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BACKGROUND: MRI is an important tool for disease diagnosis of Creutzfeldt-Jakob disease (CJD), yet its role in identifying preclinical stages of disease remains unclear. Here, we explored subtle white matter (WM) alterations in genetic CJD (gCJD) patients and in asymptomatic E200K mutation carriers using MRI, depending on total tau protein (t-tau) levels in CSF. METHODS: Six symptomatic gCJD patients and N=60 healthy relatives of gCJD patients were included. Participants underwent genetic testing for the E200K mutation, MRI scans at 3T and a lumbar puncture (LP) for t-tau. Diffusion tensor imaging (DTI) metrics were calculated along WM tracts. RESULTS: gCJD patients demonstrated higher mean diffusivity (MD), radial diffusivity (RD) and lower fractional anisotropy (FA) values compared with healthy relatives in several WM tracts (p<0.05). Out of the healthy relatives, 50% (N=30) were found to be carriers of the E200K mutation. T-tau levels in cerebrospinal fluid (CSF) were above the normal range (>290 pg/mL) in N=8 out of 23 carriers who underwent an LP. No significant differences in FA, MD, axial diffusivity (AD) and RD were detected between healthy mutation carriers (HMC) and healthy non-carriers within the WM tracts. Finally, significantly higher FA and lower MD, RD and AD along several WM tracts were found in HMC with elevated t-tau compared with HMC with normal t-tau (p<0.05). CONCLUSIONS: DTI abnormalities along WM tracts were found in healthy E200K mutation carriers with elevated t-tau in CSF. Longer follow-up is required to determine whether these subtle WM alterations are predictive of future conversion to symptomatic gCJD. TRIAL REGISTRATION NUMBER: NCT05746715.
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BACKGROUND AND PURPOSE: Subtle executive dysfunction is common in people newly diagnosed with Parkinson disease (PD), even when general cognitive abilities are intact. This study examined the Short Weekly Calendar Planning Activity (WCPA-10)'s known-group construct validity, comparing persons with PD to healthy controls (HCs) and nonmanifesting carriers of LRRK2 and GBA gene mutations to HCs. Additionally, convergent and ecological validity was examined. METHODS: The study included 73 participants: 22 with idiopathic PD (iPD) who do not carry any of the founder GBA mutations or LRRK2-G2019S, 29 nonmanifesting carriers of the G2019S-LRRK2 (n = 14) and GBA (n = 15) mutations, and 22 HCs. Known-group validity was determined using the WCPA-10, convergent validity by also using the Montreal Cognitive Assessment (MoCA) and Color Trails Test (CTT), and ecological validity by using the WCPA-10, Schwab and England Activities of Daily Living Scale (SE ADL), and Physical Activity Scale for the Elderly (PASE). RESULTS: Known-group validity of the WCPA-10 was established for the iPD group only; they followed fewer rules (p = 0.020), were slower (p = 0.003) and less efficient (p = 0.001), used more strategies (p = 0.017) on the WCPA-10, and achieved significantly lower CTT scores (p < 0.001) than the HCs. The nonmanifesting carriers and HCs were similar on all cognitive tests. Convergent and ecological validity of the WCPA-10 were partially established, with few correlations between WCPA-10 outcome measures and the MoCA (r = 0.50, r = 0.41), CTT-2 (r = 0.43), SE ADL (r = 0.41), and PASE (r = 0.54, r = 0.46, r = 0.31). CONCLUSIONS: This study affirms the known-group validity for most (four) WCPA-10 scores and partially confirms its convergent and ecological validity for PD.
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Glucosilceramidasa , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/diagnóstico , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Femenino , Masculino , Glucosilceramidasa/genética , Persona de Mediana Edad , Anciano , Función Ejecutiva/fisiología , Heterocigoto , Actividades Cotidianas , Reproducibilidad de los Resultados , Mutación , Pruebas Neuropsicológicas/normasRESUMEN
BACKGROUND: Mild cognitive impairment (MCI) is common in Parkinson's disease (PD). We aimed to assess the incidence of MCI among patients with PD, carriers of mutations in LRRK2 and GBA1 genes, based on the movement disorder society (MDS) criteria for the diagnosis of MCI in early-stage PD. METHODS: Patients with PD were included if they scored ≤2 on the Hoehn and Yahr and ≤6 years since motor symptom onset. A group of age and gender matched healthy adults served as controls. A neuropsychological cognitive battery was used covering five cognitive domains (executive functions, working memory, memory, visuospatial and language). MCI was explored while applying two methods (level I and II). Frequency of MCI was assessed in comparison between groups. RESULTS: 70 patients with idiopathic PD (iPD) (68 % males), 42 patients with LRRK2-PD (61 % males), 83 patients with GBA1-PD (63 % males) and 132 age and gender matched controls (61 % males), participated in this study. PD groups were similar in clinical characteristics. Level I criteria were positive in 57.5 % of iPD, 43 % of LRRK2-PD and 63.4 % of the GBA1-PD (p = 0.071). Level II criteria was met by 39 % of iPD, 14 % LRRK2-PD and 41 % of GBA1-PD (p < 0.001), when using a 2 standard-deviation (SD) threshold. GBA1-PD and iPD showed impairments on multiple domains even in the more conservative 2 SD, reflecting MCI. CONCLUSIONS: The majority of our PD cohort was classified as MCI when assessed with strict criteria. GBA1-PD and iPD showed a more widespread pattern of MCI compared with LRRK2-PD.
