Characterizing differences in retinal and choroidal microvasculature and structure in individuals with Huntington's Disease compared to healthy controls: A cross-sectional prospective study.

OBJECTIVE: To characterize retinal and choroidal microvascular and structural changes in patients who are gene positive for mutant huntingtin protein (mHtt) with symptoms of Huntington's Disease (HD). METHODS: This study is a cross-sectional comparison of patients who are gene positive for mHtt and exhibit symptoms of HD, either motor manifest or prodromal (HD group), and cognitively normal individuals without a family history of HD (control group). HD patients were diagnosed by Duke movement disorder neurologists based on the Unified Huntington's Disease Rating Scale (UHDRS). Fovea and optic nerve centered OCT and OCTA images were captured using Zeiss Cirrus HD-5000 with AngioPlex. Outcome metrics included central subfield thickness (CST), peripapillary retinal nerve fiber layer (pRNFL) thickness, ganglion cell-inner plexiform layer (GCIPL) thickness, and choroidal vascularity index (CVI) on OCT, and foveal avascular zone (FAZ) area, vessel density (VD), perfusion density (PD), capillary perfusion density (CPD), and capillary flux index (CFI) on OCTA. Generalized estimating equation (GEE) models were used to account for inter-eye correlation. RESULTS: Forty-four eyes of 23 patients in the HD group and 77 eyes of 39 patients in the control group were analyzed. Average GCIPL thickness and FAZ area were decreased in the HD group compared to controls (p = 0.001, p < 0.001). No other imaging metrics were significantly different between groups. CONCLUSIONS: Patients in the HD group had decreased GCIPL thickness and smaller FAZ area, highlighting the potential use of retinal biomarkers in detecting neurodegenerative changes in HD.

Ultra-Widefield Imaging of the Retinal Macrovasculature in Parkinson Disease Versus Controls With Normal Cognition Using Alpha-Shapes Analysis.

Purpose: To investigate retinal vascular characteristics using ultra-widefield (UWF) scanning laser ophthalmoscopy in Parkinson disease (PD). Methods: Individuals with an expert-confirmed clinical diagnosis of PD and controls with normal cognition without PD underwent Optos California UWF imaging. Patients with diabetes, uncontrolled hypertension, glaucoma, dementia, other movement disorders, or known retinal or optic nerve pathology were excluded. Images were analyzed using Vasculature Assessment and Measurement Platform for Images of the Retina (VAMPIRE-UWF) software, which describes retinal vessel width gradient and tortuosity, provides vascular network fractal dimensions, and conducts alpha-shape analysis to further characterize vascular morphology (complexity, Opαmin; spread, OpA). Results: In the PD cohort, 53 eyes of 38 subjects were assessed; in the control cohort, 51 eyes of 33 subjects were assessed. Eyes with PD had more tortuous retinal arteries in the superotemporal quadrant (P = 0.043). In eyes with PD, alpha-shape analysis revealed decreased OpA, indicating less retinal vasculature spread compared to controls (P = 0.032). Opαmin was decreased in PD (P = 0.044), suggesting increased vascular network complexity. No differences were observed in fractal dimension in any region of interest. Conclusions: This pilot study suggests that retinal vasculature assessment on UWF images using alpha-shape analysis reveals differences in retinal vascular network spread and complexity in PD and may be a more sensitive metric compared to fractal dimension. Translational Relevance: Retinal vasculature assessment using these novel methods may be useful in understanding ocular manifestations of PD and the development of retinal biomarkers.

Longitudinal Analysis of Retinal Microvascular and Choroidal Imaging Parameters in Parkinson's Disease Compared with Controls.

