Abstract
ObjectiveBehavioral-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.MethodsFirst, 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.ResultsSignificant 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.InterpretationDegeneration and consequent dysregulation within the hypothalamus relates to significant feeding disturbance in bvFTD. These findings provide a basis for the development of therapeutic models. Ann Neurol 2011
Highlights
Two appetite-modulating pathways are present: an appetite stimulating pathway, which starts with an empty stomach secreting the hormone ghrelin to target neurons of the arcuate nucleus of the hypothalamus that contain neuropeptide Y (NPY) and agouti-related protein (AGRP), and an appetite-suppressing pathway that starts with adipocytes secreting the hormone leptin to target arcuate neurons containing pro-opiomelanocortin and the cocaine- and amphetamine-regulated transcript (CART; Fig 1)
This study reveals a number of novel findings regarding changes in hypothalamus integrity and its relations to eating behavior in Frontotemporal dementia (FTD)
We demonstrated that patients with Behavioral-variant frontotemporal dementia (bvFTD) exhibit significant atrophy of the hypothalamus
Summary
Behavioral-variant frontotemporal dementia (bvFTD) is a progressive neurodegenerative brain disorder, clinically characterized by changes in cognition, personality, and behavior. The hypothalamus plays a critical role in feeding regulation.[9] This structure comprises a number of distinct but interconnected nuclei that directly receive and integrate metabolic input from the periphery, as well as indirect reward, motivation, and sensory input from the cortex,[10] and send signals to many regions of the central nervous system regulating food intake and body weight.[9,11] Two appetite-modulating pathways are present: an appetite stimulating pathway, which starts with an empty stomach secreting the hormone ghrelin to target neurons of the arcuate nucleus of the hypothalamus that contain neuropeptide Y (NPY) and agouti-related protein (AGRP), and an appetite-suppressing pathway that starts with adipocytes secreting the hormone leptin to target arcuate neurons containing pro-opiomelanocortin and the cocaine- and amphetamine-regulated transcript (CART; Fig 1) Activation of these pathways orchestrates a series of responses mediated by downstream centers including the paraventricular nucleus (PVN) to control thyroid hormone secretion, feeding behavior, and energy conservation, and by lateral hypothalamic (LH) orexin-producing neurons to control arousal responses and feeding behavior (see Fig 1).[12] The hypothalamus in FTD has received only limited attention[13]; its contribution to eating disturbance in FTD has not been studied to date, and may have relevance for disease management. This study aimed to determine changes in the hypothalamus in FTD by combining neuroimaging and postmortem investigations
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