Objective: Behavioral-variant frontotemporal dementia (bvFTD) is a progressive neurodegenerative brain disorder, clinically characterized by changes in cognition, personality, and behavior. Marked disturbances in eating behavior, such as overeating and preference for sweet foods, are also commonly reported. The hypothalamus plays a critical role in feeding regulation, yet the relation between pathology in this region and eating behavior in FTD is unknown. This study aimed to address this issue using 2 complementary approaches.

Methods: First, 18 early stage bvFTD patients and 16 healthy controls underwent high-resolution structural magnetic resonance imaging and assessment of eating behavior. Hypothalamic volumes were traced manually on coronal images. Second, postmortem analyses of 12 bvFTD cases and 6 matched controls were performed. Fixed hypothalamic tissue sections were stained for a cell marker and for peptides regulating feeding behaviors using immunohistochemistry. Stereological estimates of the hypothalamic volume and the number of neurons and glia were performed.

Results: Significant atrophy of the hypothalamus in bvFTD was present in both analyses. Patients with high feeding disturbance exhibited significant atrophy of the posterior hypothalamus. Neuronal loss, which was observed only in bvFTD cases with Tar DNA protein-43 deposition, was also predominant posteriorly. In contrast, orexin (hypocretin), neuropeptide Y, cocaine- and amphetamine-regulating transcript, and vasopressin-containing neurons that regulate appetite were spared in posterior nuclei known to participate in feeding regulation.

Interpretation: Degeneration and consequent dysregulation within the hypothalamus relates to significant feeding disturbance in bvFTD. These findings provide a basis for the development of therapeutic models.