Purpose: To quantify rate of change of retinal microvascular and choroidal structural parameters in subjects with Parkinson's disease (PD) compared with controls using OCT and OCT angiography (OCTA). Design: Prospective longitudinal study. Participants: Seventy-four eyes of 40 participants with PD and 149 eyes of 78 control individuals from the Eye Multimodal Imaging in Neurodegenerative Disease database. Methods: Subjects underwent OCT and OCTA imaging at 2 time points approximately 12 months apart. Main Outcome Measures: Imaging parameters included central subfield thickness, ganglion cell-inner plexiform layer (GC-IPL) thickness, peripapillary retinal nerve fiber layer thickness, choroidal vascularity index, superficial capillary plexus perfusion density (PFD), vessel density (VD), and foveal avascular zone area. Results: Participants with PD had greater rate of yearly decrease in GC-IPL (PD = -0.403µm, control = + 0.128 µm; P = 0.01), greater yearly decline in PFD in the 3 × 3 mm ETDRS circle (PD = -0.016, control = + 0.002; P < 0.001) and ring (PD = -0.016, control = + 0.002; P < 0.001); 6 × 6 mm ETDRS circle (PD = -0.021, control = 0.00; P = 0.001), and outer ring (PD = -0.022, control = 0.00; P = 0.001). Participants with PD had greater rate of yearly decline in VD in 3 × 3 mm circle (PD = -0.939/mm, control = + 0.006/mm; P < 0.001) and ring (PD = -0.942/mm, control = + 0.013/mm; P < 0.001); 6 × 6 mm circle (PD = -0.72/mm, control = -0.054/mm; P = 0.006), and outer ring (PD = -0.746/mm, control = -0.054/mm; P = 0.005). When stratified by PD severity based on Hoehn and Yahr stage, faster rates of decline were seen in Hoehn and Yahr stages 3 to 4 in the 3 × 3 mm circle PFD and VD as well as 3 × 3 mm ring VD. Conclusions: Individuals with PD experience more rapid loss of retinal microvasculature quantified on OCTA and more rapid thinning of the GC-IPL than controls. There may be more rapid loss in patients with greater disease severity. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Identifying Peripapillary Radial Capillary Plexus Alterations in Parkinson's Disease Using OCT Angiography.

PURPOSE: To compare radial peripapillary capillary (RPC) plexus vascular parameters and retinal nerve fiber layer (RNFL) thickness between those with Parkinson's disease (PD) and controls. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: A total of 151 eyes of 81 PD participants and 514 eyes of 266 controls. METHODS: Participants underwent OCT angiography (OCTA) imaging using the Zeiss Cirrus HD-5000 AngioPlex (Carl Zeiss AG). Capillary perfusion density (CPD) and capillary flux index (CFI) were assessed using a 4.5 × 4.5-mm peripapillary scan, and RNFL thickness was assessed using a 200 × 200-µm optic nerve cube OCT scan. Hoehn and Yahr clinical staging for PD was determined by an experienced movement disorders specialist. Generalized estimating equations adjusted for age and sex were used for analysis. MAIN OUTCOME MEASURES: Differences in RNFL thickness, CPD, and CFI as assessed using multivariable generalized estimating equations between individuals with PD and controls. RESULTS: After adjustment for age and sex, average CPD (0.446% ± 0.018% vs. 0.439% ± 0.017%, P < 0.001) and CFI (0.434 ± 0.031 vs. 0.426 ± 0.036, P = 0.008) were significantly higher in PD eyes. Average RNFL thickness was similar between groups (PD 89.71 ± 10.45 µm vs. control 88.20 ± 10.33 µm, P = 0.19). Significant correlations between Hoehn and Yahr stage and OCTA parameters were not observed. The OCTA parameters were not significantly different between eyes of the same patient. CONCLUSIONS: Increased peripapillary microvascular density and flux were detected in a large cohort of individuals with PD compared with controls after adjusting for age and sex; however, RNFL thickness was similar between groups. Peripapillary OCTA parameters may not correlate with the severity of PD. OCTA may serve as a noninvasive method to identify novel biomarkers for the early diagnosis of PD; as such, this methodology deserves further investigation.

Mindfulness based stress reduction in people with Parkinson's disease and their care partners.

BACKGROUND: Parkinson's Disease (PD) leads to poor quality of life and caregiver burden. Mindfulness-based stress reduction (MBSR) may improve these symptoms. We assessed the impact of a 9-week MBSR course on people with PD (PwP) and their care partners (CPs). METHODS: Participants completed questionnaires at screening, at the end of the course, and at 3-month follow-up: Parkinson's Disease Quality-39 (PDQ-39, PD only), Zarit Burden Inventory (ZBI, CP only) and Mindful Attention Awareness Scale (MAAS, both). The primary outcome measure was change in PDQ-39 (for PwP) or ZBI (for CP). Patient-reported scales were analyzed quantitatively; qualitative data on perceived effectiveness was collected. RESULTS: 53.8% PwP and 100% CPs completed the course. Among PwP, there was a significant reduction in MAAS(p < 0.001) and in PDQ-39 (p = 0.008). CPs experienced an increase in MAAS (p = 0.02) but no change in ZBI (p = 0.239). Qualitatively, both PwP and CPs expressed satisfaction with the course. DISCUSSION: MBSR improves mindful awareness in CPs and improves health-related quality of life in PwP.

