By: Nancy R. Downing, PhD, RN
The fact that HD involves a single gene mutation inherited in an autosomal dominant pattern can lead to a sense of genetic determinism among HD patients, their families, physicians, and researchers. However, increased knowledge about the impact of lifestyle and environment on health provides support for the potential to extend healthy functioning for persons with the HD gene mutation. In observational studies of people with HD, there is evidence that lifestyle and environmental factors contribute to variation in the age of onset (AO).1-4 Increased understanding of epigenetic modifications5 supports the potential for lifestyle and environment manipulation to alter AO and disease progression.
While there is a negative association between the number of CAG repeats in the mutant huntingtin gene and AO,6,7 CAG repeat length is estimated to account for only 50–70% of the variance of AO;4,8,9 however, some of these data are limited by how AO was defined or determined. In the PREDICT-HD study,10 225 participants were diagnosed using the UHDRS motor exam.11 In this analysis, there was a correlation of 0.53 between CAG repeat length and age at diagnosis.10 The range of age at diagnosis also varied widely at each CAG repeat length (e.g. a range of 31 years for CAG = 40). While in general the variation decreases with increasing CAG repeat length, 80% of affected people have 40– 48 repeats.10,12,13 Therefore, many could potentially benefit from interventions to delay AO.
My recent observational study comparing 48 people with prodromal or early HD and 27 controls was designed to provide preliminary data to support randomized controlled trials (RCTs) of lifestyle interventions to delay AO or disease progression. We collected data on physical activity using FitBit activity trackers, on diet using 3-day 24-hour diet recall, and on body composition using dual x-ray absorptiometry (DXA). Our first paper provided support for the hypothesis that physical activity is positively associated with cognitive function.14 Preliminary data exist to support positive effects of physical exercise in other neurodegenerative diseases such as Parkinson disease, with a need for further studies.15 The most promising data on the potential impact of physical exercise comes from studies of people with mild cognitive impairment, with some evidence of improved cognitive function that could potentially delay Alzheimer disease in these patients.16 Further analyses will examine lean and fat mass, branched-chain amino acid levels, dietary intake, and supplement use, to identify potential targets for intervention. An interesting finding in our data is that 34/48 (70.8%) of participants with prodromal HD reported use of dietary supplements, and half of them said they did so to prevent or delay HD. Seventeen participants stated they were advised by physicians to take the supplements, and seven of these respondents stated it was because of HD (see Table).17 The participants stated that in most cases they thought the supplements were working. However, because we collected these data as part of the 3-day diet recall, we did not obtain further details about supplement use or why participants thought they were working.
There are many challenges to studying the impact of lifestyle behavior on AO and disease progression. Recruitment for RCTs in a relatively rare disease is challenging. Middle-age adult onset and the long disease trajectory make it difficult to study the long-term impacts of interventions. Due to these limitations, it is not surprising that RCTs of these interventions are limited. For example, a 2009 Cochrane review of pharmacological and non-pharmacologic therapeutics (including supplements) to modify HD disease progression found only eight RCTs that met their criteria,18 and none that demonstrated effectiveness.
My research team is currently conducting a systematic review of the literature about lifestyle and environmental factors with the potential to modify AO or disease progression. Due to the dearth of RCTs on this topic, we included all human studies with quantitative data—including observational retrospective case studies and case series in addition to RCTs—and broadly defined health-related behaviors. Our initial search of PubMed, CINAHL, and PsychInfo yielded 449 possibly relevant papers. After reviewing the abstracts, we selected 70 papers for full review. Over half of the papers were related to nutrition and nutritional supplements, about a quarter to physical activity, physical therapy, and speech and swallowing therapy. There were no RCTs of exercise to delay HD onset. However, there is reason to be hopeful. Findings from studies such as PREDICT-HD have identified sensitive markers of disease progression that can circumvent some of the limitations of a long disease trajectory.19 An NIH-funded RCT involving an exercise intervention to slow HD disease progression in prodromal HD using motor and neuroimaging outcomes is now underway at the University of Iowa (1R21NS091055-01A1, Magnotta, PI). If successful, this study could open the way for more RCTs of lifestyle interventions to delay AO, and/or slow disease progression in HD.
Targeted genetic approaches represent the most exciting pharmaceutical interventions currently being developed for HD;20 however, these therapies have not yet been proven effective, and no disease-modifying treatment currently exists. Many individuals at risk for HD decline genetic testing, but could be counseled to make simple dietary and lifestyle modifications regardless of their gene status that might not only help them to lead healthier lives, but delay the onset of HD. Lifestyle interventions could be useful as adjuvant therapy, do not require at-risk individuals to know their gene status, and are available to most people for little or no cost, with minimal side effects. The potential benefits of these approaches clearly warrant further consideration and investigation into their efficacy.
Dr. Nancy Downing was featured in HD Insights in Fall 2015 as a “Next Generation” HD Scholar. She is now an Associate Professor at the Texas A&M University College of Nursing.
|Table. Supplement Use Among Participants (n=17) Who Took Supplements Because of HD|
|Supplement||No. of Users||Proposed Mechanism of Action||Participant Reports Working as Expected?|
|CoQ10||10||Enhances mitochondrial function||6||4|
|Fish Oil||6||Neuroprotection, enhances mitochondrial function||4||2|
|Antioxidants||2||Reduces oxidative stress||2|
|Probiotics||1||Promotes neuroimmune function||1||1|
|Creatine||3||Antioxidant, enhances mitochondrial function, supports muscle health||2||1|
|Coconut Oil||1||Promote ketones as alternative energy source for brain||1|
|Multivitamin||1||Various depending on vitamin (e.g. antioxidant, anti-inflammatory, energy metabolism, etc.)||1|
|Melatonin||1||Antioxidant, neuroprotection, sleep aid||1|
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