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Study Explores Usefulness of NfL as Biomarker Across Range of Neurological Conditions

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NEW YORK – A team led by researchers at Lund University and the University of Gothenburg has completed a study looking at the potential use of the neurodegeneration marker neurofilament light, or NfL, chain in diagnosing and managing a range of neurodegenerative disorders.

Detailed in a paper published last week in Nature Communications, the effort is one of the first that compares NfL measurements across multiple disorders to assess where it could be clinically useful, said Nicholas Ashton, an assistant professor at the University of Gothenburg and first author on the study.

A marker of neuro-axonal damage, NfL has drawn substantial interest of late as a potential tool for use in various neurological conditions and neurodegenerative diseases. In the Nature Communications study, Ashton and his colleagues set out to investigate how the marker might be useful in working up patients presenting with neurological complaints and distinguishing between different potential diagnoses.

The researchers measured NfL levels in plasma from 2,269 individuals from two independent, multicenter cohorts. The subjects included patients with 13 neurodegenerative disorders, Down syndrome, and depression, as well as cognitively unimpaired controls.

As was expected, the marker performed with different levels of effectiveness in different conditions, but in general it showed utility in evaluating whether neurodegeneration was part of the underlying picture of a disease. This, Ashton said, could prove particularly useful in conditions like Parkinson's disease that may or may not be accompanied by neurodegeneration.

"If you present with a Parkinson's syndrome, NfL is extremely useful in determining whether you have Parkinson's with dementia or pure Parkinson's disease," he said.

Another potential use is for identifying early onset dementias, like frontotemporal dementia, which can present initially as psychiatric disorders like depression.

"The study showed that if you have depression that is not caused by neurodegeneration, then your levels of [NfL] are extremely low, the normal levels that we see in the general population," Ashton said. "But if it is being caused by a neurodegenerative disorder, they are very, very high. And this is extremely important in the very early onset of a disorder where the symptoms are a bit unclear to the clinician and where a biomarker could really start to point towards an underlying brain condition, rather than a psychiatric one."

He noted that in Sweden, NfL has made its way into clinical practice for a variety of conditions.

"It is [a test] a clinician can request if they want it, and so we are doing this routinely. It has proven to be useful to physicians in their clinical workups," he said, noting that NfL had found applications ranging from assessment of adolescent neurological disorders through to older dementia patients. "It has a really broad application."

Last year, for instance, researchers at the National Institute of Health found that serum NfL could be useful for assessing patients with traumatic brain injury, determining that NfL levels were elevated in TBI patients compared to controls and were elevated in TBI patients whose symptoms lasted longer than one year post-injury compared to patients whose symptoms resolved prior to a year.

Alzheimer's disease has also been an area of interest, with a 2019 study finding that measuring the rate of change in patients' NfL levels allowed researchers to distinguish carriers of a mutation linked to familial Alzheimer's more than 16 years before the onset of symptoms.

Ashton said, however, that he and his colleagues found that the increase in NfL in Alzheimer's patients was "quite mild" and added that existing markers like phosphorylated tau would probably be more useful for diagnosing the disease. He noted, though, that elevated NfL levels in the absence of elevated phosphorylated tau could indicate non-Alzheimer's dementia.

"I don't think NfL can be used as a complete diagnostic" by itself, he said. "But it can point the clinician in a way to where they might need to order more specific and definitive tests."

He added that he and his colleagues were also interested in investigating whether the marker could be useful for tracking the progression of neurodegenerative disease and response to treatments over time.

The researchers used Quanterix's Simoa system for making the NfL measurements. Ashton noted that the Quanterix NfL assay has become widely used by researchers globally, adding that this has benefited research efforts by making it easy to compare results across laboratories.

NfL is one of Quanterix's biggest selling assays. At one point in 2019 it accounted for roughly 20 percent of the company's revenues.

That percent figure has since dropped as Quanterix's overall business has grown, said Kevin Hrusovsky, the company's chairman, president, and CEO, but the total volume of NfL sales has continued to rise.

In 2019, Quanterix purchased Swedish reagents firm UmanDiagnostics, primarily to acquire the company's NfL antibodies, which it uses in its Simoa assays. Several months later, Quanterix licensed the NfL antibodies to Siemens Healthineers, which is using the technology to develop blood-based NfL clinical tests.

Hrusovsky noted that Quanterix has seen strong demand for NfL testing from drug companies using the marker in clinical trials for drugs addressing neurodegenerative conditions, adding that in 2020 both Roche and Novartis received US Food and Drug Administration approval for multiple sclerosis drugs (Roche's Ocrevus and Novartis's Kesimpta) based on clinical trials that used NfL as a marker of the drugs' effectiveness.

He suggested that those successes were driving interest in whether the marker could be useful for demonstrating effectiveness for drug trials in other neurodegenerative conditions.

"NfL continues to be a major positive growth franchise for us," Hrusovsky said.

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