Multifactorial White Matter Damage in the Acute Phase and Pre-Existing Conditions May Drive Cognitive Dysfunction after SARS-CoV-2 Infection: Neuropathology-Based Evidence

Abstract

Background: There is an urgent need to better understand the mechanisms underlying acute and long-term neurological symptoms after COVID-19. Neuropathological studies can contribute to a better understanding of some of these mechanisms.

Methods: We conducted a detailed postmortem neuropathological analysis of 32 patients who died due to COVID-19 during 2020 and 2021 in Austria.

Results: All cases showed diffuse white matter damage with a diffuse microglial activation of a variable severity, including one case of hemorrhagic leukoencephalopathy. Some cases revealed mild inflammatory changes, including olfactory neuritis (25%), nodular brainstem encephalitis (31%), and cranial nerve neuritis (6%), which were similar to those observed in non-COVID-19 severely ill patients. One previously immunosuppressed patient developed acute herpes simplex encephalitis. Acute vascular pathologies (acute infarcts 22%, vascular thrombosis 12%, diffuse hypoxic-ischemic brain damage 40%) and pre-existing small vessel diseases (34%) were frequent findings. Moreover, silent neurodegenerative pathologies in elderly persons were common (AD neuropathologic changes 32%, age-related neuronal and glial tau pathologies 22%, Lewy bodies 9%, argyrophilic grain disease 12.5%, TDP43 pathology 6%).

Conclusions: Our results support some previous neuropathological findings of apparently multifactorial and most likely indirect brain damage in the context of SARS-CoV-2 infection rather than virus-specific damage, and they are in line with the recent experimental data on SARS-CoV-2-related diffuse white matter damage, microglial activation, and cytokine release.

Keywords: COVID-19; SARS-CoV-2; leukoencephalopathy; neuropathology; white matter.

Figure 1

Inflammatory changes. (A,D,G) Focal cellular infiltrates of CD8+ T-lymphocytes in the olfactory bulb/tract (A), case 2; (D), case 5; (G), case 22) (anti-CD8 immunohistochemistry). (B,E,H) Focal nodular accumulation of CD8+ T-lymphocytes and HLA-DR+ microglia in the medulla oblongata (B), upper panel anti-HLA-DR, lower panel anti-CD8, case 3; (E), anti-HLA-DR, case 5; (H), upper panel anti-HLA-DR, lower panel anti-CD8, case 4). (C,F) Focal cellular infiltrates of CD8+ T-lymphocytes along emerging cranial nerves (vagus) (C), case 2; (F), case 5). (I) Isolated CD8+ T-cells adjacent to the dentate gyrus of the hippocampus (case 4). Scale bars: (A,B) (upper panel), (C,G) 50 μm; (B) lower panel, (D,H) 20 μm; (E) ×0.7; (F) 100 μm; (I) 10 μm.

Figure 2

White matter pathology. (A–C) Multiple subacute hemorrhagic lesions throughout the white matter with hemosiderin-laden macrophages, surrounding Waller degeneration with axonal and myelin vacuolation ((B), luxol fast blue), proliferation of macrophages and activated microglia ((C), left panel anti-HLA-DR immunohistochemistry) and isolated CD8+ T-lymphocytes ((C), right panel; case 4). (D) Focal cellular infiltrates of CD8+ T-lymphocytes in the white matter (case 2) and prominent diffuse microglial activation, particularly in the white matter, independently of T-cell infiltrates ((E,F), anti-HLA-DR immunohistochemistry (ctx: cortex; wm: white matter). (G–I) mild to moderate diffuse vacuolation of white matter, better identified on luxol-fast-blue-stained sections, without signs of demyelination (H) and diffuse microglial activation, accentuated at the perivascular spaces ((I), anti-HLA-DR immunohistochemistry) ((G–I), case 5). Scale bars: (A,C) right panel, (I) 20 μm; (B,C) left panel, (D,F–H) 50 μm; (E) 100 μm.

Figure 3

Other conditions. (A1–A4) Alteration of the vessel wall and vascular lumen. (A1) Vascular occlusion surrounded by fresh and old blood remnants (Pearl’s blue) and reactive tissue changes with gliosis, microglia, and macrophages (case 26). (A2) Early and partial fibrin clot in a meningeal vessel with entrapped leukocytes and erythrocytes. (A3) Eccentric thickening and fibrosis of small sized arterioles and perivascular tissue rarefaction (case 25) characteristic of small vessel disease that occurs in patients with chronic vascular risk factors. (A4) Prominent perivascular tissue rarefaction status cribosus of the basal ganglia (case 1) (all HE-stained sections). Scale bars: (A1,A2) 20 μm; (A3) 50 μm; (A4) 100 μm. (B1–B4) Pre-existing neurodegenerative pathology. (B1) Alzheimer’s disease neuropathological change. ßA4-amyloid deposits in brain parenchyma in form of compact and diffuse plaques (case 1) and within the wall of leptomeningeal and cortical vessels (inset, amyloid angiopathy; case 3). (B2) Tau-positive neurofibrillary pathology with abundant fine neuropil threads, intraneuronal neurofibrillary tangles, and dystrophic neurites surrounding amyloid plaques (case 1). (B3) Tau positive argyrophilic grain pathology with several enlarged “ballooned” neurons in the amygdala (upper panel) and grain-like structures in the neuropil (lower panel; case 25). (B4) Alpha-synuclein immunoreactive Lewy bodies and Lewy neurites in the olfactory bulb (case 4). Scale bars: (B1,B2,B4) 20 μm; (B3) 10 μm. (C1–C4) Concomitant HSV-1 infection. (C1) Diffuse hypoxic cortical damage with tissue pallor, endothelial activation, and diffuse inflammatory infiltrates. Inset: intranuclear neuronal inclusion. (C2) Immunohistochemistry shows abundant HSV1 viral antigens in cortical neurons. (C3,C4) Ultrastructural identification of neuronal intranuclear viral particles with typical morphology of Herpes simplex. (case #32). Scale bars: (C1) 100 μm (C2) 20 μm; (C3) original magnification ×30,000, (C4) ×80,000.