COVID-19 Neuro

Updated September 28, 2023

15 APR 2020: Neurologic Features in Severe SARS-CoV-2 Infection (NEJM)“In this consecutive series of patients, ARDS due to SARS-CoV-2 infection was associated with encephalopathy, prominent agitation and confusion, and corticospinal tract signs. Two of 13 patients who underwent brain MRI had single acute ischemic strokes. Data are lacking to determine which of these features were due to critical illness–related encephalopathy, cytokines, or the effect or withdrawal of medication, and which features were specific to SARS-CoV-2 infection.”

26 MAY 2020: Loss of Smell and Taste in 2013 European Patients With Mild to Moderate COVID-19 (Annals of Internal Medicine)
“The prevalence of self-reported smell and taste dysfunction in our study is higher than previously reported and may be characterized by different clinical forms. Our results suggest that anosmia may not be related to nasal obstruction or inflammation. Future studies are needed to understand the pathophysiologic mechanisms underlying loss of smell and taste in COVID-19, including potential viral spread through the olfactory neuroepithelium and invasion of the olfactory bulb and central nervous system”

29 MAY 2020: Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia (JAMA)
“Based on the MRI findings … we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway and cause an olfactory dysfunction of sensorineural origin; cerebrospinal fluid and pathology studies are required to confirm this hypothesis.”

29 MAY 2020: Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019 (JAMA)
“Viral neuroinvasion may be achieved by several routes, including transsynaptic transfer across infected neurons, entry via the olfactory nerve, infection of vascular endothelium, or leukocyte migration across the blood-brain barrier. The most common neurologic complaints in COVID-19 are anosmia, ageusia, and headache, but other diseases, such as stroke, impairment of consciousness, seizure, and encephalopathy, have also been reported.”

8 JUN 2020: Neurobiology of COVID-19 (Journal of Alzheimer’s Disease)
“Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in patients with coronavirus disease-19 (COVID-19)“

1 JUL 2020: Neurologic and Radiographic Findings Associated With COVID-19 Infection in Children (JAMA Neurology)
“Of the 27 children with COVID-19 pediatric multisystem inflammatory syndrome, 4 patients (14.8%) who were previously healthy had new-onset neurological symptoms. Symptoms included encephalopathy, headaches, brainstem and cerebellar signs, muscle weakness, and reduced reflexes … all 4 patients had signal changes in the splenium of the corpus callosum on neuroimaging and required intensive care admission for the treatment of COVID-19 pediatric multisystem inflammatory syndrome.”

2 JUL 2020: Neurological associations of COVID-19 (Lancet Neurology)
“We summarise the evidence to date for COVID-19, examine putative disease mechanisms, and finally suggest a framework for investigating patients with suspected COVID-19-associated neurological disease to support clinico-epidemiological, disease mechanism, and treatment studies.”

6 JUL 2020: High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms (medRxiv preprint)
“We report [anti-neuronal] autoantibody findings in eleven critically ill COVID-19 patients presenting with a variety of neurological symptoms with unexplained etiology.” 

8 JUL 2020: The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings (Brain)
“Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness…”
Article on paper: Dozens More Cases of Neurological Problems in COVID-19 Reported (The Scientist)

9 JUL 2020: Association of neuronal injury blood marker neurofilament light chain with mild-to-moderate COVID-19 (Journal of Neurology)
“Our results indicate for the first time that COVID-19 may affect the neuro-axonal integrity also in adults with a mild-to-moderate course of the disease. This new evidence for a more general neuro-destructive capability of SARS-CoV-2 also in mild-to-moderate COVID-19 patients should raise awareness for potential long-term neurologic sequelae following COVID-19.”

