into the A11 nucleus of C57BL/6 mice and deprived a subset from dietary iron to observe whether these manipulations can induce animal behavioral changes that mimic clinical RLS. Pathologic examination demonstrated a 94% reduction in Al1 tyrosine hydroxylase-staining cells in mice injected with 6-OHDA. Iron levels in serum, brain, and spinal cord were decreased significantly after 2-month iron deprivation. Locomotor activity was increased significantly in mice that received iron deprivation or A11 lesion, whereas a combination of iron deprivation and A11 lesion further augmented the behavioral abnormality. In addition, the mice in the lesioned group were more aggressive and pugnacious. The increased activity in A11 lesion mice with or without iron deprivation was normalized after treatment with the D2/D3 agonist ropinirole, as is seen in human RLS, but was worsened by the D1 agonist SKF38393. The D2 antagonist haloperidol also worsened locomotor activity. This result suggests iron deprivation alone can increase baseline movement, but it is significantly augmented with 6-OHDA lesions in A11 dopaminergic neurons. Our results suggest that this model is consistent with human RLS in as much as an animal model can replicate a largely subjective condition, and that this could be used for therapeutic trials. [Supported by GSK, Inc.]
The Tolerability and Efficacy of Sodium Oxybate (Xyrem®) as a Treatment for Ethanol-Responsive, Medication-Refractory Myoclonus and Essential Tremor (ET)
S.J. Frucht,1 W.C. Houghton,2 Y. Bordelon,3 E.D. Louis,1 P.E. Greene.11Columbia University Medical Center, New York, NY; 2Jazz Pharmaceuticals, Palo Alto, CA; 3University of California Los Angeles Medical Center, Los Angeles, CA, USA.
Methods: Twenty patients with ethanol-responsive, medication-refractory myoclonus (6 posthypoxic, 3 myoclonus-dystonia, 2 Ramsay-Hunt) or ET (9 patients) enrolled in an open-label, dose-escalation, add-on, tolerability, and efficacy study of sodium oxybate, starting at 1 gm TID, titrating by 0.5-gm dose increments to tolerability or efficacy, with a maximum dose of 3 gm TID. Videotaped serial examinations using the Unified Myoclonus Rating Scale or Washington Heights Inwood Genetic Study of ET Rating Scale were randomized and rated blind to patient status. Paired t-tests were carried out. Results: Twelve men and eight women enrolled (mean age, 43.9 years [myoclonus], and 71.2 years [ET]). Mean kinetic tremor score in ET improved from 15.4 to 9.1 (range 0–40; P = 0.006) and postural tremor score improved from 2.4 to 1.4 (range 0–8, P = 0.006). Myoclonus at rest improved from 7.4 to 3.6 (range 0–108; P = 0.047), stimulus-sensitive myoclonus 5.8 to 2.8 (range 0–17; P = 0.001), action myoclonus 45.3 to 30.9 (range 0–160; P = 0.005), and functional performance 12.9 to 7.3 (range 0–28; P < 0.001). Average daily doses were 6.5 gm (myoclonus) and 4.3 gm (ET). Mild, transient side effects included dizziness (35%), headache (20%), emotionality (20%), and nausea (10%). Sedation (55%) or ataxia (20%) limited dose titration, resolving with reduction in dose to the previous level. Fifteen patients chose to continue the drug after trial completion. Conclusion: Sodium oxybate was effective, with acceptable tolerability, in 20 patients with treatment-refractory myoclonus and ET. Videotaped examples pre- and post-treatment will be presented. Double-blind, placebo-controlled, multicenter trials in ethanol-responsive myoclonus and ET are warranted.
Olfaction in Twins Discordant for Essential Tremor
A.R. Chade, S.M. Goldman, M. Kasten, G. Bhudhikanok, A. Gupta, C.M. Tanner. The Parkinson's Institute, Sunnyvale, CA, USA.
Background: Reduced olfaction is an early sign of Parkinson's disease (PD). Studies regarding the relationship between olfactory deficits and essential tremor (ET), however, have yielded conflicting results [Louis ED, Neurology 2002; 59:1631–1633; Shah M, Mov Disord 2005;20(Suppl. 10): S166]. Objectives: To determine whether smell identification ability is reduced in ET patients ascertained during a twin-based study of PD. Methods: Olfactory function was tested using the 40-odorant University of Pennsylvania Smell Identification Test (UPSIT) in selected members of the NAS/NRC World War II Veterans Twin Cohort born between 1917 and 1927. ET was diagnosed by consensus using modified TRIG criteria. All subjects were cognitively normal. Twins with ET were compared with neurologically normal twins, twins with PD, and published age-specific normal values. Results: The UPSIT was completed by 18 twins with ET, 51 with PD, and 24 with no neurological disease (“normal”). Mean UPSIT scores were similar in ET (32.0, SD 5.0; range 22–39) and normal twins (30.6, SD 8.1; range 6–38). ET twins had significantly higher mean UPSIT scores than did twins with PD (24.0, SD 8.9; range 7–37; P = 0.001) and published normal values (25.8; P = 0.004). Conclusions: In this study, smell identification was not reduced in twins with ET compared with neurologically normal twins or normative published data. Interestingly, because all ET patients had a twin brother with PD, one might anticipate a greater tendency toward impaired olfaction but we did not observe this. Results of this small sample should be interpreted cautiously.
Altered Mesolimbocortical and Thalamic D2 Receptor Binding in Tourette Syndrome: A Study With [F-18]fallypride PET
D.L. Gilbert,1 B.T. Christian,2 M.J. Gelfand,3 J. Mantil,2 F.R. Sallee.41Movement Disorder Clinic, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 2Department of Nuclear Medicine/PET, Kettering Medical Center, Dayton, OH; 3Department of Nuclear Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 4Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA.
Background: Tics in Tourette syndrome (TS) are often performed compulsively in response to sensory urges. Mesolimbocortical dopaminergic dysfunction has been implicated in neuropsychiatric disorders in which sensorimotor gating is impaired and aberrant behavior patterns are compulsive or disinhibited. Objective: To compare dopamine 2 (D2) receptor availability in non-striatal structures critical for sensorimotor gating and motivation in adults with TS versus healthy controls. Methods: Dynamic positron emission tomography (PET) scans were carried out in 6 adults with TS (mean age, 30.5 years) and 6 age-matched controls (mean age, 30.2 years) using [F-18]fallypride, a radiotracer that visualizes D2-like receptors in both striatal and extrastriatal areas. PET data analysis employed the distribution volume ratio method (DVR) as an index of D2 receptor binding. The cerebellum was used as a reference region. DVR parametric images were transformed into Montreal Neurological Institute (MNI) space and regions of interest of the mesolimbic structures were applied based on a predefined atlas template. Differences in [F-18]fallypride binding between groups were assessed with a two-sided Mann–Whitney U test. Results: Subjects with TS had significantly lower [F-18]fallypride binding in hippocampus (Z = −2.1, P = 0.037), orbitofrontal cortex (Z = −2.9, P = 0.004), and mediodorsal nucleus of thalamus (Z = −2.4, P = 0.016). No non-striatal regions were identified with significantly greater [F-18]fallypride binding. Conclusions: These findings suggest that reduced D2 receptor availability in mesolimbocortical systems and thalamus may contribute to impaired sensory gating and increased motivational salience of tics and other compulsive behaviors in TS.
