SEARCH

SEARCH BY CITATION

Keywords:

  • 5-I-A-85380-SPECT;
  • α4β2 nicotinic acetylcholine receptors;
  • cognitive deficits;
  • Parkinson's disease

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of interest
  9. References

Background

Idiopathic Parkinson's disease (IPD) is characterized by the clinical motor symptoms of hypokinesia, rigidity, and tremor. Apart from these motor symptoms, cognitive deficits often occur in IPD. The positive effect of cholinesterase inhibitors on cognitive deficits in IPD and findings of earlier molecular imaging studies suggest that the cholinergic system plays an important role in the origin of cognitive decline in IPD.

Methods

Twenty-five non-demented patients with IPD underwent a 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) SPECT to visualize α4β2 nicotinic acetylcholine receptors (nAchR) and cognitive testing with the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) battery to identify domains of cognitive dysfunction.

Results

In the CERAD, the IPD patients exhibited deficits in non-verbal memory, attention, psychomotor velocity, visuoconstructive ability, and executive functions. After Bonferroni correction for multiple comparisons, we found significant correlations between performance of the CERAD subtests Boston Naming Test (a specific test for visual perception and for detection of word-finding difficulties) and Word List Intrusions (a specific test for learning capacity and memory for language information) vs binding of α4β2 nAchR in cortical (the right superior parietal lobule) and subcortical areas (the left thalamus, the left posterior subcortical region, and the right posterior subcortical region).

Conclusions

These significant correlations between the results of the CERAD subtests and the cerebral α4β2 nAchR density, as assessed by 5-I-A-85380 SPECT, indicate that cerebral cholinergic pathways are relevant to cognitive processing in IPD.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of interest
  9. References

Idiopathic Parkinson's disease (IPD) is defined by the clinical motor symptoms of hypokinesia, rigidity, and tremor, which are mainly caused by a dopaminergic nigrostriatal deficit and are improved by dopaminergic, anticholinergic or NMDA receptor blocking drugs. A considerable percentage of patients with IPD develop cognitive deficits resulting in mild cognitive impairment or dementia in the later stages of the disease [1]. Cognitive deficits in IPD respond poorly to treatment with dopaminergic or NMDA receptor blocking agents and even deteriorate during treatment with anticholinergic drugs. These pharmacological differences between motor symptoms and cognitive symptoms in IPD indicate that the cognitive deficits in IPD are, in contrast to the motor symptoms, not related in a simple manner with the nigrostriatal dopaminergic degeneration. Concurring with this, neuropathological studies have revealed that the characteristic Lewy body degeneration in IPD involves further transmitter systems – for example, the serotonergic, noradrenergic, and cholinergic transmitter system – besides the dopaminergic system [2]. A recent detailed review [3] underlines that IPD is more a systemic disease involving multiple neurotransmitter systems and pervasive deficits in cortical perfusion and metabolism. As cognitive deficits in IPD respond well to cholinesterase inhibitors [1], the cholinergic transmitter system seems to play a substantial role for cognition in IPD.

5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) has been used for fifteen years to assess the density of cerebral α4β2 nicotinic acetylcholine receptors (nAchR) in healthy volunteers [4-6] and in patients [7-9] using single-photon emission computed tomography (SPECT). 5-I-A-85380 binds with high affinity to the α4β2 subtype of nAchR which is most abundant in the thalamus, but is found at moderately high concentrations throughout the cerebral cortex [10]. Two post-mortem studies have shown reduced 5-I-A-85380 binding among other things in the striatum [11, 12] and in the thalamus in IPD [12].

Of the several molecular imaging studies investigating α4β2 receptor binding in IPD, all have revealed deficits, especially in the pons [7, 13], midbrain [8, 13], striatum [7, 8], thalamus [7], anterior cingulate cortex [13], frontal and frontoparietal cortex [9, 13], and cerebellum [13]. Meyer et al. [13] found a correlation between cerebral binding of 2-[18F]-A-85380 and cognitive functions which were measured by means of the Mini-Mental State Examination (MMSE), the DemTect Scale, the Clock Drawing Test, the part V (delayed recall of figures) of the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) [14] battery, and the Trail Making Test. So far, no study has correlated the cerebral α4β2 nAchR density with single cognitive functions, evaluated by the CERAD, in IPD.

