Brad A. Racette

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.

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.

Geographic and ethnic variation in Parkinson disease: a population-based study of US Medicare beneficiaries.

Background: Parkinson disease is a common neurodegenerative disease. The racial, sex, age, and geographic distributions of Parkinson disease in the US are unknown. Methods: We performed a serial cross-sectional study of US Medicare beneficiaries aged 65 and older from the years 1995, and 2000–2005. Using over 450,000 Parkinson disease cases per year, we calculated Parkinson disease prevalence and annual incidence by race, age, sex, and county. Spatial analysis investigated the geographic distribution of Parkinson disease. Results: Age-standardized Parkinson disease prevalence (per 100,000) was 2,168.18 (±95.64) in White men, but 1,036.41 (±86.01) in Blacks, and 1,138.56 (±46.47) in Asians. The incidence ratio in Blacks as compared to Whites (0.74; 95% CI = 0.732–0.748) was higher than the prevalence ratio (0.58; 95% CI = 0.575–0.581), whereas the incidence ratio for Asians (0.69; 95% CI = 0.657–0.723) was similar to the prevalence ratio (0.62; 95% CI = 0.617–0.631). Bayesian mapping of Parkinson disease revealed a concentration in the Midwest and Northeast regions. Mean county incidence by quartile ranged from 279 to 3,111, and prevalence from 1,175 to 13,800 (per 100,000). Prevalence and incidence in urban counties were greater than in rural ones (p < 0.01). Cluster analysis supported a nonrandom distribution of both incident and prevalent Parkinson disease cases (p < 0.001). Conclusions: Parkinson disease is substantially more common in Whites, and is nonrandomly distributed in the Midwest and Northeastern US.

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.

Neurologist care in Parkinson disease A utilization, outcomes, and survival study

Objective: To investigate the utilization of neurologist providers in the treatment of patients with Parkinson disease (PD) in the United States and determine whether neurologist treatment is associated with improved clinical outcomes. Methods: This was a retrospective observational cohort study of Medicare beneficiaries with PD in the year 2002. Multilevel logistic regression was used to determine which patient characteristics predicted neurologist care between 2002 and 2005 and compare the age, race, sex, and comorbidity-adjusted annual risk of skilled nursing facility placement and hip fracture between neurologist- and primary care physician–treated patients with PD. Cox proportional hazards models were used to determine the adjusted 6-year risk of death using incident PD cases, stratified by physician specialty. Results: More than 138,000 incident PD cases were identified. Only 58% of patients with PD received neurologist care between 2002 and 2005. Race and sex were significant demographic predictors of neurologist treatment: women (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.76–0.80) and nonwhites (OR 0.83, 95% CI 0.79–0.87) were less likely to be treated by a neurologist. Neurologist-treated patients were less likely to be placed in a skilled nursing facility (OR 0.79, 95% CI 0.77–0.82) and had a lower risk of hip fracture (OR 0.86, 95% CI 0.80–0.92) in logistic regression models that included demographic, clinical, and socioeconomic covariates. Neurologist-treated patients also had a lower adjusted likelihood of death (hazard ratio 0.78, 95% CI 0.77–0.79). Conclusions: Women and minorities with PD obtain specialist care less often than white men. Neurologist care of patients with PD may be associated with improved selected clinical outcomes and greater survival.

Variables associated with return to sport following anterior cruciate ligament reconstruction: a systematic review

