Sex differences in the behavioral variant of frontotemporal dementia: A new window to executive and behavioral reserve

Abstract

AbstractBackgroundThe behavioral variant of frontotemporal dementia (bvFTD) is characterized by progressive behavioral change along with social, cognitive, and functional deterioration. In contrast Alzheimer´s disease, patients with bvFTD show an anterior pattern of neurodegeneration with selective involvement of the frontotemporal cortex. Biological sex is an increasingly recognized factor driving clinical heterogeneity in Alzheimer's disease, but its role in bvFTD is unknown.MethodIn this multicenter study, we aimed to characterize the impact of sex on clinical presentation, longitudinal decline, and cortical thickness in bvFTD. We included 216 patients with bvFTD and 235 controls with MRI. We compared the clinical characteristics and cortical thickness between men and women with bvFTD and controls. We further explored the existence of sex differences in cognitive reserve by following the residuals approach to operationalize reserve as having better cognition and fewer behavioral changes than predicted by cortical thickness (a proxy of pathology). To do this, we modeled the relationship between cognition or behavior with cortical thickness and used each individual's residual as a proxy of their reserve.ResultAt diagnosis, women with bvFTD showed greater atrophy burden in frontotemporal regions compared to men despite very subtle differences in cognitive and functional impairment, progression, and survival. For a similar amount of atrophy, women demonstrated better‐than‐expected scores on executive function and less apathy, sleep, and appetite changes than men.ConclusionOur findings suggest that women might have greater behavioral and executive reserve than men. Future studies should examine the specific mechanisms underlying the observed differences and consider biological sex for the design of research studies and clinical trials in bvFTD and other frontotemporal lobar degeneration syndromes.