Essential Tremor Pathology: A Case-Control Study From the Essential Tremor Centralized Brain Repository
E.D. Louis,1 J.P.G. Vonsattel,1 L.S. Hong,1 G.W. Ross,2 K.E. Lyons,3 R. Pahwa,31Columbia University, New York, NY; 2VA Pacific Islands Health Care System, Honolulu, HI; 3University of Kansas, Kansas City, KS, USA.
Background: Essential tremor (ET) is one of the most common neurological diseases, yet there have been few postmortems and no controlled studies. The pathology remains elusive. The Essential Tremor Centralized Brain Respository (ETCBR) is a collaborative effort between investigators at several medical centers; archival and prospectively collected postmortem brains have been obtained. Objectives: To examine the pathology of ET. Methods: There were 10 clinically diagnosed ET cases (age 86.3 ± 4.9 years, duration 27.2 ± 23.5 years) and 12 controls (age 83.4 ± 8.8 years). Sections of paraffin-embedded brain tissue were examined by one blinded neuropathologist. Results: Six (60%) ET cases had Lewy bodies (ET+LB), four of whom had an atypical and restricted distribution of brainstem Lewy bodies (locus ceruleus greatly in excess of dorsal vagal nucleus) and two with a Lewy body distribution typical of Parkinson's disease. The four (40%) remaining cases had mild degenerative cerebellar changes (ET+CP), including increased numbers of torpedoes (17.5 ± 6.1 [ET+CP], 5.1 ± 4.7 [ET+LB), 1.6 ± 1.4 [controls], test for trend P < 0.001), and Bergmann glia (100.0 ± 34.7 [ET+CP], 89.2 ± 54.3 [ET+LB], 59.5 ± 29.1 [controls], test for trend P = 0.048). Numbers of Purkinje cells were similar in cases and controls. Conclusions: There were identifiable pathological findings that distinguished ET cases from controls. Cases could be separated into two groups: those with brainstem Lewy bodies and those with mild cerebellar degenerative changes. These results expand the clinical spectrum of Lewy body disease and suggest that ET may be pathologically heterogeneous.
Posters will be staffed from Noon to 1:30 PM in Marriott Hall 3.
Poster 1 (OMD)
Ropinirole Treatment of RLS Gives Rapid Improvement in Clinician-Rated Global Symptoms: Results From an Extensive Clinical Trial Program
R. Allen,1 C. Trenkwalder,2 N. Earl.31Neurology and Sleep Medicine, Johns Hopkins University, Baltimore, MD, USA; 2Center of Parkinsonism and Movement Disorders, Paracelsus-Elena-Klinik, Universität Göttingen, Kassel, Germany; 3GlaxoSmithKline, Research Triangle Park, NC, USA.
Restless legs syndrome (RLS) can be a major cause of chronic sleep disturbance and reduction in quality of life; therefore, rapid symptom relief is important. The effects of ropinirole on clinician-rated RLS symptoms were evaluated in a pooled analysis of four double-blind phase-III trials (RESET PLM, TREAT RLS 1, TREAT RLS 2, and TREAT RLS US; protocols: 101468/191, 190, 194, and 249). Patients (18–79 years) with moderate-to-severe primary RLS were sorted randomly (1:1) to ropinirole or placebo for 12 weeks. Ropinirole, 1 to 3 hours before bedtime, was titrated from 0.25 up to a maximum of 4.0 mg/day. Efficacy endpoints included the proportion of responders (score of “much improved” or “very much improved” on the Clinical Global Impression-Improvement scale) at each visit. Adverse event (AE) data were collected throughout the study. The four studies included 953 patients. The proportion of responders at Weeks 1 to 12 ranged from 39% to 71% in the ropinirole group compared with19% to 54% with placebo. Adjusted odds ratios were significantly in favor of ropinirole at each visit from Week 1 last observation carried forward (LOCF; 2.8 [95% CI: 2.1, 3.8; P < 0.001]) through Week 12 LOCF (2.0 [95% CI: 1.5, 2.6; P < 0.001]). Ropinirole was generally well tolerated; the most common AEs were nausea, headache, and somnolence. Clinician-rated global RLS symptom relief with ropinirole occurred within Week 1 of treatment, with separation from placebo continuing through Week 12. Rapid onset of improvement that is sustained will enhance the management of RLS.
Poster 2 (PD)
A Controlled Pilot Study of the Effects of Neuromuscular Therapy in Patients with Parkinson's Disease
L.H. Craig,1 A. Svircev,1,2 M. Haber,2 J.L. Juncos.31Atlanta School of Massage, Atlanta, GA; 2Department of Biostatistics, Emory University Rollins School of Public Health, Atlanta, GA; 3Movement Disorders Program, Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
Objectives: To examine the effects of neuromuscular therapy (NMT) on motor and non-motor symptoms in Parkinson's disease (PD). Methods: Thirty-six subjects with PD were sorted randomly to NMT or music relaxation (MR or active control). Subjects received treatment twice a week for 4 weeks. Testing was conducted at baseline, after final treatment, and 8 days after final treatment. Primary outcome measures included the motor subscale of the United Parkinson's Disease Rating Scale (UPDRS) and the Clinical Global Impression Scale (CGI-Change). Secondary outcome measures included a PD-specific quality of life scale (QOL), quantitative measures of motor function, and scales for anxiety and depression symptoms. Results: NMT resulted in a significant and sustained improvement in the motor subscale of the UPDRS (P < 0.0001) most notable in the tremor scores. Also improved were the CGI scores (P < 0.0001) and the tapping speed (P = 0.003). The MR group had a slight improvement in tremor but evidenced no other change in motor function. Both groups exhibited a modest but comparable improvement in QOL. The MR group evidenced improvements in mood (P = 0.01) and anxiety (P = 0.01), whereas NMT had no effect on mood and its effect on anxiety (P = 0.005) dissipated after 8 days. Conclusion: The findings suggest that NMT can improve motor and selected non-motor symptoms in PD, and that this effect is more durable for the motor symptoms. The results of this pilot study warrant larger studies to examine dose range, durability and mechanisms of NMT on PD function.
Poster 3 (OMD)
No Evidence for Cognitive Decline or Depression in Patients With RLS: A Case–Control Study
E. Driver-Dunckley,1 C.H. Adler,1 J.N. Caviness,1 M. Sabbagh,2 D. Connor,2 N. Silverberg,2 J.G. Hentz,1 J. Hernandez,1 V.G.H. Evidente,1 H. Shill.31Mayo Clinic, Scottsdale, AZ; 2Sun Health Research Institute, Phoenix, AZ; 3Barrow Neurological Institute, Phoenix, AZ, USA.
