Neurofilament Light Chain and Mutant Huntingtin Across Huntington's Disease Integrated Staging System Stages in Huntington Disease: A Cross‐Sectional Multimodal Analysis
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: The Huntington's Disease Integrated Staging System (HD-ISS) provides a framework for staging HD but does not incorporate fluid biomarkers. OBJECTIVE: The aim of this study was to examine neurofilament light chain (NfL) and mutant huntingtin (mHTT) and total tau across HD-ISS stages and their associations with genetic burden, neuroimaging, and clinical measures. METHODS: We performed cross-sectional analysis of the Barcelona-Huntington's Disease (BCN-HD) cohort with external replication in the multicenter HDClarity study. HD gene expansion carriers were classified as HD-ISS stages 0 to 3. NfL (cerebrospinal fluid [CSF] and plasma), CSF mHTT, total tau, striatal volumes, and Unified Huntington's Disease Rating Scale measures were quantified. Group differences and associations were analyzed using adjusted models. RESULTS: The BCN-HD cohort included 78 participants (50 HD gene expansion carriers [HDGECs], 28 controls) and HDClarity included 218 participants (166 HDGECs, 52 controls). CSF NfL increased across HD-ISS stages and discriminated premanifest from manifest individuals, as well as HD-ISS stage 0 from stage 1. Plasma NfL showed parallel increases and strongly correlated with CSF NfL (ρ = 0.88, P < 0.001). More than half of HD-ISS 0 individuals had NfL levels above the age-adjusted 95th percentile (P95) and shorter predicted time to onset (13 years for CSF and 10 years for plasma). From HD-ISS 1 onward, NfL levels exceeded P95 in most individuals. Higher NfL concentrations were associated with genetic burden, striatal atrophy, and clinical measures (all P < 0.001). CSF mHTT was detectable from HD-ISS 0 but showed weaker associations, whereas CSF total tau increased only from HD-ISS 3. CONCLUSIONS: NfL identifies biological activity across the HD-ISS continuum and shows neuroaxonal injury in a subset of individuals classified as stage 0. These findings suggest that fluid biomarkers may complement current HD-ISS criteria and support biological stratification in observational studies and clinical trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Source: Movement Disorders
DOI: 10.1002/mds.70550
Authors: Jesús Pérez‐Pérez, Gonzalo Olmedo‐Saura, Arnau Puig Davi, Rocío Pérez González, Jordi Pegueroles, Andrea Horta‐Barba, Anna Vázquez Oliver, Elisa Rivas Asensio, Daniel Alcolea, Juan Fortea, Marina Guasch‐Jiménez, Tomas Xuclà Ferrarons, Frederic Sampedro Santaló, Lidia Bojtos, Óscar López‐Lombardía, Ignacio Aracil‐Bolaños, Berta Pascual‐Sedano, Carla Franch Martí, Laura Pérez Carasol, Margarita Rubio Romera, Yi Ji, Alexandre Gironell, Antonia Campolongo, Raul Martínez‐Fernández, Alberto Lleó, Javier Pagonabarraga, Saul Martínez‐Horta, Jaime Kulisevsky, BCN‐HD Working Group;, HDClarity investigators
Institutions: Universitat Autònoma de Barcelona, Instituto de Salud Carlos III, Hospital de Sant Pau, Biomedical Research Networking Center on Neurodegenerative Diseases, Institut de Recerca Sant Pau, Instituto de Neurociencias, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Hospital Universitari de Girona Doctor Josep Trueta, Vall d'Hebron Hospital Universitari
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
OpenAlex ID: W7222005377