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Disfunción Cognitiva , Glucosilceramidasa , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Masculino , Femenino , Disfunción Cognitiva/etiología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/complicaciones , Glucosilceramidasa/genética , Anciano , Persona de Mediana Edad , Mutación , Pruebas NeuropsicológicasRESUMEN
OBJECTIVES: VPS35 and VPS13 have been associated with Parkinson's disease (PD), and their shared phenotype in yeast when reduced in function is abnormal vacuolar transport. We aim to test if additional potentially deleterious variants in other genes that share this phenotype can modify the risk for PD. METHODS: 77 VPS and VPS-related genes were analyzed using whole-genome-sequencing data from 202 PD patients of Ashkenazi Jewish (AJ) ancestry. Filtering was done based on quality and functionality scores. Ten variants in nine genes were further genotyped in 1200 consecutively recruited unrelated AJ-PD patients, and allele frequencies and odds ratio calculated compared to gnomAD-AJ-non-neuro database, in un-stratified (n = 1200) and stratified manner (LRRK2-G2019S-PD patients (n = 145), GBA-PD patients (n = 235), and non-carriers of these mutations (NC, n = 787)). RESULTS: Five variants in PIK3C3, VPS11, AP1G2, HGS and VPS13D were significantly associated with PD-risk. PIK3C3-R768W showed a significant association in an un-stratified (all PDs) analysis, as well as in stratified (LRRK2, GBA, and NC) analyses (Odds ratios = 2.71, 5.32, 3.26. and 2.19 with p = 0.0015, 0.002, 0.0287, and 0.0447, respectively). AP1G2-R563W was significantly associated in LRRK2-carriers (OR = 3.69, p = 0.006) while VPS13D-D2932N was significantly associated in GBA-carriers (OR = 5.45, p = 0.0027). VPS11-C846G and HGS-S243Y were significantly associated in NC (OR = 2.48 and 2.06, with p = 0.022 and 0.0163, respectively). CONCLUSIONS: Variants in genes involved in vesicle-mediated protein transport and recycling pathways, including autophagy and mitophagy, may differentially modify PD-risk in LRRK2-carriers, GBA carriers, or NC. Specifically, PIK3C3-R768W is a PD-risk allele, with the highest effect size in LRRK2-G2019S carriers. These results suggest oligogenic effect that may depends on the genetic background of the patient. An unbiased burden of mutations approach in these genes should be evaluated in additional PD and control groups. The mechanisms by which these novel variants interact and increase PD-risk should be researched in depth for better tailoring therapeutic intervention for PD prevention or slowing disease progression.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Genotipo , Heterocigoto , Mutación , Fenotipo , Glucosilceramidasa/genética , Proteínas/genéticaRESUMEN
BACKGROUND: Creutzfeldt-Jakob Disease (CJD) is the most common prion disease in humans causing a rapidly progressive neurological decline and dementia and is invariably fatal. The familial forms (genetic CJD, gCJD) are caused by mutations in the PRNP gene encoding for the prion protein (PrP). In Israel, there is a large cluster of gCJD cases, carriers of an E200K mutation in the PRNP gene, and therefore the largest population of at-risk individuals in the world. The mutation is not necessarily sufficient for the formation and accumulation of the pathological prion protein (PrPsc), suggesting that other, genetic and non-genetic factors affect the age at symptoms onset. Here we present the protocol of a cross-sectional and longitudinal natural history study of gCJD patients and first-degree relatives of gCJD patients, aiming to identify biological markers of preclinical CJD and risk factors for phenoconversion. METHODS: The study has two groups: Patients diagnosed with gCJD, and first-degree healthy relatives (HR) (both carriers and non-carriers of the E200K mutation in the PRNP gene) of patients diagnosed with gCJD. At baseline, and at the end of every year, healthy participants are invited for an "in-depth" visit, which includes a clinical evaluation, blood and urine collection, gait assessment, brain MRI, lumbar puncture (LP), and Polysomnography (PSG). At 6 months from baseline, and then halfway through each year, participants are invited for a "brief" visit, which includes a clinical evaluation, short cognitive assessment, and blood and urine collection. gCJD patients will be invited for one "in-depth" visit, similar to the baseline visit of healthy relatives. DISCUSSION: This continuous follow-up of the participants and the frequent assessments will allow early identification and diagnosis in case of conversion into disease. The knowledge generated from this study is likely to advance the understanding of the underlying clinicopathological processes that occur at the very beginning of CJD, as well as potential genetic and environmental risk factors for the development of the disease, therefore advancing the development of safe and efficient interventions. TRIAL REGISTRATION: The study is an observational study. It has registered retrospectively in https://clinicaltrials.gov/ and has been assigned an identification number NCT05746715.
