The Role of Hypothalamic Pathology for Non-Motor Features of Huntington’s Disease

Abstract

Huntington's disease (HD) is a fatal genetic neurodegenerative disorder. It has mainly been considered a movement disorder with cognitive symptoms and these features have been associated with pathology of the striatum and cerebral cortex. Importantly, individuals with the mutant huntingtin gene suffer from a spectrum of non-motor features often decades before the motor disorder manifests. These symptoms and signs include a range of psychiatric symptoms, sleep problems and metabolic changes with weight loss particularly in later stages. A higher body mass index at diagnosis is associated with slower disease progression. The common psychiatric symptom of apathy progresses with the disease. The fact that non-motor features are present early in the disease and that they show an association to disease progression suggest that unravelling the underlying neurobiological mechanisms may uncover novel targets for early disease intervention and better symptomatic treatment. The hypothalamus and the limbic system are important brain regions that regulate emotion, social cognition, sleep and metabolism. A number of studies using neuroimaging, postmortem human tissue and genetic manipulation in animal models of the disease has collectively shown that the hypothalamus and the limbic system are affected in HD. These findings include the loss of neuropeptide-expressing neurons such as orexin (hypocretin), oxytocin, vasopressin, somatostatin and VIP, and increased levels of SIRT1 in distinct nuclei of the hypothalamus. This review provides a summary of the results obtained so far and highlights the potential importance of these changes for the understanding of non-motor features in HD.

Involvement of orexinergic system in psychiatric and neurodegenerative disorders: A scoping review

“…Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by personality changes, motor disturbances, cognitive decline and weight loss. [ 75 ] HD is caused by a defect in the gene encoding huntingtin, a protein with unclear function, which is essential for cell survival during development and in adult life. [ 76 ] In HD, there are neurodegeneration involving neostriatum and cerebral cortex, with the manifestation of intra-neuronal aggregates of misfolded huntingtin.…”

Abnormal Photic Entrainment to Phase-Delaying Stimuli in the R6/2 Mouse Model of Huntington's Disease, despite Retinal Responsiveness to Light

“…stein and Amir, 1999). Hypothalamic regions are also good candidates as alterations have been reported both in HD patients and animal models (Vercruysse et al, 2018;Cheong et al, 2019). The dorsomedial hypothalamic nucleus is responsible for relaying circadian temporal information from the SCN to the locus ceruleus (Gompf and Aston-Jones, 2008), and excitotoxic lesion of this region has been reported to decrease behavioral circadian rhythms including locomotor activity (Chou et al, 2003).…”

Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

“…CART was associated with the development of HD ( Gabery et al, 2010 ). Increased CART levels in the cerebrospinal fluid were associated with an increased number of CART immunopositivity neurons in the hypothalamus of HD patients ( Cheong et al, 2019 ).…”