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Neurofilament light chain (NfL) holds promise as a biomarker for disease progression and prognosis in Huntington's disease (HD), although clinical utility is still on the horizon.

Having better biomarkers is important, "even in a disease like Huntington's where we know it's a monogenic disease, we know the causative mutation in the Huntington gene, and we can do predictive genetic testing in individuals who are not yet symptomatic," said Erin Furr Stimming, MD, of McGovern Medical School at UTHealth Houston.

After someone tests positive for the HD gene, "the next question we'll get from individuals is 'OK, when will I become symptomatic and what will my rate of progression be?' And we can't answer with accuracy either of those questions," she added.

The CAG-CAA repeat number in the huntingtin (HTT) gene inversely correlates with age of onset, but explains only some 50-70% of the variability in onset observed between patients, noted Furr Stimming.

NfL is a cytoskeletal protein expressed only in neurons. Since circulating levels quantify neuronal damage, NfL has been investigated as a biomarker in a number of neurologic diseases, including and Alzheimer's disease. Longitudinal studies in multiple sclerosis, traumatic brain injury, and stroke "show accumulation of NfL over days followed by elevated levels over months," noted a in the Annals of Clinical and Translational Neurology.

Clinical Utility

In HD, NfL likely tracks disease severity, based on studies showing that cerebrospinal fluid and plasma levels spike early in the disease and notably increase as clinical condition worsens, said Daniel Claassen, MD, of Vanderbilt University Medical Center in Nashville.

"Right now it's a research tool and it hasn't been applied to clinical populations," he cautioned.

He agreed with Furr Stimming that there is significant potential utility in the "premanifest" phase of the disease. For instance, in a patient who has cognitive or psychiatric symptoms but not yet motor symptoms of HD, higher than expected NfL could potentially aid in earlier diagnosis, he suggested. "We really need to study these prodromal, pre- [motor] symptomatic symptoms in patients before we make conclusions about it," he said.

"The relevance otherwise is not straightforward," Claassen told 乌鸦传媒. "We would have to have some information that tells us knowing NfL, at least in Huntington's disease, is either going to change our clinical management or inform something about the patient that matters to their decision-making -- do they stay in their job or do something else?"

He predicted it might be within 5 years that NfL could reach the clinic.

Research Utility

Meanwhile, there's a good case for NfL as a biomarker for clinical trials.

"It's important to have a reliable and validated biomarker to help in determining with better precision when folks will become symptomatic, number one, and number two, what their potential rate of progression might be," Furr Stimming said, "and perhaps most importantly, with the exciting that are underway, to help us determine if indeed a disease-modifying compound is making progress."

Furr Stimming pointed out that as with most neurodegenerative diseases, there appears to be a prodromal period where neurodegeneration is occurring but symptoms are not significant enough to warrant a clinical diagnosis.

"There may a window of opportunity for us to potentially intervene when and if we have an approved disease-modifying therapy to hopefully slow or even halt neurodegeneration, as opposed to waiting until individuals have a clinical diagnosis, which in HD has been historically based on motor symptoms," she said.

With the newly released Huntington's Disease , which outlines evidence-based staging centered on biological, clinical, and functional assessments, the standardization of early disease staging might help with evaluating the benefit of disease-modifying treatments, she added. The current Total Functional Capacity scale really only applies to symptomatic, motor-manifest cases, Furr Stimming noted.

The converse is also true, Claassen said. "It could be used to mark a medication effect that is deleterious to patients," he noted. He pointed to the that was halted after a signal of harm from the novel drug tominersen in HD patients who were given more frequent doses showed no benefit over placebo when it was given less frequently.

The trial showed a "rather notable" increase in NfL in patients who got the antisense oligonucleotide therapy, Claassen said, "and it ended up being interpreted as a marker of a side effect of the drug where it was actually causing side effects and not helping patients."

And in a phase I/II amyotrophic lateral sclerosis testing another antisense oligonucleotide drug, tofersen, NfL was largely unchanged with placebo but decreased in plasma and serum from baseline to day 85 in the intervention arm.

"People are thinking it could be kind of a quantitative marker of disease modulation by medication that alters the pathogenesis of the degenerative disease state," Claassen noted.

Ultimately, some combination of biomarkers might end up being the best strategy, Furr Stimming acknowledged. "NfL is kind of a work in progress," she said. "We are cautiously optimistic."

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