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Síndrome de Creutzfeldt-Jakob , Priones , Humanos , Síndrome de Creutzfeldt-Jakob/patología , Proteínas Priónicas/genética , Estudios Transversales , Estudios Longitudinales , Estudios Prospectivos , Estudios Retrospectivos , Priones/genética , Priones/metabolismo , Mutación/genética , Estudios Observacionales como AsuntoRESUMEN
Background: Mood disorders have emerged as major non-motor comorbidities in Parkinson's disease (PD) even at the prodromal stage of the disease. Mutations in the LRRK2 and GBA genes are common among Ashkenazi Jews, with more severe phenotype reported for GBA-PD. Objective: To explore the association between genetic status and mood related disorders before and after diagnosis of PD and the association between mood-related medications, phenotype, and genetic status. Methods: Participants were genotyped for mutations in the LRRK2 and GBA genes. State of depression, anxiety and non-motor features were evaluated using validated questionnaires. History of mood disorders prior to diagnosis of PD and use of mood-related medications were assessed. Results: The study included 105 idiopathic PD (iPD), 55 LRRK2-PD and 94 GBA-PD. Scores on mood related questionnaires and frequency of depression and anxiety before diagnosis were similar between the groups (p>0.05). However, more GBA-PD patients used mood related medications before PD diagnosis than LRRK2-PD and iPD (16.5% vs 7.1% and 8.2%, p=0.044). LRRK2-PD and GBA-PD receiving mood-related medications at time of assessment had worse motor and non-motor phenotype compared to those that did not (p<0.05). LRRK2-PD receiving mood related-medications at time of assessment, scored higher on mood-related questionnaires compared to LRRK2-PD not receiving such medications (p<0.04). Conclusions: Prodromal GBA-PD are more frequently treated with mood related-medications despite equal rates of reported mood-related disorders, while LRRK2-PD with mood-related disorders experience high rates of anxiety and depression despite treatment, attesting to the need of more precise assessment and treatment of these genetic subgroups.
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INTRODUCTION: Recent studies found an association between Parkinson's disease (PD) and alterations in the innate immune system. However, whether the involvement of this system in two of the known genetic forms of PD, GBA-PD and LRRK2-PD, and in patients who do not carry these mutations is different, is yet to be determined. We aimed to test if genetic variations in the innate immune genes are differentially associated with PD in these subgroups. METHODS: Innate immune genes were identified and classified into sub-lists according to Reactome pathways. Whole-genome-sequencing (WGS) was performed on 201 unrelated Ashkenazi-Jewish (AJ) PD patients including 104 GBA-PD, 32 LRRK2-PD, and 65 non-carriers-PD (NC-PD). To identify genes with different burden between these subgroups of PD, gene-based Sequence kernel association optimal unified test (SKAT-O) analysis was performed on innate immune pathways. Candidate variants within the significant genes were further genotyped in a cohort of 1200 unrelated, consecutively recruited, AJ-PD patients, and to evaluate their association with PD-risk their allele frequencies were compared to AJ-non-neuro cases in gnomAD database, in a stratified and un-stratified manner. RESULTS: SKAT-O analysis showed significantly different burden for PSMB9 (GBA-PD versus NC-PD) and FGR (GBA-PD versus LRRK2-PD). Two candidate variants in PSMB9 showed an association with GBA-PD-risk and NC-PD-risk while one FGR variant showed an association with LRRK2-PD-risk. CONCLUSION: Our data supports differential involvement of innate immunity risk alleles in PD and emphasizes the differences between the GBA- and LRRK2-PD subgroups.
