Seventy-eight percent of mutation carriers evaluated in the earliest preclinical phase showed elevated neurofilament light chain levels in their cerebrospinal fluid, revealing neuronal damage long before brain atrophy or clinical symptoms emerge.
The study, published in Movement Disorders, analyzed 296 participants from the Barcelona BCN-HD cohort and the international HDClarity cohort. First authors Dr. Jesús Pérez-Pérez and Dr. Gonzalo Olmedo-Saura, researchers in the Movement Disorders Research Group at IR Sant Pau, led the investigation.
Huntington’s disease is triggered by a mutation in the HTT gene. The Disease Integrated Staging System categorizes the condition into four distinct stages.
Stage 0 includes gene-mutation carriers who exhibit no symptoms or detectable brain structure changes. Stage 1 involves volume loss in the basal ganglia. Stage 2 brings motor or cognitive impairments, while stage 3 involves functional decline affecting independence.
In the Barcelona cohort, 78% of participants assessed in stage 0 showed elevated neurofilament light chain levels in their cerebrospinal fluid. Among those same participants, 59% displayed elevated levels in plasma.
In the international cohort, 53% of individuals assessed at stage 0 had elevated neurofilament light chain levels in their cerebrospinal fluid. Researchers compared these measurements against reference thresholds derived from participants without the genetic mutation.
Participants carrying elevated neurofilament light chain levels stood closer to estimated clinical onset. Depending on the cohort and sample type, the median estimated time to clinical onset reached 10 to 13 years.
Individuals with biomarker concentrations below the reference threshold faced a median estimated time to clinical onset of 23 to 24 years.
“Within the earliest stage of the classification, we find individuals with different biological conditions. Some already have elevated levels of a marker of neuronal damage, even though they do not show brain atrophy. This information can help us better characterize these early changes,” Dr. Pérez-Pérez said.
Higher concentrations of the protein correlated with greater volume loss in relevant brain structures and worse performance on clinical assessments. The research team evaluated mutant huntingtin alongside total tau.
Mutant huntingtin appeared as early as stage 0, though low concentrations complicated accurate quantification. Total tau increased primarily during the stage associated with functional decline.
“The current classification provides us with a common framework for studying the disease and developing treatments, but it does not yet incorporate biomarkers measured in blood or cerebrospinal fluid. We wanted to determine what information these measurements could provide, particularly in the earliest stages, when there are still no clinical manifestations or structural damage,” Dr. Olmedo-Saura said.
The findings were presented at the European Huntington’s Disease Network congress in Kraków, Poland, held from October 22 to 24.
With this biomarker, we could monitor the effectiveness of gene therapy treatments before patients develop the disease,
Dr. Pérez-Pérez concluded.
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