Objective: Case–control study comparing neuropsychometric test results for individuals with restless legs syndrome (RLS) to controls. Background: RLS is a movement disorder that causes discomfort, impairs sleep, and reduces quality of life. Whether there is an association between RLS and either depression or cognitive functioning has not been well studied. Design/Methods: We matched individuals, 29 with RLS and 29 controls, for age (±2 years), gender (5 males/24 females per group), and education (±3 years) that are enrolled in our Brain Donor Program. The RLS cases and controls had no history of or examination findings suggestive of any other movement disorders (Parkinson's disease, tremor, etc.). RLS subjects and controls were excluded if they had a history of another neurological disorder (stroke, brain tumor) or history of a psychiatric disorder (bipolar, major depression). All subjects were examined by both a movement disorders neurologist and behavioral neurologist and had neuropsychometric testing. Results: There was less than 1% difference in mean age (75 years) or education (16 years) between groups. The mean (±SD) RLS rating scale score for the RLS cases was 8.1 ± 6.2. The Folstein MMSE was 29 in both groups. Other tests that showed no significant difference between groups included the AVLT total learning, AVLT delayed recall, digits forward (simple attention), digits backward (working memory), Trails A and B, Stroop, Controlled Oral Word Association total, animal fluency, and Judgment of Line Orientation. The Geriatric Depression Scale (GDS) means differed by only 1 point on a 0 to 30-point scale (2.9 controls, 3.9 RLS cases; 95% CI = −1 to 3) and there was no correlation between RLS score and GDS score (r = −0.04; 95% CI = −0.4 to 0.4). Conclusions: The findings in this preliminary study suggest that individuals suffering from RLS do not have a decrease in cognitive functioning and are not depressed compared with an age-, gender-, and education-matched group of neurologically normal individuals. [Funded by the Mayo Foundation for Medical Research and Education, Sun Health Research Institute, Federal Grant NS40669, and the Arizona Alzheimer's Disease Research Center contract 4001 (Arizona Parkinson's Disease Center).]
Poster 4 (PD)
Classification and Measurement of Speed and Amplitude Impairments in Patients With Parkinson's Disease: A Pilot Study
A.J. Espay,1 D.E. Beaton,2 A. Maetzel,3 F. Morgante,1 R. Chen.11Toronto Western Hospital, Toronto, ON; 2St. Michael's Hospital, Toronto, ON; 3Toronto General Research Institute, Toronto, ON, Canada.
Slowness of movement (“bradykinesia”) is the most important deficit in Parkinson's disease (PD). Current clinical rating of bradykinesia in PD, as measured by several items of the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRSm), does not separate the dimensions of slowness and amplitude reduction. Recent studies and clinical observations suggest that impairments in speed and amplitude may differentially contribute to the motor impairment of this disorder. We categorized patterns of movement in PD patients on a biaxial classification of speed and amplitude recording a standardized finger-tapping task with an electromagnetic tracking device (Polhemus). We sought to determine whether these categories differentially contribute to motor impairment and disability. Motor impairment was worst in patients with very impaired amplitude and best in patients with normal amplitude. Categories of speed impairment did not show a similar relationship. The Schwab and England disability scale decreased with higher severity levels of the amplitude category but not of speed. The timed tasks, Purdue pegboard and tapping apparatus mirrored the impairment levels in speed but did not parallel the impairment levels of amplitude. Agreement (unweighted κ) between clinician and Polhemus-derived speed-amplitude classification were moderate for speed and amplitude classifications, possibly due to the prevalence-dependent liability of κ (“paradox of κ”). Our observations suggest that amplitude and speed impairments might behave differentially in PD and both may deserve consideration in a biaxial classification system for bradykinesia.
Poster 5 (OMD)
Factors Associated With Decreased Quality of Life in Patients With Dystonia
H.H. Fernandez, P. Seignourel, V. Gosein, C.E. Jacobson, IV, S.K. Munson, J. Romrell, R.L. Rodriguez, K.D. Foote, M.S. Okun. Department of Neurology, University of Florida/McKnight Brain Institute, Gainesville, FL, USA.
Background: Little is known about the factors associated with decreased quality of life among patients with dystonia. Method: To determine the factors associated with increased disability in dystonic patients, we analyzed the Physical and Mental Composite scores of the RAND 36-item Health Survey (SF-36) and correlated them with the age, gender, region (craniocervical, upper and lower extremity, trunk), total motor Unified Dystonia Rating Scale (UDRS) scores, and the Visual Analog Mood Scale (VAMS) scores. Results: Sixty-four patients with dystonia (35 women, 29 men; 5 generalized, 3 hemi-dystonia, 18 segmental, and 38 focal) followed at the UF Movement Disorders Center had a mean age of 55.6 years (SD 18.6). Regarding overall physical disability, the SF-36 Physical Composite score was correlated only with the VAMS items “energetic” (r = 0.47; P ≤ 0.0001) and “tired” (r = −0.51; P < 0.001), but not with any regional or total UDRS motor scores, age, gender, or the other items in the VAMS. Regarding overall mental disability, the VAMS items on “afraid” (r = −0.31; P < 0.05), “confused” (r = −0.31; P < 0.05), “sad” (r = −0.51; P < 0.001), “angry” (r = −0.29; P < 0.05), “tired” (r = −0.27; P < 0.05), “happy” (r = 0.31; P < 0.05), and “tense” (r = −0.28; P < 0.05) were correlated with the SF-36 Mentation Composite Score. On regression analysis, after controlling for age, gender, and total UDRS score, the VAMS item “tired” remained significantly related to the SF-36 Physical Composite score (incremental R2 = 0.29, β = −0.55, t = −4.56, P < 0.001) and to the SF-36 Mentation Composite score (incremental R2 = 0.19, β = −0.45, t = −3.39, P < 0.01). Conclusion: In this cohort of dystonic patients, lack of energy/tiredness was the strongest predictor of decreased physical quality of life, whereas confusion, depression, lack of energy and anxiety were associated with decreased mental quality of life.
Poster 6 (PD)
Severity of Depression Parallels Cognitive Dysfunction in Parkinson's Disease
H.H. Fernandez, G.P. Crucian, P. Seignourel, L.N. Williams, B.D. Riggeal, C.E. Jacobson, IV, S.K. Munson, J. Romrell, R.L. Rodriguez, K.D. Foote, M.S. Okun. Department of Neurology, University of Florida/McKnight Brain Institute, Gainesville, FL, USA.
