The Frequency of Korean Patients With Parkinson's Disease Carrying GBA Mutations in a Subgroup With Age at Onset ≤ 55 Years Old.
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ABSTRACT:
SUBMITTER: Hwangbo J
PROVIDER: S-EPMC10236015 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
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The Frequency of Korean Patients With Parkinson's Disease Carrying GBA Mutations in a Subgroup With Age at Onset ≤ 55 Years Old.
Hwangbo Jin J Lee Myung Jun MJ Kim Sang Jin SJ Lee Jae-Hyeok JH
Journal of movement disorders 20230307 2
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Project description:Understanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson's disease (PD) given the architecture of the basal ganglia. Here, we developed a custom three-chambered microfluidic platform and established a cortico-striato-nigral microcircuit partially recapitulating the striatal presynaptic landscape in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, cortical glutamatergic projections facilitated MSN synaptic activity, and dopaminergic transmission enhanced maturation of MSNs in vitro. Replacement of wild-type iPSC-derived dopamine neurons (iPSC-DaNs) in the striatal microcircuit with those carrying the PD-related GBA-N370S mutation led to a depolarisation of resting membrane potential and an increase in rheobase in iPSC-MSNs, as well as a reduction in both voltage-gated sodium and potassium currents. Such deficits were resolved in late microcircuit cultures, and could be reversed in younger cultures with antagonism of protein kinase A activity in iPSC-MSNs. Taken together, our results highlight the unique utility of modelling striatal neurons in a modular physiological circuit to reveal mechanistic insights into GBA1 mutations in PD.
| S-EPMC11014935 | biostudies-literature
Project description:A 55-year-old former professional athlete reported out of proportion dyspnea on exertion. After a detailed cardiac investigation, a cardiopulmonary exercise test on an ergocycle demonstrated an abnormal and non-physiological ventilatory response characterized by a sharp rise in ventilation followed by a decrease while exercise workload was progressively increasing. This was accompanied by noisy breathing. A laryngoscopy with direct visualisation of larynx and vocal cord during voluntary eucapnic hyperventilation confirmed the diagnosis of exercise-induced laryngeal obstruction. The patient was treated with speech therapy and all the symptoms resolved. A second cardiopulmonary exercise test showed a normalisation of the ventilatory pattern during exercise. This case demonstrates the importance of recognizing the symptoms of an exercise-induced laryngeal obstruction regardless of age, and the effectiveness of the speech therapy on symptoms and on exercise testing.
| S-EPMC6997562 | biostudies-literature
Project description:BackgroundGBA mutations are numerically the most significant genetic risk factor for Parkinson's disease (PD), yet these mutations have low penetrance, suggesting additional mechanisms.ObjectivesThe objective of this study was to determine if the penetrance of GBA in PD can be explained by regulatory effects on GBA and modifier genes.MethodsGenetic variants associated with the regulation of GBA were identified by screening 128 common single nucleotide polymorphisms (SNPs) in the GBA locus for spatial cis-expression quantitative trail locus (supported by chromatin interactions).ResultsWe identified common noncoding SNPs within GBA that (1) regulate GBA expression in peripheral tissues, some of which display α-synuclein pathology and (2) coregulate potential modifier genes in the central nervous system and/or peripheral tissues. Haplotypes based on 3 of these SNPs delay disease onset by 5 years. In addition, SNPs on 6 separate chromosomes coregulate GBA expression specifically in either the substantia nigra or cortex, and their combined effect potentially modulates motor and cognitive symptoms, respectively.ConclusionsThis work provides a new perspective on the haplotype-specific effects of GBA and the genetic etiology of PD, expanding the role of GBA from the gene encoding the β-glucocerebrosidase (GCase) to that of a central regulator and modifier of PD onset, with GBA expression itself subject to distant regulation. Some idiopathic patients might possess insufficient GBA-encoded GCase activity in the substantia nigra as the result of distant regulatory variants and therefore might benefit from GBA-targeting therapeutics. The SNPs' regulatory impacts provide a plausible explanation for the variable phenotypes also observed in GBA-centric Gaucher's disease and dementia with Lewy bodies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, LLC on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC7496525 | biostudies-literature
Project description:Objectives:To determine whether the prevalence of cognitive limitation (CL) among Americans ages 55 to 69 years changed between 1998 and 2014, and to assess the trends in socioeconomic disparities in CL among groups defined by race/ethnicity, education, income, and wealth. Method:Logistic regression using 1998-2014 data from the biennial Health and Retirement Study, a nationally representative data set. CL is defined as a score of 0-11 on a 27-point cognitive battery of items focused on memory. Socioeconomic status (SES) measures are classified as quartiles. Results:In models controlling for age, gender, and previous cognitive testing, we find no significant change over time in the overall prevalence of CL, widening disparities in limitation by income and, in some cases, wealth, and improvements among non-Hispanic whites but not other racial/ethnic groups. Discussion:Among people 55-69, rates of CL are many times higher for groups with lower SES than those with higher SES, and recent trends show little indication that the gaps are narrowing.