In the present study, we performed 5-I-A-85380 SPECT in non-demented IPD patients and correlated the cerebral α4β2 nAchR binding with cognitive functions in IPD, which were quantified by the CERAD testing. This study did not include a control group because (i) there exist already 5-I-A-85380 SPECT studies [4-7] in healthy volunteers, (ii) a widespread reduced density of cerebral α4β2 nAchR in IPD is already known as mentioned above[7-9, 13], and (iii) we were primarily interested in the correlation between single cognitive functions and cerebral α4β2 nAchR density in IPD.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of interest
  9. References

Subjects

The study involved 25 patients with idiopathic Parkinson's disease (IPD; age: 51–75 years, mean ± SD: 64 ± 7 years, 12 women, 13 men). Four patients were at Hoehn and Yahr (H&Y) stage 1, 13 at H&Y stage 2, and eight at H&Y stage 3. No patient was at H&Y stage 4 or 5. Concerning the predominant motor type, 13 patients belonged to the akinetic-rigid type, five patients to the tremor-dominant type, and seven patients to the equivalence type. The motor deficits of the patients reached 9–51 points (23 ± 9 points, mean ± SD) in the motor part of the UPDRS score during an ‘off’ phase (12 h off drugs; cabergoline, pergolide, and prolonged formulations of ropinirole and pramipexole were discontinued at 72 h prior to the SPECT). The L-dopa equivalent daily dose (LEDD) was 100–1280 mg/day (563 ± 339 mg/day, mean ± SD). The duration of Parkinson's disease amounted to 3–17 years (7.7 ± 3.7 years, mean ± SD).

All patients had to fulfill three inclusion criteria prior to enter this study: (i) have a diagnosis of IPD according to the criteria of the UK Parkinson's Disease Society Brain Bank [15], (ii) have a normal cranial magnetic resonance imaging, and (iii) be aged 50–75 years old. We used an upper age limit of 75 years because the frequency of vascular or neurodegenerative lesions (unrelated to IPD), which may interfere with cerebral nicotinic binding, increases exponentially with age. The size of the study group was based upon a power analysis, with the assumption of a correlation coefficient r = 0.5, an error of 1st degree = 0.05, and an error of 2nd degree = 0.20. No healthy controls were included in the study.

Patients were excluded from the study if they were taking cholinergic or anticholinergic drugs. Further exclusion criteria were pregnancy or breastfeeding, a partner who was capable of childbearing, smoking in the last five years, actual or previous cerebral disease (except IPD), psychiatric disease, or severe internal disease. Apart from cholinergic or anticholinergic drugs, other antiparkinsonian medication was to be continued (‘on’ state) during the CERAD testing, as most previous studies had not shown a significant effect of dopaminergic treatment on cognitive functions in IPD [16-18].

The study protocol was approved by the Ethics Committee of the University of Würzburg, Germany, and by the German Federal Office for Radiation Protection (Bundesamt für Strahlenschutz, Salzgitter, Germany). All participants gave written informed consent prior to enter this study.

5-I-A-85380 SPECT imaging

Preparation and radiolabeling of 5-I-A-85380 was performed in house in the radiopharmaceutical facilities of the Department of Nuclear Medicine of the University of Wuerzburg under GMP (good manufacturing practice) conditions. The radiosynthesis provided 5-I-A-85380 in form of a carrier-free radiotracer with a highest possible specific activity. The specific activity – as determined from the ultraviolet absorbance at 254 nm – exceeded 125 GBq/μmol (the detection limit of our system).

Patients fasted at least 4 h before 5-I-A-85380 administration. Possible iodine uptake by the thyroid was blocked by oral medication with sodium perchlorate (Irenat®; Bayer, Leverkusen, Germany). Patients received 185 MBq of freshly prepared 5-I-A-85380 intravenously. The approximate administrated mass of an injectable solution with 185 MBq of 5-I-A-85380 was <0.001 nmol.

