Abstract
Increased neurofilament levels in biofluids, commonly used as a proxy for axonal degeneration in the brain, have been found in Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB), and correlate with MRI biomarkers. The aim of the current study was to unravel the regional distribution of cortical neurofilaments and their association with pathology load and MRI measures of atrophy and diffusivity in the post-mortem brain.
Using a within-subject post-mortem MRI-pathology approach, we included 9 PD, 12 PDD/DLB and 18 age-matched control donors. Cortical thickness and mean diffusivity (MD) metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI. After autopsy, pSer129 alpha-synuclein (pSer129-αSyn), p-tau, and amyloid-beta, together with neurofilament light-chain (NfL) and phosphorylated neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in 7 cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models.
Compared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was mainly increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. Increased p-NfM/H correlated with p-tau load, and NfL correlated with pSer129-αSyn but more strongly with p-tau load in PDD/DLB. Lastly, neurofilament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB.
Taken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increasing pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Section "Pathology image processing" in Methods clarifies the segmentation of entorhinal, parahippocampal and fusiform cortex.
Abbreviations
- Aβ
- amyloid-beta
- AD
- Alzheimer’s disease
- CSF
- cerebrospinal fluid
- DLB
- dementia with Lewy bodies
- DTI
- diffusion tensor imaging
- FDR
- false discovery rate
- FWC-MD
- free-water corrected mean diffusivity
- IHC
- immunohistochemistry
- LB
- Lewy body
- MD
- mean diffusivity
- NfL
- neurofilament light chain
- NFT
- neurofibrillary tangles
- PD
- Parkinson’s disease
- PDD
- Parkinson’s disease dementia
- p-NfM/H
- phosphorylated neurofilament medium and heavy chain
- p-tau
- phosphorylated-tau
- pSer129-αSyn
- phosphorylated Ser129 alpha synuclein
