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To compare event-related oscillations in patients with dementia with Lewy bodies (DLB) who are carriers and non-carriers of glucocerebrosidase (GBA) mutations.EEG was recorded during a visual oddball task in eight Ashkenazi Jewish DLB patients with the N370S mutation in theGBAgene (GBA-DLB) and eleven DLB non-carriers. The time-frequency power and inter-trial phase clustering were calculated from the Morlet wavelet convolution for the midline electrodes.Task performance and cognitive assessments were comparable between groups. While the within-non-GBA-DLB group analysis revealed delta-band power synchronization relative to the baseline (p = 0.01, Cohen's d = 1.0), the within-GBA-DLB-group analysis detected no event-related changes in power. Both groups showed an increase relative to the baseline in the delta and theta bands inter-trial phase clustering (all p 0.03, d 1.3). The between-group analysis revealed that event-related power - but not clustering - was lower in GBA-DLB compared to non-carriers in the delta band at Fz and Cz (p = 0.04, d = -0.9).GBA-DLB patients showed decreased delta-band power compared to non-carriers despite the similar cognitive performance, whereas inter-trial phase clustering was comparable in both groups.Preserved inter-trial phase clustering possibly compensates for the impaired power by eliciting the appropriate functional configuration needed for stimulus processing and task performance.

Background: Inflammation is an integral part of neurodegeneration including in Parkinson’s disease (PD). Ashkenazi Jews have high rates of genetic PD with divergent phenotypes among GBA-PD and LRRK2-PD. The role of inflammation in the prodromal phase of PD and the association with disease phenotype has yet to be elucidated. Objective: To assess central and peripheral cytokines among PD patients with mutations in the LRRK2 and GBA genes and among non-manifesting carriers (NMC) of these mutations in order to determine the role of inflammation in genetic PD. Methods: The following cytokines were assessed from peripheral blood and cerebrospinal fluid (CSF): TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10 and INF- γ. A comprehensive intake including general medical conditions, use of anti-inflammatory treatments, motor and cognitive assessments and additional laboratory measures were recorded, enabling the construction of the MDS probable prodromal score. Results: Data from 362 participants was collected: 31 idiopathic PD (iPD), 30 LRRK2-PD, 77 GBA-PD, 3 homozygote GBA-PD, 3 GBA-LRRK2-PD, 67 LRRK2-NMC, 105 GBA-NMC, 14 LRRK2-GBA-NMC, and 32 healthy controls. No between-group differences in peripheral or CSF cytokines were detected. No correlation between disease characteristics or risk for prodromal PD could be associated with any inflammatory measure. Conclusion: In this study, we could not detect any evidence on dysregulated immune response among GBA and LRRK2 PD patients and non-manifesting mutation carriers.

GBA variations are common risk factors for Parkinson's disease (PD), and are found in 21.7% of Ashkenazi PD patients (AJ-PD), 4.23% of them carry an allele, 370Rec, which is different from the common GBA-N370S allele. Using whole-genome-sequencing of 370Rec carriers, N370S carriers, and non-carriers, we characterize the unique 370Rec haplotype in AJ-PDs, and show that it harbors a missense variant replacing the highly conserved methionine-27 with valine in the transmembrane domain of the mitochondrial SLC25A44.

Background: Glucocerebrosidase (GBA) gene mutations and APOE polymorphisms are common in dementia with Lewy bodies (DLB), however their clinical impact is only partially elucidated. Objective: To explore the clinical impact of mutations in the GBA gene and APOE polymorphisms separately and in combination, in a cohort of Ashkenazi Jewish (AJ) patients with DLB. Methods: One hundred consecutively recruited AJ patients with clinically diagnosed DLB underwent genotyping for GBA mutations and APOE polymorphisms, and performed cognitive and motor clinical assessments. Results: Thirty-two (32%) patients with DLB were carriers of GBA mutations and 33 (33%) carried an APOE ɛ4 allele. GBA mutation carriers had a younger age of onset (mean [SD] age, 67.2 years [8.9] versus 71.97 [5.91]; p = 0.03), poorer cognition as assessed by the Mini-Mental State Examination (21.41 [6.9] versus 23.97 [5.18]; p

The phenotype of Parkinson’s disease (PD) is variable with mutations in genes such as LRRK2 and GBA explaining part of this heterogeneity. Additional genetic and environmental factors contribute to disease variability. To assess the association between biochemical markers, PD severity and probability score for prodromal PD, among GBA and LRRK2 mutation carriers. Levels of uric acid, vitamin D, C-reactive protein, microalbumin/creatinine ratio (ACR), white blood count (WBC), hemoglobin, platelets, neutrophil/lymphocyte ratio and estimated glomerular filtration rate (eGFR) were assessed from patients with PD and non-manifesting carriers (NMC) of mutations in GBA and LRRK2, together with disease related questionnaires enabling the construction of the MDS prodromal probability score. A total of 241 patients with PD: 105 idiopathic PD (iPD), 49 LRRK2-PD and 87 GBA-PD and 412 non-manifesting subjects; 74 LRRK2-NMC, 118 GBA-NMC and 220 non-manifesting non-carriers (NMNC), participated in this study. No significant differences in biochemical measures were detected among patients with PD or non-manifesting carriers. Among GBA-PD patients, worse motor performance was associated with ACR (B = 4.68, 95% CI (1.779–7.559); p = 0.002). The probability score for prodromal PD among all non-manifesting participants was associated with eGFR; NMNC (B = − 0.531 95% CI (− 0.879 to − 0.182); p

