Brain changes appear decades before Huntington's disease diagnosis

— These results could have implications for understanding other neurodegenerative diseases

by Judy George, Deputy Editor, MedPage Today January 17, 2025

Alterations in cerebrospinal fluid (CSF) neurofilament light protein (NfL) and proenkephalin (PENK) appeared decades before clinically diagnosable Huntington's disease.

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About 23 years before a clinical diagnosis, CSF analysis showed very early signs of neurodegeneration with elevated NfL protein, a marker of axonal injury, and reduced PENK, a surrogate marker of striatal medium spiny neuron status, reported Sarah Tabrizi, PhD, of University College London, and co-authors.

These signs were accompanied by brain atrophy, mainly in the caudate nucleus and putamen. A longitudinal increase in the somatic cytosine-adenine-guanine (CAG) repeat expansion ratio in blood was a significant predictor of caudate nucleus and putamen atrophy, the researchers wrote in Nature Medicine.

This research provides two significant results, observed co-author Rachael Scahill, PhD, also of University College London.

“First, we demonstrate that a critical disease process — somatic CAG repeat expansion — can be detected in blood more than two decades before individuals with the Huntington's disease gene expansion are expected to receive a clinical motor diagnosis,” she told MedPage Today.

“Second, we identify early disease markers in brain imaging, blood, and spinal fluid, which show the very earliest pathological changes,” she said.

L' study evaluated 57 Huntington's disease patients and 46 controls over 4.5 years, and is the first to directly link somatic CAG repeat expansion to early brain changes in humans decades before clinical diagnosis.

“This research is a major step forward, paving the way for future prevention trials in Huntington's disease,” Tabrizi told MedPage Today. “It also holds broader implications for understanding and potentially intervening in other neurodegenerative diseases, such as Alzheimer's disease. »

Huntington's disease is an autosomal dominant genetic disorder caused by prolonged CAG trinucleotide repeats in the huntingtin gene (HTT). The sequence tends to continually expand in a process known as somatic CAG expansion, accelerating neurodegeneration.

Research has suggested that expansion may involve two thresholds in Huntington's disease: an inherited CAG length that leads to somatic expansion, and a threshold above which neuronal dysfunction and death occur.

Consistent with this, a postmortem study published this week suggested that neurons can experience decades of silent repeat expansion, followed by neuronal damage triggered by a cascade of dysregulation once CAG repeats exceed 150.

In Cell, Steven McCarroll, PhD, of the Broad Institute of MIT and Harvard in Boston, and his co-authors identified a pattern in how repetitions HTT CAGs expanded in striatal projection neurons. Expansion from 40 to 150 CAGs had no apparent effect, but striatal projection neurons with 150 to 500 or more CAGs rapidly degenerated and died.

McCarroll and his colleagues figured that the repeat pathways expanded slowly over the first two decades of life, like a "ticking DNA clock." Once they reached about 80 CAGs, the pace accelerated.

Tabrizi and his co-authors suggested that there may be a treatment window for people at risk of developing Huntington's disease who are functioning normally but have detectable measures of early neurodegeneration. By targeting somatic CAG repeat expansion early in the neurodegenerative process, treatments may be able to delay or prevent the onset of clinical signs.

“With new therapies in development to target the DNA repair proteins that are known to influence somatic expansion, our results are timely in demonstrating its association with measurable disease markers,” they wrote.