Early functional brain imaging abnormalities in familial frontotemporal dementia (FTD) associated with granulin gene mutations (GRN) has not been well characterized. We used functional MRI to evaluate brain activation during increasingly complex matrix reasoning in asymptomatic carriers of GRN mutations and non-carrier family members. Participants performed a version of Raven’s Progressive Matrices previously shown to specifically recruit the prefrontal cortex. Participants were randomly presented with one of three types of relational integration problems: 0-relational required no relational reasoning, 1-relational processing of a single relation, 2-relational the integration of two relations. Participants included 5 mutation carriers (age 51+9.5 years) and 11 non-carriers (age 53+7.6 years). Mutation carriers’ task performance did not significantly differ from those of non-carriers at any relational level. Whole brain analysis, uncorrected p < 0.005, extension=50 voxels, was performed. Two vs. 1-relational problems revealed abnormal activation in carriers compared to non-carriers in the rostro- dorsolateral and medial prefrontal cortex (PFC) (cluster size 1245) and posterior cingulate gyrus (313). One vs. 0-relational contrast revealed abnormal activation in carriers compared to non-carriers in the right precuneus (81), left lateral PFC (68), and caudate (58). These regions of abnormal activation in GRN mutation carriers highly overlap with regions implicated in relational processing in healthy adults. These findings suggest the existence of very early functional brain changes associated with complex problem-solving in GRN-related neurodegeneration. Task-based fMRI may be a marker of these abnormalities.
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