BACKGROUND The phenotype of Parkinson's disease (PD) is milder among patients with LRRK2-PD and more severe among patients with GBA-PD; however, whether an additive phenotypical effect occurs among dual-mutation carriers requires validation. OBJECTIVE The objective of this study was to explore the phenotypic expression of patients with PD who carry mutations in both genes compared with a single-mutation presentation. METHODS Patients with PD were genotyped for the G2019S-LRRK2 mutation and 9 mutations in the GBA gene. Subjects were classified into 5 groups: idiopathic PD, mild GBA-PD, severe GBA-PD, LRRK2-PD, and LRRK2+GBA-PD. Clinical symptoms were evaluated using performance-based measures. RESULTS A total of 1090 patients with idiopathic PD, 155 patients with LRRK2-PD, 155 patients with mild GBA-PD, 56 patients with severe GBA-PD, and 27 patients with LRRK2+GBA-PD participated in this study. The patients with LRRK2-PD and LRRK2+GBA-PD exhibited lower scores on total Unified Parkinson's Disease Rating Scale (P

Background GBA variants are the most common genetic risk factors for Parkinson's disease (PD) world-wide, and can be found in up to 20% of Ashkenazi PD patients. The E326K variant, which is not considered a Gaucher's disease causing mutation, was recently shown to increase the risk for PD. Since E326K is a common variant among Europeans, Finnish and Ashkenazi (2.4, 8.6 and 1.2% carrier rate, respectively), we aimed to refine its involvement in PD. Methods 1200 consecutively recruited PD patients of a full Ashkenazi origin were genotyped for 10 GBA variants, the LRRK2-G2019S and the SMPD1-L302P. Alleles' frequencies were compared to controls, composed of 378 elderly healthy individuals and the non-neuro gnomAD Ashkenazi database. Odds-Ratio (OR) and age-at-motor-symptom-onset (AAO) were also calculated for all genotypes. Results All allelic variations tested had significant allelic ORs, demonstrating a wide range (1.86–12.84). The lowest allelic OR was observed for E326K (p = .013). Forty-five patients (of 1200, 3.75%) had at least two mutations (of the 12 tested), compared to 2 (0.53%) among 378 controls (p = .0013). Of the E326K carrier patients, 37% (10/27) carried additional mutations and the genotypic OR for individuals who carried only the E326K variant was 1.07. It did not reach statistical significance even when simulating the expected carrier frequency of E326K in 100,000 Ashkenazi controls (p = .39). In addition, an additive effect was demonstrated for risk in carriers of two mutations, the LRRK2-G2019S and a mild-GBA mutation (N370S or R496H), compared to carriers of only one mutation in one of these genes (simulated OR 11.79 compared to 7.58 and 2.49, respectively). An additive effect was also suggested for earlier AAO (5.0 years earlier than in non-carriers, compared to 3.1 and 2.2 years, respectively). Conclusions Compared to previous studies, we demonstrate here a higher frequency of PD patients that carry two mutations. The GBA-E326K is more likely to affect PD risk when accompanied by another mutation, and an additive effect on risk and earlier AAO was proposed for carriers of LRRK2/mild-GBA double mutations. Altogether, these data support an oligogenic approach to PD genetics.

Introduction. In dementia with Lewy bodies (DLB), mutations in the GBA gene are associated with a more severe cognitive phenotype. In basic science, event-related oscillations have traditionally been used to explore the neurophysiological underpinnings of various aspects of cognitive performance. Here, we aimed to compare event-related oscillations in DLB patients who are carriers and non-carriers of GBA mutations.Method. EEG was recorded during a visual oddball task in eight clinically diagnosed Ashkenazi Jewish DLB patients with the N370S mutation in the GBA gene (GBA-DLB) and eleven DLB non-carriers. The time-frequency power and inter-trial phase coherence were calculated from the Morlet wavelet convolution from the Fz electrode.Results. Task performance and cognitive assessments were comparable between groups. While the within-non-GBA-DLB group analysis revealed a significant increase relative to the baseline in the delta-band power (p=0.01, Cohen's d=1.0), the within-GBA-DLB-group analysis did not detect any event-related power change. In contrast, both subgroups showed an increase relative to the baseline in the delta and theta bands inter-trial phase coherence (all p1.3). The between-group analysis revealed that event-related power - but not coherence - was lower in GBA-DLB compared to non-carriers in the delta band (p=0.04, d=-0.9).Conclusions. GBA-DLB patients showed decreased delta-band power compared to non-carriers despite the similar cognitive performance, whereas inter-trial phase coherence was comparable in both groups. These findings suggest that in carriers, preserved inter-trial phase coherence possibly compensates for the impaired power by eliciting the appropriate functional configuration needed for stimulus processing and task performance.

