In this post my aim is to understand whether there are any environmental modifiers for age of onset in Huntington’s Disease.  Short answer: none that we know of.

The most oft-cited study on genetic heritability of Huntington’s Disease age of onset [U.S.–Venezuela Collaborative Research Project 2004] suggested that 22% of the variance in residual age of onset (after controlling for CAG length) might lie in environmental factors shared between siblings, and 41% in non-shared environmental factors.  Together with that study’s ~37% estimate of additive genetic heritability, this implies that 100% of the variance could be explained by genetic or environmental modifiers, which I’m not sure that I buy.  If we accept that there are truly sporadic forms of Alzheimer’s disease and prion diseases, then why does age of onset in genetic neurodegenerative diseases need to be fully explainable?  Couldn’t some of the variance lie in stochastic variation between individuals?  At this point, we don’t know the answer.

But since there is a suggestion out there that environmental factors might modify age of onset, I decided to do a bit of searching to see if any studies had yet claimed to identify environmental factors.  The short answer is, there is nothing convincing out there.

A review [van Dellen & Hannan 2004] makes the case that environmental modifiers must exist, since environmental enrichment and caloric restriction have both been found to affect disease severity in mice.  (The review also mentioned Clifford 2002, who tested fatty acid supplementation in HD mice, but I’d consider that a therapeutic trial rather than an environmental influence).

Environmental enrichment means giving the mice lots of things to play with in their cages.  Two studies [van Dellen 2000, Hockly 2002] found that genetic HD mouse models (the R6/1 and R6/2 models respectively) take longer to develop HD-like phenotypes if they have enriched environments.  The enrichment in the former study consisted of “cardboard, paper and plastic objects, which were changed every two days, from the age of 4 weeks” in addition to the feed and bedding that all mice get.  The study is interesting, but it’s pretty hard to say whether you doing an extra sudoku on the train during your commute would provide you with as much marginal enrichment as the mice get from these objects.  We humans already live pretty enriched lives compared to mice.

As for diet, Duan 2003 tested caloric restriction in the form of periodic fasting. The study used mice with a mutant HD human transgene (HD-N171-82Q mice).  Control mice got as much food as they wanted all the time – ‘ad libitum’ feeding.  The test group of mice got zero food every other day.  The periodically fasting mice got later onset, survived longer and, bizarrely, actually kept their weight on better as the disease progressed (weight loss is a symptom of HD in mice and humans).   The periodically fasting mice also did better on several biochemical phenotypes related to HD: higher BDNF levels, fewer huntingtin aggregates, less caspase activation towards apoptosis.

Duan’s study was pretty good.  But I’m not quite ready to jump to the conclusion that people with HD should fast every other day, especially since HD causes pathological weight loss (one study suggests this happens even in early stages [Djousse 2002]) and one study has suggested that increased caloric intake should be recommended for HD patients, even before symptoms arise [Karder 2009].  Duan notes that intermittent fasting has also been shown to prolong life in wild-type mice, citing Goodrick 1990 – and if you read Goodrick’s abstract you’ll see it’s far from clear-cut: the effects depend on the strain of mouse and the age at which fasting is started.

More broadly, there is a whole literature on whether caloric restriction will make people (just any people, not necessarily with HD) live longer.  This has led to a series of very long-running studies on non-human primates.  Since primates live so long, studies started in the 1980s are just finishing now.  One large study from Wisconsin, Colman 2009, reported that the calorie-restricted rhesus macaques had lived significantly longer than controls and had a lower incidence of age-related diseases.  This made a lot of people pretty excited about restricting their diet.  Then last year, Mattison 2012 (ft), also studying rhesus macaques, reported no improved survival due to calorie restriction.  In Mattison’s study, the calorie-restricted monkeys did have slightly lower incidence of age-related diseases, but the difference was not statistically significant except for cancer.  Overall the difference in survival was not at all significant, and although the study is not over yet (many monkeys are still alive), the conditional likelihood (given the data already collected on deceased monkeys) leaves just a 0.1% chance that the calorie-restricted monkeys will end up having lived significantly longer on the whole.  There are a host of reasons why the two studies may have differed: different diets, different breeds of rhesus, and the fact that Colman threw out all the “non-age-related” deaths from the analysis – read this New York Times article for a comparison of the studies.  In short, the evidence for calorie restriction improving lifespan has never been clear cut, so I’m not ready to jump off on believing it for Huntington’s Disease either.

Moving on, there have been a couple claims of environmental modifiers for HD onset from studies on humans as well, but none are very believable yet.  One observational study on 80 people, presented at a conference [conference abstract: Duru 2010] claimed that caffeine consumption led to earlier onset in HD, sparking some surprisingly uncritical secondary press from Nature and a much more appropriately cautious HDBuzz post. The fact that it’s 2013 and this study was never published in a peer-reviewed journal may give us some hint as to how well the results validated.  Don’t believe everything you hear at a conference.  Obviously, we have no basis to rule out caffeine as a modifier – but this study doesn’t look like very strong evidence. Interesting aside: caffeine is an adenosine antagonist; another study tested an adenosine agonist and tried to show a reduction in HD symptoms in R6/2 mice [Huang 2011].  The results weren’t too strong – they found improvements on one mouse phenotype (rotarod performance) and one chemical phenotype (BDNF levels) but no significantly extended survival.

I also did a PubMed search for “huntington’s exercise”.  Of 57 results, only 5 appear to address the question of whether exercise is helpful for HD: four are studies of exercise in HD model mice, with a range of positive and negative results [Renoir 2012, Cepeda 2010, Pang 2006, Potter 2010] and one paper (for it cannot be called a study) on humans (rather, a human): Altschuler 2006 claims, based on the example of one person, that exercise is not helpful.  Safe to say there’s no solid evidence at this point.  Even for more deeply studied diseases, the contribution of exercise is really hard to pinpoint.  For instance, Head 2012 tried to determine whether exercise would reduce risk of Alzheimer’s by imaging amyloid deposition in active vs. sedentary asymptomatic people (n = 201 total), and found that exercise appeared to reduce amyloid deposition only in APOE E4 carriers (see also NYT blog post on Head’s study).  Even for Alzheimer’s, the evidence for preventative effects of exercise is interesting but not conclusive.  For HD, there is not any evidence to speak of.

Finally, several studies have examined the potential of medical marijuana and its extracts in Huntington’s.  An clinical trial of cannabidol in symptomatic HD patients found no significant effect on symptoms [Consroe 1991].  In the past few years, one group has published several studies claiming a therapeutic benefit of Sativex, a pharmaceutical extract of THC and cannabinol [Sagredo 2011, Sagredo 2012, Valdeolivas 2012].  Important note: those researchers are funded by GW Pharmaceuticals, which makes Sativex.  Also of note: the studies used chemical lesion models of HD rather than genetic models of HD.  HDBuzz was appropriately skeptical of this research.

And that’s all I could find in my searches for environmental modifiers of Huntington’s Disease.  Relatively few studies have looked for environmental modifiers of age of onset, and those that have done so have not yet produced anything super convincing.