| S-EPMC6019031 | biostudies-literature
Project description:ObjectiveGlucosylceramidase (GBA) variants and onset age significantly affect clinical phenotype and progression in Parkinson's disease (PD). The current study compared clinical characteristics at baseline and cognitive and motor progression over time among patients having GBA-related PD (GBA-PD), early-onset idiopathic PD (early-iPD), and late-onset idiopathic PD (late-iPD).MethodsWe recruited 88 GBA-PD, 167 early-iPD, and 488 late-iPD patients in this study. A subset of 50 GBA-PD, 81 early-iPD, and 223 late-iPD patients was followed up at least once, with a 3.0-year mean follow-up time. Linear mixed-effects models helped evaluate the rate of change in the Unified Parkinson's Disease Rating Scale motor and Montreal Cognitive Assessment scores.ResultsAt baseline, the GBA-PD group showed more severe motor deficits and non-motor symptoms (NMSs) than the early-iPD group and more NMSs than the late-iPD group. Moreover, the GBA-PD group had more significant cognitive and motor progression, particularly bradykinesia and axial impairment, than the early-iPD and late-iPD groups at follow-up. However, the early-onset GBA-PD (early-GBA-PD) group was similar to the late-onset GBA-PD (late-GBA-PD) group in baseline clinical features and cognitive and motor progression.ConclusionGBA-PD patients exhibited faster cognitive and motor deterioration than early-iPD and late-iPD patients. Thus, subtype classification based on genetic characteristics rather than age at onset could enhance the prediction of PD disease progression.
| S-EPMC10848098 | biostudies-literature
Project description:Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.
| S-EPMC6935749 | biostudies-literature
Project description:IntroductionParkinson's disease patients carrying a heterozygous mutation in the gene glucocerebrosidase (GBA-PD) show faster motor and cognitive decline than idiopathic Parkinson's disease (iPD) patients, but the mechanisms behind this observation are not well understood. Successful dual tasking (DT) requires a smooth integration of motor and nonmotor operations. This study compared the DT performances between GBA-PD and iPD patients.MethodsEleven GBA-PD patients (p.N370S, p.L444P) and eleven matched iPD patients were included. Clinical characterization included a motor score (Unified PD Rating Scale-III, UPDRS-III) and nonmotor scores (Montreal Cognitive Assessment, MoCA, and Beck's Depression Inventory). Quantitative gait analysis during the single-task (ST) and DT assessments was performed using a wearable sensor unit. These parameters corrected for UPDRS and MoCA were then compared between the groups.ResultsUnder the DT condition "walking while checking boxes," GBA-PD patients showed slower gait and box-checking speeds than iPD patients. GBA-PD and iPD patients did not show significant differences regarding dual-task costs.ConclusionThis pilot study suggests that DT performance with a secondary motor task is worse in GBA-PD than in iPD patients. This finding may be associated with the known enhanced motor and cognitive deficits in GBA-PD compared to iPD and should motivate further studies.
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Project description:PURPOSE:The mortality risk of stage II differentiated thyroid cancer (DTC) based on the American Joint Committee on Cancer (AJCC) staging system requires further investigation. METHODS:Retrospective study of DTC in the US Surveillance, Epidemiology, and End Results program for disease-specific mortality risk in various AJCC stages, with patient age stratification of stage II disease. RESULTS:Using AJCC staging system 6.0, hazard ratios (HRs) of mortality for stage II DTC in patients <45 yo and patients ≥45 yo and stages III, IVA, IVB, and IVC compared with stage I were 46.95, 4.95, 9.82, 57.37, 222.10, and 468.68, respectively, showing a robustly higher mortality risk in stage II disease in patients <45 yo than in older patients (P < 0.001), comparable with stage IVA (P = 0.482). Similar results were obtained with AJCC 7.0. With AJCC 8.0, HRs of mortality for stage II in patients <55 yo and patients ≥55 yo and stages III, IVA, and IVB compared with stage I were 75.16, 11.23, 69.45, 134.94, and 235.70, respectively, showing a robustly higher risk in stage II disease in patients <55 yo than in older patients (P < 0.001), comparable with stage III (P = 0.57). Kaplan-Meier survival curves displayed a sharp decline with stage II disease in patients <45/55 yo compared with older patients. CONCLUSIONS:The mortality risk of stage II DTC was sharply differentiated at patient age 45/55 years, being robustly high in younger patients and comparable with stage III/IVA. This emphasizes the importance of considering age when managing stage II DTC and not treating it as a uniformly low-risk disease.
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Project description:CoronaVac is an inactivated SARS-CoV-2 vaccine that has been rolled out in several low and middle-income countries including Brazil, where it was the mainstay of the first wave of immunization of healthcare workers and the elderly population. We aimed to assess the T cell and antibody responses of vaccinated individuals as compared to convalescent patients. We detected IgG against SARS-CoV-2 antigens, neutralizing antibodies against the reference Wuhan SARS-CoV-2 strain and used SARS-CoV-2 peptides to detect IFN-g and IL-2 specific T cell responses in a group of CoronaVac vaccinated individuals (N = 101) and convalescent (N = 72) individuals. The frequency among vaccinated individuals, of whom 96% displayed T cell and/or antibody responses to SARS-CoV-2, is comparable to 98.5% responses of convalescent individuals. We observed that among vaccinated individuals, men and individuals 55 years or older developed significantly lower anti-RBD, anti-NP and neutralization titers against the Wuhan strain and antigen-induced IL-2 production by T cells. Neutralizing antibody responses for Gamma variant were even lower than for the Wuhan strain. Even though some studies indicated CoronaVac helped reduce mortality among elderly people, considering the appearance of novel variants of concern, CoronaVac vaccinated individuals above 55 years old are likely to benefit from a heterologous third dose/booster vaccine to increase immune response and likely protection.
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Project description: Not available
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