Cerebral SPECT imaging was acquired with a dual-head rotating gamma camera (E. Cam Duet, Siemens Medical Solutions; Hoffman Estates, Illinois, USA) equipped with medium energy collimators. At 4 h after injection of the radiotracer, one hundred and twenty 40 s views were acquired over a 360° circular orbit into a 128 × 128 matrix with a pixel size of 3.9 mm. Imaging at 4 h after injection was chosen in accordance with previous kinetic modeling data in healthy volunteers (Mamede et al. 2004, Fujita et al. 2003) and for practical reasons concerning scanning the patients. Images were reconstructed with filtered back-projection with a Butterworth filter (order 8, cutoff 0.4) followed by attenuation correction according to the Chang method [19], with an attenuation coefficient of 0.11/cm to generate the transversal slices. The resulting spacing between slices was 3.9 mm.

For further data analysis, the reconstructed transverse sections were transferred to a Hermes workstation (Hermes Medical Solutions, Stockholm, Sweden). Brain regions were analyzed using the brain analysis program BRASS (version 3.5; Hermes Medical Solutions). Each image volume was recorded to match to the built-in ECD template using an affine transform (nine parameters). Manual fitting was necessary, because of the low background uptake resulting in insufficient contrast for delineating the brain contour.

The ECD template consisted of a three-dimensional region of interest (ROI) map of 46 predefined brain regions. The mean count per voxel was determined for each region in both hemispheres. To compensate for intersubject variability in global tracer uptake, the ratio of mean count per voxel to mean count per voxel of the global 5-I-A-85380 brain uptake (=average of all 46 measured brain regions) was calculated for each region and each subject, resulting in intensity-normalized data.

CERAD testing

The initial version of CERAD, the CERAD-NP test, was developed by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) [14]. The CERAD-NP test was developed in the English language, but a German language version (the CERAD Plus test) [20] was subsequently developed and validated at the Memory Clinic of the University hospital of Basel (Switzerland). All patients in our study underwent the CERAD Plus test. We did not evaluate the Mini-Mental State Examination (MMSE), the Trail Making Test A and the Trail Making Test B due to the following reasons: In contrast to all other CERAD subtests, the MMSE does not examine one or few specific cognitive domains – as it was the goal of this study – but represents a general screening test for cognitive functions. The Trail Making Test A and B – valuable tests in the examination in patients with Alzheimer's disease – can be influenced by motor slowness and tremor in IPD patients and do therefore not allow an exact evaluation of cognitive functions in IPD patients. The remaining applied subtests concern single cognitive functions and are explained in detail below:

Verbal Fluency: The subject must name as many animals as possible within 1 min and is awarded one point for each animal. This subtest examines verbal velocity and capacity, semantic memory, speech, executive function, and cognitive flexibility.

Modified Boston Naming Test: 15 drawings of daily objects are shown, which the subject must name within 10 s. The maximum score is 15 points (one point for each correctly named drawing). This subtest examines visual perception and reveals word-finding difficulties.

Word List (Learning, Recall, Intrusions, Saving, and Recognition): In the first step (Word List Learning), ten words are read out to the subject, who must memorize them and directly reproduce the words within 90 s. This procedure is repeated three times with the same words but with the word order changed (up to 3 × 10 points). The percentage of words remembered in the three runs altogether is defined as Word List Saving. After an interval, in which another subtest is performed, the same words are asked again (Word List Recall; up to ten points). The term Word List Intrusions denotes wrongly remembered words which are produced by the subject although they have not been read out by the examiner. In a further step, 20 words, the ten words from the first step (old words) and ten new words, are read out to the subject. The subject has to identify the ten old words (up to ten points) and the ten new words (also up to ten points, Word List Recognition). The subtest Word List examines learning capacity and memory for language information.

