Cognitive performance of GBA mutation carriers with early-onset PD

Abstract

Objective: To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). Methods:We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age-and PD duration-matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed.

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

“…Mutations in GBA are now recognized as an independent risk factor for development of cognitive impairment in patients with PD (24)(25)(26)(27). The Gba D409V/D409V mice present several distinct features of synucleinopathies, including cognitive impairment and pathogenic accumulation of α-synuclein, ubiquitin, and tau aggregates (21,22).…”

Glucocerebrosidase Mutations in Parkinson Disease

“…Heterozygotes have a 10-30% chance of developing PD by age 80, which constitutes a 20-fold increase compared to non-carriers [7][8][9][10], and approximately 5-25% of "idiopathic" PD patients carry GBA mutations, making GBA mutations the greatest risk factor for PD discovered to date [11,12].…”

“…Several studies assessed the difference in cognitive performance between PD patients with and without GBA mutations [10,55,58,[61][62][63][65][66][67][68][69][70]; according to a recent meta-analysis, the risk of cognitive impairment is estimated to be 3 times higher for patients with GBA mutations [49]. However, significant differences in cognitive function between PD patients with and without GBA mutations were not confirmed in some studies [13,62,71,72].…”

“…There is poor agreement on the role of the GBA polymorphisms E326K on cognition: one study found that both E326K patients and GBA mutation patients have a higher risk of cognitive deterioration [75], another found that the association between GBA and cognitive decline was significant in E326K patients but not in PD patients with GBA mutations [53] and, finally, patients with PD and GBA mutations but not E326K or other polymorphisms progress to dementia more rapidly than non-carriers [52]. Specific cognitive profiles have been associated with GBA mutations in PD patients: one study focused on memory and visuospatial domains [10], while another on abstraction and orientation domains [61]. Impairment in working memory, executive function and visuospatial abilities seemed to be a characteristic of PD both with GBA mutations and E326K variant [75].…”

Glucocerebrosidase, a new player changing the old rules in Lewy body diseases

“…The frequency of GBA1 mutation in subjects with mixed pathology of LB-type and AD-type was in between that of pure LB and pure AD subjects, suggesting a strong association between GBA1 mutation and LB-type neuropathological changes. Another study suggested that GBA1 mutation status might be an independent risk factor for cognitive impairment in patients with PD (Alcalay et al , 2012 ) (also see below for the relationship between GBA1 mutation and LB pathology).…”