Non-manifesting carriers (NMCs) of Parkinson’s disease (PD)-related mutations such as LRRK2 and GBA are at an increased risk for developing PD. Dopamine transporter (DaT)-spectral positron emission computed tomography is widely used for capturing functional nigrostriatal dopaminergic activity. However, it does not reflect other ongoing neuronal processes; especially in the prodromal stages of the disease. Resting-state fMRI (rs-fMRI) has been proposed as a mode for assessing functional alterations associated with PD, but its relation to dopaminergic deficiency remains unclear. We aimed to study the association between presynaptic striatal dopamine uptake and functional connectivity (FC) patterns among healthy first-degree relatives of PD patients with mutations in LRRK2 and GBA genes. N = 85 healthy first-degree subjects were enrolled and genotyped. All participants underwent DaT and rs-fMRI scans, as well as a comprehensive clinical assessment battery. Between-group differences in FC within striatal regions were investigated and compared with striatal binding ratios (SBR). N = 26 GBA-NMCs, N = 25 LRRK2-NMCs, and N = 34 age-matched nonmanifesting noncarriers (NM-NCs) were included in each study group based on genetic status. While genetically-defined groups were similar across clinical measures, LRRK2-NMCs demonstrated lower SBR in the right putamen compared with NM-NCs, and higher right putamen FC compared to GBA-NMCs. In this group, higher striatal FC was associated with increased risk for PD. The observed differential SBR and FC patterns among LRRK2-NMCs and GBA-NMCs indicate that DaTscan and FC assessments might offer a more sensitive prediction of the risk for PD in the pre-clinical stages of the disease.

Objective The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genome-wide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these two proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value = 1.1E-07; age-at-onset top variant: P-value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. This article is protected by copyright. All rights reserved.

Background Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are risk factors for Parkinson's disease (PD). Objective To explore the association between GCase activity, PD phenotype, and probability for prodromal PD among carriers of mutations in the GBA and LRRK2 genes. Methods Participants were genotyped for the G2019S-LRRK2 and nine GBA mutations common in Ashkenazi Jews. Performance-based measures enabling the calculation of the Movement Disorder Society (MDS) prodromal probability score were collected. Results One hundred and seventy PD patients (102 GBA-PD, 38 LRRK2-PD, and 30 idiopathic PD) and 221 non-manifesting carriers (NMC) (129 GBA-NMC, 45 LRRK2-NMC, 15 GBA-LRRK2-NMC, and 32 healthy controls) participated in this study. GCase activity was lower among GBA-PD (3.15 ± 0.85 μmol/L/h), GBA-NMC (3.23 ± 0.91 μmol/L/h), and GBA-LRRK2-NMC (3.20 ± 0.93 μmol/L/h) compared to the other groups of participants, with no correlation to clinical phenotype. Conclusions Low GCase activity does not explain the clinical phenotype or risk for prodromal PD in this cohort. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objective to determine the occurrence of homozygous rare, in-silico damaging variants in a genetically relatively homogenous group of amyotrophic lateral sclerosis (ALS) patients. Methods Whole-exome-sequencing of 43 ALS patients of North-Africa Jewish origin was performed. Data were filtered to identify very rare homozygous recessive in-silico damaging variants, in genes annotated to ALS-associated cellular pathways. Results We identified a rare missense homozygous variant, p.Arg663Cys in MFN2, predicted to be damaging, in a patient with an early age at disease onset (36 years) and fast progression. An additional ALS patient carried the mutation and together established its association to ALS (p = .01). Additional homozygous variants were identified, including the risk allele p.Arg261His in NEK1, as well as variants in genes known to be associated with other neurodegenerative diseases, such as HTT (Huntington's disease), ATM (Ataxia-Telangiectasia), and ZFYVE26 (SPG15), and variants in genes previously reported as upregulated (LZTS3) or downregulated (ARMC4, CFAP54, and MTHFSD) in ALS patients. Altogether, 13 patients (30%) carried at least one homozygous rare in-silico damaging variant, of them 10 carried either another rare homozygous variant and/or a variant in a known ALS gene, which is categorized as pathogenic, likely-pathogenic or variant of uncertain significance. Conclusions Our results suggest the contribution of recessive alleles to ALS and the possibility of burden of mutations, emphasizing the complexity of ALS genetics.

Background and ObjectivesAmyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron degeneration, with juvenile ALS (jALS) defined as disease with age at onset (AAO) before 25 years. We aimed to identify the genetic basis of 2 unrelated patients with jALS with very rapid deterioration and early age intellectual disability (ID) and to assess association of genetic findings with both phenotypes in a large cohort of patients with ALS and controls, and in the literature.MethodsExome sequencing was performed in 2 unrelated probands and their parents. Trio analyses included de novo, rare homozygosity, and compound heterozygosity analyses. A TaqMan genotyping assay was used to genotype ALS cohorts. A systematic literature review was conducted and additional information from authors obtained to assess prevalence of fused in sarcoma (FUS)-ALS associated with ID.ResultsA de novo mutation FUS-P525L was identified in both patients. Additional variations were identified in other genes related to intellectual disabilities. Among 8 additional unrelated juvenile patients, one carried the same FUS mutation and had a similar medical history of mild ID and fulminant ALS, whereas the others did not carry any FUS coding mutations and had no reported learning or intellectual disabilities (p = 0.0083). In addition, 486 patients with ALS with AAO ≥25 years were negative for this mutation. An extensive literature review showed that among all patients with FUS-related ALS with full phenotype reports, 10.3% exhibited additional learning/intellectual disabilities.DiscussionFUS-P525L mutation was identified in 3 among 10 patients with jALS (30%) in our clinical cohort, all with a very aggressive disease course and ID. Together with literature reports, these results support a novel association between mutations in FUS and early life ID. Additional variations identified in genes related to ID and brain development in our patients (GPT2, DNAH10, and SCUBE2) may suggest a complex oligogenic inheritance for this phenotype. We propose that this mutation should be screened in patients with ALS with very early AAO, aggressive disease course, and sporadic occurrence, especially when ALS is accompanied by ID.

