Abstract
The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.
Highlights
The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy
The relationship between structure and cognition was similar in both groups, the coupling between function and cognition was stronger for presymptomatic carriers, and increased as they approached the expected onset of disease
These results suggest that people can maintain good cognitive abilities and successful day-to-day functioning despite significant neuronal loss and atrophy
Summary
The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy We investigate this phenomenon in familial frontotemporal dementia (FTD). Three main genes account for 10% to 20% of FTD cases: chromosome 9 open reading frame 72 (C9orf72), granulin (GRN), and microtubule-associated protein tau (MAPT) These genes vary in their phenotypic expression and in the age at onset.[9] Despite pleiotropy[10] and environmental and secondary genetic moderation[11,12] all three mutations cause significant structural brain changes in key regions over a decade before the expected age at disease onset,[7,13] confirmed by longitudinal studies.[14,15]
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