Background: Depression is the most common psychological disturbance in Parkinson's disease (PD), and may be reversibly treated. Likewise, emerging data suggest that dementia, affecting 30 to 40% of PD patients, may be alleviated by cognition-enhancing agents. Some studies find depression as a risk factor for dementia in PD. Method: To determine whether the severity of depressive symptoms was associated with cognitive decline, we correlated the 21-item Beck Depression Inventory (BDI) scores to the Mini-Mental State Examination (MMSE) and total Dementia Rating Scale (DRS) scores of random PD patients followed at the UF Movement Disorders Center. SPSS software was used for all statistical analyses. Results: Eighty-two PD patients (58 men, 24 women) had a mean age of 67.7 years (SD 9.96), mean formal education of 14.8 years (SD 3.46), mean PD duration of 101 months (SD 72.97), UPDRS-motor score of 36.96 (SD 12.31), MMSE score of 27.8 (SD 2.31; range 19–30), and BDI score of 10.23 (SD 8.65). The BDI scores did not correlate with disease duration or total motor UPDRS scores in the off state, but inversely correlated with the MMSE scores (r = −0.40; P < 0.001) and total DRS scores (r = −0.33; P < 0.01). After controlling for age, gender, education, and total UPDRS score on regression analysis, BDI scores had a significant and unique relationship with MMSE score (incremental R2 = 0.10; β = −0.38; t = −3.55; P < 0.01), and DRS Total Score (incremental R2 = 0.050; β = −0.33; t = −3.01; P < 0.01). Conclusion: In this PD cohort, the severity of depression parallels cognitive decline. It remains unclear whether depression actually influences the course of cognitive decline or is simply a risk factor for dementia. Larger epidemiological studies are needed to answer these questions.
Poster 7 (PD)
Laterality, Location, Type and Severity of Motor Dysfunction May Predict Cognitive Decline in Parkinson's Disease
H.H. Fernandez, G.P. Crucian, P. Seignourel, L.N. Williams, B.D. Riggeal, C.E. Jacobson, IV, S.K. Munson, J. Romrell, R.L. Rodriguez, M.S. Okun. Department of Neurology, University of Florida/McKnight Brain Institute, Gainesville, FL, USA.
Background: Approximately 30% to 40% of PD patients become demented. We recently reported that cognitive decline parallels motor progression in PD. We now attempt to define aspects of motor dysfunction that correlate best with cognitive decline. Method: We compared neuropsychological profiles (including MMSE and Dementia Rating Scale [DRS]) of PD patients, followed at UF Movement Disorders Center, to their off UPDRS-motor subscores. Result: One hundred six PD patients (76 men, 30 women) had a mean age of 67.1 years (SD 10.52), an average formal education of 14.8 years (SD 3.38), with a mean disease duration of 110.4 months (SD 74.43) and average UPDRS motor score of 38.4 (SD 13.5). Correlations between UPDRS motor subsets and the MMSE/DRS are itemized in Table 1. After controlling for age, gender, and education, UPDRS total (minus tremor) was significantly related to MMSE score (incremental R2 = 0.092, β = −0.31, t = −3.23, P < 0.01), and DRS total score (incremental R2 = 0.104, β = −0.33, t = −3.45, P < 0.01). Conclusions: In this cohort, the severity of motor symptoms paralleled cognitive dysfunction. Bradykinesia and postural/gait dysfunction were most correlated with cognitive function whereas tremor was not. Axial signs seemed more correlated than did appendicular signs; parkinsonism on the right side correlated more with cognitive function than did the left side. Disease duration was not related to cognitive functioning.
|UPDRS subset||MMSE||Total DRS|
|Total motor score||−0.32||<0.001||−0.31||<0.01|
|Total motor score minus tremor items||−0.34||<0.001||−0.34||<0.001|
Poster 8 (OMD)
A Randomized, Double-Blind, Placebo-Controlled, Staggered Withdrawal Study in Patients With Huntington's Disease Treated With Tetrabenazine
S. Frank,1 W. Ondo,2 C. Hunter,2 F. Marshall,3 F. Walker,4 S. Eberly,3 S. Factor,5 S. Fahn,6 V. Hunt,4 D. Oakes,3 S. Plumb,3 A. Shinaman,3 I Shoulson,3 H. Zhao,3 J. Jankovic.21Boston University, Boston, MA; 2Baylor College of Medicine, Houston, TX; 3University of Rochester, Rochester, NY; 4Wake Forest, University College of Medicine, Winston-Salem, NC; 5Emory University, Atlanta, GA; 6Columbia University, New York, NY, USA.
Background: Tetrabenazine (TBZ) is a dopamine-depleting agent used to treat chorea associated with Huntington's disease (HD). This study assessed TBZ efficacy by evaluating the change in chorea resulting from TBZ withdrawal in chronically treated patients. Methods: Thirty HD subjects clinically responsive to TBZ were sorted randomly into one of three groups for this 5-day study: 12 subjects stopped TBZ on Day 1 (withdrawal group), 12 on Day 3 (partial withdrawal group), and 6 subjects continued on TBZ (non-withdrawal group). Subjects were withdrawn in a double-blind fashion by replacing TBZ with placebo tablets. The primary outcome measure was the difference between the Unified Huntington Disease Rating Scale (UHDRS) chorea score on Day 1 and Day 3. Results: The three groups were generally comparable on baseline characteristics, but the non-withdrawal group had a worse baseline total UHDRS motor score (P = 0.0016) without a significantly worse chorea score. Baseline chorea scores ranged from 2 to 25. No serious adverse events were reported after abrupt withdrawal of TBZ. Adjusted mean chorea scores for subjects withdrawn on Day 1 increased by 5.3 units, whereas those remaining on TBZ increased by 3.0 units (P = 0.0773). A post-hoc analysis of the linear trend was positive for re-emergent chorea (P = 0.0486). Conclusions: The trend for re-emergence of chorea in HD patients withdrawn from TBZ is consistent with our previous studies showing the effectiveness of TBZ in reducing chorea [Parkinson Study Group, Mov Disord 2004;19:1122]. Further studies are required to characterize the magnitude and timeframe for the re-emergence of chorea after TBZ withdrawal.
Poster 9 (PD)
Treatment of “Delayed” Runaway Dyskinesia Following Fetal Transplantation for Parkinson's Disease
J. Graff-Radford,1 K.D. Foote,1 R.L. Rodriguez,1 R.A. Hauser,2 H.H. Fernandez,1 M.S. Okun.11University of Florida, Gainesville, FL; 2University of South Florida, Tampa, FL, USA.
Objective: To describe a patient treated successfully for runaway dyskinesia following fetal transplant for treatment of Parkinson's disease. Background: At least five open label and two NIH sponsored double-blind intracerebral transplants of fetal mesencephalon studies have been published. Graft induced dyskinesias in the off state have been reported frequently in the double-blind, and rarely in open label studies. There are only a few reports of the successful treatment of patients with this side effect. Methods: Review of a case of fetal transplantation referred for management to the movement disorder center at University of Florida. Results: A patient was referred for evaluation of intractable right arm dyskinesia. The patient had received fetal transplants in 1993 as part of the Hauser open label study. On–off UPDRS testing revealed the dyskinesia was present when evaluating the patient in a 12-hour off medication condition. The dyskinesia was characterized as a groping movement of his right hand, which was so severe the friction of the movement resulted in large holes through his right upper pants leg. The dyskinesia had become severe over the 3 years before presentation. Deep brain stimulation of the globus pallidus resulted in resolution of the runaway dyskinesia. Of note in this case was the delayed development of a runaway dyskinesia that seemed to develop after his last study visit. This side effect was not observed 24 months after transplant surgery in their 1999 long-term follow-up. Conclusion: Runaway dyskinesia may be a delayed manifestation of fetal transplants for Parkinson's disease, and may be treated by globus pallidus DBS.