Figure Drawing: The subject must draw four figures of increasing difficulty (up to eleven points depending on the accuracy of the drawn figure). This subtest examines visuoconstructive ability. After an interval, in which two other subtests are performed, all four figures must be drawn from memory (Figure Recall, up to eleven points). The percentage of figures remembered is defined as Figure Saving. These Figure Recall/Figure Saving subtests investigate non-verbal memory.

Phonemic Fluency ‘s’-words: Subjects must say as many words as possible beginning with the consonant ‘s’ within 1 min. For each word, the subject gets one point. This subtest examines strategy-oriented verbal fluency.

The results of the individual subtests can be expressed in two ways: as an absolute value (=raw value) or as a relative value. The absolute value gives the number of points that were obtained in a subtest. The performance (=absolute value) of each patient in each subtest was standardized according to a normal population of the same age, sex, and educational standard, resulting in a relative value. The relative value is expressed as standard deviations of the mean value of the normal population. For example, a relative value of +1.0 (standard deviations) means that the individual subject is better than 68% of the healthy volunteers of the same age, sex, and educational standard. A relative value of −2.0 (standard deviations) means that the individual subject is worse than 95% of the control group, etc. The CERAD testing was performed by a neurologist who was blinded to the results of the 5-I-A-85380 SPECT.

Statistical analysis

Descriptive data are given as mean and standard deviation (SD). Correlations were calculated using Pearsons's correlation coefficient for normally distributed data. In the case of not normally distributed data, we used the Spearman's correlation coefficient. As correlation coefficients were calculated from the same data, we performed Bonferroni correction for multiple comparisons: In a first step, we correlated the 15 subtests of the CERAD testing with 5-I-A-85380 accumulation in all studied 46 brain regions resulting in 15 × 46 = 690 correlation coefficients. In a second step, we identified the brain regions and the CERAD subtests with the highest correlation coefficients with the intention of reducing the number of correlation coefficients. Then, the P value was compared with the Bonferroni-corrected significance level as quotient 0.05/number of calculated correlations. A correlation coefficient was considered to be significant, if its P value was smaller than the Bonferroni-corrected significance level.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of interest
  9. References

Performance of the CERAD testing

Over all 25 patients, there was no significant correlation between the performance of any CERAD subtest and the duration of Parkinson's disease (P > 0.05; Pearsons's correlation coefficient) or the Levodopa equivalent daily dose. Mean results of the CERAD testing for the 25 investigated IPD patients were within the range of scores for matched subjects in the subscores Verbal Fluency, Modified Boston Naming Test, Word List Learning, Word List Recall, Word List Intrusions, Word List Saving, Word List Recognition, Figure Drawing, and Phonemic Fluency ‘s’ words (Table 1). All the subtests resulting in normal performance studied verbal functions; the only subtest investigating a non-verbal function being Figure Drawing.

Table 1. Performance (raw values) in the single CERAD subtests over all 25 patients
CERAD SubtestMean ± SDMedianRange (Min./Max.)
  1. Mean ± SD = mean ± standard deviation of the absolute test values (raw values) of all 25 patients in the according subtest; Min/Max = minimal number/maximal number of reached points.

Verbal Fluency (points)21 ± 62211/39
Modified Boston Naming Test (points)14 ± 2149/15
Word List Learning (points)20 ± 42113/26
Word List Recall (points)7 ± 273/10
Word List Intrusions (points)1 ± 200/9
Word List Saving (%)89 ± 178860/100
Word List Recognition (%)96 ± 59580/100
Figure Drawing (points)10 ± 1117/11
Figure Recall (points)8 ± 394/11
Figure Saving (%)78 ± 228240/100
Phonemic Fluency s-words (points)15 ± 6144/27

Performance was impaired, compared with a normal population, in the subtests Figure Recall and Figure Saving. These both subtests examined non-verbal functions, namely non-verbal memory and visuoconstructive ability. In no subtest were the 25 IPD patients clearly better (=have significantly better scores) than the reference values for healthy controls.