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Enfermedad de Parkinson , Humanos , Alelos , Frecuencia de los Genes , Genotipo , Glucosilceramidasa/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismoRESUMEN
Introduction: MAPT locus is associated with Parkinson's disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk allele carrier status, and to further characterize genetic alterations that might contribute to its effect. Methods: LD analysis was performed using whole-genome sequencing data of 202 unrelated Ashkenazi Jewish (AJ) PDs. A haplotype-divergent variant was genotyped in a cohort of 1200 consecutively recruited AJ-PDs. The odd ratios were calculated using AJ-non-neuro cases from the gnomAD database as the controls in an un-stratified and a stratified manner according to the mutation carrier status, and the effect on the Age at Motor Symptom Onset (AMSO) was examined. Expression and splicing quantitative trait locus (eQTL and sQTL) analyses were carried out using brain tissues from a database. Results: The H2 haplotype exhibited significant association with PD protection, with a similar effect size in GBA1 carriers, LRRK2-G2019S carriers, and non-carriers (OR = 0.77, 0.69, and 0.82, respectively), and there was no effect on AMSO. The LD interval was narrowed to approximately 1.2 Mb. The H2 haplotype carried potential variants in candidate genes (MAPT and SPPL2C); structural deletions and segmental duplication (KANSL1); and variants affecting gene expression and intron excision ratio in brain tissues (LRRC37A/2). Conclusions: Our results demonstrate that H2 is associated with PD and its protective effect is not influenced by the GBA1/LRRK2 risk allele carrier status. This effect may be genetically complex, resulting from different levels of variations such as missense mutations in relevant genes, structural variations, epigenetic modifications, and RNA expression changes, which may operate independently or in synergy.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Genes Reguladores , Alelos , Intrones , Sitios de Carácter Cuantitativo , Proteínas tau/genéticaRESUMEN
OBJECTIVE: To compare event-related oscillations in patients with dementia with Lewy bodies (DLB) who are carriers and non-carriers of glucocerebrosidase (GBA) mutations. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. SIGNIFICANCE: Preserved inter-trial phase clustering possibly compensates for the impaired power by eliciting the appropriate functional configuration needed for stimulus processing and task performance.
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Glucosilceramidasa , Enfermedad por Cuerpos de Lewy , Glucosilceramidasa/genética , Humanos , Enfermedad por Cuerpos de Lewy/genética , MutaciónRESUMEN
Background and Objectives: Amyotrophic 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. Methods: Exome 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. Results: A 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. Discussion: FUS-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.
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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.
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Glucosilceramidasa , Enfermedad de Parkinson , Glucosilceramidasa/genética , Heterocigoto , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación/genética , Enfermedad de Parkinson/complicacionesRESUMEN
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.
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Proteína C9orf72/genética , Enfermedad de Parkinson/genética , Secuencias Repetitivas de Ácidos Nucleicos , Anciano , Alelos , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
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.
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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-1ß, 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.
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Glucosilceramidasa , Inflamación , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Biomarcadores/análisis , Citocinas/análisis , Glucosilceramidasa/genética , Humanos , Inflamación/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patologíaRESUMEN
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.
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Sistemas de Transporte de Aminoácidos/genética , Predisposición Genética a la Enfermedad , Mitocondrias/genética , Proteínas Mitocondriales/genética , Enfermedad de Parkinson/genética , Proteínas Transportadoras de Solutos/genética , Alelos , Femenino , Genoma Humano/genética , Genotipo , Haplotipos/genética , Heterocigoto , Humanos , Judíos/genética , Masculino , Metionina/metabolismo , Mutación/genética , Enfermedad de Parkinson/patología , Factores de Riesgo , Secuenciación Completa del GenomaAsunto(s)
Metilación de ADN/genética , Predisposición Genética a la Enfermedad , Enfermedad de Parkinson/genética , Amidohidrolasas/genética , Proteínas de Transporte de Catión/genética , Humanos , Proteínas de Transporte de Monosacáridos/genética , Proteínas Nucleares/genética , Enfermedad de Parkinson/patología , Fosfoproteínas/genética , ARN/genética , Factores de Riesgo , Proteínas de Unión al GTP rab/genéticaRESUMEN
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 É4 allele. GBA mutation carriers had a younger age of onset (mean [SD] age, 67.2 years [8.9] versus 71.97 [5.91]; pâ=â0.03), poorer cognition as assessed by the Mini-Mental State Examination (21.41 [6.9] versus 23.97 [5.18]; pâ<â0.005), and more severe parkinsonism as assessed with the Unified Parkinson's Disease Rating Scale motor part III (34.41 [13.49] versus 28.38 [11.21]; pâ=â0.01) compared to non-carriers. There were statistically significant interactions between the two genetic factors, so that patients who carried both a mild GBA mutation and the APOE É4 allele (nâ=â9) had more severe cognitive (pâ=â0.048) and motor dysfunction (pâ=â0.037). CONCLUSION: We found a high frequency of both GBA mutations and the APOE É4 allele among AJ patients with DLB, both of which have distinct effects on the clinical disease phenotype, separately and in combination.
Asunto(s)
Apolipoproteínas E/genética , Glucosilceramidasa/genética , Enfermedad por Cuerpos de Lewy/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Heterocigoto , Humanos , Judíos , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: 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. OBJECTIVE: To assess the association between biochemical markers, PD severity and probability score for prodromal PD, among GBA and LRRK2 mutation carriers. METHODS: 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. RESULT: 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). CONCLUSION: 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.