Neurofilament light chain is increased in the parahippocampal cortex and associates with pathological hallmarks in Parkinson’s disease dementia

Abstract

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.

Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks

“…It has been proposed that the development of cognitive decline prior to or simultaneous with the manifestation of motor symptoms should be included in the diagnostic procedures of PD [ 450 , 451 ]. The prospective assessment and validation of PD-CI and a deeper understanding of the interaction of multiple pathogenic factors will be achieved by modern fluid biomarkers (reduced αSyn and Aβ-42 levels, increased p-tau 181, glial fibrillary acidic protein/GFAP/and NfL) as well as in post-mortem brain tissue [ 452 , 453 , 454 , 455 , 456 , 457 , 458 ] that will also enable a differentiation between PD-CI and AD. In order to elucidate these and other open questions, a combined assessment of in vivo neuroimaging and liquid biomarkers in multicentric longitudinal clinico-pathological studies is warranted that also may contribute to the development of meaningful disease-modifying therapies and preventive measures to slow the progression of PD and associated cognitive deterioration.…”

Regional differences in synaptic degeneration are linked to alpha-synuclein burden and axonal damage in Parkinson’s disease and dementia with Lewy bodies

“…Using a whole-slide scanner (Vectra Polaris, 20x objective) images of NfL, pSer129 α-synuclein, amyloid-β and p-tau immunostained sections were taken and quantified using QuPath 0.2.3 stardist ( https://qupath.readthedocs.io/en/0.2/ ) [ 38 ]. ROIs containing all cortical layers were delineated in straight areas of the cortex to avoid over- or underestimation of pathology in sulci and gyri, respectively [ 39 ], as described before [ 29 , 40 ]. The cortex was further segmented into superficial (I-III) and deep (IV-VI) cortical layers based on the haematoxylin counterstaining.…”

“…Moreover, limited information is available on the neuropathological alterations linked to synaptic loss in PD, PDD and DLB. In fact, besides α-synuclein pathology, Alzheimer’s disease (AD) co-pathology [ 26 – 28 ] and axonal degeneration [ 29 , 30 ] are often present in the cortex of PDD and DLB patients, and might contribute to regional synaptic degeneration in these phenotypes. Taken together, studying regional differences in synaptic degeneration, and which neuropathological processes contribute to it, may provide insights into the selective vulnerability and neuropathological disease progression of PD(D) and DLB cases.…”

Regional differences in synaptic degeneration are linked to alpha-synuclein burden and axonal damage in Parkinson’s disease and Dementia with Lewy bodies

“…Using a whole-slide scanner (Vectra Polaris, 20× objective) images of NfL, pSer129 α-synuclein, amyloid-β and p-tau immunostained sections were taken and quantified using QuPath 0.2.3 stardist (https://qupath.readthedocs.io/en/0.2/) [38]. ROIs containing all cortical layers were delineated in straight areas of the cortex to avoid over-or underestimation of pathology in sulci and gyri, respectively [39], as described before [29, 40]. The cortex was further segmented into superficial (I-III) and deep (IV-VI) cortical layers based on the haematoxylin counterstaining.…”