Association of cortical morphology, white matter hyperintensity, and glymphatic function in frontotemporal dementia variants

Abstract INTRODUCTION Frontotemporal dementia (FTD) can be phenotypically divided into behavioral variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). However, the neural underpinnings of this phenotypic heterogeneity remain elusive. METHODS Cortical morphology, white matter hyperintensities (WMH), diffusion tensor image analysis along the perivascular space (DTI‐ALPS), and their interrelationships were assessed in subtypes of FTD. Neuroimaging‐transcriptional analyses on the regional cortical morphological deviances among subtypes were also performed. RESULTS Changes in cortical thickness, surface area, gyrification, WMH, and DTI‐ALPS were subtype‐specific in FTD. The three morphologic indices are related to whole‐brain WMH volume and cognitive performance, while cortical thickness is related to DTI‐ALPS. Neuroimaging‐transcriptional analyses identified key biological pathways linked to the formation and/or spread of TDP‐43/tau pathologies. DISCUSSION We found subtype‐specific changes in cortical morphology, WMH, and glymphatic function in FTD. Our findings have the potential to contribute to the development of personalized predictions and treatment strategies for this disorder. HIGHLIGHTS Cortical morphologic changes, white matter hyperintensities (WMH), and glymphatic dysfunction are subtype‐specific. Cortical morphologic changes, WMH, and glymphatic dysfunction are inter‐correlated. Cortical morphologic changes and WMH burden contribute to cognitive impairments.