25 JUL 2020: Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study (Lancet Psychiatry)
“Complete clinical datasets were available for 125 (82%) of 153 patients. 77 (62%) of 125 patients presented with a cerebrovascular event, of whom 57 (74%) had an ischaemic stroke, nine (12%) an intracerebral haemorrhage, and one (1%) CNS vasculitis. 39 (31%) of 125 patients presented with altered mental status, comprising nine (23%) patients with unspecified encephalopathy and seven (18%) patients with encephalitis. The remaining 23 (59%) patients with altered mental status fulfilled the clinical case definitions for psychiatric diagnoses as classified by the notifying psychiatrist or neuropsychiatrist, and 21 (92%) of these were new diagnoses. Ten (43%) of 23 patients with neuropsychiatric disorders had new-onset psychosis, six (26%) had a neurocognitive (dementia-like) syndrome, and four (17%) had an affective disorder. 18 (49%) of 37 patients with altered mental status were younger than 60 years and 19 (51%) were older than 60 years, whereas 13 (18%) of 74 patients with cerebrovascular events were younger than 60 years versus 61 (82%) patients older than 60 years.”

3 AUG 2020: Cerebral Micro-Structural Changes in COVID-19 Patients – An MRI-based 3-month Follow-up Study (Lancet)
“COVID-19 patients had statistically significantly higher bilateral gray matter volumes (GMV) in olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl’s gyrus and right cingulate gyrus and a general decline of MD, AD, RD accompanied with an increase of FA in white matter, especially AD in the right CR, EC and SFF, and MD in SFF compared with non-COVID-19 volunteers” 

4 AUG 2020: SARS-CoV-2 infects human neural progenitor cells and brain organoids (Nature Letter to the Editor)
“The finding that SARS-CoV-2 can productively infect human brain organoids highlights the potential of direct viral involvement in neurological symptoms in COVID-19 patients. These results provided insight on the pathognomonic symptoms of anosmia (loss of smell) and ageusia (loss of taste) as well as other neurological manifestations of COVID-19 including seizure, encephalopathy, encephalitis, Guillain-Barre syndrome, and Miller Fisher syndrome.” 

8 AUG 2020: Pre-existing cerebrovascular disease and poor outcomes of COVID-19 hospitalized patients: a meta-analysis (Journal of Neurology)
“In meta-analysis, COVID-19 patient with pre-existing CeVD had 2.67-fold (1.75–4.06) higher odds of poor outcomes.”

5 OCT 2020: Neuropathology of patients with COVID-19 in Germany: a post-mortem case series (Lancet Neurology)
“The presence of SARS-CoV-2 RNA and proteins in the brains of patients with COVID-19 in this study is in line with the hypothesis that SARS-CoV-2 can infiltrate the CNS. However, the presence of SARS-CoV-2 was not associated with the severity of neuropathological changes. Thus, CNS damage and neurological symptoms might be due to additional factors such as cytokine storm, neuroimmune stimulation, and systemic SARS-CoV-2 infection, rather than by direct CNS damage caused by the virus. We saw a surprisingly uniform presentation of neuropathological findings (ie, activation of microglia, infiltration with CD8-positive T cells) in our patients, irrespective of the clinical severity of COVID-19 in each case.”

13 OCT 2020: Neuropsychiatric complications of covid-19 (BMJ)

16 DEC 2020: The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice (Nature)
“We show that intravenously injected radioiodinated S1 (I-S1) readily crossed the blood–brain barrier in male mice, was taken up by brain regions and entered the parenchymal brain space. I-S1 was also taken up by the lung, spleen, kidney and liver.” 
Press Release

5 MAY 2021: SARS-CoV-2 causes brain inflammation and induces Lewy body formation in macaques (bioRxiv preprint)
“Post-mortem analysis demonstrated infiltration of T-cells and activated microglia in the brain”

9 JUN 2021: Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions (Immunity)
“This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.”

18 AUG 2021: Brain imaging before and after COVID-19 in UK Biobank (medRxiv preprint)
“By using automated, objective and quantitative methods, we uncovered a consistent spatial pattern of longitudinal abnormalities in limbic brain regions forming a mainly olfactory network. Whether these abnormal changes are the hallmark of the spread of the pathogenic effects, or of the virus itself in the brain, and whether these may prefigure a future vulnerability of the limbic system in particular, including memory, for these participants, remains to be investigated.”

