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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Nicholas J. Ashton
  • Antoine Leuzy
  • Yau Mun Lim
  • Claire Troakes
  • Tibor Hortobágyi
  • Kina Höglund
  • Dag Aarsland
  • Simon Lovestone
  • Michael Schöll
  • Kaj Blennow
  • Henrik Zetterberg
  • Abdul Hye
Organisations
External organisations
  • King's College London
  • Stavanger University Hospital
  • University of Oxford
  • University College London
  • Sahlgrenska University Hospital
  • University of Gothenburg
  • South London and Maudsley NHS Foundation Trust
  • University of Debrecen
  • Warneford Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology

Keywords

  • Blood biomarkers, Braak, Neurofilament light chain, Post-mortem, Tau
Original languageEnglish
Article number5
JournalActa neuropathologica communications
Volume7
Issue number1
Publication statusPublished - 2019 Jan 9
Publication categoryResearch
Peer-reviewedYes