Characterization of Retinal Microvascular and Choroidal Structural Changes in Parkinson Disease.

Importance: Noninvasive retinal imaging may detect structural changes associated with Parkinson disease (PD) and may represent a novel biomarker for disease detection. Objective: To characterize alterations in the structure and microvasculature of the retina and choroid in eyes of individuals with PD and compare them with eyes of age- and sex-matched cognitively healthy control individuals using optical coherence tomography (OCT) and OCT angiography (OCTA). Design, Setting, and Participants: This cross-sectional study was conducted at the Duke Neurological Disorders Clinic in Durham, North Carolina. Individuals aged 50 years or older with a diagnosis of PD were eligible for inclusion and underwent an evaluation and diagnosis confirmation before enrollment. Control individuals aged 50 years or older and without subjective cognitive dysfunction, a history of tremor, or evidence of motor dysfunction consistent with parkinsonism were solicited from the clinic or the Duke Alzheimer's Disease Prevention Registry. Individuals with diabetes, glaucoma, retinal pathology, other dementias, and corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity worse than 20/40 Snellen were excluded. Data were analyzed between January 1, 2020, and March 30, 2020. Exposures: All participants underwent OCT and OCTA imaging. Main Outcomes and Measures: Generalized estimating equation analysis was used to characterize the association between imaging parameters and PD diagnosis. Superficial capillary plexus vessel density (VD) and perfusion density (PFD) were assessed within the ETDRS 6 × 6-mm circle, 6 × 6-mm inner ring, and 6 × 6-mm outer ring, as was the foveal avascular zone area. Peripapillary retinal nerve fiber layer thickness, macular ganglion cell-inner plexiform layer thickness, central subfield thickness, subfoveal choroidal thickness, total choroidal area, luminal area, and choroidal vascularity index (CVI) were measured. Results: A total of 124 eyes of 69 participants with PD (39 men [56.5%]; mean [SD] age, 71.7 [7.0] years) and 248 eyes of 137 control participants (77 men [56.2%]; mean [SD] age, 70.9 [6.7] years) were analyzed. In the 6 × 6-mm ETDRS circle, VD (ß coefficient = 0.37; 95% CI, 0.04-0.71; P = .03) and PFD (ß coefficient = 0.009; 95% CI, 0.0003-0.018; P = .04) were lower in eyes of participants with PD. In the inner ring of the 6 × 6-mm ETDRS circle, VD (ß coefficient = 0.61; 95% CI, 0.20-1.02; P = .003) and PFD (ß coefficient = 0.015; 95% CI, 0.005-0.026; P = .004) were lower in eyes of participants with PD. Total choroidal area (ß coefficient = -1.74 units2; 95% CI, -3.12 to -0.37 units2; P = .01) and luminal area (ß coefficient = -1.02 units2; 95% CI, -1.86 to -0.18 units2; P = .02) were greater, but CVI was lower (ß coefficient = 0.5%; 95% CI, 0.2%-0.8%; P < .001) in eyes of individuals with PD. Conclusions and Relevance: This study found that individuals with PD had decreased retinal VD and PFD as well as choroidal structural changes compared with age- and sex-matched control participants. Given the observed population differences in these noninvasive retinal biomarkers, further research into their clinical utility in PD is needed.

Repeatability of Peripapillary OCT Angiography in Neurodegenerative Disease.

