Blood Biomarker Can Play a Role in Neurodegeneration Monitoring

Niklas Mattsson, MD, PhD

New evidence suggests that plasma neurofilament light (NfL) may be useful as a noninvasive biomarker to monitor neurodegeneration in patients with Alzheimer disease.

The study, published in JAMA Neurology, included data from 1583 patients from the Alzheimer’s Disease Neuroimaging Initiative study who had annual plasma NfL samples collected from September 2005 through June 2016.

Investigators sought to examine the utility of plasma NfL as a biomarker since current methods of monitoring, including advanced imaging and cerebrospinal fluid analysis, are both invasive and expensive.

“Neurofilament light (NfL) in CSF is a sensitive biomarker for neuroaxonal damage, and recent developments have allowed for measurement of NfL levels in blood samples,” the researchers, led by Niklas Mattsson, MD, PhD, of Lund University and Skane University Hospital in Sweden, wrote. “Plasma NfL is a candidate marker to track neurodegeneration in AD, in which levels are increased and correlate with future atrophy, hypometabolism, and cognitive decline.”

The primary outcome of the study was the association between baseline exposures, including diagnosis, cerebrospinal fluid biomarkers, imaging measures, and cognition, and longitudinal plasma NfL. Secondary outcomes included the associations between the “ATN” system (amyloid-beta [Aβ], tau, and neurodegeneration) and plasma NfL levels, as well as longitudinal changes in plasma NfL levels and changes in other measures.

Participants (45.2% women) were aged 55 to 90 years, with a Mini Mental State Exam (MMSE) score of ≥24 and a Clinical Dementia Rating Scale (CDR) score of 0. Of the cohort, 855 patients had mild cognitive impairment (MCI), 327 had Alzheimer disease dementia (AD dementia), and 401 participants were cognitively unimpaired, resulting in 4326 measures of plasma NfL from samples collected annually for up to 11 years. Notably, plasma NfL levels at baseline were positively correlated with age, but not education level or sex.

Overall, baseline plasma NfL levels were higher in patients with MCI and AD dementia compared with controls. Significant level increases were observed across all groups, with a greater increase among participants with MCI versus controls, as well as a greater increase among patients with AD dementia compared with both controls and those with MCI. When stratified by Aβ status, controls who were Aβ positive had increased baseline levels of plasma NfL compared with controls who were Aβ negative; similarly, Aβ-positive patients with MCI showed increased baseline levels of plasma NfL compared with those who were Aβ-negative. Notably, not significant difference in plasma NfL levels was observed between patients with AD dementia who were Aβ positive or negative.

All baseline variables — cerebrospinal fluid Aβ42, t-tau level, p-tau levels, hippocampal volume, entorhinal cortical thickness, ventricular volume, temporal cortical thickness, FDG-PET findings, white matter lesions, MMSE score, CDR-SB score, and ADAS-Cog score – were associated with greater baseline and rapid increase of plasma NfL levels. Based on ATN stratification, increased NfL levels at baseline were recorded in neurodegeneration-positive patients (A–T+N+, A+T–N+, and A+T+N+ (P&thinsp;<.001); increased longitudinal rates were also observed in this population, as well as those who were only tau-positive.

“Taken together, these findings suggest that the NfL level is a dynamic biomarker that changes throughout the course of AD and is sensitive to progressive neurodegeneration,” the researchers concluded. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in AD.”

Reference

Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association between longitudinal plasma neurofilament light and neurodegeneration in patients with alzheimer disease. JAMA Neurol. Published online April 22, 2019. Accessed April 25, 2019. doi:10.1001/jamaneurol.2019.0765