•Neurons segmented automatically in phase contrast CT of postmortem brain tissue.•Optimal transport analysis quantifies morphometric differences between samples.•Cytoarchitecture in granular cell ...layer differs in MS and control group.•Nuclei of granular cell neurons in human cerebellum become more compact in MS.
We investigate structural properties of neurons in the granular layer of human cerebellum with respect to their involvement in multiple sclerosis (MS). To this end we analyze data recorded by X-ray phase contrast tomography from tissue samples collected post mortem from a MS and a healthy control group. Using automated segmentation and histogram analysis based on optimal transport theory (OT) we find that the distributions representing nuclear structure in the granular layer move to a more compact nuclear state, i.e. smaller, denser and more heterogeneous nuclei in MS. We have previously made a similar observation for neurons of the dentate gyrus in Alzheimer’s disease, suggesting that more compact structure of neuronal nuclei which we attributed to increased levels of heterochromatin, may possibly represent a more general phenomenon of cellular senescence associated with neurodegeneration.
We have studied the three-dimensional (3D) cytoarchitecture of the human hippocampus in neuropathologically healthy and Alzheimer's disease (AD) individuals, based on phase-contrast X-ray computed ...tomography of postmortem human tissue punch biopsies. In view of recent findings suggesting a nuclear origin of AD, we target in particular the nuclear structure of the dentate gyrus (DG) granule cells. Tissue samples of 20 individuals were scanned and evaluated using a highly automated approach of measurement and analysis, combining multiscale recordings, optimized phase retrieval, segmentation by machine learning, representation of structural properties in a feature space, and classification based on the theory of optimal transport. Accordingly, we find that the prototypical transformation between a structure representing healthy granule cells and the pathological state involves a decrease in the volume of granule cell nuclei, as well as an increase in the electron density and its spatial heterogeneity. The latter can be explained by a higher ratio of heterochromatin to euchromatin. Similarly, many other structural properties can be derived from the data, reflecting both the natural polydispersity of the hippocampal cytoarchitecture between different individuals in the physiological context and the structural effects associated with AD pathology.
The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in ...the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.
Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and ...elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (M
) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M
induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the M
-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
A subgroup of patients with multiple sclerosis (MS) presents focal paramagnetic rims at the border between cortex and white matter (juxtacortical paramagnetic rims JPRs). We investigated the presence ...of this finding in our in vivo MS cohort and explored its potential clinical relevance. Moreover, we exploited postmortem MRI of fixed whole MS brains to (1) detect those rims and (2) investigate their histologic correlation.
Quantitative susceptibility mapping (QSM) and magnetization-prepared 2 rapid acquisition gradient-echo (MP2RAGE) images at 3T-MRI of 165 patients with MS from the in vivo cohort were screened for JPRs and the presence of cortical lesions. Five postmortem brains from patients with MS were imaged with 3T-MRI to obtain QSM and MP2RAGE sequences. Tissue blocks containing JPRs were excised and paraffin-embedded slices stained by immunohistochemistry for myelin basic protein (for myelin) and anti-CR3/43 (for major histocompatibility complex II-positive microglia/macrophages). DAB-Turnbull stain was performed to detect iron.
JPRs are present in approximately 10% of in vivo patients and are associated with increased cortical lesion load. One of the 5 postmortem brains showed JPRs. Histologically, JPRs correspond to an accumulation of activated iron-laden phagocytes and are associated with demyelination of the whole overlying cortical ribbon.
JPRs are a novel potential MRI biomarker of focal cortical demyelination, which seems related to global cortical pathology and might be useful for diagnostic and stratification purposes in a clinical setting.
Objectives
Neuropathological studies have shown that multiple sclerosis (MS) lesions are heterogeneous in terms of myelin/axon damage and repair as well as iron content. However, it remains a ...challenge to identify specific chronic lesion types, especially remyelinated lesions, in vivo in patients with MS.
Methods
We performed 3 studies: (1) a cross‐sectional study in a prospective cohort of 115 patients with MS and 76 healthy controls, who underwent 3 T magnetic resonance imaging (MRI) for quantitative susceptibility mapping (QSM), myelin water fraction (MWF), and neurite density index (NDI) maps. White matter (WM) lesions in QSM were classified into 5 QSM lesion types (iso‐intense, hypo‐intense, hyperintense, lesions with hypo‐intense rims, and lesions with paramagnetic rim legions PRLs); (2) a longitudinal study of 40 patients with MS to study the evolution of lesions over 2 years; (3) a postmortem histopathology‐QSM validation study in 3 brains of patients with MS to assess the accuracy of QSM classification to identify neuropathological lesion types in 63 WM lesions.
Results
At baseline, hypo‐ and isointense lesions showed higher mean MWF and NDI values compared to other QSM lesion types (p < 0.0001). Further, at 2‐year follow‐up, hypo‐/iso‐intense lesions showed an increase in MWF. Postmortem analyses revealed that QSM highly accurately identifies (1) fully remyelinated areas as hypo‐/iso‐intense (sensitivity = 88.89% and specificity = 100%), (2) chronic inactive lesions as hyperintense (sensitivity = 71.43% and specificity = 92.00%), and (3) chronic active/smoldering lesions as PRLs (sensitivity = 92.86% and specificity = 86.36%).
Interpretation
These results provide the first evidence that it is possible to distinguish chronic MS lesions in a clinical setting, hereby supporting with new biomarkers to develop and assess remyelinating treatments. ANN NEUROL 2022;92:486–502
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