Purpose: To assess the repeatability of peripapillary OCT angiography (OCTA) in those with Alzheimer disease (AD), mild cognitive impairment (MCI), Parkinson disease (PD), or normal cognition. Design: Cross-sectional. Participants: Patients with a clinical diagnosis of AD, MCI, PD, or normal cognition were imaged. Those with glaucoma, diabetes mellitus, vitreoretinal pathology, and poor-quality images were excluded. Methods: Each eligible eye of each participant underwent 2 OCTA 4.5 × 4.5-mm peripapillary scans in a single session using a Zeiss Cirrus HD-OCT 5000 with AngioPlex (Carl Zeiss Meditec). The Zeiss software (v11.0.0.29946) quantified measures of perfusion in the radial peripapillary capillary (RPC) plexus in 4 sectors (superior, nasal, inferior, temporal). The average of these sectors was calculated and reported. Main Outcome Measures: Radial peripapillary capillary plexus perfusion was quantified using 2 parameters: capillary perfusion density (CPD) and capillary flux index (CFI). Intraclass correlation coefficients (ICCs) were used to quantify repeatability. For subjects who had both eyes included, the average values of each scan pair were used to assess interocular symmetry of CPD and CFI. Results: Of 374 eyes, 46 were from participants who had AD, 85 were from participants who had MCI, 87 were from participants who had PD, and 156 were from participants who had normal cognition. Capillary perfusion density ICC in AD = 0.88 (95% confidence interval [CI], 0.79-0.93), MCI = 0.95 (0.92-0.96), PD = 0.91 (0.87-0.94), and controls = 0.90 (0.87-0.93). Capillary flux index ICC in AD = 0.82 (0.70-0.90), MCI = 0.87 (0.80-0.91), PD = 0.91 (0.87-0.94) and controls = 0.85 (0.79-0.89). There were no significant differences in interocular variation in average CPD and CFI in AD, MCI, or PD (all P > 0.05). Isolated interocular sectoral CPD differences were noted in AD (nasal, P = 0.049; temporal, P = 0.024), PD (nasal, P = 0.036), and controls (nasal, P = 0.016). Interocular differences in CFI in the superior sector in MCI (P = 0.028) and in average CFI for controls (P = 0.035) were observed. Conclusions: Peripapillary OCTA repeatability in AD, MCI, and PD is good-excellent and similar to those with normal cognition. Insignificant interocular asymmetry in peripapillary OCTA suggests neurodegeneration may proceed uniformly; future studies may reveal the appropriateness of single-eye imaging.

Safety of Converting From Tetrabenazine to Deutetrabenazine for the Treatment of Chorea.

Importance: Tetrabenazine is efficacious for chorea control; however, tolerability concerns exist. Deutetrabenazine, a novel molecule that reduces chorea, was well tolerated in a double-blind, placebo-controlled study. Objectives: To evaluate the safety and explore the efficacy of conversion from tetrabenazine to deutetrabenazine in patients with chorea associated with Huntington disease (HD). Design, Setting, and Participants: In this ongoing, open-label, single-arm study that started on December 21, 2013, 37 patients at 13 Huntington Study Group sites in the United States and Australia who were taking stable doses of tetrabenazine that provided a therapeutic benefit were switched overnight to deutetrabenazine therapy. After week 1, the deutetrabenazine dose was titrated on a weekly basis for optimal chorea control. Interventions: Deutetrabenazine administration at a dosage thought to provide comparable systemic exposure to the active metabolites of the prior, stable tetrabenazine regimen. Main Outcomes and Measures: Safety measures included adverse events (AEs), clinical laboratory tests, vital signs, electrocardiograms, and validated scales. Changes in the Unified Huntington's Disease Rating Scale total maximal chorea score and total motor score were efficacy end points. Results: Of the 53 patients with HD screened for the study, 37 ambulatory patients with manifest HD (mean [SD] age, 52.4 [11.5] years; 22 [59%] male and 15 [41%] female; 36 white [97.3%]) were enrolled. Deutetrabenazine was generally well tolerated, with low rates of neuropsychiatric AEs. Safety scales did not reveal subclinical toxicity with deutetrabenazine treatment. Rates of dose reduction or suspension attributable to AEs were also low. Chorea control, as measured by the total maximal chorea score, was maintained at week 1 and significantly improved at week 8 (mean [SD] change from baseline, 2.1 [3.2]; P < .001). Conclusions and Relevance: In patients with chorea, overnight conversion to deutetrabenazine therapy provided a favorable safety profile and effectively maintained chorea control.