4 SEP 2021: COVID-19 mRNA vaccination leading to CNS inflammation: a case series (Neurology)
“We report clinical and MRI features of seven individuals who received the Moderna (n = 3) or Pfizer (n = 4) SARS-CoV-2 mRNA vaccines. Within one to 21 days of either the first (n = 2) or second (n = 5) vaccine dose, these patients developed neurologic symptoms and MRI findings consistent with active CNS demyelination of the optic nerve, brain, and/or spinal cord.”

25 SEP 2021: Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study (Lancet)
“A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19.” 

21 OCT 2021: The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells (Nature)
“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 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice.”

22 OCT 2021: Assessment of Cognitive Function in Patients After COVID-19 Infection (JAMA Neuro Research Letter)
In this study, we found a relatively high frequency of cognitive impairment several months after patients contracted COVID-19. Impairments in executive functioning, processing speed, category fluency, memory encoding, and recall were predominant among hospitalized patients. The relative sparing of memory recognition in the context of impaired encoding and recall suggests an executive pattern. This pattern is consistent with early reports describing a dysexecutive syndrome after COVID-19”

25 OCT 2021: Anti–SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms (JAMA)
“A subset of pediatric patients with COVID-19 and subacute neuropsychiatric symptoms have intrathecal antineural autoantibodies, suggesting central nervous system autoimmunity in pediatric patients with COVID-19 and recent neuropsychiatric symptoms.”

25 OCT 2021: Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection (Nature Medicine)
“this population-based study identifies and quantifies several rare neurological adverse events that are specific to the ChAdOx1nCoV-19 and BNT162b2 vaccines, as well as SARS-CoV-2 infection.”

29 OCT 2022: Neuro-COVID long-haulers exhibit broad dysfunction in T cell memory generation and responses to vaccination (medRxiv preprint)

2 NOV 2021: Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb (Cell)
“SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.”

3 DEC 2021: Interactions between SARS-CoV-2 N-Protein and α-Synuclein Accelerate Amyloid Formation (ACS Chem Neuroscience)
“Our results point toward direct interactions between the N-protein of SARS-CoV-2 and α-synuclein as molecular basis for the observed correlation between SARS-CoV-2 infections and Parkinsonism.”
Press Release:

5 DEC 2021: Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity (medRxiv preprint)

10 JAN 2022: Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain (medRxiv preprint)
“Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice.” 
Twitter Thread from one of the authors

13 JAN 2022: Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer’s dementia (The Journal of Alzheimers)
“Neurodegenerative biomarkers were elevated to levels observed in AD dementia and associated with encephalopathy and worse outcomes among hospitalized COVID-19 patients.”

18 JAN 2022: Cerebrospinal Fluid Offers Clues to Post-COVID ‘Brain Fog’ (UCSF Press Release)
“They found that 10 of 13 participants with cognitive symptoms had anomalies in their cerebrospinal fluid. But all four of the cerebrospinal samples from participants with no post-COVID cognitive symptoms were normal.” 

20 JAN 2022: Nervous system consequences of COVID-19 (Science)
MedXpress Press Release: Researchers highlight COVID-19 neurological symptoms and need for rigorous studies

1 FEB 2022: SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology (medRxiv preprint)
“Here, we show that SARS-CoV-2 invades the brains of five patients with COVID-19 and Alzheimers, autism, frontotemporal dementia or no underlying condition by infecting neurons and other cells in the cortex. SARS-CoV-2 induces or enhances Alzheimers-like neuropathology with manifestations of beta-amyloid aggregation and plaque formation, tauopathy, neuroinflammation and cell death.”

2 FEB 2022: Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination (NEJM)
“The possibility that anti-idiotype antibodies or other immune-mediated mechanisms targeting neuropilin 1 may be involved in vaccine-related complications, including neurologic sequelae, should be considered during clinical evaluations and investigated to improve the current vaccines.”

