Brain Changes Emerge Decades Before Huntington’s Diagnosis

Changes in neurofilament light (NfL), cerebrospinal fluid (CSF), and proenkephalin (PENK) protein appeared decades before the emergence of clinically diagnosable Huntington’s disease.

About 23 years before clinical diagnosis, CSF analysis showed very early signs of neurodegeneration with elevated NfL protein, a marker of axonal damage, and decreased PENK, a surrogate marker for the fatal condition of medium spiny neurons, reported Sarah Tabrizi, Ph.D., of University College London, and co-authors.

These signs were accompanied by brain atrophy, especially in the caudate and putamen. The researchers wrote in the study that a longitudinal increase in the ratio of cytosine-adenine-guanine (CAG) repeat expansion in the blood was an important predictor of caudate and putamen atrophy. Natural medicine.

This research offers two important findings, notes co-author Rachel Scahill, Ph.D., also of University College London.

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

“Secondly, we identified early signs of the disease in imaging of the brain, blood and spinal fluid, which show very early pathological changes,” she said.

the He studies He evaluated 57 Huntington’s patients and 46 male patients over 4.5 years, and was the first to establish a direct link between somatic CAG expansion recurrence and early brain changes in humans decades before clinical diagnosis.

“This research is a big step forward and paves the way for future prevention trials in Huntington’s disease,” Tabrizi said. 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 disorder caused by an extended CAG trinucleotide repeat in huntingtin (HTT) gene. The cascade tends to continually expand in a process known as somatic CAG expansion, which leads to accelerated neurodegeneration.

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

Consistent with this, a post-mortem study published this week suggested that neurons may face decades of quiescent repeat expansion, followed by neuronal damage caused by a cascade of dysregulation once CAG repeats exceed 150.

in cellStephen McCarroll, Ph.D., of the Broad Institute of MIT and Harvard University in Boston, and co-authors identified a pattern in the way HTT Expanded CAG repeats in projection neurons. Expansion from 40 to 150 CAGs had no obvious effect, but striatal projection neurons containing 150 to 500 or more CAGs rapidly degenerated and died.

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

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

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