Linkage of familial essential tremor to chromosome 5q35.

BACKGROUND: Essential tremor is a neurological condition characterized by tremor during voluntary movement. To date, 3 loci linked to familial essential tremor have been identified. METHODS: We examined 48 essential tremor patients in 5 large essential tremor pedigrees in our data set for genetic linkage using an Affymetrix Axiom array. Linkage analysis was performed using an affecteds-only dominant model in SIMWALK2. To incorporate all genotype information, GERMLINE was used to identify genome segments shared identical-by-descent in pairs of affecteds. Exome sequencing was performed in pedigrees showing evidence of linkage. RESULTS: For one family, chromosomes 5 and 18 showed genome-wide significant linkage to essential tremor. Shared segment analysis excluded the 18p11 candidate region and reduced the 5q35 region by 1 megabase. Exome sequencing did not identify a potential causative variant in this region. CONCLUSION: A locus on chromosome 5 is linked to essential tremor. Further research is needed to identify a causative variant. © 2016 International Parkinson and Movement Disorder Society.

Ropinirole 24-hour prolonged release and ropinirole immediate release in early Parkinson's disease: a randomized, double-blind, non-inferiority crossover study.

OBJECTIVE: This study compares once-daily ropinirole 24-h prolonged release and three-times-daily ropinirole immediate release in patients with early Parkinson's disease. METHODS: This multicentre, double-blind, non-inferiority crossover study involved 161 patients randomized to one of four formulation sequences: (1) immediate release-immediate release-prolonged release; (2) immediate release-prolonged release-prolonged release; (3) prolonged release-prolonged release-immediate release; (4) prolonged release-immediate release-immediate release. During a 12-week dose-titration period, ropinirole immediate release was titrated according to the approved labelling; titration of ropinirole 24-h prolonged release started at a higher dose and was more rapid. Patients then entered three consecutive, flexible-dose, 8-week maintenance periods. At the end of the first maintenance period, half of the patients in each formulation group switched to the same or closest dose of the alternative formulation; remaining patients switched at the end of the second maintenance period. RESULTS: At the end of titration, before the first dose switch, there were substantial reductions in mean Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. During maintenance periods, both groups showed similar efficacy on the UPDRS motor score. Overall mean (standard error) change from period baseline was -0.1 (0.28) for ropinirole 24-h prolonged release, and 0.6 (0.30) for ropinirole immediate release (adjusted mean treatment difference -0.7; 95% confidence interval [CI]: -1.51, 0.10; p = 0.0842). The upper limit of the 95% CI was less than the predefined threshold of 3 points for non-inferiority. Ropinirole 24-h prolonged release was well-tolerated when titrated more rapidly than ropinirole immediate release; overnight switching between formulations was also well-tolerated. Study limitations included complexity of the non-inferiority study design and the forced dose-titration schedule. CONCLUSION: Ropinirole 24-h prolonged release was effective and well-tolerated in patients with early Parkinson's disease.

Pesticide exposure and risk of Parkinson's disease: a family-based case-control study.

BACKGROUND: Pesticides and correlated lifestyle factors (e.g., exposure to well-water and farming) are repeatedly reported risk factors for Parkinson's disease (PD), but few family-based studies have examined these relationships. METHODS: Using 319 cases and 296 relative and other controls, associations of direct pesticide application, well-water consumption, and farming residences/occupations with PD were examined using generalized estimating equations while controlling for age-at-examination, sex, cigarette smoking, and caffeine consumption. RESULTS: Overall, individuals with PD were significantly more likely to report direct pesticide application than their unaffected relatives (odds ratio = 1.61; 95% confidence interval, 1.13-2.29). Frequency, duration, and cumulative exposure were also significantly associated with PD in a dose-response pattern (p

Smoking, caffeine, and nonsteroidal anti-inflammatory drugs in families with Parkinson disease.