Poster 10 (OMD)
Functional MRI in Writer's Cramp
V.K. Hinson,1,2 D.J. Vincent,1–3 M.W. Hurd,3,4 R.H. Floyd,5 K. Bergmann.11Department of Neurosciences, Medical University of South Carolina (MUSC), Charleston, SC; 2Murray Center for Research on Parkinson's Disease and Related Disorders, MUSC, Charleston, SC; 3Department of Radiology, MUSC, Charleston, SC; 4Department of Psychology, College of Charleston, Charleston, SC; 5Department of Medicine, MUSC, Charleston, SC, USA.
Objective: To examine brain activation in writer's cramp (WC) using BOLD functional MRI (fMRI). Background: WC is a type of idiopathic focal dystonia with incompletely understood pathophysiology. Although the basal ganglia are thought to play a role in the pathogenesis, recent investigations suggest cortical sensorimotor abnormalities. Methods: Three subjects with WC and three age- and gender-matched controls (right handed, age 49–57 years) were studied. Two self-paced motor tasks alternating with rest were carried out in a block design. The tasks were loop writing and random finger tapping. Structural T1 images and two functional T2 image sequences were acquired at 1.5T. Results: Structural MRIs were normal in all subjects. The writing task induced dystonia in all WC patients. Group analysis of dystonia patients compared with control subjects for BOLD activation was carried out. During the writing task, increased activation was observed in the left dorsal prefrontal cortex (DPFC) and right parietal association cortex. Decreased activation was observed in the left primary motor cortex and the cerebellum. During the tapping task, increased activation in the left DPFC was observed as well as decreased activation in the left primary motor cortex and cerebellum without parietal overactivation. Conclusion: Brain activation patterns are different in patients with WC compared with that in matched controls during writing and a non-specific motor task that does not elicit dystonia. Decreased primary motor cortex and cerebellar activation suggest an abnormality in the motor executive system, whereas the parietal overactivation during writing may represent a change in movement strategy or impaired sensory integration.
Poster 11 (OMD)
Behavioral Symptoms in Huntington's Disease: A Retrospective Chart Review Study
J.A. Jaglin, K.M. Shannon, J. Wuu, S. Leurgans. Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
Objective: To assess the presence and clinical correlates of irritability, apathy, and aggression in Huntington's disease (HD) patients by chart review. Background: Behavioral abnormalities occur in 98% of HD patients, but their clinical correlates are not well reported. We carried out chart reviews of prospectively collected measures of behavior and function in HD. Design/Methods: The Unified Huntington's Disease Rating Scale (UHDRS) and Total Functional Capacity (TFC) are routinely assessed among patients attending our subspecialty HD clinic and caregivers are asked to rate behavioral changes using validated irritability and apathy [Burns et al., J Nerv Ment Dis 1990;178:20–26] and aggression [Yudofsky et al., Am J Psychiatry 1986;143:35–39] scales. We reviewed charts in our HD data repository and abstracted the following data: demographics, UHDRS motor/behavioral subscales, TFC, and presence of dementia and depression. Interrelationships between irritability, apathy, and aggression were assessed by Spearman rank correlations. Relationships between these behaviors and clinical variables were analyzed using Spearman rank correlations or Wilcoxon rank-sum tests. Results: Patients were 34 moderately impaired HD patients (21 men, 13 women; mean age 48.6 years, range 20–68 years; mean disease duration 6.1 years, range 1–17 years). Most took medications for behavioral control (antidepressants 65%, neuroleptics 32%, anxiolytics 21%); 50% were demented; 35% were depressed; 71% had irritability; 56% had apathy; and 56% had aggression. Irritability and aggression were positively correlated (P < 0.0001). Apathy was more severe in patients with lower TFC (P = 0.0034). Conclusions: Caregivers report apathy, irritability, or aggression in most HD patients. Apathy correlates with disease severity, although irritability and aggression do not. Symptoms may not be addressed adequately by currently used medication.
Poster 12 (PD)
Protective Effect of the HFE C282Y Mutation in Parkinson's Disease
H.M. Kim,1 A. Samii,1,2 A. Griffith,3 J.W. Roberts,4 A.D. Mosley,3 B.C. Leis,3 D. Yearout,1,5 H. Payami,6 C.P. Zabetian.1,51Neurology, University of Washington, Seattle, WA; 2Northwest Parkinson's Disease Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA; 3Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, WA; 4Neurology, Virginia Mason Medical Center, Seattle, WA; 5Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA; 6Wadsworth Center, New York State Department of Health, Albany, NY, USA.
Background: Oxidative stress may play an important role in neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease. Free iron can mediate oxidative damage and increased levels of iron are found within the substantia nigra in PD. Homozygosity for the C282Y variant of the hemochromatosis (HFE) gene results in iron overload in many tissues and provides an interesting model for studying the role of CNS iron homeostasis in PD. Methods: We genotyped C282Y in DNA samples from 946 PD patients and 910 matched controls using the TaqMan 5′ exonuclease assay. All PD cases met standardized diagnostic criteria as determined by a movement disorder specialist. Results: Both control and PD groups were in Hardy–Weinberg Equilibrium. We observed a significant underrepresentation of the 282Y allele in the PD versus the control group (OR, 0.73; 95% CI, 0.56–0.96; P = 0.022). Conclusions: Our results suggest a seemingly paradoxical protective effect for the 282Y allele in PD, and are in agreement with the results of a previous study in a large Australian PD cohort.
Poster 13 (PD)
Tremor as a Sign of Neurotoxicity in Welders: The Bay Bridge Cohort
W.C. Koller,1 R. Bowler,2 D. Mergler,3 H. Roels.41University of North Carolina, Chapel Hill, NC, USA; 2San Francisco State University, San Francisco, CA, USA; 3UQAN, Montreal, QC, Canada; 4Katholieke Universiteit Leuven, Leuven, Belgium.
Background: Manganese (Mn) exposure is known to cause neurological dysfunction such as parkinsonism. There is debate, however, if welding using Mn rods is associated with neurological signs. Objective: We examined a cohort of welders who had a high exposure to manganese for signs of a movement disorder. Methods: Forty-nine welders (82% of the total bridge welders; 45 males, 4 females; average age 43.9 years), who had 15.5 months of unprotected exposure of Mn fumes while working on the Bay Bridge in confined, non-ventilated spaces, were evaluated by the UPDRS motor scale and an objective measure of tremor (kinesimeter). Results: Tremors, sleep disturbances, and fatigue were frequent complaints. Mean Mn levels were elevated (9.6 μg/l, range 5.1–14.2 μg/l; normal range less than 10.0 μg/l); 55% (27/49) had a postural and/or kinetic tremor of mild to moderate severity on clinical examination and 73.8% (36/49) had tremor by the graphometer. Tremor could not be explained by drug use or a comorbid condition. No rest tremor was observed and bradykinesia and rigidity occurred infrequently. There were no other neurological signs. Conclusion: An action tremor is a common sign of manganese neurotoxicity and may represent an early manifestation of neurological dysfunction in welders.
