Intact working memory in non‐manifesting LRRK2 carriers – an fMRI study

Cognitive impairments are prevalent in patients with Parkinson's disease. Mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene are the most common cause of genetic Parkinsonism. Non‐manifesting carriers of the G2019S mutation in the LRRK2 gene were found to have lower executive functions as measured by the Stroop task. This exploratory study aimed to assess whether the cognitive impairment in non‐manifesting carriers is specific for executive functions or includes other cognitive domains such as working memory. We recruited 77 non‐manifesting first‐degree relatives of Parkinson's disease patients (38 carriers). A block‐design fMRI N‐back task, with 0‐back, 2‐back and 3‐back conditions, was used in order to assess working memory. Participants were well matched on the Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test, Unified Parkinson's Disease Rating Scale part III, digit span, age, gender and Beck Depression Inventory. The task achieved the overall expected effect in both groups with longer reaction times and lower accuracy rates with increasing task demands. However, no whole‐brain or region‐of‐interest between‐groups differences were found on any of the task conditions. These results indicate that non‐manifesting carriers of the G2019S mutation in the LRRK2 gene have a specific cognitive profile with executive functions, as assessed by the Stroop task, demonstrating significant impairment but with working memory, as assessed with the N‐back task, remaining relatively intact. These finding shed light on the pre‐motor cognitive changes in this unique ‘at risk’ population and should enable more focused cognitive assessments of these cohorts.