Introduction: The GBA‐N370S mutation is one of the most frequent risk factors for dementia with Lewy bodies (DLB) and Parkinson's disease (PD). We looked for genetic variations that contribute to the outcome in N370S‐carriers, whether PD or DLB. Methods Whole‐genome sequencing of 95 Ashkenazi‐N370S‐carriers affected with either DLB (n = 19) or PD (n = 76) was performed, and 564 genes related to dementia and PD analyzed. Results We identified enrichment of linked alleles in PINK1 locus in DLB patients (false discovery rate P = .0412). Haplotype analysis delineated 1.8 Mb interval encompassing 29 genes and 87 unique variants, of them, KIF17‐R869C received the highest functional prediction score (Combined Annotation Dependent Depletion = 34). Its frequency was significantly higher in 26 DLB‐N370S‐carriers compared to 140 PD‐N370S‐carriers (odds ratio [OR] = 33.4 P = .001, and OR = 70.2 when only heterozygotes were included). Discussion Because KIF17 was shown to be important for learning and memory in mice, our data further suggest, for the first time, its involvement in DLB, and possibly in human dementia.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods: We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value=2.5E-08, beta=1.27, SE=0.23, risk allele: C) met genome-wide significance for the penetrance model. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value=1.1E-07; age-at-onset top variant: P-value=9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations.

The phenotype of Parkinson's disease (PD) is variable with mutations in genes such as LRRK2 and GBA explaining part of this heterogeneity. Additional genetic and environmental factors contribute to disease variability.To assess the association between biochemical markers, PD severity and probability score for prodromal PD, among GBA and LRRK2 mutation carriers.Levels of uric acid, vitamin D, C-reactive protein, microalbumin/creatinine ratio (ACR), white blood count (WBC), hemoglobin, platelets, neutrophil/lymphocyte ratio and estimated glomerular filtration rate (eGFR) were assessed from patients with PD and non-manifesting carriers (NMC) of mutations in GBA and LRRK2, together with disease related questionnaires enabling the construction of the MDS prodromal probability score.A total of 241 patients with PD: 105 idiopathic PD (iPD), 49 LRRK2-PD and 87 GBA-PD and 412 non-manifesting subjects; 74 LRRK2-NMC, 118 GBA-NMC and 220 non-manifesting non-carriers (NMNC), participated in this study. No significant differences in biochemical measures were detected among patients with PD or non-manifesting carriers. Among GBA-PD patients, worse motor performance was associated with ACR (B = 4.68, 95% CI (1.779-7.559); p = 0.002). The probability score for prodromal PD among all non-manifesting participants was associated with eGFR; NMNC (B = - 0.531 95% CI (- 0.879 to - 0.182); p 0.001, LRRK2-NMC (B = - 1.014 95% CI (- 1.663 to - 0.366); p 0.001) and GBA-NMC (B = - 0.686 95% CI (1.300 to - 0.071); p = 0.029).Sub-clinical renal impairment is associated with increased likelihood for prodromal PD regardless of genetic status. While the mechanism behind this finding needs further elucidation, it suggests that kidney function might play a role in PD pathogenesis.

In order toevaluate the influence of the metabolic syndrome (MS) (obesity, hypertension, elevated triglycerides, reduced levels of HDL cholesterol and glucose impairment) on the phenotype of LRRK2 and GBA Parkinson’s disease (PD), and on the prevalence of prodromal features among individuals at risk, we collected, laboratory test results, blood pressure, demographic, cognitive, motor, olfactory and affective information enabling the assessment of each component of MS and the construction of the MDS prodromal probability score. The number of metabolic components and their levels were compared between participants who were separated based on disease state and genetic status. One hundred and four idiopathic PD, 40 LRRK2-PD, 70 GBA-PD, 196 healthy non-carriers, 55 LRRK2-NMC and 97 GBA-NMC participated in this study. PD groups and non manifesting carriers (NMC) did not differ in the number of metabolic components (p = 0.101, p = 0.685, respectively). LRRK2-PD had higher levels of triglycerides (p = 0.015) and higher rates of prediabetes (p = 0.004), while LRRK2-NMC had higher triglyceride levels (p = 0.014). NMC with probability rates for prodromal PD above 50% had higher frequencies of hypertriglyceridemia and prediabetes (p LRRK2 carriers, MS does not seem to influence GBA and LRRK2-PD phenotype.

