Sant Pau: elevated NfL found in 78% of presymptomatic Huntington's mutation carriers at HD-ISS stage 0, 296 people

Researchers at the Institut de Recerca Sant Pau (IR Sant Pau) in Barcelona have detected elevated levels of neurofilament light chain (NfL), a protein marker of neuronal injury, in carriers of the Huntington's disease mutation who are classified in the earliest disease stage. These people have no motor or cognitive impairments and no visible brain volume loss, according to the study reported by news-medical.net news-medical.netnews-medical.netnews-medical.netOpen source ↗.

The work was published in Movement Disorders and analyzed 296 participants from the Barcelona BCN-HD cohort and the international HDClarity cohort. The first authors are Dr. Jesús Pérez-Pérez and Dr. Gonzalo Olmedo-Saura. The team compared biomarkers measured in cerebrospinal fluid and blood with clinical assessments and brain imaging.

Staging and NfL levels

Huntington's disease is caused by a mutation in the HTT gene. The Huntington's Disease Integrated Staging System (HD-ISS) has four stages. Stage 0 covers mutation carriers without symptoms and without detectable changes in brain structure. Stage 1 is defined by volume loss in the basal ganglia, stage 2 by motor or cognitive impairment, and stage 3 by functional decline affecting independence.

In the Barcelona cohort, 78% of individuals in stage 0 had elevated NfL in cerebrospinal fluid and 59% had elevated levels in plasma. Thresholds were taken from participants without the mutation, adjusted for age and sex. In the international cohort, 53% of stage 0 individuals had elevated levels in cerebrospinal fluid news-medical.netnews-medical.netnews-medical.netOpen source ↗.

By predictive models, individuals with elevated NfL had a median estimated time to clinical onset of about 10 to 13 years, versus about 23 or 24 years for those below the threshold. The authors note that these are estimates, not longitudinal follow-up until symptom onset.

Blood, CSF and other markers

Higher NfL was associated with greater volume loss in brain structures involved in the disease and with worse clinical assessment results. NfL concentrations in plasma and cerebrospinal fluid correlated strongly. Measurements in cerebrospinal fluid, however, distinguished the earliest stages better than blood measurements, the authors reported.

The team also studied mutant huntingtin and total tau. Mutant huntingtin was detected already in stage 0, but low concentrations made accurate quantification difficult. Total tau rose mainly in the stage associated with functional decline news-medical.netnews-medical.netnews-medical.netOpen source ↗.

The authors propose biomarkers as a complement to HD-ISS for characterizing stages and selecting participants for clinical trials. Before wider use, reference thresholds must be validated and their ability to predict clinical changes confirmed.