Joel S. Perlmutter

Genome-wide association study reveals genetic risk underlying Parkinson's disease

We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinsons disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding α-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 × 10−16) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 × 10−16). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 × 10−8) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 × 10−5). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

We conducted a meta-analysis of Parkinsons disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinsons disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10−16). We also show six risk loci associated with proximal gene expression or DNA methylation.

A stereotactic method of anatomical localization for positron emission tomography.

Surgicalxtant methods for anatomical localization within a physiological image are inadequate for precise regional correlations between anatomy and physiology. We have developed a method for determining the location of any region of interest within a positron emission tomographic (PET) image by transformation of the tomographic location coordinates into coordinates within a stereotactic atlas of the human brain. The specific anatomical assumptions of this approach were identified and validated within groups of normal subjects by means of measurements made from lateral skull radiographs and nuclear magnetic resonance proton images. A high degree of accuracy and reproducibility was demonstrated when this technique was applied to groups of normal subjects by determining the anatomical location of two physiologically defined PET areas: the cavernous sinus and visually responsive cortex. This method is simple to implement and highly objective. Generalization of the localization procedure for use with structural tomography is readily accomplished.

Welding-related parkinsonism Clinical features, treatment, and pathophysiology

Objective: To determine whether welding-related parkinsonism differs from idiopathic PD. Background: Welding is considered a cause of parkinsonism, but little information is available about the clinical features exhibited by patients or whether this is a distinct disorder. Methods: The authors performed a case-control study that compared the clinical features of 15 career welders, who were ascertained through an academic movement disorders center and compared to two control groups with idiopathic PD. One control group was ascertained sequentially to compare the frequency of clinical features, and the second control group was sex- and age-matched to compare the frequency of motor fluctuations. Results: Welders were exposed to a mean of 47,144 welding hours. Welders had a younger age at onset (46 years) of PD compared with sequentially ascertained controls (63 years; p < 0.0001). There was no difference in frequency of tremor, bradykinesia, rigidity, asymmetric onset, postural instability, family history, clinical depression, dementia, or drug-induced psychosis between the welders and the two control groups. All treated welders responded to levodopa. Motor fluctuations and dyskinesias occurred at a similar frequency in welders and the two control groups. PET with 6-[18F]fluorodopa obtained in two of the welders showed findings typical of idiopathic PD, with greatest loss in posterior putamen. Conclusions: Parkinsonism in welders is distinguished clinically only by age at onset, suggesting welding may be a risk factor for PD. These preliminary data cannot exclude a genetic contribution to susceptibility in these exposed individuals.

Swallowing abnormalities and their response to treatment in Parkinson's disease

We investigated swallowing abnormalities in patients with Parkinsons disease, the relationship between these abnormalities and general parkinsonian signs, as well as the response to therapy. Twenty patients and 13 controls were evaluated with clinical rating scales and modified barium swallows before and after oral levodopa (in combination with carbidopa). Fifteen patients, but only 1 control, had abnormal swallows (χ2 = 11.722, df = l, p < 0.001). Abnormalities included disturbances of oral and pharyngeal phases of swallowing. Patients without dysphagia frequently had abnormal swallows, including silent aspiration. Seven patients had improved swallowing after levodopa, whereas 1 worsened. Improvement in general parkinsonian signs was not a reliable indicator of improved swallowing.

Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD

Objective: To assess whether subthalamic nuclei (STN) stimulation’s primary mechanism of action is to drive or inhibit output neurons. Methods: Cerebral blood flow responses to STN stimulation were measured using PET in 13 patients with Parkinson disease. Patients were scanned with stimulators off and on (six scans each condition). Clinical ratings, EMG, and videotaping of movements were obtained at each scan. Scans with observable tremor or movement were eliminated from analysis. Brain regions where STN stimulation significantly altered blood flow were identified. Results: STN stimulation increased blood flow in midbrain (including STN), globus pallidus, and thalamus, primarily on the left side, but reduced blood flow bilaterally in frontal, parietal, and temporal cortex. Conclusions: These data suggest that STN stimulation increases firing of STN output neurons, which increases inhibition of thalamocortical projections, ultimately decreasing blood flow in cortical targets. STN stimulation appears to drive, rather than inhibit, STN output neurons.

Resting state functional connectivity of the striatum in Parkinson's disease.

