Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathology and neurodegeneration

Abstract

Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles and widespread neuronal loss in the brain. In recent years, blood biomarkers have emerged as a realistic prospect to highlight accumulating pathology for secondary prevention trials. Neurofilament light chain (NfL), a marker of axonal degeneration, is robustly elevated in the blood of many neurological and neurodegenerative conditions, including AD. A strong relationship with cerebrospinal fluid (CSF) NfL suggests that these biomarker modalities reflect the same pathological process. Yet, the connection between blood NfL and brain tissue pathology has not been directly compared. In this study, longitudinal plasma NfL from cognitively healthy controls (n = 12) and AD participants (n = 57) were quantified by the Simoa platform. On reaching post-mortem, neuropathological assessment was performed on all participants, with additional frozen and paraffin-embedded tissue acquired from 26 participants for further biochemical (Aβ_1-42, Aβ_1-40, tau) and histological (NfL) evaluation. Plasma NfL concentrations were significantly increased in AD and correlated with cognitive decline, independent of age. Retrospective stratification based on Braak staging revealed that baseline plasma NfL concentrations were associated with higher neurofibrillary tangle pathology at post-mortem. Longitudinal increases in plasma NfL were observed in all Braak groupings; a significant negative association, however, was found between plasma NfL at time point 1 and both its rate of change and annual percentage increase. Immunohistochemical evaluation of NfL in the medial temporal gyrus (MTG) demonstrated an inverse relationship between Braak stages and NfL staining. Importantly, a significant negative correlation was found between the plasma NfL measurement closest to death and the level of NfL staining in the MTG at post-mortem. For the first time, we demonstrate that plasma NfL associates with the severity of neurofibrillary tangle pathology and neurodegeneration in the post-mortem brain.

Keywords: Blood biomarkers; Braak; Neurofilament light chain; Post-mortem; Tau.

Fig. 1

Plasma neurofilament light chain (NfL) concentrations in healthy controls (CTL) versus Alzheimer’s disease (AD) patients at time point 1 (p < 0.001). The horizontal dashes indicate median (long) and quartiles (short)

Fig. 2

Time point 1 plasma neurofilament light chain (NfL) concentrations in comparison to global cognition (MMSE; rho = − 0.49, p < 0.001)

Fig. 3

Time point 1 plasma neurofilament light chain (NfL) concentrations and Braak staging at post-mortem. The horizontal dashes indicate median (long) and quartiles (short). Clinical classification was determined at plasma time point 1

Fig. 4

Longitudinal neurofilament light chain (NfL) concentrations by Braak stage. Circles, triangles, and squares indicate median values for isocortical (Braak V/VI), limbic (Braak III/IV) and transentorhinal (Braak I/II) stages, respectively. Significant increases were seen across all groups, between time point 1 and subsequent time points (time point 2, p < 0.01; time point 3, p < 0.001)

Fig. 5

Formalin-fixed paraffin-embedded MTG sections stained for mouse anti-neurofilament light chain (clone DA2), one representative section from each Braak stage (I-VI) is displayed (a-f). The relationship between % NfL staining in the MTG and Braak staging at post-mortem (rho = − 0.34, p = 0.102) (g). A significant negative correlation between plasma NfL time point closest to death and % NfL staining in the MTG at post-mortem (rho = − 0.47, p < 0.01 (h)