Table 1.

Summary of studies investigating SARS-CoV-2 neurotropism and associated pathologies in humans.

Tissue Examined	Subject/Cohort Description	Post-Mortem Interval	Method of SARS-CoV-2 Detection in CNS	Detection Information	Associated Pathologies	Ref
CSF	Multiple, systematic review	Not reported	qPCR	Detected in 4/18 subjects	Not reported	[51]
Brain Biopsies				Detected in 8/34 subjects
Brain tissue	Case report, 74-year-old Hispanic male with Parkinson’s disease; PCR positive NP swab. Febrile, hypotensive, thrombocytopenic, declining SpO2, elevated CRP, D-dimer, ferritin	Not reported	Transmission electron microscopic detection of viral-like particles	Detection of viral-like particles in frontal lobe, inside endothelial cell vesicles, and blebbing from endothelial membrane. Additionally, in neurons.	Vacuolization of neuronal cytoplasm	[55]
Brain tissue			qPCR	Detected
CSF (post-mortem)			qPCR	Not detected
CSF	13 subjects with severe SARS-CoV-2, NP swab confirmed and presenting with pneumonia, seizures and/or encephalopathy	N/A, subjects were alive	qPCR (LOD 181 copies/mL)	SARS-CoV-2 not detected in CSF, but verified in NP swabs, some taken on same day.	No pleocytosis in CSF except in once case of hemorrhage. 9/11 examined had abnormal MRI/CT, evidence of subcortical hypoxic/ischemic injury	[58]
CSF, brain CT/MRI	58 patients with NP swab confirmed SARS-CoV-2 and neurological manifestations, 47 had acute respiratory failure	N/A, subjects were alive	qPCR (LOD 500 copies/mL)	SARS-CoV-2 detected in 4/58 subjects; 3 below LOD	In CSF: 10 had increased WBCs, 19 had elevated albumin quotient, 21 had elevated IgG, 5–7 had elevated IL-6 and TNF-a. 36/53 subjects evaluated had CT/MRI abnormalities.	[59]
Post-mortem FFPE and frozen brain tissues	43 patients confirmed with NP swab, age range 51–94. 40 had chronic medical conditions, 13 had pre-existing neurological disease, 12 died in ICU; deaths were primarily from viral pneumonia	0–9 days (3.3 mean)	qPCR, S and N histochemistry	9/23 total had RNA detected; 9 in frozen frontal lobe, 4 in FFPE medulla oblongata. 16/40 had S and/or N detected in medulla oblongata and along cranial nerves; 14/16 S+, 7/16 N+. 21/40 had RNA or protein detected; Of 16 brains with RNA and protein measured, 8 had both, 4 had protein only, 4 had RNA only.	Brain edema (53%), Arteriosclerosis (100%), Gross macroscopic abnormalities (30%), Fresh ischemic lesions of cerebral arteries (14%), no cerebral bleeding/small vessel thrombosis, astrogliosis in olfactory bulb, basal ganglia, brainstem, cerebellum, microgliosis in brainstem and cerebellum, HL-DR in subpial and subependymal regions.	[60]
Post-mortem FFPE brain sections	Three subjects who died of severe COVID-19; respiratory failure, on ventilator, PCR positive postmortem lung. All had comorbidities (hypertension, obesity, or kidney transplantation)	Not reported	S1 histochemistry	S1 detected in cortical neurons and endothelial cells; positive viral staining detected around infarcts in one patient	No leukocyte infiltration in regions with S1 staining	[61]
Tissue Examined	Subject/Cohort Description	Post-Mortem Interval	Method of SARS-CoV-2 Detection in CNS	Detection Information	Associated Pathologies	Ref
FFPE brain tissue sections	18 subjects with PCR-confirmed COVID-19 age 48–90. Neurologic sequalae: myalgia (3), headache (3), loss of taste (1). Co-morbidities: diabetes (12), hypertension (11), cardiovascular disease (5), hyperlipidemia (5), chronic kidney disease (4), prior stroke (4), dementia (4), anaplastic astrocytoma (1)	20–102 h	qPCR for SARS-CoV-2 nucleocapsid mRNA and histochemistry for N protein: frontal lobe/olfactory nerve and medulla for all patients; cingulate/corpus collosum, hippocampus, occipital lobe, basal ganglia, thalamus, cerebellum, midbrain, pons were additionally tested in two subjects	Equivocal detection (<5 copies/cm3) in 5/10 and 4/10 sections from the two subjects with 10 regions assessed; in 16 subjects with 2 regions assessed, 5 subjects had > 5 copies/cm3, 8 subjects had equivocal detection, and 3 subjects had no detectable mRNA. N protein not detected.	All subjects had evidence of acute hypoxic changes in the cerebrum and cerebellum, no microscopic abnormalities of olfactory bulb/olfactory tracts, neuronal loss in hippocampus, cerebrum and cerebellum but no thrombi or vasculitis. Perivascular lymphocyte foci detected in 2/18 subjects.	[62]
Post-mortem FFPE and frozen brain tissue	19 patients confirmed with NP swab, age range 5–73	5–368 h	qPCR, RNAscope	SARS-CoV-2 not detected	Out of 19: Vascular pathology (11), perivascular infiltrates (13), acute hypoxic/ischemic neuronal damage (6), no path findings (2)	[63]
CSF, brain CT/MRI	Case report, 55-year-old previously healthy woman with PCR-confirmed COVID-19, pulmonary ground glass opacities. Found unresponsive in bed without hemodynamic or respiratory issues.	N/A, patient survived and was discharged.	qPCR	CSF was collected on day 9, 12, 14, and 26 from first symptoms, SARS-CoV-2 detected only on day 14 (cycle threshold = 34.29)	CSF day 9: no pleocytosis, but elevated albumin. CSF day 12: no pleocytosis, albumin normal, IgG elevated without autoantibodies. Elevated GFAP, NFL, tau, and IL-6. CSF day 14: further increases in NFL and tau and reductions in GFAP and IL-6, increases in CSF total protein, and appearance of oligoclonal bands. CT and MRI: symmetrical hypodensities in thalami that progressed to midbrain; acute necrotizing encephalitis	[64]