Poster 14 (OMD)
Is Focal Task-Specific Dystonia Limited to the Hand and Face?
S.E. Lo, S.J. Frucht. Neurological Institute, Columbia University Medical Center, New York, NY, USA.
Focal task-specific dystonia (FTSD) of the hand (e.g., writer's cramp, musician's cramp) and face (e.g., idiopathic lower cranial dystonia, embouchure dystonia) have been well described; however, FTSD of the leg is exceedingly rare. We describe the clinical features and demonstrate by videotape 2 unusual patients with FTSD affecting the leg. In each case, movements were triggered specifically by the act of walking down steps. The first patient is a 25-year-old man and the second a 40-year old woman. Family history was negative for dystonia, and neither patient had been exposed to dopamine-receptor blocking agents. Aside from dystonia, neurological examination and imaging studies were normal. Both patients exhibited a similar, complex proximal movement of the right leg, selectively triggered only by walking down steps. Muscles involved included the iliopsoas, hamstrings, and gastrocnemius. Walking and running on level ground, rapid foot taps, walking up steps, and walking down steps sideways or backwards did not trigger dystonic movements. When patients imagined they were walking upstairs or backwards while walking downstairs, dystonic movements were partially alleviated. Treatment with trihexyphenidyl (both cases) and EMG-guided botulinum toxin injection (second patient) was unsuccessful. FTSD of the hand and face is thought to be linked to the performance of skilled activities, requiring concentrated attention and sustained practice over years. Our patients demonstrate that FTSD may also affect a body part and an activity that is subconscious, and perhaps even automatic.
Poster 15 (PD)
Lipoic Acid for Fatigue in PD: A Double-Blind, Placebo-Controlled Pilot Study
J.S. Lou, B. Coakley, A. Reeves, T. Benice, R. Eaton, B. Oken, D. Kramer, C. Morris, J. Nutt. Oregon Health and Science University, Portland, OR, USA.
Objective: To investigate if LA is effective in reducing physical fatigue and mental fatigue in PD. Background: Lipoic acid (LA), an antioxidant, is a commonly used dietary supplement. PD patients reported more physical fatigue and mental fatigue than normal controls do. Studies have demonstrated that LA improves motor and cognitive function in animals. LA may reduce physical and mental fatigue in PD subjects by improving their motor and cognitive function. Design/Methods: Fifteen PD subjects were randomly assigned to the treatment group (6 subjects; mean age 65.3 ± 7.1 years) or placebo group (9 subjects; mean age 59.8 ± 11.2 years). The disease severity was not different between the two groups. Each subject took LA 600 mg TID or placebo for 12 weeks. The primary outcome measure included the Multidimensional Fatigue Inventory (MFI), which measured five dimensions of fatigue (general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity) and finger tapping. The secondary outcome measure included The Center of Epidemiological Study-Depression Scale (CES-D), the Epworth Sleepiness Scale (ESS), Tower of London (TOL), and Paced Auditory Serial Addition Task (PASAT). We used repeated measures ANOVA to analyze the data obtained before and after LA or placebo. Results: The effects of LA were not different from those of placebo on the scores of the physical fatigue (before and after LA, 10.2 ± 4.6 vs. 12.2 ± 5.7; placebo, 9.7 ± 4.4 vs. 12.6 ± 5.1) or mental fatigue (before and after LA, 13.7 ± 2.6 vs. 13.2 ± 2.5; placebo, 10.4 ± 3.4 vs. 10.9 ± 4.2) in the MFI, finger tapping, ESS, CES-D, TOL, or PASAT. Conclusions: This small double-blind, placebo-controlled study demonstrated that LA at a dose of 1,800 mg per day did not improve physical fatigue or mental fatigue in PD subjects. [Supported by The Oregon Center for Complementary and Alternative Medicine in Neurological Disorders (ORCCAMIND); The National Institutes of Health supports ORCCAMIND (NIH-NCCAM P50 AT00066).]
Poster 16 (PD)
A Comparison of Mood Profiles Across Parkinson's Disease, Essential Tremor, and Dystonia Patients
K.M. Miller, D. Bowers, H.H. Fernandez, C. Jacobson, K.D. Foote, M.S. Okun. University of Florida, Gainesville, FL, USA.
Background: The present study sought to determine whether patients with Parkinson's disease (PD) display higher levels of depressed-mood symptoms on the Beck Depression Inventory (BDI) and Visual Analog Mood Scales (VAMS) compared with patients with essential tremor (ET) and dystonia. Accumulating evidence suggests that depression in PD may be secondary to the underlying neuroanatomical degeneration, rather than simply a reaction to psychosocial stress and disability. Whereas previous studies have compared depression symptoms among PD patients and other disabled populations and reported higher levels of depression symptoms in PD, these studies have not compared PD patients to other movement-disorders groups. We hypothesized that if depression symptoms in PD are a direct result of affected neural circuitry, PD patients would endorse more depression symptoms on the BDI than dystonia and ET patients as well as higher levels of Sadness, Tiredness, Tension, Fear, and Anger, and lower levels of Energy and Happiness on the VAMS. Methods: Three hundred fifty-one PD patients, 59 ET patients, and 90 dystonia patients were administered the VAMS and BDI. Results: No significant between-groups difference was found on the BDI, even when covarying for age, education, and symptom duration. On the VAMS, PD patients endorsed significantly more Sadness and Tiredness than did ET patients only. Conclusions: Further studies comparing mood symptoms in PD patients and other movement-disorders groups are needed, as our results suggests that PD patients do not display higher levels of depressed-mood symptoms. This result supports the notion that non-motor circuitry in PD is similarly affected in dystonia and ET.
Poster 17 (OMD)
Unilateral Cortical Stimulation in Essential Tremor
R. Pahwa,1 S.B. Wilkinson,2 K.E. Lyons.11University of Kansas Medical Center, Kansas City, KS; 2Independence Regional Medical Center, Independence, MO, USA.
