Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer’s disease

Abstract

BackgroundA growing body of evidence suggests that the plasma concentration of the neurofilament light chain (NfL) might be considered a plasma biomarker for the screening of neurodegeneration in Alzheimer’s disease (AD).MethodsWith a single molecule array method (Simoa, Quanterix), plasma NfL concentrations were measured in 99 subjects with AD at the stage of mild cognitive impairment (MCI-AD; n = 25) or at the stage of early dementia (ADD; n = 33), and in nondemented controls (n = 41); in all patients, the clinical diagnoses were in accordance with the results of the four core cerebrospinal fluid (CSF) biomarkers (amyloid β (Aβ)1–42, Aβ42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm. The influence of preanalytical storage procedures on the NfL in plasma was tested on samples exposed to six different conditions.ResultsNfL concentrations significantly increased in the samples exposed to more than one freezing/thawing cycle, and in those stored for 5 days at room temperature or at 4 °C. Compared with the control group of nondemented subjects (22.0 ± 12.4 pg/mL), the unadjusted plasma NfL concentration was highly significantly higher in the MCI-AD group (38.1 ± 15.9 pg/mL, p < 0.005) and even further elevated in the ADD group (49.1 ± 28.4 pg/mL; p < 0.001). A significant association between NfL and age (ρ = 0.65, p < 0.001) was observed; after correcting for age, the difference in NfL concentrations between AD and controls remained significant (p = 0.044). At the cutoff value of 25.7 pg/mL, unconditional sensitivity, specificity, and accuracy were 0.84, 0.78, and 0.82, respectively. Unadjusted correlation between plasma NfL and Mini Mental State Examination (MMSE) across all patients was moderate but significant (r = −0.49, p < 0.001). We observed an overall significant correlation between plasma NfL and the CSF biomarkers, but this correlation was not observed within the diagnostic groups.ConclusionsThis study confirms increased concentrations of plasma NfL in patients with Alzheimer’s disease compared with nondemented controls.

The diagnostic performance of neurofilament light chain in CSF and blood for Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis: A systematic review and meta‐analysis

“…Twelve studies compared blood (i.e., plasma and serum) NfL concentration in AD cases and cognitively unimpaired controls [4,9,25,30,42,[47][48][49][50][51][52][53]; however, three of these studies used largely overlapping data from the ADNI database [49,50,53]. To avoid bias, the largest of the three overlapping studies was selected for inclusion in the meta-analysis [53]; thus, 10 studies comparing 471 AD cases to 518 cognitively unimpaired controls were included in the meta-analysis.…”

“…2D). Of these studies, 5 studies (365 AD cases and 357 cognitively unimpaired controls) compared NfL concentration in plasma, with an average ratio of 2.11 (95% CI 0.78-5.73) [25,30,47,48,53]. The remaining 5 studies (106 AD cases and 161 cognitively unimpaired controls) compared serum NfL concentration [4,9,42,51,52], with an average ratio of 3.22 (95% CI 1.37-7.57).…”

“…Age and sex have been determined to be important considerations in the application of NfL as a biomarker. NfL correlates with age in both healthy individuals and those with most neurodegenerative diseases [41,48,[82][83][84]. In addition, CSF NfL concentration is significantly higher in males compared with females in healthy individuals and several neurodegenerative diseases [19,41]; however, mixed findings, with more modest differences, have been noted for blood NfL [66,[82][83][84].…”

Plasma amyloid beta levels are associated with cerebral amyloid and tau deposition

“…Reduced plasma Ab has also been linked to poorer cognition [6,7,19,21,[27][28][29][30]. In addition, some studies have suggested that plasma levels of Ab42 and Ab40 are associated with the levels of cerebral Ab on positron emission tomography (PET), cerebrospinal fluid levels of Ab and tau, and AD-like brain atrophy [4,7,8,11,16,17,24,[31][32][33][34][35][36][37][38], while others have not seen such an association [25,39,40]. These conflicting results may be due to the type of plasma markers measured and the methodologies used to extract these values.…”

The Interplay between Diabetes and Alzheimer’s Disease—In the Hunt for Biomarkers

“…Lately, there is a growing body of evidence that the measurement of NFL concentrations in plasma might be considered a potential marker for neurodegenerative changes characteristic of AD. Lewczuk et al identified elevated NFL levels in cases with AD compared to healthy controls, which were inversely correlated with MMSE results [133].…”