Cognitive Functioning of Glucocerebrosidase (GBA) Non-manifesting Carriers

Moran, Eileen; Bressman, Susan; Ortega, Roberto A.; Raymond, Deborah; Nichols, William C.; Palmese, Christina A.; Elango, Sonya; Swan, Matthew; Shanker, Vicki; Perera, Imali; Wang, Cuiling; Zimmerman, Molly E.; Saunders‐Pullman, Rachel

doi:10.3389/fneur.2021.635958

Cited by 17 publications

(14 citation statements)

References 31 publications

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“…A total of 4 GBA +DBS+ subjects with clinical and genetic data were available for review (2005–2019). Participants were genotyped for both LRRK2 ‐G2019S and the 11 most common GBA mutations among Ashkenazim: N370S, 84GG, IVS2+1, V394L, D409G, L444P, A456P, RecNcil, R496H, E326K, or T369M, as previously described 24 …”

Section: Methodsmentioning

confidence: 99%

Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers

Pal

Mangone

Hill

et al. 2022

Annals of Neurology

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Objective This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN‐DBS) in Parkinson disease. Methods Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS‐), and noncarriers with or without DBS (GBA‐DBS+, GBA‐DBS‐). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. Results Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS‐, 98 GBA‐DBS+, and 128 GBA‐DBS‐ subjects), who were longitudinally followed (range = 36–60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA‐DBS‐ subjects (95% confidence interval [CI] = −2.35 to −1.69), 1.71 points/yr more than GBA+DBS‐ subjects (95% CI = −2.14 to −1.28), and 1.49 points/yr more than GBA‐DBS+ subjects (95% CI = −1.80 to −1.18). Interpretation Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN‐DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision‐making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN‐DBS so that alternative options may be considered. ANN NEUROL 2022;91:424–435

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Section: Methodsmentioning

confidence: 99%

Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers

Pal

Mangone

Hill

et al. 2022

Annals of Neurology

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“…These regions were subjected to allele‐specific primer extension, hybridized to specific Luminex beads via Universal Tags, and sorted on a Luminex 100 IS platform (Luminex Corporation, Austin, TX, USA). Genotyping was then completed using the Tag‐It Data Analysis Software (Luminex Molecular Diagnostics), and as previously described 34‐36 …”

Section: Methodsmentioning

confidence: 99%

“…Genotyping was then completed using the Tag-It Data Analysis Software (Luminex Molecular Diagnostics), and as previously described. [34][35][36] Family history of parkinsonism in first-degree relatives of probands was determined by self-report through family history screen (standardized family history questionnaire or clinical research screen) or by pedigree review. 7…”

Section: Subjectsmentioning

confidence: 99%

Differences in Sex‐Specific Frequency of Glucocerebrosidase Variant Carriers and Familial Parkinsonism

et al. 2022

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Background Although men and women with the LRRK2 G2019S variant appear to be equally likely to have Parkinson's disease (PD), the sex‐distribution among glucocerebrosidase (GBA) variant carriers with PD, including limited to specific variant severities of GBA, is not well understood. Further, the sex‐specific genetic contribution to PD without a known genetic variant is controversial. Objectives To better understand sex differences in genetic contribution to PD, especially sex‐specific frequencies among GBA variant carriers with PD (GBA PD) and LRRK2‐G2019S variant carriers with PD (LRRK2 PD). Methods We assess differences in the sex‐specific frequency in GBA PD, including in subsets of GBA variant severity, LRRK2 PD, and idiopathic PD in an Ashkenazi Jewish cohort with PD. Further, we expand prior work evaluating differences in family history of parkinsonism. Results Both idiopathic PD (267/420 men, 63.6%) (P < 0.001) and GBA PD overall (64/107, 59.8%) (P = 0.042) were more likely to be men, whereas no difference was seen in LRRK2 PD (50/99, 50.5%) and LRRK2/GBA PD (5/10, 50%). However, among GBA PD probands, severe variant carriers were more likely to be women (15/19 women, 79.0%) (P = 0.005), whereas mild variant carriers (44/70 men, 62.9%) (P = 0.039) and risk‐variant carriers (15/17 men, 88.2%) (P = 0.001) were more likely to be men. Conclusions Our study demonstrates that the male‐sex predominance present in GBA PD overall was not consistent across GBA variant severities, and a female‐sex predominance was present among severe GBA variant carriers. Therefore, research and trial designs for PD should consider sex‐specific differences, including across GBA variant severities. © 2022 International Parkinson and Movement Disorder Society.

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“…Deficient clearance mechanisms of a-synuclein in GBA1 mutants leading to accelerated a-synuclein pathology in cortical areas is thought to underlie the increased rates of cognitive impairment and ultimately, dementia in GBA1 -PD patients (Jesus et al 2016 ). Partial support exists for a subtle alteration in cognitive functioning in GBA1 mutation-positive individuals without PD (Avenali et al 2019 ; Moran et al 2021 ). Ongoing longitudinal studies aim to identify cognitive decline, other NMS and motor abnormalities in individuals harbouring GBA1 mutations prior to the onset of PD symptoms (Higgins et al 2021 ).…”

Section: Features Of Gba1 -Associated Parkinson Di...mentioning

confidence: 99%

Glucocerebrosidase mutations and Parkinson disease

Vieira

Schapira

2022

J Neural Transm

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The discovery of glucocerebrosidase (GBA1) mutations as the greatest numerical genetic risk factor for the development of Parkinson disease (PD) resulted in a paradigm shift within the research landscape. Efforts to elucidate the mechanisms behind GBA1-associated PD have highlighted shared pathways in idiopathic PD including the loss and gain-of-function hypotheses, endoplasmic reticulum stress, lipid metabolism, neuroinflammation, mitochondrial dysfunction and altered autophagy–lysosomal pathway responsible for degradation of aggregated and misfolded a-synuclein. GBA1-associated PD exhibits subtle differences in phenotype and disease progression compared to idiopathic counterparts notably an earlier age of onset, faster motor decline and greater frequency of non-motor symptoms (which also constitute a significant aspect of the prodromal phase of the disease). GBA1-targeted therapies have been developed and are being investigated in clinical trials. The most notable are Ambroxol, a small molecule chaperone, and Venglustat, a blood–brain-barrier-penetrant substrate reduction therapy agent. It is imperative that further studies clarify the aetiology of GBA1-associated PD, enabling the development of a greater abundance of targeted therapies in this new era of precision medicine.

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Cognitive Functioning of Glucocerebrosidase (GBA) Non-manifesting Carriers

Cited by 17 publications

References 31 publications

Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers

Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers

Differences in Sex‐Specific Frequency of Glucocerebrosidase Variant Carriers and Familial Parkinsonism

Glucocerebrosidase mutations and Parkinson disease

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