Objective: To evaluate the effectiveness of motor cortex stimulation for essential tremor (ET). Background: Cortical stimulation is relatively non-invasive and has been reported to be effective in PD. The investigational device is implanted under general anesthesia with no contact between the electrode and brain tissue. Methods: Two ET patients with disabling hand tremor underwent unilateral cortical stimulation. At baseline, both patients were assessed with the Fahn-Tolosa-Marin tremor rating scale (TRS). A two-element strip electrode was implanted on the dura over the contralateral primary motor hand cortex. Using standard tunneling procedures, the electrode was connected to a subclavicularly implanted pulse generator (IPG). One week after surgery, IPGs were programmed to provide stimulation without causing adverse effects. One month after surgery, the TRS was repeated with the device activated. Results: Patient I was a 75-year-old male with tremor for 20 years. His baseline total TRS score was 61 and his TRS 1 month after surgery was 57. His IPG was set at 30 Hz, 3 mA, and 250-μsec pulse width. Patient II was a 60-year-old male with tremor for 8 years. His baseline total TRS was 47 and it was 43 1 month after surgery. His IPG was set at 50 Hz, 5 mA, and 250-μsec pulse width. There were no adverse effects. Conclusions: Unilateral cortical stimulation of the primary hand motor cortex was ineffective for the treatment of ET using these stimulation parameters. Future research examining other stimulation parameters is necessary to understand fully the role of cortical stimulation for ET. [Funded by Northstar Neuroscience, Inc.]
Poster 18 (PD)
Different Involvement of the Basal Ganglia and Cerebellar Pathways in Self-Paced and Externally Triggered Movements
J. Purzner,1,2 G. Paradiso,1,2 D. Cunic,1,2 J.A. Saint-Cyr,1–3 T. Hoque,1–3 A.M. Lozano,1–3 E. Moro,1,2,4 A.E. Lang,1,2,4 R. Chen.1,2,41The Krembil Neuroscience Centre, Toronto, ON; 2Toronto Western Research Institute, Toronto, ON; 3Division of Neurosurgery, University of Toronto, Toronto, ON; 4Division of Neurology, University of Toronto, Toronto, ON, Canada.
We compared the involvement of the basal ganglia-thalamocortical and cerebello-thalamocortical circuits in different types of movement preparation. Local field potentials were recorded from deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN) of 7 patients with Parkinson's disease and ventral intermediate nucleus of the thalamus (VIM, cerebellar thalamus) in 5 patients with tremor, with EEG simultaneously recorded from scalp electrodes during self-paced and externally cued (“ready,” “go”/“no-go”) movements. The trials for each patient were back averaged from EMG onset for self-paced movement and from the ready signal for externally cued movement to reveal potentials that were time and phase locked to movement. During self-paced movement a pre-movement related potential (pMRP) was observed from cortical, STN, and VIM electrodes in all patients. The onset time for the pMPR recorded from the STN (−2,299 ± 762 msec) and the cortex (−2,067 ± 585 msec) were not different. The onset of the VIM pMPR (−1,494 ± 811 msec), however, occurred later than did both cortical and STN potentials. During externally cued movements, a slow potential similar to the contingent negative variation was observed after the ready signal in cortical and STN electrodes but not consistently in the VIM electrodes. The contact with maximum amplitude or phase reversal was localized within the STN or VIM using postsurgical MRI verification. These findings suggest the basal ganglia circuit is involved in preparation for both cued and self-paced movements whereas the cerebellar pathway is involved mainly in the preparation of self-paced movement.
Poster 19 (OMD)
Dystonia and Tremor Associated With a Duplication in the Chromosome 1q32-q42 Region
R.L. Rodriguez, H.H. Fernandez, M.S. Okun. University of Florida, Movement Disorders Center, Gainesville, FL, USA.
Background: Several movement disorders have been associated with genetic abnormalities of chromosome 1, including several of the PARK mutations. Duplication of chromosome 1q32-42 is a rare genetic anomaly with only very few reported cases in the literature. It is characterized by prominent and wide forehead, midface hypoplasia, and psychomotor retardation. We report on the case of a patient with a chromosome 1q32-q42 duplication who presented with a movement disorder. Case Report: A 16-year-old Hispanic man presented with slowly progressive bilateral upper extremity tremor for 1 year. The tremors were most pronounced while pouring liquids and with handwriting. Prenatal and perinatal history was normal. He had a history of surgical correction of left eye ptosis. There was a delay in developmental milestones during infancy and early childhood, although at presentation he was in 11th grade with satisfactory performance. On general examination it was noted that he had low-set ears and prominent forehead. On neurological examination, he had dystonic posturing of both hands associated with a postural-intention tremor more pronounced on the right. There was no rigidity, bradykinesia, or postural instability. Brain imaging, metabolic, and Wilson's disease screens were normal. Karyotype analysis revealed a chromosome 1q32-q42 duplication. Treatment with trihexyphenidyl 2 mg twice daily provided significant improvement of his dystonia and tremors. Conclusion: Multiple movement disorders are associated with genetic abnormalities in chromosome 1 including parkinsonism, dystonia, and choreoathetosis. This is to our knowledge the first reported case of tremor and dystonia associated with duplication of chromosome 1q32-q42.
Poster 20 (OMD)
Cerebellar Outflow Tremor Treated Successfully With Surgical Resection of a Pineal Region Tumor
R.L. Rodriguez, E. Dunbar, H.H. Fernandez, A.A. Smith, K.D. Foote, M.S. Okun. University of Florida, Movement Disorders Center, Gainesville, FL, USA.
Background: Cerebellar outflow tremor (COT) may occur as a result of lesions or disruptions in the cerebello-thalamo-cortical loop, particularly in the area of the brainstem. The severity of the tremor can be associated with marked disability, and treatment is frequently unsuccessful. There are a handful of cases of compressive brainstem lesions resulting in COT. We report a case of complete abolition of COT after a pineal tumor resection. Case Report: An 18-year-old man presented with a 2-month history of altered mental status, headaches, nausea, vomiting, and blurred vision. He developed a tremor in the left upper extremity that occurred with rest, posture, and action. On examination, he was lethargic. During arousal, a low-frequency resting tremor was observed in the left upper extremity that worsened with posture and intention. Associated signs and symptoms included paresis of vertical gaze, fixed pupils (partial Parinaud's syndrome), and mild weakness of the right upper extremity. Brain MRI revealed a large pineal gland mass with associated mass effect on the midbrain and thalamus. Surgical resection of the tumor was carried out after unsuccessful radiotherapy and chemotherapy and there was a subsequent resolution of tremor a few weeks after surgical resection. Pathology revealed a non-germinomatous germ cell tumor. Conclusion: Rapid surgical resection should be considered in cases of COT associated with tremor. More study will be required to evaluate the importance of rapid decompression in these cases.
Poster 21 (PD)
Regulation of DNA Repair in the MPTP Mouse Model of Parkinson's Disease
V. Sava, A. Velazquez, S. Song, J. Sanchez-Ramos. University of South Florida and James Haley VA Hospital, Tampa, FL, USA.
