Brain Changes Emerge Decades Before Huntington’s Diagnosis

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Findings may have implications for understanding other neurodegenerative diseases

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

Changes in cerebrospinal fluid (CSF) neurofilament light (NfL) protein and proenkephalin (PENK) emerged decades before clinically diagnosable Huntington’s disease.

Approximately 23 years before a clinical diagnosis, CSF analysis showed very early signs of neurodegeneration with elevated NfL protein, a marker of axonal damage, and reduced PENK, a surrogate marker for the state of striatal medium spiny neurons, reported Sarah Tabrizi, PhD, of University College London, and co-authors.

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

This research delivers two significant findings, 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.

The study evaluated 57 Huntington’s patients and 46 controls over 4.5 years, and is the first to establish a direct link between somatic CAG repeat expansion and early brain changes in humans decades before a 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 is an autosomal dominant genetic disorder caused by extended CAG trinucleotide repeats in the huntingtin (HTT) gene. The sequence tends to expand continually in a process known as somatic CAG expansion, accelerating neurodegeneration.

Research has suggested 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 may experience decades of quiet repeat expansion, followed by neuronal damage triggered by a cascade of dysregulation once CAG repeats go beyond 150.

In Cell, Steven McCarroll, PhD, of the Broad Institute of MIT and Harvard in Boston, and co-authors identified a pattern in the way HTT CAG repeats 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 degenerated quickly and died.

McCarroll and colleagues estimated that repeat tracts grew slowly during the first two decades of life, like a “ticking DNA clock.” Once they reached about 80 CAGs, the rate accelerated.

Tabrizi and co-authors suggested 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 at the start of the neurodegenerative process, treatments may be able to delay or prevent the appearance 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.