Blood Biomarker for Neurodegeneration: Closer But Not There Yet

Diagnosing neurodegeneration via a blood test is a wonderful idea, and a new study may bring it closer to reality.

Plasma neurofilament light (NFL) was increased in patients with mild cognitive impairment and Alzheimer disease dementia (mean 42.8 ng/L and 51.0 ng/L, respectively, versus 34.7 ng/L for controls, P<0.001), according to Niklas Mattsson, MD, PhD, of Sweden's Lund University, and colleagues writing in JAMA Neurology.

High plasma NFL also correlated with worse cognitive test scores at baseline for groups with Alzheimer disease and mild cognitive impairment.

Plasma NFL levels identified patients with Alzheimer's disease dementia with high accuracy (area under the curve 0.87).

"Together, these findings support that plasma NFL is a promising biomarker for neuronal injury in Alzheimer disease, which may have potential for prognosis and monitoring of disease progression," the authors concluded.

NFL levels also correlated significantly with longitudinal Mini-Mental State Examination scores for the mild cognitive impairment group.

"In a clinical trial scenario, it is possible that plasma NFL may be used (together with demographics and APOE ε4 genotype data) to predict longitudinal disease progression," Mattsson's group suggested.

"However, increased plasma NFL concentrations are also found in several other neurodegenerative disorders, such as progressive supranuclear palsy, frontotemporal dementia, and human immunodeficiency virus with brain engagement, meaning that it lacks disease specificity for Alzheimer disease. Therefore, we do not envision plasma NFL as a tool to differentiate Alzheimer disease from other neurodegenerative diseases. Rather, it may be valuable as a general biomarker for neurodegeneration."

However, an accompanying editorial suggested the biomarker is not ready for prime time.

"Unfortunately, the degree of overlap between Alzheimer disease or mild cognitive impairment and controls for plasma NFL was too large to allow this biomarker to become a stand-alone diagnostic test," wrote Douglas Galasko, MD, of University of California, San Diego.

"The idea that a single biomarker may reflect the complex pathogenesis of Alzheimer disease may be overly simplistic: in recent years, the use of biomarkers across the spectrum of brain imaging and cerebrospinal fluid has identified significant changes in biomarkers of brain structure, connectivity, glucose use, and synaptic damage, as well as inflammation in Alzheimer disease, in addition to biomarkers related to the core neuropathologic features of amyloid and tau aggregates," Galasko said.

Mattsson's prospective study from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database compared assays from 193 cognitively healthy controls, 197 people with mild cognitive impairment, and 180 patients with Alzheimer disease dementia.

Blood-based NFL concentrations correlated significantly, though imperfectly with cerebrospinal fluid NFL (Spearman r=0.59, P<0.001).

"Plasma NFL levels correlated with the scores of timed or executive function tests rather than with memory tests, again consistent with the idea that this biomarker relates to damage to large-caliber projection fiber tracts," the editorialist commented.

Galasko noted that the ADNI analysis was limited by the under-representation of patients with vascular risk factors. This, he wrote, may explain the lack of correlation between plasma NFL and white matter on MRI, a biomarker related to vascular cognitive impairment.

"A different application for plasma NFL may be as an index of progressive neurodegeneration in longitudinal studies, including clinical trials," he suggested. "To evaluate this possibility, data from longitudinally collected plasma samples from patients with different initial stages of Alzheimer disease will need to be analyzed."

"Understanding how they are generated and what biological processes and events they map onto will allow us to build a more comprehensive map of Alzheimer disease. The study by Mattsson et al makes important contributions to this map and will fuel many further investigations."