Sleep disturbances and nocturnal hypokinesia are common in Parkinson's disease (PD). Recent work using wearable technologies showed fewer nocturnal movements in PD when compared with controls. However, it is unclear how these manifest across the disease spectrum.We assessed the prevalence of sleep disturbances and nocturnal hypokinesia in early and advanced PD and their relation to nonmotor symptoms and dopaminergic medication.A total of 305 patients with PD with diverse disease severity (Hoehn and Yahr [HY] stage 1 = 47, HY stage 2 = 181, HY stage 3 = 77) and 205 healthy controls continuously wore a tri-axial accelerometer on the lower back for at least 2 days. Lying, turning, and upright -time at night were extracted from the acceleration signals. Percent upright time and nighttime walking were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed were used to evaluate nocturnal movements.Nocturnal lying time was similar among all groups (healthy controls, 7.5 ± 1.2 hours; HY stage 1, 7.3 ± 0.9 hours; HY stage 2, 7.2 ± 1.3 hours; HY stage 3, 7.4 ± 1.6 hours; P = 0.501). However, patients with advanced PD had more upright periods, whereas the number and velocity of their turns were reduced (P ≤ 0.021). Recently diagnosed patients (1 year from diagnosis) were similar to controls in the number of nocturnal turns (P = 0.148), but showed longer turning time (P = 0.001) and reduced turn magnitude (P = 0.002). Reduced nocturnal movements were associated with increased PD motor severity and worse dysautonomia and cognition and with dopaminergic medication.Using wearable sensors for continuous monitoring of movement at night may offer an unbiased measure of disease severity that could enhance optimal nighttime dopaminergic treatment and utilization of turning strategies. © 2020 International Parkinson and Movement Disorder Society.

BackgroundThe Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.MethodsThis cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023.FindingsBetween Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p

Mutations in the glucocerebrosidase (GBA) gene are divided into mild and severe (mGBA, sGBA) based on their contribution to the phenotype of Gaucher disease (GD) among homozygotes. We conducted a longitudinal analysis of Parkinson's disease (PD) patients carrying mutations in the GBA gene to better characterize genotype-phenotype correlations.Patients underwent a comprehensive assessment of medical, neurological, cognitive and non-motor functions. Data from these patients was explored to evaluate differences in disease phenotype based on genotype.A total of 355 PD patients participated in this study; 152 idiopathic PD patients, 139 mGBA, 48 sGBA and 16 GD-PD. Groups were similar in age, sex, years of education and age of onset. Both sGBA and GD-PD had higher Unified Parkinson Disease Rating Scale (UPDRS) scores (p = 0.041), higher frequencies of REM sleep behavior disorder (RBD) (p = 0.022) and hallucinations (p 0.0001) compared to the other groups of patients. sGBA experienced more non-motor symptoms (p 0.0001), depression (p 0.001) and worse hyposmia (p = 0.010). Trail making test was significantly longer in GD-PD followed by sGBA, mGBA and iPD (p = 0.005).Motor, cognitive, olfactory and psychiatric symptoms are more severe in sGBA and GD-PD compared to mGBA and iPD, reinforcing the notion that the severity of the PD phenotype is related to the severity of the mutation in the GBA gene.

Pathogenic C9orf72-G4C2 repeat expansions are associated with ALS/FTD, but not with Parkinson’s disease (PD); yet the possible link between intermediate repeat lengths and PD remains inconclusive. We aim to study the potential involvement of these repeats in PD. The number of C9orf72-repeats were determined by flanking and repeat-primed PCR assays, and the risk-haplotype was determined by SNP-array. Their association with PD was assessed in a stratified manner: in PD-patients-carriers of mutations in LRRK2, GBA, or SMPD1 genes (n = 388), and in PD-non-carriers (NC, n = 718). Allelic distribution was significantly different only in PD-NC compared to 600 controls when looking both at the allele with higher repeat’s size (p = 0.034) and at the combined number of repeats from both alleles (p = 0.023). Intermediate repeats (20–60 repeats) were associated with PD in PD-NC patients (p = 0.041; OR = 3.684 (CI 1.05–13.0)) but not in PD-carriers (p = 0.684). The C9orf72 risk-haplotype, determined in a subgroup of 588 PDs and 126 controls, was observed in higher frequency in PD-NC (dominant model, OR = 1.71, CI 1.04–2.81, p = 0.0356). All 19 alleles within the risk-haplotype were associated with higher C9orf72 RNA levels according to the GTEx database. Based on our data, we suggest a model in which intermediate repeats are a risk factor for PD in non-carriers, driven not only by the number of repeats but also by the variants’ genotypes within the risk-haplotype. Further studies are needed to elucidate this possible role of C9orf72 in PD pathogenesis.

