Abstract
Huntington's disease (HD) is an inherited neurodegenerative disorder typified by involuntary body movements, and psychiatric and cognitive abnormalities. Many HD patients also exhibit metabolic changes including progressive weight loss and appetite dysfunction. Here we have investigated metabolic function in pre-manifest and manifest HD subjects to establish an HD subject metabolic hormonal plasma signature. Individuals at risk for HD who have had predictive genetic testing showing the cytosine-adenine-guanine (CAG) expansion causative of HD, but who do not yet present signs and symptoms sufficient for the diagnosis of manifest HD are said to be “pre-manifest.” Pre-manifest and manifest HD patients, as well as both familial and non-familial controls, were evaluated for multiple peripheral metabolism signals including circulating levels of hormones, growth factors, lipids, and cytokines. Both pre-manifest and manifest HD subjects exhibited significantly reduced levels of circulating growth factors, including growth hormone and prolactin. HD-related changes in the levels of metabolic hormones such as ghrelin, glucagon, and amylin were also observed. Total cholesterol, HDL-C, and LDL-C were significantly decreased in HD subjects. C-reactive protein was significantly elevated in pre-manifest HD subjects. The observation of metabolic alterations, even in subjects considered to be in the pre-manifest stage of HD, suggests that in addition, and prior, to overt neuronal damage, HD affects metabolic hormone secretion and energy regulation, which may shed light on pathogenesis, and provide opportunities for biomarker development.
Highlights
Huntington’s disease (HD) is a neurodegenerative disorder involving the extrapyramidal motor system and is characterized by chorea, progressive dementia, and other psychiatric symptoms (Walker, 2007; Ross and Tabrizi, 2011; Weir et al, 2011)
Compared to the Baltimore Longitudinal Study of Aging (BLSA) control group (21.48 ± 1.18 pg/mL), pre-manifest HD subjects showed a significant increase in circulating Agouti-related protein (AgRP) (33.28 ± 3.05 pg/mL, p = 0.007) (Figure 1C), and the same trend was observed when compared to the familial controls (25.14 ± 1.60 pg/mL, p = 0.056)
With respect to PRL levels we found a consistent effect, i.e., reduced PRL levels, in both pre-manifest and manifest HD subjects when compared to the respective BLSA control groups (Figure 1D)
Summary
Huntington’s disease (HD) is a neurodegenerative disorder involving the extrapyramidal motor system and is characterized by chorea, progressive dementia, and other psychiatric symptoms (Walker, 2007; Ross and Tabrizi, 2011; Weir et al, 2011). HD is caused by a dominant genetic mutation in the huntingtin (HTT) gene that results in an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG). This CAG repeat codes for an expanded polyglutamine repeat near the N-terminus of the HTT protein, which undergoes a conformational change, and causes cellular damage (Walker, 2007). The onset of HD typically occurs around the age of 30–40, and as the disease develops patients progressively lose independence and, eventually, die
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