OBJECTIVE: To assess associations between Parkinson disease (PD) and putatively protective factors-smoking, caffeine (coffee, tea, and soft drinks), and nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen, and naproxen). DESIGN: Family-based case-control study. SETTING: Academic medical center clinic. PARTICIPANTS: A total of 356 case subjects and 317 family controls who self-reported environmental exposures. MAIN OUTCOME MEASURES: Associations between PD and environmental measures (history, status, dosage, duration, and intensity) of smoking, coffee, caffeine, nonsteroidal anti-inflammatory drugs, and non-aspirin nonsteroidal anti-inflammatory drugs were examined using generalized estimating equations with an independent correlation matrix while controlling for age and sex. RESULTS: Individuals with PD were significantly less likely to report ever smoking (odds ratio = 0.56; 95% confidence interval, 0.41-0.78). Additional measures of smoking revealed significant inverse associations with PD (P<.05) and trends in odds ratios (P<.005). Increasing intensity of coffee drinking was inversely associated with PD (test for trend P = .05). Increasing dosage (trend P = .009) and intensity (trend P = .01) of total caffeine consumption were also inversely associated, with high dosage presenting a significant inverse association for PD (odds ratio = 0.58; 95% confidence interval, 0.34-0.99). There were no significant associations between nonsteroidal anti-inflammatory drugs and PD. CONCLUSIONS: Inverse associations of smoking and caffeine were corroborated using families with PD, thus emphasizing smoking and caffeine as important covariates to consider in genetic studies of PD.

NOS2A and the modulating effect of cigarette smoking in Parkinson's disease.

OBJECTIVE: Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking. METHODS: We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations. RESULTS: Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two-SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers. INTERPRETATION: Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking.

Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism.

BACKGROUND: Parkinson disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. Genes contributing to rare mendelian forms of PD have been identified, but the genes involved in the more common idiopathic PD are not well understood. OBJECTIVES: To identify genes important to PD pathogenesis using microarrays and to investigate their potential to aid in diagnosing parkinsonism. DESIGN: Microarray expression analysis of postmortem substantia nigra tissue. PATIENTS: Substantia nigra samples from 14 unrelated individuals were analyzed, including 6 with PD, 2 with progressive supranuclear palsy, 1 with frontotemporal dementia with parkinsonism, and 5 control subjects. MAIN OUTCOME MEASURES: Identification of genes significantly differentially expressed (P<.05) using Affymetrix U133A microarrays. RESULTS: There were 142 genes that were significantly differentially expressed between PD cases and controls and 96 genes that were significantly differentially expressed between the combined progressive supranuclear palsy and frontotemporal dementia with parkinsonism cases and controls. The 12 genes common to all 3 disorders may be related to secondary effects. Hierarchical cluster analysis after exclusion of these 12 genes differentiated 4 of the 6 PD cases from progressive supranuclear palsy and frontotemporal dementia with parkinsonism. CONCLUSIONS: Four main molecular pathways are altered in PD substantia nigra: chaperones, ubiquitination, vesicle trafficking, and nuclear-encoded mitochondrial genes. These results correlate well with expression analyses performed in several PD animal models. Expression analyses have promising potential to aid in postmortem diagnostic evaluation of parkinsonism.

Genomic convergence to identify candidate genes for Parkinson disease: SAGE analysis of the substantia nigra.

Genomic convergence is a multistep approach that combines gene expression with genomic linkage to identify and prioritize susceptibility genes for complex disease. As a first step, we previously performed linkage analysis on 174 multiplex Parkinson's disease (PD) families, identifying five peaks for PD risk and two for genes affecting age at onset (AAO) in PD [Hauser et al., Hum Mol Genet 2003;12:671-677]. We report here the next step: serial analysis of gene expression [SAGE; Scott et al., JAMA 2001;286:2239-2242] to analyze substantia nigra tissue from three PD patients and two age-matched controls. We find 933 differentially expressed genes (P<0.05) between PD and controls, but of these, only 50 genes represented by unique SAGE tags map within our previously described PD linkage regions. Furthermore, genes encoded by mitochondrial DNA are expressed 1.5-fold higher in PD patients versus controls, without an increase in the corresponding nuclear-encoded mitochondrial components, suggesting an increase in mtDNA genomes in PD or a disjunction with nuclear expression. The next step in the genomic convergence process will be to screen these 50 high-quality candidate genes for association with PD risk susceptibility and genetic effects on AAO.

Linkage disequilibrium and haplotype tagging polymorphisms in the Tau H1 haplotype.