Density of cerebral α4β2 nicotinic acetylcholine receptors (nAchR)

The most intense accumulation of 5-I-A-85380 was detected in both thalami, pons and midbrain, and both nuclei lentiformes (Fig. 1, Table 2). We found no correlation between the 5-I-A-85380 uptake into any studied brain region vs the age of the patients, the duration of Parkinson's disease or the LEDD (P > 0.05; Pearsons's correlation coefficient).

Table 2. Summary of intensity-normalized 5-I-A-85380 uptake values obtained from the region of interest in the SPECT imaging 4 h after injection
ROI, unpaired brain regionsVoxels of the ROI5-I-A-85380 uptake Mean ± SD
Pons and midbrain6841.347 ± 0.117
Other subcortical region2141.061 ± 0.088
ROI, paired brain regionLeft brain hemisphereRight brain hemisphereRight vs Left
Voxels of the ROI5-I-A-85380 uptake Mean ± SDVoxels of the ROI5-I-A-85380 uptake Mean ± SDSide-to-side difference?
  1. ROI = region of interest; ctx = cortex. All significant P values are written in bold-faced.

Cerebellar cortex12851.039 ± 0.07412851.037 ± 0.075n.s.
Cerebellar white matter2031.166 ± 0.1072031.194 ± 0.119 P  = 0.0222
Nucleus lentiformis1921.343 ± 0.1261921.355 ± 0.135n.s.
Nucleus caudatus1260.910 ± 0.1651260.897 ± 0.176n.s.
Thalamus2001.753 ± 0.2222001.714 ± 0.250n.s.
Sensorimotor cortex18231.075 ± 0.06518231.032 ± 0.063 P  = 0.0042
Occipital cortex17090.892 ± 0.05517090.867 ± 0.051 P  = 0.0004
Superior parietal lobe5810.929 ± 0.0885810.887 ± 0.095 P  = 0.0017
Anterior dorsal frontal ctx5790.864 ± 0.0735790.867 ± 0.071n.s.
Posterior dorsal frontal ctx8180.982 ± 0.0678180.979 ± 0.066n.s.
Anterior orbital frontal ctx4960.797 ± 0.1304960.788 ± 0.125n.s.
Posterior orbital cortex3570.824 ± 0.0903570.822 ± 0.104n.s.
Parietotemporal cortex12081.003 ± 0.04412080.934 ± 0.051 P  < 0.0001
Medial temporal lobule2810.978 ± 0.1182810.957 ± 0.148n.s.
Lateral temporal lobule7590.953 ± 0.0437590.922 ± 0.062n.s.
Posterior temporal lobule4861.171 ± 0.0924861.101 ± 0.082 P  = 0.0010
Temporal pole2860.718 ± 0.0582860.698 ± 0.066n.s.
Insular cortex2681.117 ± 0.0822681.126 ± 0.099n.s.
Anterior gyrus cinguli3540.838 ± 0.0783540.840 ± 0.083n.s.
Posterior gyrus cinguli2370.987 ± 0.0862370.964 ± 0.084 P  = 0.0382
Anterior subcortical region6920.978 ± 0.0846920.981 ± 0.088n.s.
Posterior subcortical region14201.137 ± 0.08114201.096 ± 0.075 P  = 0.0012
image

Figure 1. Typical example of transverse section images in the level of the striatum from the same patient with 5-I-A-85380-SPECT (A), image fusion (B), and magnetic resonance imaging MRI (C). Note the high 5-I-A-85380 uptake in the region of the thalamus.

Download figure to PowerPoint

When we compared the α4β2 nAchR density of paired bilateral brain regions, we found significant differences for eight studied brain regions. The right cerebellar white matter revealed a significantly higher 5-I-A-85380 uptake than the left cerebellar white matter. Remarkably, all seven paired supratentorial brain regions with significantly side-to-side differences showed a significantly higher 5-I-A-85380 uptake for the left brain hemisphere than for the right brain hemisphere (ANOVA, Bonferroni post-test, Table 2).

