Early neurodegeneration biomarkers linked to CAG repeat growth
Biomarkers evident years before Huntington's symptoms, study finds
Subtle biomarkers of neurodegeneration are evident decades before the onset of overt Huntington’s disease symptoms in people with disease-causing mutations, a study found.
Somatic CAG repeat expansions — a phenomenon in which Huntington’s-causing mutations grow, or expand, during a person’s lifetime — were associated with these neurodegenerative biomarkers.
The researchers said the findings demonstrate that somatic CAG expansions are important disease drivers and could be targeted to slow or halt Huntington’s onset in people who don’t yet have symptoms. Clinical trials testing such preventive approaches could use the identified biomarkers to monitor treatment responses, they said.
“Our study underpins the importance of somatic CAG repeat expansion driving the earliest neuropathological changes of the disease,” Sarah Tabrizi, MD, PhD, professor at University College London and the study’s senior author, said in a university news story. “We hope that clinical trials aimed at preventing Huntington’s disease will become a reality in the next few years.”
The study, “Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington’s disease decades before clinical motor diagnosis,” was published in Nature Medicine.
CAG repeat expansions
Huntington’s disease is caused by mutations in the HTT gene that lead to the production of an abnormal version of the huntingtin protein that toxically clumps in nerve cells.
Huntington’s mutations are characterized by the excessive repetition of a trio of DNA building blocks — a cytosine (C), an adenine (A), and a guanine (G) — in the HTT gene code. In general, longer CAG repeats are associated with earlier onset and more severe disease.
CAG repeat expansions are not stable, and they can grow longer in the course of a person’s lifetime (somatic CAG expansions). These somatic expansions are believed to contribute to disease onset and progression.
Since Huntington’s runs in families, people may know they have a mutation that will cause Huntington’s disease decades before symptoms appear. That means there’s an opportunity to develop preventive treatments that slow or halt disease onset before extensive and irreversible neurodegeneration sets in.
But to know when such treatments should be administered, there’s a need for better biomarkers of very early disease stages when a person doesn’t yet have obvious motor or cognitive problems.
To learn more, the scientists looked at data from 57 people involved in the HD Young Adult Study who had tested positive for Huntington’s mutations but did not yet have symptoms. At the time they entered the study, they were predicted to be an average of 23 years from clinical diagnosis.
Participants underwent a comprehensive series of tests, including blood and spinal fluid sampling, brain scans, motor and cognitive assessments at study entry and again at a follow-up about 4.5 years later. The data were compared to findings from a control group of people matched for factors such as age, sex, and education, but who didn’t have a Huntington’s mutation.
Those in the Huntington’s group showed no declines in clinical function, including motor, cognitive, and neuropsychiatric assessments, during the study period. But subtle changes were detected that scientists believe could indicate the beginning of neurodegenerative processes.
In spinal fluid, those with Huntington’s mutations exhibited greater increases in neurofilament light chain (NfL), a known biomarker of nerve cell damage, relative to controls, as well as decreases in proenkephalin, a marker of the health of nerve cells known to degenerate in Huntington’s.
Brain imaging showed signs of accelerated atrophy, or tissue wasting, in the Huntington’s group relative to the controls. It was mainly observed in the caudate and putamen, the two brain regions known to be predominately affected in the neurodegenerative disease.
An increased rate of somatic CAG repeat expansions were detected in the blood of the Huntington’s mutation group over time, and people who had longer CAG repeats to begin with showed faster increases.
Increase in somatic expansions was a significant predictor of atrophy in the caudate and putamen, and also tended to correlate with the other biomarkers measured in spinal fluid.
Certain atypical Huntington’s-associated mutations were also associated with faster brain atrophy.
The researchers said therapeutic strategies to suppress somatic expansions, which are being evaluated, could help to preserve nerve cell health and slow disease progression. The identified biomarkers could be used to recruit participants and monitor outcomes for preventive clinical trials testing such approaches.
“We have identified robust measures of early pathology with potential to act as possible biomarker surrogates of disease progression, and identified the ideal cohort for intervention to delay or prevent clinical motor diagnosis,” they wrote.
The study’s findings “are particularly timely as the Huntington’s disease therapeutic landscape expands and progresses toward preventive clinical trials,” said Mena Farag, a UCL researcher and one of the study’s first authors.
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