We and others have previously detected association of the Tau H1 haplotype on chromosome 17 with risk of idiopathic Parkinson disease (PD). The H1 haplotype appears to have a fundamental importance in neurodegeneration, as multiple studies have shown it is also associated with an increased risk for progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration syndromes, and primary progressive aphasia. Therefore, to divide the H1 haplotype into sub-haplotypes that could be more significantly associated with the risk of developing PD, and to delimit the genes lying in the H1 haplotype, we analyzed 34 single nucleotide polymorphisms (SNPs) spanning over 3.15 megabases in the region containing Tau. These SNPs are located in or flank the corticotropin-releasing hormone receptor 1, presenilin homolog 2, Tau, Saitohin, and KIAA1267 genes. Analysis of linkage disequilibrium (LD) using these 34 SNPs suggests that the H1 haplotype extends over about 1.3 megabases, making it the largest region of LD reported to date. Of the 29 SNPs lying in this region of LD, 5 were identified as "haplotype tagging" SNPs (htSNPs), capturing 96% of the sample's haplotype diversity. Association analysis with these htSNPs revealed a new H1 sub-haplotype that is significantly associated with PD ( P<0.02). These results define the genes and regulatory regions included in this region of LD, containing an important susceptibility allele contributing to increased risk of neurodegeneration.

Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease.

The pathogenic process responsible for the loss of dopaminergic neurons within the substantia nigra of patients with Parkinson disease (PD) is poorly understood. Current research supports the involvement of fibroblast growth factor (FGF20) in the survival of dopaminergic cells. FGF20 is a neurotrophic factor that is preferentially expressed within the substantia nigra of rat brain. The human homologue has been mapped to 8p21.3-8p22, which is within an area of PD linkage revealed through our published genomic screen. To test whether FGF20 influences risk of PD, we genotyped five single-nucleotide polymorphisms (SNPs) lying within the FGF20 gene, in a large family study. We analyzed our sample (644 families) through use of the pedigree disequilibrium test (PDT), the genotype PDT, the multilocus-genotype PDT, and the family-based association test to assess association between risk of PD and alleles, genotypes, multilocus genotypes, and haplotypes. We discovered a highly significant association of PD with one intronic SNP, rs1989754 (P=.0006), and two SNPs, rs1721100 (P=.02) and ss20399075 (P=.0008), located in the 3' regulatory region in our overall sample. Furthermore, we detected a haplotype (A-G-C-C-T) that is positively associated with risk of PD (P=.0003), whereas a second haplotype (A-G-G-G-C) was found to be negatively associated with risk of PD (P=.0009). Our results strongly support FGF20 as a risk factor for PD.

A case of combined orthostatic tremor and primary gait ignition failure.

We report a case of a woman with both orthostatic tremor and primary gait ignition failure, a novel combination. We review the literature on both of these conditions, and discuss possible neuroanatomic substrates.

Association study of Parkin gene polymorphisms with idiopathic Parkinson disease.

BACKGROUND: Previously, we detected linkage of idiopathic Parkinson disease (PD) to the region on chromosome 6 that contains the Parkin gene (D6S305; logarithm of odds score, 5.47) in families with at least one individual with age at onset younger than 40 years (families with early-onset disease). Further study demonstrated the presence of Parkin mutations in this data set. However, previous case-control studies have reported conflicting results regarding the role of more common Parkin polymorphisms as susceptibility alleles for idiopathic PD. OBJECTIVE: To investigate the association of 7 previously studied Parkin single-nucleotide polymorphisms (SNPs) throughout the promoter and most of the open reading frame with PD in a large cohort of patients with primarily late-onset PD. METHODS: One promoter, 3 intronic, and 3 exonic Parkin SNPs were genotyped in 1580 individuals belonging to 397 families, and their association with PD was evaluated using family-based association tests. RESULTS: No significant association (P>.05) between PD and any Parkin SNP allele or genotype was detected. Haplotype analysis and stratification by age at onset or family history also failed to produce significant results. CONCLUSIONS: These results suggest that these common variants of Parkin are not associated with PD in white patients, although Parkin mutations are known to cause early- and late-onset PD.

Parkin mutations and susceptibility alleles in late-onset Parkinson's disease.

Parkin, an E2-dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late-onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early-onset and 2% of late-onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late-onset form of Parkinson disease.