Due to these significant side-to-side differences, we observed only the 17 IPD patients in early stages of IPD (Hoehn and Yahr stage 1 and 2). In these 17 patients, we did not find any significant differences between the right and left brain hemisphere (P > 0.05; ANOVA, Bonferroni post-test) when we compared the α4β2 nAchR density of paired bilateral brain regions.

Furthermore, we studied in these 17 IPD patients (at Hoehn and Yahr stage 1 and 2) whether there were differences of the α4β2 nAchR densities in the brain hemisphere contralateral to the clinically more affected body side (=contralateral hemisphere) compared to the brain hemisphere ipsilateral to the clinically more affected body side (=ipsilateral hemisphere). There was no significant difference of the α4β2 nAchR densities for any brain region between the contralateral and ipsilateral brain hemisphere.

Correlation between CERAD testing and cerebral 5-I-A-85380 binding

In the following, we correlated performance in the individual CERAD subtests with local α4β2 nAchR binding, as determined by 5-I-A-85380 accumulation in the individual brain areas. We found high correlation coefficients for four brain regions (right superior parietal lobule, left thalamus, right posterior subcortical region, and left posterior subcortical region) and two CERAD subtests (Word List Intrusions and Boston Naming Test), some of them were statistically significant. In this case, the Bonferroni-corrected significance level is 0.05/8 = 0.00625.

In detail, the performance of the subtest Word List Intrusions correlated significantly with 5-I-A-85380 accumulation in the left thalamus, the left posterior subcortical region, and the right posterior subcortical region (Table 3). As further shown in Table 3, the results of the Boston Naming Test correlated significantly with the 5-I-A-85380 uptake in the right superior parietal lobule.

Table 3. Correlation between verbal functions in the CERAD and local α4β2 nAchR binding
 Boston Naming TestWord List Intrusions
  1. We calculated the correlation between the CERAD subtests and the α4β2 nicotinic acetylcholine receptor binding 4 h p.i.; significant correlation coefficients after correction for multiple comparisons. Adjusted P-value (Bonferroni-corrected P-value) = 0.05/8 = 0.00625.

Right superior parietal lobuler = +0.579; P = 0.0026n. s.
Right posterior subcortical regionn.s.r = −0.535; P = 0.0059
Left thalamusn.s.r = −0.583; P = 0.0022
Left posterior subcortical regionn.s.r = −0.676; P = 0.0002

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of interest
  9. References

To the best of our knowledge, this is the first study which correlates single cognitive functions with the α4β2 nAchR density of several brain regions in idiopathic Parkinson's disease (IPD). A previous study using 2-[18F]FA-85380-PET [13] correlated cerebral α4β2 nAchR density only with the Mini-Mental State Examination, the DemTect Scale, the Clock Drawing Test, the part V (delayed recall of figures) of the CERAD Test, and the Trail Making Test in IPD.

Our study involved non-demented IPD patients. The study was specifically powered to allow the correlation with individual test scores. We did not investigate healthy volunteers because (i) there are already a number of published reports [4-7] on 5-I-A-85380 SPECT in healthy subjects, (ii) a widespread reduced density of cerebral α4β2 nAchR in IPD is also known [7-9, 13], and (iii) we were primarily interested in the correlation between single cognitive functions and cerebral α4β2 nAchR density in IPD. The cited studies [7-9, 13] reported a widespread reduced density of cerebral α4β2 nAchR in IPD which was pronounced in the cerebellum, pons, midbrain, striatum, thalamus, anterior cingulate cortex, frontal, and frontoparietal cortex.

Using 5-I-A-85380 SPECT, we were able to correlate performance of the single CERAD subtests with the α4β2 nAchR density on the specific brain areas in IPD patients. The performance of the subtest Word List Intrusions correlated significantly with 5-I-A-85380 accumulation in the left thalamus, left posterior subcortical region, and right posterior subcortical region. The performance of the Boston Naming Test correlated significantly with the 5-I-A-85380 uptake in the right superior parietal lobule. Further correlations between the performance of CERAD subtests and the α4β2 nAchR density were nearly significant but did not reach the Bonferroni-corrected significance level. This might be due to the relatively small number of patients enrolled in the present study. The above-mentioned significant correlations between cognitive functions and the cerebral 5-I-A-85380 binding might indicate that the reduced α4β2 nAChR density in the according brain areas plays an important role in the origin of certain cognitive deficits in non-demented IPD patients.