Oxidative DNA damage, and its repair by enzymes such as 8-oxoguanosine DNA glycosylase (OGG1), has been implicated in the pathogenesis of PD. Steady-state levels of oxidative DNA damage, indicated by measures of 8-hydroxy-2′ deoxyguanosine (8-oxodG) are increased in the substantia nigra (SN), basal ganglia and cortex of PD cases [Sanchez-Ramos, Neurodegeneration (Exp Neurol) 1994;3:197–204]. Recently, the expression of mitochondrial isoforms of OGG1 enzymes were found to be increased in SN in cases with short duration of PD and decreased in those cases with long duration of disease [Fukae et al., Acta Neuropathol (Berl) 2005;109:256–262]. Study of the regulation of OGG1 in mouse brain might shed light on vulnerability of nigral neurons. Mice exhibit an age-dependent accumulation of 8-oxodG in midbrain, striatum, and cerebellum; levels of 8-oxodG were associated with a decline in spontaneous locomotor activity and balance. OGG1 activity can be upregulated in vitro and in vivo in mouse brain by agents that increase oxidative stress; the extent of DNA repair activity is proportional to cellular survival [Cardozo-Pelaez et al., Free Radic Biol Med 2002;33:292–298; Sava et al., Free Radic Biol Med 2004;36:1144–1154]. In the present report, we will describe results from study of the temporal course of the DNA repair response across 44 brain regions of mouse treated with a single dose of MPTP. All regions across the brain upregulated OGG1 activity immediately, but SN and striatum were unable to maintain OGG1 repair beyond 72 hours. In summary, regulation of DNA repair in postmitotic cells is a critical determinant of cellular vulnerability to oxidative stress.
Poster 22 (OMD)
Ropinirole Improves Restless Legs Syndrome (RLS) Symptoms at Starting Dose: Results From TREAT RLS US
K. Sethi,1 S.W. Carson.21Medical College of Georgia, Augusta, GA; 2GlaxoSmithKline, Research Triangle Park, NC, USA.
Restless legs syndrome (RLS) is a chronic neurological disorder characterized by a compelling urge to move the legs, accompanied or caused by sensations often described as creeping/crawling, tingling, burning, or pulling. The urge to move occurs primarily in the evening and at rest, and is relieved temporarily by movement. In large double-blind, placebo-controlled trials (TREAT RLS 1, TREAT RLS 2, and TREAT RLS US; protocols: 101468/190, 194, and 249), ropinirole demonstrated significant efficacy compared with placebo at Week 12. Because patients with RLS often have sleep disturbances and may have impairment of daily activities due to their symptoms, early relief of symptoms is a clinically relevant goal. Here we report the temporal course of improvement with ropinirole. In TREAT RLS US, patients with moderate-to-severe primary RLS were assigned randomly to ropinirole (n = 187) or placebo (n = 193) in a 12-week trial. Ropinirole was flexibly titrated as needed and tolerated from 0.25 mg to a maximum of 4.0 mg once daily. Efficacy was assessed using the International Restless Legs Scale (IRLS) at Day 3 and Weeks 1, 2, 3, 4, 5, 6, 8, and 12. Compared with placebo, ropinirole significantly improved IRLS scores at every measurement beginning at Day 3 (adjusted mean treatment difference [AMTD]: −2.2 points, 95% CI: −3.6, −0.7; P < 0.003 post-hoc) and Week 1 (AMTD: −4.1, 95% CI: −5.6, −2.7; P < 0.0001) through Week 12 (AMTD: −3.7; 95% CI: −5.4,−2.0; P < 0.0001). Ropinirole significantly improved symptoms of RLS at every time point measured. Patients with moderate-to-severe RLS obtained initial clinically relevant relief at starting doses of ropinirole.
Poster 23 (PD)
The Perception of Heaviness in Patients with Parkinson's Disease
P.J. Tuite,1 K. Krawczewski,2 K.A. Pickett,2 S. Majestic,1 M. Maschke,3 J. Konczak.11Department of Neurology, University of Minnesota, Minneapolis, MN, USA; 2Department of Kinesiology, University of Minnesota, Minneapolis, MN, USA; 3Department of Neurology, University of Essen, Essen, Germany.
This study examined perception of heaviness in patients with Parkinson's disease (PD). The ability to detect and discriminate between loads is related to the perception of weight and is mediated by haptic information (pressure) and proprioception. Eleven patients with mild/moderate PD and 15 age-matched healthy controls participated. Subjects had to indicate when they detected a load force that pulled on their index finger. We monitored finger extensor EMG and recorded finger position with an electrogoniometer. Patients with substantial finger tremor were excluded from the study. PD patients showed largely elevated detection thresholds of 51.1 g on their affected side and 48.6 g on their less-affected side. In contrast, healthy controls had a significantly lower threshold of 32.5 g. Increasing pressure by decreasing the surface area on the finger over which the load was applied decreased the threshold for the patients' affected side. It had no significant effect on thresholds of the controls. We conclude that weight perception is significantly impaired already in the early stages of PD. In conjunction with our recent study [Maschke et al., Brain 2003;126:2312–2322] that demonstrated an impaired limb position sense in PD, the results of the current study underline growing evidence that proprioceptive, and possibly haptic, dysfunction is a common feature of PD.
Poster 24 (PD)
A Lipophilic Metalloporphyrin Catalytic Antioxidant Ameliorates MPTP Neurotoxicity
M. Patel,1 L.-P. Liang,1 B.J. Day.21University of Colorado Health Sciences Center, Denver, CO; 2National Jewish Medical and Research Center, Denver, CO, USA.
Parkinson's disease (PD) is an age-related neurodegenerative disease in which the role of free radicals is strongly implicated. Scavenging reactive oxygen species (ROS) is an important therapeutic avenue for the treatment of PD. Manganic porphyrins are a class of catalytic antioxidants that scavenge a wide range of reactive oxygen species. We have previously demonstrated the neuroprotective effects of manganic porphyrins in vitro and in vivo. Recently, the glyoxylate series of metalloporphyrins have been developed that have superior potencies as inhibitors of lipid peroxidation and high lipid solubility allowing these compounds to better penetrate the blood brain barrier (BBB). We tested the effects of a prototypical glyoxylate manganic porphyrin (AEOL 11207) in the mouse MPTP model of Parkinsonism. Groups of adult mice were administered MPTP (15 mg/kg s.c., 3 times in 24-hour intervals) with or without Aeol 11207 (5, 10, 15, 25 mg/kg s.c.). AEOL 11207 was administered 1 hour prior to the first dose of MPTP and daily thereafter until day 5. Neurotoxicity was assessed by measurement of striatal dopamine levels one week after the first dose of MPTP. AEOL 11207 inhibited MPTP-induced striatal dopamine depletion in a dose-dependent manner (one-ANOVA, P < 0.001, n = 6–12 mice/group). Neuroprotection correlated with AEOL 11207 concentrations in the brain measured by HPLC-EC. To confirm if antioxidant properties underlie protection by Aeol 11207, we further characterized the effects of AEOL 11207 in rat brain mitochondria. AEOL 11207 inhibited both aconitase inactivation and H2O2 production in isolated mitochondria. Together, these data suggest that AEOL 11207 scavenges MPP+-induced mitochondrial ROS production, penetrates the BBB and attenuates MPTP neurotoxicity in vivo.