Early-onset Parkinson's disease (EOPD) is less common than the typical adult-onset PD and may be associated with a genetic etiology. Mutations in several genes are known to cause autosomal recessive (AR) PD. This study aimed to detect the etiology of EOPD in consanguineous families or families living in a specific small geographic region in Israel. Six families with EOPD affecting more than a single individual were recruited. Homozygous mapping analysis using a single-nucleotide polymorphism-based array was performed in all families, followed by Sanger sequencing of related genes based on the mapping results. In addition, all families underwent PARK2 sequencing and testing for large deletions and duplications in PD-associated genes. Different truncating mutations were detected in the PARK2 gene among affected individuals of three families: c.996C>A (p.Cys332X) and c.101delA in either homozygous or compound heterozygous fashion. Exon 4 deletion was detected in a heterozygous manner in a late-onset PD and in homozygous state in early-onset disease in the same family. No disease-causing mutations were detected in any other tested genes. In total, mutations in the PARK2 gene were detected in four of the six tested families with a history of EOPD. These results further demonstrate the role of PARK2 in AR PD. We recommend genetic analysis for the PARK2 gene when AR PD is suspected.

In genetic epidemiological studies, family history data are collected on relatives of study participants and used to estimate the age-specific risk of disease for individuals who carry a causal mutation. However, a family member's genotype data may not be collected because of the high cost of in-person interview to obtain blood sample or death of a relative. Previously, efficient nonparametric genotype-specific risk estimation in censored mixture data has been proposed without considering covariates. With multiple predictive risk factors available, risk estimation requires a multivariate model to account for additional covariates that may affect disease risk simultaneously. Therefore, it is important to consider the role of covariates in genotype-specific distribution estimation using family history data. We propose an estimation method that permits more precise risk prediction by controlling for individual characteristics and incorporating interaction effects with missing genotypes in relatives, and thus, gene-gene interactions and gene-environment interactions can be handled within the framework of a single model. We examine performance of the proposed methods by simulations and apply them to estimate the age-specific cumulative risk of Parkinson's disease (PD) in carriers of the LRRK2 G2019S mutation using first-degree relatives who are at genetic risk for PD. The utility of estimated carrier risk is demonstrated through designing a future clinical trial under various assumptions. Such sample size estimation is seen in the Huntington's disease literature using the length of abnormal expansion of a CAG repeat in the HTT gene but is less common in the PD literature. Copyright © 2017 John Wiley & Sons, Ltd.

Background: Worldwide prevalence estimates of Huntington disease (HD) vary widely, with no reliable information regarding the Jewish population in Israel. Methods: This specialized tertiary single-center cross-sectional study assessed clinical, cognitive, and demographic characteristics of 84 HD patients who were treated at the Movement Disorder Unit of the Tel Aviv Medical Center, Israel. Results: Our cohort was composed of one-third Ashkenazi Jews, 27% Mountain Jews (Caucasus Jews), 18% Sephardi Jews, and 21% Karaites, with both Mountain Jews and Karaites over-represented compared to their relevant proportion in the population of the state of Israel, which is less than 1%. No between-group differences were detected regarding the number of CAG (cytosine-adenine-guanine) repeats, age at onset, disease duration, years from symptom onset to diagnosis, gender, years of education, Unified Huntington Disease Rating Scale scores, or the Montreal Cognitive Assessment scores. Conclusion: We detected clustering of HD among the population treated at our Medical Center, which has the only specialized HD clinic in the country, with a high percentage of HD among 2 relatively small subpopulations of Jews: Mountain Jews and Karaites.

Mutations in the ryanodine receptor-1 (RYR1) may cause disorders inherited in an autosomal dominant/recessive fashion. Sequencing of RYR1 in an infant of Ashkenazi Jewish descent with severe hypotonia, dislocation of hip, torticollis and scoliosis, and paternal family history of autosomal dominant mild disease. The child was compound heterozygote for a missense variant c.7042G > A inherited from her father associated with autosomal dominant disease, and a missense variant of unknown significance c.5309C > T inherited from an asymptomatic mother. This case raises the possibility of a dominant disease complicated by a second variant in the other allele serving as a modifier.

Non‐manifesting carriers (NMC) of the G2019S mutation in the LRRK2 gene represent an “at risk” group for future development of Parkinson's disease (PD) and have demonstrated task related fMRI changes. However, resting‐state networks have received less research focus, thus this study aimed to assess the integrity of the motor, default mode (DMN), salience (SAL), and dorsal attention (DAN) networks among this unique population by using two different connectivity measures: interregional functional connectivity analysis and Dependency network analysis (D(EP)NA). Machine learning classification methods were used to distinguish connectivity between the two groups of participants. Forty‐four NMC and 41 non‐manifesting non‐carriers (NMNC) participated in this study; while no behavioral differences on standard questionnaires could be detected, NMC demonstrated lower connectivity measures in the DMN, SAL, and DAN compared to NMNC but not in the motor network. Significant correlations between NMC connectivity measures in the SAL and attention were identified. Machine learning classification separated NMC from NMNC with an accuracy rate above 0.8. Reduced integrity of non‐motor networks was detected among NMC of the G2019S mutation in the LRRK2 gene prior to identifiable changes in connectivity of the motor network, indicating significant non‐motor cerebral changes among populations “at risk” for future development of PD.

