Multidisciplinary rehabilitation reduces hypothalamic grey matter volume loss in individuals with preclinical Huntington's disease: A nine-month pilot study

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Abstract

Background

Hypothalamic pathology is a well-documented feature of Huntington's disease (HD) and is believed to contribute to circadian rhythm and habitual sleep disturbances. Currently, no therapies exist to combat hypothalamic changes, nor circadian rhythm and habitual sleep disturbances in HD.

Objective

To evaluate the effects of multidisciplinary rehabilitation on hypothalamic volume, brain-derived neurotrophic factor (BDNF), circadian rhythm and habitual sleep in individuals with preclinical HD.

Methods

Eighteen individuals with HD (ten premanifest and eight prodromal) undertook a nine-month multidisciplinary rehabilitation intervention (intervention group), which included exercise, cognitive and dual task training and social events, and were compared to a community sample of eleven individuals with premanifest HD receiving no intervention (control group). Hypothalamic volume, serum BDNF, salivary cortisol and melatonin concentrations, subjective sleep quality, daytime somnolence, habitual sleep-wake patterns, stress and anxiety and depression symptomatology were evaluated.

Results

Hypothalamus grey matter volume loss was significantly attenuated in the intervention group compared to the control group after controlling for age, gender, Unified Huntington's Disease Rating Scale-Total Motor Score and number of cytosine-adenine-guanine repeats. Serum BDNF levels were maintained in the intervention group, but decreased in the control group following the study period. Both groups exhibited decreases in cortisol and melatonin concentrations. No changes were observed in sleep or mood outcomes.

Conclusions

This exploratory study provides evidence that multidisciplinary rehabilitation can reduce hypothalamic volume loss and maintain peripheral BDNF levels in individuals with preclinical HD but may not impact on circadian rhythm. Larger, randomised controlled trials are required to confirm these findings.

Introduction

Hypothalamic pathology, including grey matter volume loss and microglial activation, has been reported as early as a decade prior to clinical manifestation of Huntington's disease (HD) [2,27,33,51,53,59]. Degeneration within the hypothalamus, particularly the suprachiasmatic nucleus (SCN), which is responsible for controlling the circadian rhythms, is believed to underpin sleep and circadian deficits in individuals with HD [1,6,43,45,58].

Disturbances in circadian rhythmicity and sleep are documented in HD mouse models, as well as in humans [34,39,44]. Circadian changes appear to commence during the premanifest stages of HD and worsen as the course of the disease lengthens. In particular, early changes in the circadian regulation of cortisol and melatonin and a delay of the habitual sleep timing have been noted in individuals with premanifest HD [1,3,4,32,63]. Furthermore, studies in the R6/2 HD mouse model have revealed altered night-day activity ratios, which has also been reported in individuals with manifest HD [45]. These alterations in circadian rhythm could potentially mediate sleep deficits that have been reported in HD [39]. Lazar et al. [39] reported early changes in sleep architecture, particularly increased sleep fragmentation, prior to clinical onset of HD. Given that the onset of circadian rhythm and disturbances occur during the premanifest phase of HD, early treatments aimed at reducing or ameliorating degeneration of the hypothalamus or targeting circadian rhythm and habitual sleep disturbances are warranted.

Evidence from animal models and other clinical populations suggests that interventions comprising exercise have the potential to improve circadian rhythm and sleep outcomes [19,46]. It is not known, however, if these improvements are mediated by changes in the hypothalamus. In patients with HD, our team has previously shown that nine months of multidisciplinary rehabilitation, involving exercise and cognitive training, enhances brain volume in the striatum and prefrontal cortex and improves cognition and motor function [18,61]. The exact mechanism by which multidisciplinary rehabilitation improves brain volume in these areas is not yet known. A possibility is that multidisciplinary rehabilitation exerts its effects on the brain by upregulating levels of brain derived neurotrophic factor (BDNF), since BDNF is vital for neurogenesis following environmental enrichment in animal models [57]. This is supported by studies in HD mouse models, in which BDNF levels were rescued following environmental enrichment, as well as by research into other neurodegenerative and clinical populations, whereby increases in BDNF levels have been reported following intervention paradigms comprising an exercise component [17,24,60].

In the present study, we aimed to examine the effects of a nine-month multidisciplinary rehabilitation intervention on BDNF levels, hypothalamic volume, circadian rhythm, and habitual sleep outcomes in individuals with premanifest HD. In line with findings suggesting an increase in BDNF levels following multimodal exercise paradigms [46] and with the proposed role of the hypothalamus in circadian rhythm disturbances in HD [2,6], we hypothesised that multidisciplinary rehabilitation would increase BDNF levels, attenuate hypothalamic volume loss and improve circadian rhythm and habitual sleep outcomes in individuals with premanifest HD.

Section snippets

Study design

The present investigation was a controlled, non-randomised, non-blinded exploratory study. This study design was adopted due to the rarity of the disease (9.7 per 100,000 in Australia [55]), the widespread distribution of individuals across Australia and the proof-of-concept nature of the study. The aim was to investigate the effects of nine months of multidisciplinary rehabilitation on hypothalamic volume as the primary outcome and blood-based BDNF, markers of circadian rhythm and habitual

Demographic and clinical characteristics

Two participants withdrew from the study prior to baseline testing and four withdrew following baseline testing. Analyses were conducted on data obtained from ten premanifest HD and eight prodromal HD participants in the intervention group and 11 premanifest HD participants in the allocated control group.

Demographic and clinical characteristics for the intervention and control groups are presented in Table 1. Age differed between the intervention group (p = .029) and the control group, but no

Discussion

Pathological disturbances in circadian rhythmicity and sleep are debilitating features of HD, thought to occur primarily due to degeneration within the hypothalamus. To date, no proven therapies exist to treat circadian rhythm and habitual sleep disturbances in individuals with HD. Here we show, for the first time, that multidisciplinary rehabilitation attenuated grey matter volume loss within the hypothalamus in individuals with preclinical HD.

Studies by our team and others show that

Acknowledgements

We would like to acknowledge Genesis Fitness Bentley and Kelmscott, ECU Sports and Fitness Mt. Lawley and Vario gymnasiums for in-kind use of their facilities. We would also like to acknowledge the assistance of Ms. Linda Hoult throughout the study.

Funding

This study was supported by a Lotterywest grant (MZ and TC; #107/20090827). ASL is supported by a grant from the Wellcome trust (207799/Z/17/Z). PRE is supported by a NHMRC Senior Research Fellowship (ID 1136548).

Declaration of Competing Interest

The authors declare that there is no conflict of interest.

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