Classical accounts of the pathophysiology of Parkinsons disease have emphasized degeneration of dopaminergic nigrostriatal neurons with consequent dysfunction of cortico-striatal-thalamic loops. In contrast, post-mortem studies indicate that pathological changes in Parkinsons disease (Lewy neurites and Lewy bodies) first appear primarily in the lower brainstem with subsequent progression to more rostral parts of the neuraxis. The nigrostriatal and histological perspectives are not incompatible, but they do emphasize different anatomical structures. To address the question of which brain structures are functionally most affected by Parkinsons disease, we performed a resting-state functional magnetic resonance imaging study focused on striatal functional connectivity. We contrasted 13 patients with advanced Parkinsons disease versus 19 age-matched control subjects, using methodology incorporating scrupulous attention to minimizing the effects of head motion during scanning. The principal finding in the Parkinsons disease group was markedly lower striatal correlations with thalamus, midbrain, pons and cerebellum. This result reinforces the importance of the brainstem in the pathophysiology of Parkinsons disease. Focally altered functional connectivity also was observed in sensori-motor and visual areas of the cerebral cortex, as well the supramarginal gyrus. Striatal functional connectivity with the brainstem was graded (posterior putamen > anterior putamen > caudate), in both patients with Parkinsons disease and control subjects, in a manner that corresponds to well-documented gradient of striatal dopaminergic function loss in Parkinsons disease. We hypothesize that this gradient provides a clue to the pathogenesis of Parkinsons disease.

Abnormal cortical responses in patients with writer's cramp

We evaluated sensorimotor processing in patients with writers cramp using PET and H2 15O blood flow scans. The study included six right-handed patients with unilateral writers cramp and eight right-handed normals. Subjects had blood flow scans at rest and during vibration of either the “affected” or “unaffected” hand. Vibration produced a consistent peak response in primary sensorimotor area (PSA) and supplementary motor area (SMA), both contralateral to the vibrated hand. Both responses were significantly reduced approximately 25% in patients with writers cramp (PSA, p = 0.002; SMA, p = 0.02) whether vibrating the affected or unaffected hand. This indicates that patients with unilateral writers cramp have bilateral brain dysfunction. These data provide objective evidence of abnormal central sensorimotor processing in writers cramp.

Stimulation of STN impairs aspects of cognitive control in PD

Objective: To test the hypothesis that subthalamic nucleus (STN) stimulation in Parkinson disease (PD) patients affects working memory and response inhibition performance, particularly under conditions of high demand on cognitive control. Methods: To test this hypothesis, spatial working memory (spatial delayed response [SDR]) and response inhibition (Go–No–Go [GNG]) tasks requiring varying levels of cognitive control were administered to patients with PD with previously implanted bilateral STN stimulators (n = 24). Patients did not take PD medications overnight. Data were collected while bilateral stimulators were on and off, counterbalancing the order across subjects. Results: On the SDR task, STN stimulation decreased patients’ working memory performance under a high but not low memory load condition (effect of stimulator condition on high load only and condition × load interaction, p < 0.05). On the GNG task, STN stimulation reduced discriminability on a high but not medium inhibition condition (effect of stimulator condition on high inhibition level only, p = 0.05; condition × inhibition level interaction, p = 0.07). Conclusion: STN stimulation reduces working memory and response inhibition performance under conditions of greater challenge to cognitive control despite significant improvement of motor function.

Prevalence of parkinsonism and relationship to exposure in a large sample of Alabama welders

Objective: To estimate the prevalence of parkinsonism in welders in Alabama and to compare this prevalence with that in a general population sample. Methods: The authors screened 1,423 welders from Alabama who were referred for medical–legal evaluation for Parkinson disease (PD). Standardized videotaped assessments using the Unified Parkinson’s Disease Rating Scale motor subsection 3 (UPDRS3) were obtained. Patients provided information regarding exposure to welding fumes and job titles. Job titles were matched with Department of Labor Standard Occupational Codes (SOCs). Diagnoses were assigned based on quantitative criteria for the diagnosis of PD using two thresholds for diagnosis. With use of the number of active welders in this screening with parkinsonism as the numerator and the age-adjusted number of welders in each SOC as the denominator, the prevalence of parkinsonism in Alabama welders was estimated using conservative assumptions and compared with general population data from Copiah County, MS. Results: With use of conservative and liberal case definitions of parkinsonism, the estimated prevalence of parkinsonism among active male welders age 40 to 69 statewide was 977 to 1,336 cases/100,000 population. The prevalence of parkinsonism was higher among welders vs age-standardized data for the general population (prevalence ratio = 10.19, 95% CI 4.43 to 23.43). Conclusion: The estimated prevalence of parkinsonism was higher within a sample of male Alabama welders vs the general population of male residents of Copiah County, MS.