Our previous immunoprecipitation analysis of nicotinic acetylcholine receptors (nAChRs) in the mouse superior cervical ganglion (SCG) revealed that approximately 55%, 24%, and 21% of receptors are comprised of α3β4, α3β4α5, and α3β4β2 subunits, respectively. Moreover, mice lacking β4 subunits do not express α5‐containing receptors but still express a small number of α3β2 receptors. Here, we investigated how synaptic transmission is affected in the SCG of α5β4‐KO and α5β2‐KO mice. Using an ex vivo SCG preparation, we stimulated the preganglionic cervical sympathetic trunk and measured compound action potentials (CAPs) in the postganglionic internal carotid nerve. We found that CAP amplitude was unaffected in α5β4‐KO and α5β2‐KO ganglia, whereas the stimulation threshold for eliciting CAPs was significantly higher in α5β4‐KO ganglia. Moreover, intracellular recordings in SCG neurons revealed no difference in EPSP amplitude. We also found that the ganglionic blocking agent hexamethonium was the most potent in α5β4‐KO ganglia (IC 50: 22.1 μmol/L), followed by α5β2‐KO (IC 50: 126.7 μmol/L) and WT ganglia (IC 50: 389.2 μmol/L). Based on these data, we estimated an IC 50 of 568.6 μmol/L for a receptor population consisting solely of α3β4α5 receptors; and we estimated that α3β4α5 receptors comprise 72% of nAChRs expressed in the mouse SCG. Similarly, by measuring the effects of hexamethonium on ACh‐induced currents in cultured SCG neurons, we found that α3β4α5 receptors comprise 63% of nAChRs. Thus, in contrast to our results obtained using immunoprecipitation, these data indicate that the majority of receptors at the cell surface of SCG neurons consist of α3β4α5.

Background: Sleep interruptions and nocturnal hypokinesia are common in Parkinson's disease (PD). Pilot work using wearable technologies showed fewer nocturnal movements in patients with advanced PD compared to controls. However, the prevalence of these impairments in early stage of the disease and the influence of non-motor symptoms, and dopaminergic medication are unknown. Methods: This study evaluated wearable sensor data collected in 305 patients with PD at different Hohen and Yahr disease stages (HY HY H&Y3=77) and 205 healthy controls (HC). Subjects wore a tri-axial accelerometer continuously (24/7) on the lower back for at least 2 days. Percent upright-time and nighttime walking were defined based on the vertical axis of the acceleration signal and were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed during the night evaluated nocturnal movements. Findings: Nocturnal lying-time was similar between PD and controls (p=0.501), however, the number of turns and the turn velocity significantly decreased (p

Background Reduced arm swing is a well-known clinical feature of Parkinson's disease (PD), often observed early in the course of the disease. We hypothesized that subtle changes in arm swing and axial rotation may also be detectable in the prodromal phase. Objective The purpose of this study was to evaluate the relationship between the LRRK2-G2019S mutation, arm swing, and axial rotation in healthy nonmanifesting carriers and noncarriers of the G2019S mutation and in patients with PD. Methods A total of 380 participants (186 healthy nonmanifesting controls and 194 PD patients) from 6 clinical sites underwent gait analysis while wearing synchronized 3-axis body-fixed sensors on the lower back and bilateral wrists. Participants walked for 1 minute under the following 2 conditions: (1) usual walking and (2) dual-task walking. Arm swing amplitudes, asymmetry, variability, and smoothness were calculated for both arms along with measures of axial rotation. Results A total of 122 nonmanifesting participants and 67 PD patients were carriers of the G2019S mutation. Nonmanifesting mutation carriers walked with greater arm swing asymmetry and variability and lower axial rotation smoothness under the dual task condition when compared with noncarriers (P < .04). In the nonmanifesting mutation carriers, arm swing asymmetry was associated with gait variability under dual task (P = .003). PD carriers showed greater asymmetry and variability of movement than PD noncarriers, even after controlling for disease severity (P < .009). Conclusions The G2019S mutation is associated with increased asymmetry and variability among nonmanifesting participants and patients with PD. Prospective studies should determine if arm swing asymmetry and axial rotation smoothness may be used as motor markers of prodromal PD. © 2016 International Parkinson and Movement Disorder Society

Genes involved in cytoskeletal stability and trafficking, such as MAPT and SNCA, are important risk factors for Parkinson's disease (PD). Two members of the cytoskeletal Septin family, SEPT4 and SEPT5, were implicated in PD pathobiology. We aimed to determine whether Septin genes are associated with Parkinson's disease. To this end, six SNPs located in four different Septin loci were analyzed in 720 PD patients and 740 controls, all of Ashkenazi-Jewish origin. In addition, SEPT14 was sequenced and its expression was determined in different human tissues. Our results revealed that two SNPs in the SEPT14 locus, rs11981883 and rs10241628, were associated with a reduced risk for PD (p = 0.02 and p = 0.005). A third SNP, rs77231105, was localized in the putative promoter of SEPT14 and was predicted to affect the binding of the transcription factor Nkx2.5. This SNP was also associated with a reduced risk for PD (OR = 0.28, p

The term isolated ectopia lentis (EL; subluxation or dislocation of the human crystalline lens) is applied to patients with EL, without skeletal features and in the absence of aortic root dilatation. To date, the only gene shown to cause autosomal-recessive isolated EL is ADAMTSL4. Here we report a novel founder mutation in ADAMTSL4 gene in children of Bukharian Jewish origin presenting with early-onset bilateral EL. A carrier frequency of 1:48 was determined among unrelated healthy Bukharian Jews. Given the complications associated with disease and the allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, pre-implantation or early postnatal diagnosis.

