Longitudinal dynamics of mutant huntingtin and neurofilament light in Huntington's disease: the prospective HD-CSF study

The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington’s disease (HD) – mutant huntingtin (mHTT) and neurofilament light (NfL) – are incompletely defined, but could help understand the natural history of the disease and how these biomarkers might help in therapeutic development and the clinic. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), and NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status and subsequent clinical progression and brain atrophy, better than did the rate of change in analytes. Overall NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT possesses prognostic value and is a valuable pharmacodynamic marker for huntingtin-lowering trials. ### Competing Interest Statement FBR, LMB, RT, EBJ, PAW, DCA, SJT, RIS, AH, HZ, EJW are University College London employees. MA is a University College London Hospitals NHS Foundation Thrust employee. EDV is a King’s College London employee. NG, RH, HF, SS are full-time employees of F. Hoffmann-LaRoche. FBR has provided consultancy services to GLG and F. Hoffmann-La Roche Ltd. LMR has provided consultancy services to GLG, F. Hoffmann-La Roche Ltd, Genentech and Annexon. RIS has undertaken consultancy services for Ixitech Ltd. SJT receives grant funding for her research from the Medical Research Council UK, the Wellcome Trust, the Rosetrees Trust, Takeda Pharmaceuticals Ltd, Vertex Pharmaceuticals, Cantervale Limited, NIHR North Thames Local Clinical Research Network, UK Dementia Research Institute, and the CHDI Foundation. In the past 2 years, S.J.T. has undertaken consultancy services, including advisory boards, with Alnylam Pharmaceuticals Inc., Annexon Inc., DDF Discovery Ltd, F. Hoffmann-La Roche Ltd, Genentech, PTC Bio, Novartis Pharma, Takeda Pharmaceuticals Ltd, Triplet Theraputics, UCB Pharma S.A., University College Irvine and Vertex Pharmaceuticals Incorporated. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College London. HZ has served at scientific advisory boards for Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Biogen and Alzecure, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. EJW reports grants from Medical Research Council, CHDI Foundation, and F. Hoffmann-La Roche Ltd during the conduct of the study; personal fees from Hoffman La Roche Ltd, Triplet Therapeutics, PTC Therapeutics, Shire Therapeutics, Wave Life Sciences, Mitoconix, Takeda, Loqus23. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College London. University College London Hospitals NHS Foundation Trust, has received funds as compensation for conducting clinical trials for Ionis Pharmaceuticals, Pfizer and Teva Pharmaceuticals. ### Clinical Protocols [http://dx.doi.org/doi:10.5522/04/11828448.v1][1] ### Funding Statement This work was supported by the Medical Research Council UK, the CHDI foundation, the Huntington’s disease Society of America, the Hereditary Disease Foundation, the Wellcome Trust (Wellcome Collaborative Award In Science 200181/Z/15/Z and Wellcome/EPSRC Centre for Medical Engineering [WT 203148/Z/16/Z]), the Department of Health's NIHR Biomedical Research Centres funding scheme, the UK Dementia Research Institute, F. Hoffmann-La Roche Ltd, Horizon 2020 Framework Programme, Engineering and Physical Sciences Research Council, the Swedish Research Council, the European Research Council, and Swedish State Support for Clinical Research, and the Innovative Medicines Initiative Joint Undertaking under EMIF grant. Funders had no role in study design, data collection, analysis, or interpretation, or writing of the report. The corresponding author had full access to data and final responsibility for the decision to submit for publication. ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that support the findings of this study are available on request from the corresponding author, EJW. The data are not publicly available due to their containing information that could compromise the privacy of research participants. [1]: http://dx.doi.org/10.5522/04/11828448.v1