ABSTRACT
In a neuropathological series of 20 COVID-19 cases, we analyzed six cases (three biopsies and three autopsies) with multiple foci predominantly affecting the white matter as shown by MRI. The cases presented with microhemorrhages evocative of small artery diseases. This COVID-19 associated cerebral microangiopathy (CCM) was characterized by perivascular changes: arterioles were surrounded by vacuolized tissue, clustered macrophages, large axonal swellings and a crown arrangement of aquaporin-4 immunoreactivity. There was evidence of blood-brain-barrier leakage. Fibrinoid necrosis, vascular occlusion, perivascular cuffing and demyelination were absent. While no viral particle or viral RNA was found in the brain, the SARS-CoV-2 spike protein was detected in the Golgi apparatus of brain endothelial cells where it closely associated with furin, a host protease known to play a key role in virus replication. Endothelial cells in culture were not permissive to SARS-CoV-2 replication. The distribution of the spike protein in brain endothelial cells differed from that observed in pneumocytes. In the latter, the diffuse cytoplasmic labeling suggested a complete replication cycle with viral release, notably through the lysosomal pathway. In contrast, in cerebral endothelial cells the excretion cycle was blocked in the Golgi apparatus. Interruption of the excretion cycle could explain the difficulty of SARS-CoV-2 to infect endothelial cells in vitro and to produce viral RNA in the brain. Specific metabolism of the virus in brain endothelial cells could weaken the cell walls and eventually lead to the characteristic lesions of COVID-19 associated cerebral microangiopathy. Furin as a modulator of vascular permeability could provide some clues for the control of late effects of microangiopathy.
ABSTRACT
Neuropathological examination of the temporal lobe provides a better understanding and management of a wide spectrum of diseases. We focused on inflammatory diseases, epilepsy, and neurodegenerative diseases, and highlighted how the temporal lobe is particularly involved in those conditions. Although all these diseases are not specific or restricted to the temporal lobe, the temporal lobe is a key structure to understand their pathophysiology. The main histological lesions, immunohistochemical markers, and molecular alterations relevant for the neuropathological diagnostic reasoning are presented in relation to epidemiology, clinical presentation, and radiological findings. The inflammatory diseases section addressed infectious encephalitides and auto-immune encephalitides. The epilepsy section addressed (i) susceptibility of the temporal lobe to epileptogenesis, (ii) epilepsy-associated hippocampal sclerosis, (iii) malformations of cortical development, (iv) changes secondary to epilepsy, (v) long-term epilepsy-associated tumors, (vi) vascular malformations, and (vii) the absence of histological lesion in some epilepsy surgery samples. The neurodegenerative diseases section addressed (i) Alzheimer's disease, (ii) the spectrum of frontotemporal lobar degeneration, (iii) limbic-predominant age-related TDP-43 encephalopathy, and (iv) α-synucleinopathies. Finally, inflammatory diseases, epilepsy, and neurodegenerative diseases are considered as interdependent as some pathophysiological processes cross the boundaries of this classification.