Background As one of the purposes of anterior cruciate ligament reconstruction (ACLR) is to return athletes to their preinjury activity level, it is critical to understand variables influencing return to sport. Associations between return to sport and variables representing knee impairment, function and psychological status have not been well studied in athletes following ACLR. Purpose The purpose of this review was to summarise the literature reporting on variables proposed to be associated with return to sport following ACLR. Study design Systematic review. Methods Medline, EMBASE, CINAHL and Cochrane databases were searched for articles published before November 2012. Articles included in this review met these criteria: (1) included patients with primary ACLR, (2) reported at least one knee impairment, function or psychological measure, (3) reported a return to sport measure and (4) analysed the relationship between the measure and return to sport. Results Weak evidence existed in 16 articles suggesting variables associated with return to sport included higher quadriceps strength, less effusion, less pain, greater tibial rotation, higher Marx Activity score, higher athletic confidence, higher preoperative knee self-efficacy, lower kinesiophobia and higher preoperative self-motivation. Conclusions Weak evidence supports an association between knee impairment, functional and psychological variables and return to sport. Current return to sport guidelines should be updated to reflect all variables associated with return to sport. Utilising evidence-based return to sport guidelines following ACLR may ensure that athletes are physically and psychologically capable of sports participation, which may reduce reinjury rates and the need for subsequent surgery.

Novel THAP1 sequence variants in primary dystonia

Background: THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and regulates cell proliferation. An exon 2 insertion/deletion frameshift mutation in THAP1 is responsible for DYT6 dystonia in Amish-Mennonites. Subsequent screening efforts in familial, mainly early-onset, primary dystonia identified additional THAP1 sequence variants in non-Amish subjects. Objective: To examine a large cohort of subjects with mainly adult-onset primary dystonia for sequence variants in THAP1. Methods: With high-resolution melting, all 3 THAP1 exons were screened for sequence variants in 1,114 subjects with mainly adult-onset primary dystonia, 96 with unclassified dystonia, and 600 controls (400 neurologically normal and 200 with Parkinson disease). In addition, all 3 THAP1 exons were sequenced in 200 subjects with dystonia and 200 neurologically normal controls. Results: Nine unique melting curves were found in 19 subjects from 16 families with primary dystonia and 1 control. Age at dystonia onset ranged from 8 to 69 years (mean 48 years). Sequencing identified 6 novel missense mutations in conserved regions of THAP1 (G9C [cervical, masticatory, arm], D17G [cervical], F132S [laryngeal], I149T [cervical and generalized], A166T [laryngeal], and Q187K [cervical]). One subject with blepharospasm and another with laryngeal dystonia harbored a c.-42C>T variant. A c.57C>T silent variant was found in 1 subject with segmental craniocervical dystonia. An intron 1 variant (c.71+9C>A) was present in 7 subjects with dystonia (7/1,210) but only 1 control (1/600). Conclusions: A heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia.

[18F]FDOPA PET and clinical features in parkinsonism due to manganism

Manganese exposure reportedly causes a clinically and pathophysiologically distinct syndrome from idiopathic Parkinsons disease (PD). We describe the clinical features and results of positron emission tomography with 6‐[18F]fluorodopa ([18F]FDOPA PET) of a patient with parkinsonism occurring in the setting of elevated blood manganese. The patient developed parkinsonism associated with elevated serum manganese from hepatic dysfunction. [18F]FDOPA PET demonstrated relatively symmetric and severely reduced [18F]FDOPA levels in the posterior putamen compared to controls. The globus pallidum interna had increased signal on T1‐weighted magnetic resonance imaging (MRI) images. We conclude that elevated manganese exposure may be associated with reduced striatal [18F]FDOPA uptake, and MRI may reveal selective abnormality within the internal segment of the pallidum. This case suggests that the clinical and pathophysiological features of manganese‐associated parkinsonism may overlap with that of PD.

Haplotypes and gene expression implicate the MAPT region for Parkinson disease The GenePD Study

Background: Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum. Methods: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR. Results: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT. Conclusions: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.

Mutation, sequence analysis, and association studies of α-synuclein in Parkinson's disease

A mutation within the α-synuclein gene on human chromosome 4 has been reported to segregate with PD in an Italian family. We screened a sample of familial cases of PD for mutation in the α-synuclein gene. None of the familial cases of PD carried a mutation within the α-synuclein gene, and no association was detected between PD and alleles of a dinucleotide repeat marker within the α-synuclein gene. We conclude that variation within the α-synuclein gene does not play a significant role in the risk for PD in our sample.