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.

Keywords: Huntington’s disease; hypocretin; hypothalamus; orexin; oxytocin; vasopressin.

Fig. 1

Overview of main hypothalamic changes in Huntington’s disease. Altered immunoreactivity and gene expression levels of cell populations detected in specific hypothalamic nuclei. Changes that result in upregulation and downregulation are indicated by the arrows. The location of specific hypothalamic nuclei is indicated by the dashed arrows on the cross-sectional human hypothalamic section stained for Cresyl violet and Luxol fast blue. Hypothalamic changes are also detected in the blood and cerebrospinal fluid as well as from different imaging paradigms. These changes are thought to be a key contributor to the clinical features in Huntington’s disease. CART, cocaine and amphetamine regulated transcript; CREB-1, cyclic AMP-responsive element-binding protein 1; D2R, dopamine D2 receptor; FOXO3, Forkhead box O3; HPA, hypothalamic–pituitary–adrenal; LHA, lateral hypothalamic area; MCH, melanin-concentrating hormone; NTL, nucleus tuberalis lateralis; NKX2-1, NK2 homeobox 1; OX2R, Orexin 2 receptor; PVN, paraventricular nucleus; PDYN, prodynorphin, SIRT1, sirtuin 1; VIP, vasoactive intestinal peptide; VMH, ventromedial hypothalamus.

Fig. 2

Limbic system changes in Huntington’s disease. Schematic representation of the structures of the limbic system and overview of the main upregulated and downregulated changes (indicated by the arrows). A, amygdala; CC, cingulate cortex; F, fornix; fMRI, functional magnetic resonance imaging; HIPP, hippocampus; HYP, hypothalamus; PFC, prefrontal cortex; R, raphe nucleus; V, ventral tegmental area; VS, ventral striatum.