Neurofilament Protein a "Valuable" Biomarker of Early Neurodegeneration

By Reuters Staff 

NEW YORK—Elevated levels of neurofilament light (NfL) protein in cerebrospinal fluid (CSF) are associated with increased risk for mild cognitive impairment (MCI) in older cognitively normal adults, new research suggests.

NfL protein is a "putative marker of subcortical large-caliber axonal degeneration and has recently been highlighted for its potential as a biomarker of AD progression," the research team notes in an article in JAMA Neurology online November 12.

Dr. Michelle Mielke from the Mayo Clinic in Rochester, Minnesota and a multicenter team looked for associations between NfL and neurogranin (Ng), another potential marker for neurodegeneration, and cognitive decline in 648 adults (mean age, 72, 56.5% male) participating in the Mayo Clinic Study on Aging.

They all had normal cognitive function at baseline. During an average follow up of 3.8 years, 96 (14.8%) developed MCI.

Compared with individuals in the bottom quartile of CSF NfL, those in the top quartile had a 3.1-fold increased risk of developing MCI (hazard ratio, 3.13; 95% confidence interval, 1.36 to 7.18) in multivariate models.

Neither CSF total tau, phosphorylated tau, nor Ng was associated with risk of incident MCI and there was no interaction between amyloid beta-42 and NfL.

The combination of elevated CSF NfL and CSF total tau (an established measure of neurodegeneration) was not better than CSF NfL alone in determining risk for MCI, the researchers report. Low levels of CSF amyloid beta-42 were associated with an increased risk of MCI, as expected. However, the associations between CSF NfL and risk for MCI were independent of CSF amyloid beta-42.

Taken together, these results suggest that in a community-based sample of cognitively normal older adults, CSF NfL is more strongly associated with risk of MCI compared with other CSF markers of neurodegeneration, the researchers say.

They note that in prior studies, elevated CSF NfL levels have been found to correlate with faster cognitive decline in patients with MCI and shorter survival in patients with Alzheimer's dementia, suggesting that CSF NfL is a marker of clinical progression in symptomatic patients.

The current results extend these findings to earlier in the clinical disease spectrum by showing that high CSF NfL levels are also strongly associated with risk of MCI in a community-based study of cognitively healthy adults, Dr. Mielke and colleagues say.

The large community-based sample is a strength of the study, they note. The fact that all CSF markers were measured at one point is a limitation. "Thus, we could not incorporate time-varying measures and the association between intraindividual change in these markers and cognition could not be assessed," they note.

Also, when assessing CSF amyloid beta-42 as an effect modifier, the lowest tertile was considered indicative of elevated brain amyloid and it's possible that the subtle effects of emerging amyloid pathology in participants with slightly higher CSF amyloid beta-42 levels were overlooked.

Despite these caveats, the researchers say their findings suggest that CSF NfL is a "valuable biomarker of early neurodegeneration but not specific for AD pathobiology. In the newly published revisions of the 2018 National Institute on Aging-Alzheimer Association criteria, NfL is discussed as a neurodegeneration marker in the N+ group. These data suggest that NfL may be the preferred N+ CSF biomarker in the A/T/N classification," they conclude.

The study was supported by funding from the National Institutes of Health, the GHR Foundation, and Roche Diagnostics Ltd. Dr. Mielke served as a consultant to Eli Lilly and Lysosomal Therapeutics, Inc. A complete list of author disclosures is available with the original article.

SOURCE: https://bit.ly/2zezEmz

JAMA Neurol 2018.

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