Blood and Spinal Fluid Biomarker May Help Track Early Huntington’s Disease

Huntington’s disease is a genetic disorder caused by a mutation in the HTT gene that progressively affects movement, cognition, behavior, and independence. Although mutation carriers can be identified years before symptoms appear, detecting early biological changes remains challenging because current disease staging does not incorporate blood or cerebrospinal fluid biomarkers. New findings suggest that signs of neuronal injury may be detectable in some individuals at the earliest stage of the disease, potentially supporting earlier assessment and monitoring.

Researchers at Institut de Recerca Sant Pau (IR Sant Pau; Barcelona, Spain) evaluated neurofilament light chain (NfL), a biomarker of neuronal injury, in individuals carrying the Huntington’s disease mutation. The study focused on participants classified under the Huntington’s Disease Integrated Staging System (HD-ISS), including stage 0, when symptoms and detectable structural brain changes are absent. Researchers compared NfL levels in cerebrospinal fluid and blood with clinical assessments and brain imaging findings.

Image: Researchers compared Huntington’s disease biomarkers in CSF and blood with clinical assessments and brain imaging to better understand changes before clinical onset (Image Credit: Adobe Stock)

The study included 296 participants from the Barcelona BCN-HD cohort and the international HDClarity cohort. Under the HD-ISS framework, stage 1 is characterized by basal ganglia volume loss, stage 2 by motor or cognitive impairment, and stage 3 by functional decline affecting independence. The findings were published in Movement Disorders and presented at the European Huntington’s Disease Network congress, held October 22–24 in Kraków, Poland.

In the Barcelona cohort, elevated NfL levels were detected in 78% of stage 0 participants through cerebrospinal fluid testing and 59% through plasma testing. Similarly, 53% of stage 0 participants in the international cohort had elevated cerebrospinal fluid NfL. These elevations were determined using age- and sex-adjusted reference thresholds established from individuals without the Huntington’s disease mutation.

Participants with elevated NfL were also closer to predicted clinical onset, with median estimates ranging from approximately 10 to 13 years, depending on the cohort and sample type. In contrast, those with NfL levels below the reference threshold had estimated times to onset of 23–24 years. Higher NfL concentrations were also associated with greater volume loss in brain regions affected by Huntington’s disease and poorer performance on clinical assessments.

The strong correlation between plasma and cerebrospinal fluid NfL levels supports further investigation of blood-based testing for disease monitoring and clinical trials. Researchers also evaluated mutant huntingtin and total tau, finding that mutant huntingtin was detectable as early as stage 0 but difficult to quantify at low concentrations. Total tau, meanwhile, increased primarily at the stage associated with functional decline.

“Being able to measure NfL through a blood sample would facilitate its use in studies involving larger numbers of participants. However, in our study, measurements in cerebrospinal fluid showed a greater ability to distinguish the earliest stages. We need to take these differences into account when assessing what information each type of sample provides,” said Dr. Jesús Pérez-Pérez, researcher in the Movement Disorders Research Group at IR Sant Pau.

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