Researchers detect signs of neuronal damage in the earliest stage of Huntington's disease

by Sant Pau Research Institute

edited by Sadie Harley, reviewed by Andrew Zinin

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Before motor or cognitive impairments appear and before brain volume loss becomes evident, some individuals carrying the genetic mutation that causes Huntington's disease already show signs of neuronal injury. This is demonstrated by a study conducted by the Institut de Recerca Sant Pau (IR Sant Pau), which has detected elevated levels of neurofilament light chain (NfL), a protein that indicates this damage, in individuals classified in the earliest stage of the disease.

The finding suggests that different biological conditions may coexist within the presymptomatic phase of the disease, which current criteria cannot distinguish.

The study, published in Movement Disorders, analyzed 296 participants from the Barcelona BCN-HD cohort and the international HDClarity cohort. The findings were also presented at the European Huntington's Disease Network congress, held from Oct. 22 to 24 in Kraków, Poland.

Its first authors are Dr. Jesús Pérez-Pérez and Dr. Gonzalo Olmedo-Saura, researchers in the Movement Disorders Research Group at IR Sant Pau. The team compared biomarkers measured in cerebrospinal fluid and blood with clinical assessments and brain imaging to better understand what happens before the disease becomes clinically apparent.

"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," explains Pérez-Pérez.

A disease that begins before its clinical manifestations

Huntington's disease is caused by a mutation in the HTT gene and can progressively affect movement, cognitive abilities, behavior and patients' independence. Its genetic origin makes it possible to identify individuals carrying the mutation many years before clinical manifestations appear and to study what happens during this period.

To describe this process, the Huntington's Disease Integrated Staging System (HD-ISS) distinguishes four stages. Stage 0 includes individuals with the genetic mutation who have not yet developed symptoms and in whom no changes in brain structure can be detected. Stage 1 is defined by volume loss in the basal ganglia, the brain structures responsible for controlling movement, cognition and behavior; stage 2, by the onset of motor or cognitive impairments; and stage 3, by functional decline affecting independence.

"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," explains Olmedo-Saura.

Signs of neuronal injury in stage 0

In the Barcelona cohort, 78% of individuals assessed in stage 0 had elevated NfL levels in cerebrospinal fluid, and 59% had elevated levels in plasma. These levels were compared with reference thresholds obtained from participants without the genetic mutation, adjusted for age and sex. In the international cohort, 53% of individuals assessed at this stage had elevated levels in cerebrospinal fluid.

Individuals with elevated NfL levels were also closer to the estimated clinical onset according to predictive models. Depending on the cohort and sample type, the median estimated time to clinical onset was approximately 10 to 13 years, compared with around 23 or 24 years among individuals whose levels were below the reference threshold. These figures are estimates and do not reflect longitudinal follow-up of participants until symptom onset.

"The results indicate that NfL can provide complementary information about disease activity in individuals who do not yet show clinical manifestations. This is relevant for research into early treatments because we need to identify more precisely the biological condition of each participant," says Olmedo-Saura.

Overall, higher NfL concentrations were associated with greater volume loss in brain structures involved in Huntington's disease and worse performance on clinical assessments. The biomarker showed differences between the earliest stages, as well as between these and more advanced stages.

The potential of a blood-based measurement

The study shows a strong relationship between NfL concentrations in plasma and cerebrospinal fluid. This finding supports the value of exploring blood-based measurements to facilitate the use of this biomarker in large-scale studies and clinical trials.

"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," explains Pérez-Pérez.

The team also studied mutant huntingtin, the protein directly involved in the disease, and total tau. Mutant huntingtin was detected as early as stage 0, but its low concentrations made accurate quantification difficult, particularly in the initial stages. Its role is complementary to that of NfL, as it allows researchers to directly assess the effects of treatments designed to reduce this protein.

Total tau, meanwhile, increased mainly in the stage associated with functional decline, suggesting a stronger relationship with more advanced neurodegenerative processes.

The findings support the investigation of biomarkers as a complement to the HD-ISS to better characterize disease stages and select participants for clinical trials. Before this approach can be implemented more widely, reference thresholds will need to be validated and their ability to predict clinical changes confirmed.

"With this biomarker, we could monitor the effectiveness of gene therapy treatments before patients develop the disease," concludes Pérez-Pérez.

More information

Jesús Pérez‐Pérez et al., Neurofilament Light Chain and Mutant Huntingtin Across Huntington's Disease Integrated Staging System Stages in Huntington Disease: A Cross‐Sectional Multimodal Analysis, Movement Disorders (2026). DOI: 10.1002/mds.70550

Key medical concepts

Huntington's DiseaseNeurofilament light chain

Clinical categories

NeurologyLaboratory medicine Provided by Sant Pau Research Institute Who's behind this story?

Sadie Harley

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