Potential biomarker breakthrough for Huntington's disease (2017)

Huntington's disease, with a single genetic cause and correlation between age of onset and length of the CAG repeat in the huntingtin gene (HTT), has long served as a model for neurodegenerative diseases. Predictive genetic testing has made it possible to define the natural history of the disease and to show that regional brain atrophy, especially of the striatum, begins many years before diagnosable motor onset and progresses steadily through the premanifest and manifest periods.1Ross CA Aylward EH Wild EJ et al.Huntington disease: natural history, biomarkers and prospects for therapeutics.Nat Rev Neurol. 2014; 10: 204-216Crossref PubMed Scopus (622) Google Scholar, 2Tabrizi SJ Scahill RI Owen G et al.Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data.Lancet Neurol. 2013; 12: 637-649Summary Full Text Full Text PDF PubMed Scopus (564) Google Scholar, 3Paulsen JS Long JD Ross CA et al.Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study.Lancet Neurol. 2014; 13: 1193-1201Summary Full Text Full Text PDF PubMed Scopus (168) Google Scholar Structural neuroimaging enables excellent tracking of progressive atrophy; however, it requires an expensive apparatus and does not provide a direct chemical reflection of brain injury. Lauren Byrne and colleagues report in The Lancet Neurology4Byrne LM Rodrigues FB Blennow K et al.Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis.Lancet Neurol. 2017; (published online June 7)http://dx.doi.org/10.1016/S1474-4422(17)30124-2Summary Full Text Full Text PDF PubMed Scopus (193) Google Scholar a remarkable new study of 298 participants enrolled in the TRACK-HD study.2Tabrizi SJ Scahill RI Owen G et al.Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data.Lancet Neurol. 2013; 12: 637-649Summary Full Text Full Text PDF PubMed Scopus (564) Google Scholar It shows that plasma concentrations of neurofilament light (NfL) chain are substantially increased in Huntington's disease and correlate well with age and CAG repeat length.4Byrne LM Rodrigues FB Blennow K et al.Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis.Lancet Neurol. 2017; (published online June 7)http://dx.doi.org/10.1016/S1474-4422(17)30124-2Summary Full Text Full Text PDF PubMed Scopus (193) Google Scholar NfL concentrations were as much as 3·6 times greater in patients with manifest Huntington's disease compared with controls, and there was a very clear gradient from controls to early premanifest (far from expected motor onset), late premanifest (close to expected motor onset), and then to manifest Huntington's disease. The NfL increases in manifest Huntington's disease were similar to those in multiple sclerosis relapses,5Bergman J Dring A Zetterberg H et al.Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS.Neurol Neuroimmunol Neuroinflamm. 2016; 3: e271Crossref PubMed Scopus (90) Google Scholar and were at least as great as in other neurodegenerative diseases including progressive supranuclear palsy,6Rojas JC Karydas A Bang J et al.Plasma neurofilament light chain predicts progression in progressive supranuclear palsy.Ann Clin Transl Neurol. 2016; 3: 216-225Crossref PubMed Scopus (126) Google Scholar multiple system atrophy,7Hansson O Janelidze S Hall S et al.Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder.Neurology. 2017; 88: 930-937Crossref PubMed Scopus (271) Google Scholar and corticobasal syndrome.7Hansson O Janelidze S Hall S et al.Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder.Neurology. 2017; 88: 930-937Crossref PubMed Scopus (271) Google Scholar In Parkinson's disease7Hansson O Janelidze S Hall S et al.Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder.Neurology. 2017; 88: 930-937Crossref PubMed Scopus (271) Google Scholar and Alzheimer's disease,8Mattsson N Andreasson U Zetterberg H Blennow K Alzheimer's Disease Neuroimaging InitiativeAssociation of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease.JAMA Neurol. 2017; 74: 557-566Crossref PubMed Scopus (477) Google Scholar plasma and blood NfL concentrations are not substantially different from those of controls, partly because of the wide range of disease severity and subtypes within those diseases. In Huntington's disease, since patients can be genetically tested and subgrouped by time to expected motor onset, NfL concentrations have the potential to be used to study disease biology directly. The use of Huntington's disease as a model has the great advantage of genetic homogeneity and the ability to correlate variables of interest with age and CAG repeat length, for instance with the CAG-Age-Product (CAP) score. The large number of participants and great depth of phenotype information in the TRACK-HD study2Tabrizi SJ Scahill RI Owen G et al.Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data.Lancet Neurol. 2013; 12: 637-649Summary Full Text Full Text PDF PubMed Scopus (564) Google Scholar made possible the intriguing correlations with clinical variables, as extensively described in the Article by Byrne and colleagues.4Byrne LM Rodrigues FB Blennow K et al.Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis.Lancet Neurol. 2017; (published online June 7)http://dx.doi.org/10.1016/S1474-4422(17)30124-2Summary Full Text Full Text PDF PubMed Scopus (193) Google Scholar The investigators were also able to show that NfL concentrations have prognostic value for subsequent conversion from the premanifest to the manifest state, and to enable a number of other predictions of subsequent clinical variables during the 3 year follow-up. The data suggest that NfL concentrations increase most rapidly early in the premanifest period and then level off. Although the striatum is selectively affected early in the course of the disease, it was whole-brain volume that was more closely associated with the NfL concentrations. This association may be seen because NfL concentrations are likely to reflect global neuronal damage but, at the same time, this finding also suggests that the early increase in NfL concentrations must come from areas of the brain besides the striatum. Additionally, in an independent cohort of 37 participants, a striking correlation was seen between CSF and plasma concentrations. As in any good study, many intriguing questions are raised. Ultimately, it would be interesting to know whether NfL concentrations could be a biomarker for response to neuroprotective treatments. More immediately, it would be good to know what pathological changes in the neurons correlate with NfL release. For instance, must there be neuronal death, or perhaps axonal or terminal degeneration (which in Huntington's disease can be especially related to repeat-associated non-AUG translation products9Bañez-Coronel M Ayhan F Tarabochia AD et al.RAN translation in Huntington disease.Neuron. 2015; 88: 667-677Summary Full Text Full Text PDF PubMed Scopus (215) Google Scholar)? How early in the course of Huntington's disease can increases in NfL concentrations be observed? Is the NfL in the brain released directly into the bloodstream or does much of it come via the CSF? Some of these questions might be approached in animal model studies. It would also be important to replicate the results in other human samples. It would also be important to replicate the results in other human samples, such as those from the PREDICT-HD study,3Paulsen JS Long JD Ross CA et al.Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study.Lancet Neurol. 2014; 13: 1193-1201Summary Full Text Full Text PDF PubMed Scopus (168) Google Scholar which was also designed to collect biosamples and obtain brain imaging. A truly prospective study would also be important. Fortunately, a prospective multi-site CSF biomarker study called HDClarity has just begun in Europe and North America. It would be optimal if this study could have a longitudinal component and, ideally, some neuroimaging. In summary, the study reported by Byrne and colleagues4Byrne LM Rodrigues FB Blennow K et al.Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis.Lancet Neurol. 2017; (published online June 7)http://dx.doi.org/10.1016/S1474-4422(17)30124-2Summary Full Text Full Text PDF PubMed Scopus (193) Google Scholar represents a major advance in the field of Huntington's disease and neurodegeneration in general, and it seems likely to presage further advances in disease biology and, most importantly, in experimental therapeutics. We thank Ed Wild and Lauren Byrne for responding to questions, and Kaj Blennow for helpful discussions. We declare no competing interests. Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysisNfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease. Full-Text PDF Open Access