Concentrations of mutant huntingtin protein and neurofilament light proteins in cerebrospinal fluid and blood may be the first signs of progression in Huntington’s disease, according to a paper published online Sept. 12 in Science Translational Medicine.
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In a cohort of 40 Huntington’s mutation carriers with manifest disease, 20 carriers without clinical symptoms, and 20 healthy controls, researchers examined levels of mutant huntingtin (mHTT) and neurofilament light (NfL) protein in biofluids, in parallel with clinical evaluations and MRI imaging.
They found that concentrations of mHTT in the cerebrospinal fluid (CSF) and concentrations of NfL proteins in the CSF and plasma were significantly higher in participants with manifest Huntington’s disease (HD) than in those without manifest disease or in controls.
Researchers also saw that CSF concentrations of mHTT showed the earliest detectable change in progression of the disease, followed by plasma and CSF levels of NfL. After that came changes in caudate and global brain volume, motor score, word reading, and other clinical measures.
“These results suggest that as our understanding grows further, analysis of mHTT and NfL might be useful for developing HD therapeutics and for clinical management,” wrote Lauren M. Byrne of the Huntington’s Disease Centre at the University College London Institute of Neurology and her coauthors.
Plasma concentrations of NfL showed the strongest association with clinical severity, even after adjusting for the number of CAG (or cytosine, adenine, and guanine) repeats – a measure of disease severity – and age.
“Our previous work suggests that NfL is a dynamic marker of ongoing neuronal damage in HD that predicts subsequent progression,” the authors wrote. “This perhaps reflects that NfL, as a marker of axonal damage, has a more direct relationship with the development of clinical manifestations and brain atrophy.”
NfL concentrations in CSF more closely predicted brain volume than did plasma NfL or CSF concentrations of mHTT.
In participants who carried the Huntington’s mutation, CSF concentrations of mHTT and NfL were strongly correlated. Researchers also noted that mutation carriers had a significantly higher CSF-to-plasma ratio of NfL than did controls.
The study also showed that mHTT in the CSF and NfL in the cerebrospinal fluid and plasma, were very stable within individuals over 4-8 weeks.
“The very high intraclass correlation values of the three markers revealed them to be highly stable, suggesting that intraindividual variation in these analytes is likely to be a minimal source of noise in natural history and therapeutic studies,” the authors wrote.
This work was supported by the Medical Research Council U.K., the CHDI Foundation, the Wellcome Trust, the U.K. Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme, the U.K. Dementia Research Institute, F. Hoffmann-La Roche, the Horizon 2020 Framework Programme, and the Engineering and Physical Sciences Research Council. A number of authors disclosed consulting or serving on advisory boards for F. Hoffmann-La Roche and/or other companies. Three authors are full-time employees of F. Hoffmann-La Roche.
SOURCE: Byrne L et al. Sci Transl Med. 2018;10:eaat7108. doi: 10.1126/scitranslmed.aat7108.