Cognitive Functioning of Glucocerebrosidase (GBA) Non-manifesting Carriers.

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

doi:10.3389/fneur.2021.635958

Abstract

Mutations and variants in the glucocerebrosidase (GBA) gene are among the most common genetic risk factors for the development of Parkinson's disease (PD). Yet, penetrance is markedly reduced, and less is known about the burden of carrying a single mutation among those without diagnosed PD. Motor, cognitive, psychiatric, and olfactory functioning were assessed in 30 heterozygous GBA mutation carriers without PD (the majority of whom had mild GBA mutations) and 49 non-carriers without PD. Study focus was on domains affected in GBA mutation carriers with PD, as well as those previously shown to be abnormal in GBA mutation carriers without PD. GBA mutation carriers showed poorer performance on the Stroop interference measure of executive functioning when controlling for age. There were no group differences in verbal memory, Montreal Cognitive Assessment (MoCA), overall motor score, or presence of REM sleep behavior disorder or depression. Although total olfaction scores did not differ, GBA mutation carriers with hyposmia had lower global cognition scores than those without hyposmia. As anticipated by the low penetrance of GBA mutations, these findings suggest that pre-manifest non-motor or motor features of PD may not present in most GBA mutation carriers. However, there is support that there may be a subtle difference in executive functioning among some non-manifesting heterozygous GBA mutation carriers, and, combined with olfaction, this may warrant additional scrutiny as a potential biomarker for pre-manifest and pre-clinical GBA related PD.

Highlights

GBA mutations are a common genetic risk factor for Parkinson disease (PD) and dementia with Lewy Bodies (DLB) [1,2,3]
UPDRS-III, Montreal Cognitive Assessment (MoCA), Hopkins Verbal Learning Test—Revised (HVLT-R) Z-score, and Stroop interference T-score, and University of Pennsylvania Smell Identification Test (UPSIT) scores did not differ between groups
Findings from this study detail key associations between GBA mutation status and symptoms related to Parkinson’s disease (PD)

Summary

Introduction

GBA mutations are a common genetic risk factor for Parkinson disease (PD) and dementia with Lewy Bodies (DLB) [1,2,3]. While harboring two copies of certain GBA mutations may lead to Gaucher disease, both mono- and biallelic GBA mutation carriers are at an increased risk of developing PD. GBA related PD (GBA-PD) may have earlier age of onset and more prominent non-motor features than idiopathic PD [4,5,6]. This includes an increased risk of mild. GBA Non-manifesting Carriers cognitive impairment [7] and dementia [8,9,10]. GBA-PD may exhibit a specific cognitive profile, with greater weakness in working memory/executive functioning [9], and visuospatial processing relative to idiopathic PD [9]. Biallelic carriers may have significant olfactory disturbance [12], and monoallelic carriers experience more olfactory dysfunction relative to non-carriers [4], though the relationship between GBA status and olfaction has not been universally demonstrated [13]

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