TY - JOUR
T1 - Neurofilament light chain is increased in the parahippocampal cortex and associates with pathological hallmarks in Parkinson?s disease dementia
AU - Frigerio, Irene
AU - Laansma, Max A.
AU - Lin, Chen-Pei
AU - Hermans, Emma J. M.
AU - Bouwman, Maud M. A.
AU - Bol, John G. J. M.
AU - Galis-de Graaf, Yvon
AU - Hepp, Dagmar H.
AU - Rozemuller, Annemieke J. M.
AU - Barkhof, Frederik
AU - van de Berg, Wilma D. J.
AU - Jonkman, Laura E.
N1 - Funding Information: We would like to thank all brain donors and their next of kin for brain donation. We would also like to thank the autopsy teams of the Netherlands Brain Bank (NBB) and Normal Aging Brain collection Amsterdam (NABCA). Funding Information: This study was funded by The Michael J. Fox Foundation (grant #17253) and Stichting ParkinsonFonds (grant #1881). F.B. is supported by the NIHR biomedical research centre at the University College Hospital of London (UCLH). The authors have no relevant financial or non-financial interests to disclose. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Background: Increased neurofilament levels in biofluids are commonly used as a proxy for neurodegeneration in several neurodegenerative disorders. In this study, we aimed to investigate the distribution of neurofilaments in the cerebral cortex of Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) donors, and its association with pathology load and MRI measures of atrophy and diffusivity. Methods: 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, pathological hallmarks (pSer129-αSyn, p-tau and amyloid-β load) together with neurofilament light-chain (NfL) and phosphorylated-neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in seven cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models. Results: Compared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. The 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. Conclusions: Taken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increased pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.
AB - Background: Increased neurofilament levels in biofluids are commonly used as a proxy for neurodegeneration in several neurodegenerative disorders. In this study, we aimed to investigate the distribution of neurofilaments in the cerebral cortex of Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) donors, and its association with pathology load and MRI measures of atrophy and diffusivity. Methods: 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, pathological hallmarks (pSer129-αSyn, p-tau and amyloid-β load) together with neurofilament light-chain (NfL) and phosphorylated-neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in seven cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models. Results: Compared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. The 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. Conclusions: Taken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increased pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.
KW - Axonal degeneration
KW - Cortical atrophy
KW - Cortical thickness
KW - Dementia with Lewy bodies
KW - Mean diffusivity
KW - Neurofilament
KW - NfL
KW - Parkinson’s disease
KW - Parkinson’s disease dementia
UR - http://www.scopus.com/inward/record.url?scp=85146636516&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s40035-022-00328-8
DO - https://doi.org/10.1186/s40035-022-00328-8
M3 - Article
C2 - 36658627
SN - 2047-9158
VL - 12
JO - Translational Neurodegeneration
JF - Translational Neurodegeneration
IS - 1
M1 - 3
ER -