Plasma neurofilament light chain as prognostic marker of cognitive decline in neurodegenerative diseases, a clinical setting study

Abstract

Background: Analysis of selected research cohorts has highlighted an association between plasma neurofilament light (NfL) protein and cross-sectional cognitive impairment as well as longitudinal cognitive decline. However, the findings have yielded inconsistent results regarding its possible application in clinical practice. Despite its potential prognostic significance, the role of plasma NfL in daily clinical practice with unselected patients suffering from cognitive impairment remains largely unexplored.

Methods: This retrospective, cross-sectional and longitudinal monocentric study enrolled 320 patients with Alzheimer's disease ([AD], n = 158), dementia with Lewy body ([DLB], n = 30), frontotemporal dementia ([FTD], n = 32), non-neurodegenerative diseases ([NND], n = 59) or subjective cognitive decline ([SCD], n = 41). Plasma NfL levels were measured at baseline on the Simoa platform. AD, DLB, and FTD patients were also analyzed altogether as a 'degenerative conditions' subgroup, whereas SCD and NND were grouped as a 'non-degenerative conditions' subgroup. We assessed the relationship between plasma NfL levels and cross-sectional cognitive performance, including global cognition and six specific cognitive domains. A subset of 239 patients had follow-up mini-mental state examinations (MMSE) up to 60 months. Models were adjusted on age, education level, glomerular filtration rate and body mass index.

Results: In 320 patients, baseline plasma NfL levels were negatively associated with global cognition (β=-1.28 (-1.81 ; -0.75) P < 0.001), memory (β=-1.48 (-2.38 ; -0.59), P = 0.001), language (β=-1.72(-2.49 ; -0.95) P < 0.001), praxis (β=-2.02 (-2.91 ; -1.13) P < 0.001) and executive functions (β=-0.81, P < 0.001). Across diagnosis, plasma NfL levels were negatively associated with cross-sectional global cognition in all but the SCD subgroup, specifically with executive functions and memory in AD (respectively β=-0.71(-1.21 ; -0.211), P = 0.005 and β=-1.29 (-2.17 ; -0.42), P = 0.004), and with attention in LBD (β=-0.81(-1.16 ; -0.002), P = 0.03). Linear mixed-effects models showed that plasma NfL predicted MMSE decline in the global population (β_{PlasmaNfLxTime}=-0.15 (-0.26 ; -0.04), P = 0.006), as in the neurodegenerative condition subgroup (β_{PlasmaNfLxTime}=-0.21 (-0.37 ; - 0.06), P = 0.007), but not in non-neurodegenerative condition subgroup.

Conclusion: In our clinical cohort, plasma NfL was associated with faster cognitive decline in neurodegenerative dementia, which corroborates data obtained in research cohorts. Yet, plasma NfL was not predictive of accelerated cognitive decline in individuals without neurodegeneration, suggesting its use as a neurodegeneration-specific predictive biomarker.

Keywords: Alzheimer’s disease; Cognitive decline; Cognitive domains performance; Neurodegenerative diseases; Neurofilament proteins; Neuroimaging.

Fig. 1

Association of plasma NfL with cognitive function across diagnosis subgroups Plasma NfL association with global cognition and specific cognitive domains by diagnosis subgroups, including AD, FTD, LBD, NND and SCD. Standardized estimates with the corresponding 95% CI were plotted for the association of baseline plasma NfL levels with baseline cognitive domain scores for each diagnosis group. Linear regressions were adjusted on age, sex and education level.

Fig. 2

Association of plasma NfL and confounding variables with MMSE over time in the whole cohort, neurodegenerative conditions group and non-neurodegenerative conditions group (A) Factors associated with MMSE in cross-sectional analysis in the whole cohort. (B) Factors associated with MMSE change over time in the whole cohort (C) Factors associated with baseline MMSE in the neurodegenerative condition group. (D) Factors associated with MMSE decline in the neurodegenerative condition group. (E) Factors associated with baseline MMSE in the non-degenerative condition group. (F) Factors associated with MMSE decline in the non-degenerative group. Standardized estimates with the corresponding 95% CI were plotted for the association of baseline plasma NfL levels and confounding variables with MMSE scores at baseline (cross-sectional) and during follow-up (longitudinal) in the different groups. All models represented are linear mixed models with fixed effects on plasma NfL, age, education level, body mass index and glomerular filtration rate. Random intercepts and slopes were included. All variables were log-transformed prior to analysis.

Fig. 3

Predicted MMSE trajectories at hypothesized 10th, 50th and 90th deciles plasma NfL levels in the non-neurodegenerative and degenerative subgroups Predicted MMSE trajectories for hypothesized individuals with plasma NfL levels at the 10th, 50th and 90th centiles, respectively with a non-neurodegenerative (blue curves) and a degenerative (red curves) disorder, computed using mixed model coefficients. Age, sex, education level, glomerular filtration rate and body mass index used for analysis are, respectively, the mean of the neurodegenerative group and non-neurodegenerative groups. The stratified lines represent the estimated slope across time for each baseline plasma NfL levels (Q10 = 9.27 pg/mL; Q50 = 19.18 pg/mL; Q90 = 35.48 pg/mL).