Multimodal Correlates of Longitudinal Functional Decline in Behavioral Variant Frontotemporal Dementia (bvFTD)

Background and Objectives: Functional decline is a major determinant of disability, caregiver burden, and loss of independence in behavioral variant frontotemporal dementia (bvFTD). Although bvFTD is characterized by early and rapidly progressive deterioration in everyday functioning, the multimodal contributors associated with longitudinal functional change remain insufficiently understood. The present study aimed to identify the strongest cognitive, behavioral, personality, and neuroimaging correlates of longitudinal functional deterioration in bvFTD using an integrated multimodal framework over a 12-month follow-up period. Methods: Twenty-seven patients diagnosed with bvFTD were recruited from the 2nd Neurology Clinic of the "AHEPA" University Hospital in Thessaloniki, Greece, and underwent comprehensive face-to-face neuropsychological assessment for the evaluation of a wide range of cognitive domains, alongside caregiver-based evaluations of behavioral disturbances, personality changes, and functional abilities, at baseline, 6 months, and 12 months. Brain perfusion single-photon emission computed tomography (SPECT) was acquired only at baseline, with regional cerebral blood flow (rCBF) quantified using a Brodmann area (BA)-based approach. Functional status was assessed using the Disability Assessment for Dementia (DAD) as the primary outcome, while the Frontotemporal Dementia Rating Scale (FRS) served as a secondary measure. Repeated-measures analysis of variance (ANOVA) was used to characterize longitudinal changes across cognitive, behavioral, personality, and functional domains, while linear mixed-effects (LME) models were applied to identify longitudinal correlates of functional decline and sources of inter-individual variability in functional outcomes. Results: Significant progressive decline in functional abilities was observed over the 1-year follow-up period, consistent with an aggressive and rapidly deteriorating clinical course in bvFTD. Reductions in functional performance were evident across both basic and instrumental activities of daily living, with deterioration being more pronounced in instrumental activities. Based on the final LME model, greater apathy-related (negative) behavioral symptoms, global cognitive impairment, attentional and processing speed deficits, and impaired inhibitory control were independently associated with poorer longitudinal functional outcomes (p < 0.001). At the neuroimaging level, reduced baseline perfusion in the right BA 24 within the anterior cingulate cortex was also significantly associated with greater loss of functional independence over time (p < 0.001). Conclusions: Longitudinal functional decline in bvFTD reflects the combined disruption of behavioral regulation, global cognition, executive control, and frontal-cingulate network integrity. The findings provide a preliminary foundation for future research investigating factors associated with accelerated functional decline. Further validation in larger, multicenter longitudinal cohorts is needed to determine the prognostic relevance of these factors and their potential applicability to patient stratification and individualized care planning.