People who will develop Huntington’s disease have subtle biological evidence of brain damage decades before the onset of symptoms, a new study indicates. This finding could be important to determine when to begin treatments for Huntington’s.
The study, “Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington’s disease Young Adult Study (HD-YAS): a cross-sectional analysis,” was published in The Lancet Neurology.
Huntington’s disease is caused by mutations in the huntingtin gene. People carrying these mutations typically manifest symptoms in the latter decades of life. With the advent of genetic testing, it is possible to identify individuals with “pre-Huntington’s disease” (preHD) — that is, people with the genetics of Huntington’s, but who have not yet developed clinical disease.
As therapies for Huntington’s are being developed, a question emerges: when is the best time to start treatment?
“Ultimately, our goal is to deliver the right drug at the right time to effectively treat this disease — ideally we would like to delay or prevent neurodegeneration while function is still intact, giving gene carriers many more years of life without impairment,” Sarah Tabrizi, PhD, a professor at University College London (UCL) and co-author of the new study, said in a press release.
Researchers analyzed 64 people with preHD and 67 people without (controls) who were recruited to participate in the Huntington’s disease Young Adult Study (HD-YAS).
The two groups were matched in terms of age (averaging about 29 years), sex (slightly more women), and education (averaging about 16 years). Mathematical modeling suggested that, on average, the preHD group was 23.6 years away from the onset of clinical disease.
Participants underwent a comprehensive battery of evaluations, including cognitive and psychiatric tests, brain imaging, and measurements of compounds in the blood and cerebrospinal fluid (CSF, the fluid around the brain and spinal cord). Not all participants were measured for every assessment.
“We aimed to assess how early disease-related changes can be identified (i.e., when there is a measurable biomarker of early neurodegeneration but clinical function is still intact), and which measures are most sensitive in early preHD,” the researchers wrote.
There were no significant differences between preHD and controls in any cognitive or psychiatric measurement.
Most brain imaging measurements also were not significantly different between the two groups. There were slight, though statistically significant, differences in the size of part of the brain called the putamen (5.5% smaller in the preHD group, on average), but putamen size was not significantly associated with estimated time to clinical disease onset.
“The small effect size and absence of association with disease burden indicates [putamen size] might have little use as a marker of progression at this stage of Huntington’s disease,” the researchers wrote.
Levels of mutant huntingtin protein in CSF were not high enough to be reliably measured in more than half of people with preHD. So, although lowering levels of this protein is a goal of many Huntington’s treatments, the protein itself probably isn’t a reliable marker for disease at this early stage (at least with currently available measuring techniques).
Relative to controls, people with preHD had significantly higher levels of neurofilament light chain (NfL) in their CSF. Furthermore, NfL levels were significantly higher in individuals who were closer to predicted onset of clinical disease.
NfL is a structural protein found in neurons. When neurons are damaged, NfL is released into the surrounding space; as such, levels of NfL in the CSF are indicative of neuronal damage. These findings suggest slight brain damage in people with Huntington’s, decades before the onset of clinical disease.
“CSF NfL had the highest effect size of any measure in this study and was the only measure showing a significant increasing association with estimated years to onset,” the researchers wrote. “NfL is therefore a potential candidate to provide a measure of disease progression in early preHD and might eventually be used as a marker of response to treatment in future preventive trials,” they added.
“As the field makes great strides with the drug development, these findings provide vital new insights informing the best time to initiate treatments in the future, and represent a significant advance in our understanding of early Huntington’s,” Tabrizi said.
Study co-author Rachael Scahill, PhD, a researcher at UCL, added: “Other studies have found that subtle cognitive, motor and neuropsychiatric impairments can appear 10–15 years before disease onset. We suspect that initiating treatment even earlier, just before any changes begin in the brain, could be ideal, but there may be a complex trade-off between the benefits of slowing the disease at that point and any negative effects of long-term treatment.”
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