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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.

Well-characterized, high-quality brain tissue of non-neurological control subjects is a prerequisite to study the healthy aging brain, and can serve as a control for the study of neurological disorders. The Normal Aging Brain Collection Amsterdam (NABCA) provides a comprehensive collection of post-mortem (ultra-)high-field MRI (3Tesla and 7 Tesla) and neuropathological datasets of non-neurological controls. By providing MRI within the pipeline, NABCA uniquely stimulates translational neurosciences; from molecular and morphometric tissue studies to the clinical setting. We describe our pipeline, including a description of our on-call autopsy team, donor selection, in situ and ex vivo post-mortem MRI protocols, brain dissection and neuropathological diagnosis. A demographic, radiological and pathological overview of five selected cases on all these aspects is provided. Additionally, information is given on data management, data and tissue application procedures, including review by a scientific advisory board, and setting up a material transfer agreement before distribution of tissue. Finally, we focus on future prospects, which includes laying the foundation for a unique platform for neuroanatomical, histopathological and neuro-radiological education, of professionals, students and the general (lay) audience. Keywords: Brain banking, Non-neurological controls, MRI, Neuropathology