Disturbances in reward processing occur in Parkinson’s disease (PD) however it is unclear whether these are solely drug-related. We applied an event-related fMRI gambling task to a group of non-manifesting carriers (NMC) of the G2019S mutation in the LRRK2 gene, in order to assess the reward network in an “at risk” population for future development of PD. Sixty-eight non-manifesting participants, 32 of which were non-manifesting non-carriers (NMNC), performed a gambling task which included defined intervals of anticipation and response to both reward and punishment in an fMRI setup. Behavior and cerebral activations were measured using both hypothesis driven and whole brain analysis. NMC demonstrated higher trait anxiety scores (p = 0.04) compared to NMNC. Lower activations were detected among NMC during risky anticipation in the left nucleus accumbens (NAcc) (p = 0.05) and during response to punishment in the right insula (p = 0.02), with higher activations among NMC during safe anticipation in the right insula (p = 0.02). Psycho-Physiological Interaction (PPI) analysis from the NAcc and insula revealed differential connectivity patterns. Whole brain analysis demonstrated divergent between-group activations in distributed cortical regions, bilateral caudate, left midbrain, when participants were required to press the response button upon making their next chosen move. Abnormal neural activity in both the reward and motor networks were detected in NMC indicating involvement of the ventral striatum regardless of medication use in “at risk” individuals for future development of PD.

The G2019S mutation in the LRRK2 gene generates a milder PD phenotype compared with GBA-PD; however, genetic based survival studies are lacking.To compare mortality rates between LRRK2-PD, GBA-PD, and idiopathic PD patients (iPD).Patients were screened for the G2019S mutation in the LRRK2 gene and the seven common GBA mutations among Ashkenazi Jews, classified as mild and severe (mGBA, sGBA). Motor symptoms onset and date of death were ascertained, with mortality rates calculated for each group of patients.Overall, 380 of 1,086 idiopathic PD patients, 49 of 159 LRRK2-PD, 56 of 148 mGBA-PD, and 13 of 49 sGBA-PD participants died by the time of analysis. LRRK2-PD tended to have longer survival compared to idiopathic PD whereas GBA status did not affect mortality. Genetic status did not predict mortality in a multivariate analysis.Survival of patients with PD does not seem to be related to GBA status, whereas LRRK2 might confer higher survival rates.

Cerebral atrophy has been detected in patients with Parkinson’s disease (PD) both with and without dementia, however differentiation based on genetic status has thus far not yielded robust findings. We assessed cortical thickness and subcortical volumes in a cohort of PD patients and healthy controls carriers of the G2019S mutation in the LRRK2 gene and the common GBA mutations, in an attempt to determine whether genetic status influences structural indexes. Cortical thickness and subcortical volumes were computed and compared between six groups of participants; idiopathic PD, GBA-PD, LRRK2-PD, non-manifesting non-carriers (NMNC), GBA-non-manifesting carriers (NMC) and LRRK2-NMC utilizing the FreeSurfer software program. All participants were cognitively intact based on a computerized cognitive assessment battery. Fifty-seven idiopathic PD patients, 9 LRRK2-PD, 12 GBA-PD, 49 NMNC, 41 LRRK2-NMC and 14 GBA-NMC participated in this study. Lower volumes among patients with PD compared to unaffected participants were detected in bilateral hippocampus, nucleus accumbens, caudate, thalamus, putamen and amygdala and the right pallidum (p = 0.016). PD patients demonstrated lower cortical thickness indexes in a majority of regions assessed compared with non-manifesting participants. No differences in cortical thickness and subcortical volumes were detected within each of the groups of participants based on genetic status. Mutations in the GBA and LRRK2 genes are not important determinants of cortical thickness and subcortical volumes in both patients with PD and non-manifesting participants. PD is associated with a general reduction in cortical thickness and sub-cortical atrophy even in cognitively intact patients.

We characterized the C9orf72 hexanucleotide repeat expansion (RE) mutation in amyotrophic lateral sclerosis (ALS) patients of 2 distinct origins, Ashkenazi and North Africa Jews (AJ, NAJ), its frequency, and genotype-phenotype correlations. In AJ, 80% of familial ALS (fALS) and 11% of sporadic ALS carried the RE, a total of 12.9% of all AJ-ALS compared to 0.3% in AJ controls (odds ratio [OR] = 44.3, p < 0.0001). In NAJ, 10% of fALS and 9% of sporadic ALS carried the RE, a total of 9.1% of all NAJ-ALS compared to 1% in controls (OR = 9.9, p = 0.0006). We identified a risk haplotype shared among all ALS patients, although an association with age at disease onset, fALS, and dementia were observed only in AJ. Variations were identified downstream the repeats. The risk haplotype and these polymorphisms were at high frequencies in alleles with 8 repeats or more, suggesting sequence instability. The different genotype-phenotype correlations and OR, together with the large range in age at onset, suggest that other modifiers and risk factors may affect penetrance and phenotype in ALS.