A cognitive fMRI study in non-manifesting LRRK2 and GBA carriers

Mutations in the GBA and LRRK2 genes account for one-third 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. PD patient who carry mutations in the GBA gene demonstrates more significant cognitive decline compared to idiopathic PD patients. We assessed cognitive domains using fMRI among NMC of both LRRK2 and GBA mutations to better understand pre-motor cognitive functions in these populations. Twenty-one LRRK2-NMC, 10 GBA-NMC, and 22 non-manifesting non-carriers (NMNC) who participated in this study were evaluated using the standard questionnaires and scanned while performing two separate cognitive tasks; a Stroop interference task and an N-Back working memory task. Cerebral activation patterns were assessed using both whole brain and predefined region of interest (ROI) analysis. Subjects were well matched in all demographic and clinical characteristics. On the Stroop task, in spite of similar behavior, GBA-NMC demonstrated increased task-related activity in the right medial frontal gyrus and reduced task-related activity in the left lingual gyrus compared to both LRRK2-NMC and NMNC. In addition, GBA-NMC had higher activation patterns in the incongruent task compared to NMNC in the left medial frontal gyrus and bilateral precentral gyrus. No whole-brain differences were noted between groups on the N-Back task. Paired cognitive and task-related performance between GBA-NMC, LRRK2-NMC, and NMNC could indicate that the higher activation patterns in the incongruent Stroop condition among GBA-NMC compared to LRRK2-NMC and NMNC may represent a compensatory mechanism that enables adequate cognitive performance.