Neurofilament Light Protein Shows Strong Potential as Biomarker for Huntington’s Disease

Measurement of neurofilament light proteins (NfLs) in blood plasma was highly predictive of the clinical onset of Huntington’s disease (HD) in individuals with premanifest disease loads and of disease progression in individuals with diagnosed HD, according to a retrospective study published in Lancet Neurology.¹ Concentrations of NfL were significantly higher in individuals carrying the HTT gene mutations at all stages of HD compared with non-HD controls.

The multinational team of investigators examined blood plasma samples taken annually from a cohort of 201 huntingtin gene (HTT) carriers (58 with early premanifest HD, 46 with late premanifest HD, 66 with stage 1 HD, and 31 with stage 2 HD) from the TRACK-HD study and 97 controls. Plasma NfL levels corresponded to clinical measures and magnetic resonance imaging (MRI) findings at all time points during the 3-year follow-up period.

In addition, high baseline NfL concentrations were also independently associated with multiple measures of disease progression observed over the next 3 years of the study. These included cognitive decline, measured by the symbol-digit modality test (r=−0.374, P <.0001) and the Stroop Color- Word Test (r=−0.248, P =.0033), total functional capacity (r=−0.289, P =.0264), and multiple measures of brain atrophy (caudate r=0.178, P =.0087; whole-brain r=0.602, P <.0001; grey matter r=0.518, P <.0001; white matter r=0.588, P <.0001; and ventricular expansion r=-0.589, P <.0001).

The most pronounced increases in NfL were found in patients with premanifest HD at baseline and patients with increasing CAG triplet repeat counts. Neurology Advisor asked study co-investigator Dr Edward Wild, MRC clinician scientist, University College London (UCL) Institute of Neurology and consultant neurologist, National Hospital for Neurology & Neurosurgery, in the United Kingdom, if any mechanism common to other neurological diseases was recognized. “In a way, NfL is letting us measure more rapidly and chemically a shared mechanism that we were already aware of, namely that damaged neurons and axons release their structural proteins. In that sense it is a very downstream, shared mechanism for many diseases — hence we see NfL changes in such diverse conditions as HD, Alzheimer’s, multiple sclerosis and traumatic brain injury,” he responded.

The consistent patterns of NfL reported in the study indicate that it holds particular promise as a biomarker of HD disease activity in patients already identified with the HTT mutation. “NfL has been described as being a bit like a CRP [C-reactive protein] or troponin for the brain — if it goes up, something bad has happened, but NfL alone can’t tell us what,” Dr Wild explained. “That’s not really a problem for us because the genetic test tells us for sure which patients have HD pathology ongoing, and we can then use NfL to measure activity of the disease we know they have,” he added.

The investigators evaluated an additional small London cohort of 37 individuals (23 HTT carriers and 14 controls), which showed that increases in plasma NfL corresponded closely to increases in cerebrospinal (CSF) levels of NfL. Despite the compelling evidence supporting the prognostic value of NfL levels, the investigators recommended that future trials aim at quantifying NfL increases for a more accurate biomarker of disease onset and progression. “It gives us a very clear, immediate way forward,” Dr Wild stated, adding, “I would certainly urge the inclusion of NfL in both blood and CSF in any clinical trial of a novel drug aiming to reduce neuronal damage and death in Huntington’s disease, as an exploratory biomarker. Only then can we answer the next big question: if you slow HD down, does NfL level fall? It should, but we have to test it experimentally in clinical trials. Only then can we start to think about using NfL as an endpoint for trials to prevent the onset of HD in mutation carriers.”

Dr Wild also saw other potential uses for NfL. “Once we have drugs that work, I can imagine testing patients regularly for blood NfL level as a means of guiding decisions about when to start treatment. But again that requires more evidence than we have now about how NfL predicts and measures treatment response,” he said.

Reference

Byrne, 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 [published online June 7, 2017]. Lancet Neurol. pii:S1474-4422(17)30124-2. doi:10.1016/S1474-4422(17)30124-2