In this connection, it has to be discussed in which manner the α4β2 nAchR density – measured by the 5-I-A-85380 SPECT – reflects the functional integrity of the cholinergic system: The α4β2 nAchR density quantifies the function of the post-synaptic cholinergic neuron but not the function of the presynaptic cholinergic neuron. A complete analysis of the cholinergic system requires also the measurement of the presynaptic cholinergic nerve function. The latter can be quantified by means of the acetylcholinesterase (AChE) PET. The AChE is localized in cholinergic cell bodies and axons [21] and shows its highest activity in the basal ganglia and the nucleus basalis of Meynert [22]. AChE PET studies disclosed that the degeneration of cerebral cholinergic projections contributes to cognitive and motor dysfunction in IPD [23-26]. Two cerebral nuclei are often affected in IPD patients which provide relevant cerebral cholinergic projections: (i) the pedunculopontine tegmental nucleus (PPN) – located in the dorsal tegmentum of the midbrain and in the upper pons and (ii) the nucleus basalis of Meynert (nbM) in the forebrain.

The PPN receives cholinergic input from the laterodorsal tegmental nucleus and provide cholinergic projections to the intralaminar and associative nuclei of the thalamus [27]. The degeneration of cholinergic PPN neurons is associated with gait abnormalities [26]. The nbM receives non-cholinergic input from the substantia nigra, the raphe nuclei, and the nucleus locus coeruleus and provides cholinergic projections to the amygdala and to the whole cerebral cortex except the hippocampal and olfactory cortex [28]. A reduced cortical AChE activity is associated with a significantly lower global cognitive performance compared with a normal cortical AChE activity [23].

In summary, the measurement of the presynaptic AChE activity and of the post-synaptic α4β2 nAchR density – including the results of the present study – indicates that cholinergic denervation contributes to cognitive deficits in IPD. In addition, 5-I-A-85380 SPECT is a valuable non-invasive innovative tool for in vivo investigations of nAchR density (status) in neurological disorders such as IPD or Alzheimer′s disease and thus warrants further large-scale clinical trials.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of interest
  9. References

