Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s40478-018-0649-3
Keywords
Neurofilament light chain; Blood biomarkers; Braak; Tau; Post-mortem
Categories
Funding
- National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust
- King's College London
- UK Medical Research Council
- Brains for Dementia Research programme - Alzheimer's Research UK
- Brains for Dementia Research programme - Alzheimer's Society
- Wallenburg Centre for Molecular and Translational Medicine
- Hungarian Brain Research Program
- Knut och Alice Wallenberg Foundation (the Wallenberg Centre for Molecular and Translational Medicine)
- Swedish Research Council
- Swedish Alzheimer Foundation
- Swedish Brain Foundation
- European Research Council
- UK Dementia Research Institute at UCL
- Research Centre for Mental Health and Biomedical Research Unit for Dementia
- MRC [MR/L016397/1] Funding Source: UKRI
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Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid- (A) 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 (A(1-42), A(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.
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