Neurofilament Light Chain as Prognostic Biomarker in ALS

A retrospective, longitudinal study of patients with different clinical subtypes of ALS supports the value of neurofilament light chain (NfL) as a biomarker for disease progression. In the work, published March 6 in JAMA Neurology, Gianni Sorarù and colleagues at the University of Padua in Padova, Italy, detail a strong correlation between cerebrospinal fluid NfL and rapid progression or shorter survival in a group of 94 patients. NfL fared less well as a diagnostic marker. The researchers found significant overlap in NfL levels among patients with ALS, frontotemporal dementia (FTD), and other motor neuronopathies.

“This study supports previous findings that NfL is elevated in ALS and FTD, and provides solid data on NfL in different types of ALS,” said Lucie Bruijn of the ALS Association, Washington, D.C. “Perhaps most important, the work confirms that NfL could be an important tool for distinguishing fast and slow progressors. For that reason, it could be a good stratifying measure in clinical trials,” Bruijn said. She added that the study adds some important details about NfL, including showing that levels are not affected by sex or age.

When axons fall apart, they release neurofilament protein, which scientists are pursuing as a biomarker for neurodegeneration in many diseases. Researchers first reported a marked elevation of NfL in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis two decades ago (Rosengren et al., 1996). Subsequent work established that high CSF or blood levels of NfL tracked with poorer prognosis and shorter survival (see Jun 2015 news; Weydt et al., 2016; Steinacker et al., 2016).

To ask whether NfL might be diagnostically useful, first author Alexandra Gaiani and colleagues analyzed CSF collected from 176 patients in Padua between 2010 and 2016. The group included the 94 patients diagnosed with ALS, 20 with FTD, 18 with motor neuropathies, and 44 controls. Each CSF sample was obtained between six months and two years after disease onset and stored. All were analyzed for NfL in 2016.

As expected, the ALS group had significantly higher CSF NfL than the other motor neuropathies or the control group. The FTD patients had intermediate levels. NfL in ALS and FTD had previously only been studied separately, Sorarù told Alzforum.

The researchers further divided the ALS patients into typical ALS (58 subjects), flail arm or flail leg syndrome (11 patients), progressive muscular atrophy (PMA, 9), progressive bulbar palsy (PBP, 9), and upper motor neuron dominant ALS (UMND, 7). The highest NfL levels occurred in patients with traditional ALS and in variants associated with upper motor neuron degeneration (progressive bulbar palsy and upper motor neuron dominant ALS). Only modest elevations accompanied the clinically milder forms (flail arm or flail leg syndrome and progressive muscular atrophy), which involve mainly lower motor neurons.

Those results harken back to the original 1996 report in which researchers already noted a difference in neurofilament in upper and lower motor neuron forms of the disease (see also Brettschneider et al., 2012). More recently, diffusion tensor imaging, which measures the integrity of large axons, has directly linked degradation of upper motor neurons in the corticospinal tract to the rise in NfL in ALS (Menke et al., 2015).

What about prognosis? The researchers followed patients for up to 80 months after their lumbar puncture. In agreement with previous findings, NfL concentration in the CSF inversely correlated with speed of disease progression as well as with overall survival, even after adjusting for sex, age, ALS subtype, and disease duration.

UMND ALS presented the one exception to the rule. Although it is mild and slow-progressing, patients with this form had CSF NfL as high as typical ALS. The authors speculated this reflects the predominantly upper corticospinal tract breakdown in UMND ALS.

Could NfL be useful for diagnosis? Based on their numbers, the authors suggest NfL on its own can distinguish ALS from controls with nearly 90 percent sensitivity and specificity. However, the marker cannot distinguish ALS from FTD or other motor neuron disease with such certainty.

“I’m less convinced about the diagnostic part of their study, but I think the evidence that correlates NfL to survival is very strong,” said Merit Cudkowicz, Harvard Medical School. “Because they looked at a greater diversity of motor neuron diseases and mimics, they have more power to show the spread of neurofilament values, and its strength as a good prognostic marker.” Cudkowicz pointed out that in cases of lower motor neuron involvement, clinicians don’t know if patients will stay that way or develop classical ALS. “A lower NfL value at the beginning is a good prognostic sign,” she said.

The tight link to progression means that NfL could help clinicians select subjects for clinical trials. “If you take all comers, you get huge variability in how people progress, and then you need large sample sizes to see any effects,” noted Cudkowicz. That’s a big challenge for the field, she added. “If NfL could help to pick a group of people who are progressing faster, then we might be able to study smaller groups,” she said.

“The study is really strong and well-conducted,” said Henrik Zetterberg, University of Gothenberg, Sweden. By replicating previous studies, it makes the case for NfL in ALS even stronger, he said.

The latest development in the field, a very sensitive blood test for NfL based on single molecule array analysis, should expand the reach of the test to many more people, and allow for easier, repeat, longitudinal analysis, noted Zetterberg (see Hansson et al., 2017).


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Image on home page: Neurofilaments, cultured rat brain cells, Gerry Shaw. Wikimedia Commons.

disease-als NfL topic-biomarkers topic-clinical
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