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 (Aβ1–42, Aβ1–40, 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.
Highlights
In recent years, there has been an increasing emphasis on developing a blood biomarker to predict the clinical onset of Alzheimer’s disease (AD) or to identify the underlying pathophysiology at its earliest stage
Plasma Neurofilament light chain (NfL) correlates with age and with poorer cognition independent of age Across all subjects, plasma concentrations of NfL positively correlated with age, the correlation coefficient was stronger in CTL participants than AD participants
Poorer Mini-Mental State Examination (MMSE) scores were associated with increasing post-mortem Braak stages across all subjects; among sub-groups, statistical significance of this correlation held only among AD subjects
Summary
There has been an increasing emphasis on developing a blood biomarker (plasma or serum) to predict the clinical onset of Alzheimer’s disease (AD) or to identify the underlying pathophysiology at its earliest stage. Structural imaging (MRI) and positron emission tomography (PET) techniques using 18F-fluorodeoxyglucose, amyloid tracers, and, more recently, tau ligands are costly, and access is limited to specialised centres. Cerebrospinal fluid (CSF) sampling is becoming routine in neurology clinics and the cost for the core AD CSF immunological assays (Aβ1–42, phosphorylated tau [P-tau] and total tau [T-tau]) are much lower per patient than for PET scans. A blood-based marker would complement CSF and molecular imaging biomarkers as a simplified initial triage step in a multi-stage assessment for early diagnosis, secondary prevention trial participant selection or monitoring of response to intervention over time (for review see, (Lewczuk et al 2017))
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