Objective: To assess the cognitive profile of non-manifesting carriers of GBA and LRRK2 mutations using two fMRI tasks: a Stroop interference and N-Back working memory task.

Background: Mutations in the GBA and LRRK2 genes account for 1/3 of the prevalence of Parkinson’s disease (PD) in Ashkenazi Jews. Non-manifesting carriers (NMC) of these mutations represent a population at risk for future development of PD. High rates of cognitive impairment have been documented in PD patients with up to a quarter of patients demonstrating cognitive impairments at diagnosis. While NMC of the G2019S mutation in the LRRK2 gene have been thoroughly investigated, little is currently known about NMC of mutations in the GBA gene.

Methods: Participants were scanned while performing two separate tasks, a Stroop color word interference and an N-Back working memory task (0, 2, 3-Back). Demographic data was collected, participants were evaluated using the Unified Parkinson’s disease Rating Scale (UPDRS), the Montreal Cognitive Assessment test (MoCA), the Beck Depression Inventory (BDI) and Spielberger’s Trait and State Anxiety Inventory (STAI). Reaction times and error rates of the tasks were analyzed as well. Cerebral activation patterns were assessed using both a whole brain analysis and a predefined region of interest (ROI) analysis.

Results: Twenty-one LRRK2-NMC, 10 GBA-NMC and 22 non-manifesting non-carriers (NMNC) of either mutations participated in this study. Subjects were well matched in all aspects assessed herein

group charectaristics

	NUMBER	AGE	UPDRS III	MOCA	STAI-T	STAI-S	BDI
LRRK2-NMC	21	47.9(1.79)	2.231(0.51)	27.09(0.49)	35.52(1.56)	31.47(2.04)	2.26(2.27)
GBA-NMC	10	50.41(2.34)	0.71(0.39)	28.00(0.42)	35.20(2.74)	34.00(4.23)	4.30(1.43)
NMNC	22	50.04(2.61)	1.27(0.31)	26.72(0.37)	30.72(1.40)	29.13(1.73)	2.91(0.64)
P	NS	NS	NS	NS	NS	NS	NS

NMC-non-manifesting carrier, NMNC- non-manifesting non-carrier, NS- non-significant, BDI-Beck Depression Inventory, STAI (T,S) – State-Trait Anxiety Inventory, UPDRS III- part III Unified Parkinson’s disease Rating Scale, MoCA-Montreal Cognitive Assessment“. On the Stroop task, GBA-NMC demonstrated different activation patterns in the right medial frontal gyrus and left lingual gyrus compared to both LRRK2-NMC and NMNC. No significant differences between GBA-NMC and NMNC were noted in the ROI analysis. On the N-back task, GBA-NMC did not demonstrate any significant activation differences compared to NMNC on whole brain analysis. However, in an ROI analysis, differential activation patterns in the posterior cingulate cortex and left lateral prefrontal cortex were detected.

Conclusions: Paired cognitive and task related performance between GBA-NMC, LRRK2-NMC and NMNC could indicate that the higher activation patterns in the less challenging Stroop and N-back conditions in GBA-NMC compared to LRRK2-NMC and NMNC might represent a compensatory mechanism, with a breakdown of this mechanisms in more demanding conditions.

This abstract has been submitted to the 2016 AAN conference.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-cognitive-fmri-study-of-non-manifesting-lrrk2-and-gba-carriers/