This study was funded by a grant of Novartis Pharma GmbH, Germany.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of interest
  9. References
  • 1
    Deuschl G, Krack P. Morbus Parkinson. In: Hopf HC et al., eds. Neurologie in Praxis und Klinik, Vol. 2. Stuttgart, New York: Georg Thieme Company, 1999:4969.
  • 2
    Braak H, Ghebremedhin E, Rüb U, Bratzke HJ, del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res 2004;318:12134.
  • 3
    Borghammer P. Perfusion and metabolism imaging studies in Parkinson's disease. Dan Med J 2012;59:B4466.
  • 4
    Fujita M, Ichise M, van Dyck CH et al. Quantification of nicotinergic acetylcholine receptors in human brain using [123I]5-I-A-85380 SPET. Eur J Nucl Med Mol Imaging 2003;30:16209.
  • 5
    Mamede M, Ishizu K, Ueda M et al. Quantification of human nicotinic acetylcholine receptors with 123I-5IA-SPECT. J Nucl Med 2004;45:145870.
  • 6
    Staley JK, van Dyck CH, Weinzimmer D et al. 123I-5-IA-85380 SPECT measurement of nicotinic acetylcholine receptors in human brain by the constant infusion paradigm: feasibility and reproducibility. J Nucl Med 2005;46:146672.
  • 7
    Fujita M, Ichise M, Zoghbi SS et al. Widespread decrease of nicotinic acetylcholine receptors in Parkinson's disease. Ann Neurol 2006;59:1747.
  • 8
    Kas A, Bottlaender M, Gallezot JD et al. Decrease of nicotinic receptors in the nigrostriatal system in Parkinson's disease. J Cereb Blood Flow Metab 2009;29:16018.
  • 9
    Oishi N, Hashikawa K, Yoshida H et al. Quantification of nicotinic acetylcholine receptors in Parkinson's disease with (123)I-5IA SPECT. J Neurol Sci 2007;256:5260.
  • 10
    Mukhin AG, Gündisch D, Horti AG, Koren AO, Tamagnan G, Kimes AS. 5-iodo-A-85380, an α4β2 subtype-ligand for nicotinic acetylcholine receptors. Mol Pharmacol 2000;57:6429.
  • 11
    Pimlott SL, Piggott M, Owens J et al. Nicotinic acetylcholine receptor distribution in Alzheimer′s disease, dementia with Lewy bodies, Parkinson's disease and vascular dementia: In vitro binding study using 5-[125I]-A-85380. Neuropsychopharmacology 2004;29:10816.
  • 12
    Schmaljohann J, Gündisch D, Minnerop M et al. In vitro evaluation of nicotinic acetylcholine receptors with 2-[18F]F-A85380 in Parkinson's disease. Nucl Med Biol 2006;33:3059.
  • 13
    Meyer PM, Strecker K, Kendziorra K et al. Reduced alpha4beta2-nicotinic acetylcholine receptor binding and its relationship to mild cognitive and depressive symptoms in Parkinson disease. Arch Gen Psychiatry 2009;66:86677.
  • 14
    Morris JC, Heyman A, Mohs RC et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer's disease. Neurology 1989;39:115965.
  • 15
    Hughes A, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:1814.
  • 16
    Miah IP, Olde DK, Stoffers D, Deijen JB, Berendse HW. Early-stage cognitive impairment in Parkinson's disease and the influence of dopamine replacement therapy. Eur J Neurol 2012;19:5106.
  • 17
    Molloy SA, Rowan EN, O'brien JT, McKeith IG, Wesnes K, Burn DJ. Effect of levodopa on cognitive function in Parkinson's disease with and without dementia and dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 2006;77:13238.
  • 18
    Morrison CE, Borod JC, Brin MF, Hälbig TD, Olanow CW. Effects of levodopa on cognitive functioning in moderate-to-severe Parkinson's disease (MSPD). J Neural Transm 2004;111:133341.
  • 19
    Chang LT. A method for attenuation correction in radionuclide computed tomography. IEEE Trans Nucl Sci 1978;25:63843.
  • 20
    Berres M, Monsch AU, Bernasconi F, Thalmann B, Stähelin HB. Normal ranges of neuropsychological tests for the diagnosis of Alzheimer's disease. Stud Health Technol Inform 2000;77:1959.
  • 21
    Bohnen NI, Albin RL. The cholinergic system and Parkinson's disease. Behav Brain Res 2011;221:56473.
  • 22
    Atack JR, Perry EK, Bonham JR, Candy JM, Perry RH. Molecular forms of acetylcholinesterase and butyrylcholinesterase in the aged human central nervous system. J Neurochem 1986;47:26377.
  • 23
    Bohnen NI, Müller ML, Kotagal V et al. Heterogeneity of cholinergic denervation in Parkinson's disease without dementia. J Cereb Blood Flow Metab 2012;32:160917.
  • 24
    Kotagal V, Müller ML, Kaufer DI, Koeppe RA, Bohnen NI. Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders. Neurosci Lett 2012;514:16972.
  • 25
    Müller MLTM, Bohnen NI. Cholinergic dysfunction in Parkinson's disease. Curr Neurol Neurosci Rep 2013;13:37786.
  • 26
    Bohnen NI, Frey KA, Studenski S et al. Gait speed in Parkinson's disease correlates with cholinergic degeneration. Neurology 2013;81:16116.
  • 27
    Benarroch EE. Pedunculopontine nucleus: functional organization and clinical implications. Neurology 2013;80:114855.
  • 28
    Mesulam MM. Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer′s disease. J Comp Neurol 2013;521:412444.