June 9, 2011 (Toronto, Ontario) — A new study suggests high caffeine intake may accelerate age at onset of Huntington's disease (HD).

Findings suggest that levels of caffeine consumption equal to about 2 cups of coffee per day are associated with an age at onset that was about 4 years earlier than those HD patients with lower caffeine intakes.

"We confirm in a large cohort that caffeine could be the first environmental modifier [of age at onset of HD]," the researchers, with lead study author Cécile Duru, MD, Service de Neurologie at CHU Amiens in Amiens, France, conclude.

Dr. Pierre Krystkowiak

"Of course, we can't say it's an environmental modifier; at the moment we can just say there's a link," study coauthor Pierre Krystkowiak, MD, PhD, also from the Service de Neurologie at CHU Amiens, told Medscape Medical News. To establish that caffeine truly is a modifier of the disease process will require further study, "so we're very cautious."

Similarly, it's too early to warn against drinking coffee for those who are genetically disposed to develop HD, he added. "I would not say 'stop drinking caffeine.' Perhaps it will be true, but at the moment, from a scientific point of view, I can't say this. I can only say there is an association."

The results were presented here at the Movement Disorders Society 15th International Congress of Parkinson's Disease and Movement Disorders.

Factors Associated With Variance

The expression of phenotype in Huntington's is variable, the study authors point out. Mutation in the IT15/HD1 gene predicts age at onset statistically, but on an individual basis, it accounts for only 60% of this variance, leaving some 40% to be affected potentially by other genetic or perhaps environmental factors.

Age at onset has previously been associated with polymorphisms in different genes, such as ADORA2A, but no environmental factors have been described to date, they note.

Caffeine consumption has previously been shown to be associated with reduced risks for Alzheimer's and Parkinson's disease, Dr. Krystkowiak noted. Caffeine is a nonselective A2 adenosine (A2A) receptor antagonist; A2A receptors are selectively localized on striatal medium-spiny neurons expressing enkephalin and dopaminergic D2 receptors that are known to be most vulnerable in Huntington's.

"Previous preclinical data suggest that blockade of those receptors is deleterious in the disease," he noted.

In this report, the researchers studied 80 HD patients from 8 sites participating in the Huntington French Speaking Network to assess whether caffeine intake would indeed influence age at onset.

Information was collected using a validated self-questionnaire on caffeine and alcohol consumption and smoking status during the last 10 years, and all underwent evaluation with the Unified Huntington's Disease Rating Scale.

Although the population was relatively small, they found that, after adjustment for CAG repeat length and smoking, those with higher caffeine consumption, defined as above the median consumption of 190 mg/day, had a significantly earlier age at onset by some 4.1 years, at an average of 45.4 years of age, compared with 49.5 years for those consuming less than 190 mg/day.

"190 mg/day represents 2 cups of coffee per day — 2 small cups, not 2 mugs — so it's rather low intake," he noted. They also did the analysis ruling out outlier subjects who were consuming very large amounts of caffeine each day, he added, "and the results are the same."

If caffeine consumption can be confirmed as an environmental modifier of disease, it would account for 4.4% of the 40% variance in age at onset still not explained by mutation in the IT15/HD1 gene, based on these results. "So if it's confirmed, it's very important," he added.

"Of course, the study is retrospective, and we'll need a prospective study that we're going to propose to the European Huntington's Disease Network in premanifest carriers of the disease to see to what extent their caffeine intake could influence age at onset, but in a prospective way," Dr. Krystkowiak said.

Their results also have implications for A2A receptor antagonist drugs now in the pipeline for treatment of Huntington's disease, he added. "We suggest that you should not antagonize such receptors because it could be deleterious. We should rather take agonistic drugs."

A 'Compelling Need'

Huntington's disease is an incurable hereditary brain disease that is dominantly inherited, and first-degree relatives of HD patients are at 50% risk of inheriting the disease, Kathleen Shannon, MD, at Rush University Medical Center in Chicago, Illinois, pointed out in a comment to Medscape Medical News.

...since limiting caffeine is harmless, people who are at risk of the disease or people who carry the gene but do not yet have symptoms might want to consider going caffeine free.

"Given that there is no cure, there is a compelling need to better define those factors that determine disease onset and progression," Dr. Shannon said.

It's been clear for a number of years that severity of the genetic mutation, that is, CAG repeat length, accounts for between 50% and 60% of the variance in age at onset, leaving 40% attributable to other factors, she noted. The current study suggests that caffeine consumption equivalent to 2 cups of coffee daily or more is related to earlier disease onset and that about 4% of the remaining variability in the age at onset could be attributed to caffeine.

"This is fascinating because, while it seems like a small amount, limiting caffeine is an easy fix, but mostly because caffeine has been thought to be neuroprotective in another degenerative illness, Parkinson's disease," Dr. Shannon said.

"It's always best that something like this be replicated in other studies to be completely sure, but since limiting caffeine is harmless, people who are at risk of the disease or people who carry the gene but do not yet have symptoms might want to consider going caffeine free," she added.

"It is important to point out that just because something could delay onset of illness doesn't necessarily mean there would be any role in slowing disease progression, so more work would need to be done in this area before any recommendations could be made for patients who already have the disease."

Movement Disorders Society (MDS): 15th International Congress of Parkinson's Disease and Movement Disorders: Abstract 180. Presented June 6, 2011.

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