Neurofilament Light and mean Free Water as prognostic enrichment biomarkers for cognitive worsening and small vessel disease progression

Abstract

AbstractBackgroundPlasma neurofilament light (NfL) and free water (FW), a DTI‐derived measure, are considered, individually, sensitive markers of axonal damage that relate to cognition. A significant remaining challenge for clinical trials resides in identifying biomarkers able to detect, simultaneously, early SVD abnormalities and baseline cognitive impairment, particularly in non‐demented participants, who are also at risk of cognitive worsening and SVD progression during the trial.MethodThis study includes 200 non‐demented individuals from the MarkVCID‐UH3 cohort who had baseline NfL and baseline and follow‐up (1.3±0.5 years) cognitive assessment and MRI (Table 1). We used a composite measure of global cognitive function (GCF) using scores from the NACC‐UDS. WMH volumes were log‐transformed and corrected for intracranial volume. Annual change (Δ) in GCF and WMH was computed using baseline and follow‐up measures. A threshold, determined from 3 independent cohorts, was applied to FW measures to group individuals (low: <0.22 and high > = 0.22). Low and high NfL levels were defined using age‐based NfL z‐scores (low←0.5SD and high> = ‐0.5SD). We finally grouped individuals with both high NfL and FW levels (MULTIBIO+) vs. individuals with at least one biomarker with low level (MULTIBIO‐). We used linear regressions with either baseline GCF, baseline WMH, ΔGCF or ΔWMH as the dependent variable and, separately, baseline FW, NfL and MULTIBIO as the independent variable. Analyses were adjusted for relevant confounding variables.ResultsWe found that, as compared with MULTIBIO‐, MULTIBIO+ group had significantly lower baseline GCF and higher baseline WMH (p = 0.033 and p<0.001), as well as accelerated ΔGCF and larger ΔWMH (pvalues<0.01, Table 2, Figure 1). Individually, although FW was associated with baseline WMH and accelerated ΔGCF, neither FW nor NfL levels simultaneously explained baseline cognition and SVD burden, or simultaneous ΔGCF and ΔWMH (Table 2).ConclusionThese findings emphasize the potential of combining NfL and FW measures as a prognostic enrichment biomarker panel for identifying individuals with both early SVD abnormalities and cognitive impairment and who are also at risk of cognitive worsening and substantial SVD burden progression during clinical trials.Data collection and sharing for this project was funded by NINDS/NIA as part of the MarkVCID Consortium (U24NS100591, UH2NS100599, UH2NS100605, UH2NS100588, UH2NS100608, UH2NS100606, UH2NS100598, UH2NS100614)