1 MAR 2022: Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID (Neurology: Neuroimmunology & Neuroinflammation)
“Among evaluated patients with long COVID, prolonged, often disabling, small-fiber neuropathy after mild SARS-CoV-2 was most common, beginning within 1 month of COVID-19 onset. Various evidence suggested infection-triggered immune dysregulation as a common mechanism.”

2 MAR 2022: Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and signs of neurodegeneration: a prospective cross-sectional study (medRxiv preprint)
“Neuro-COVID class III patients had a strong, peripheral immune response resulting in (1) BBB impairment (2) ingress of (auto-)antibodies, (3) microglia activation and neuronal damage signatures.”

7 MAR 2022: SARS-CoV-2 is associated with changes in brain structure in UK Biobank (Nature)
We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised”
Forbes article:

24 MAR 2022: Post-acute sensory neurological sequelae in patients with severe acute respiratory syndrome coronavirus 2 infection: the COVID-PN observational cohort study (PAIN)

31 MAR 2022: SARS-CoV-2 spike protein induces cognitive deficit and anxiety-like behavior in mouse via non-cell autonomous hippocampal neuronal death (nature)
“our data suggest a novel pathogenic mechanism for the COVID-19-associated neurological symptoms that involves glia activation and non-cell autonomous hippocampal neuronal death by the brain-infiltrating S1 protein.”

8 APR 2022: Brain Inflammation and Intracellular α-Synuclein Aggregates in Macaques after SARS-CoV-2 Infection (viruses)
Postmortem analysis demonstrated the infiltration of T-cells and activated microglia in the parenchyma of all infected animals, even in the absence of viral antigen or RNA. Moreover, intracellular α-synuclein aggregates were found in the brains of both macaque species. The heterogeneity of these manifestations in the brains indicates the virus’ neuropathological potential and should be considered a warning for long-term health risks, following SARS-CoV-2 infection.”

20 APR 2022: A 62-Year-Old Man Presenting with Bilateral Tremor of the Upper Limb After a Diagnosis of COVID-19 with Confirmed Volumetric Brain Loss (American Journal of Case Reports)

9 MAY 2022: The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure (Front Cellular Neuroscience)
From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.”

20 MAY 2022: SARS-CoV-2 Infects Peripheral and Central Neurons of Mice Before Viremia, Facilitated by Neuropilin-1 (bioRxiv preprint)
“Our data show that SARS-CoV-2 rapidly invades and establishes productive infection in previously unassessed sites in the nervous system via direct invasion of neurons before viremia, which m

12 JUN 2022: Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (Cell)
“Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels.  … These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.”

13 JUN 2022: Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19 (Nature)
“The neurological effects of COVID-19 share similarities to neurodegenerative diseases in which the presence of cytotoxic aggregated amyloid protein or peptides is a common feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we identified two peptides from the SARS-CoV-2 proteome that self-assemble into amyloid assemblies. Furthermore, these amyloids were shown to be highly toxic to neuronal cells. We suggest that cytotoxic aggregates of SARS-CoV-2 proteins may trigger neurological symptoms in COVID-19.”

AUG 2022: Orbito-Frontal Cortex Hypometabolism in Children With Post-COVID Condition (Long COVID): A Preliminary Experience (The Pediatric Infectious Disease Journal)
“In conclusion, we provided evidence of orbitofrontal cortex hypometabolism in children with persistent neuropsychiatric symptoms after SARS-CoV-2 infection, highlighting the need to implement research and raising funds for children with long COVID.”

11 AUG 2022: Morphological, cellular, and molecular basis of brain infection in COVID-19 patients (PNAS Neuroscience)
“Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.”

30 SEP 2022: SARS-CoV-2 Spike protein S2 subunit modulates γ-secretase and enhances amyloid-β production in COVID-19 neuropathy (Nature Cell Discovery)
“The Spike protein could function as an immune switch to increase γ-secretase activity and Aβ production and contribute to neurological changes in COVID-19 patients.”

1 OCT 2022: A Case Report: Multifocal Necrotizing Encephalitis and Myocarditis after BNT162b2 mRNA Vaccination against COVID-19 (Vaccines)
“only spike protein but no nucleocapsid protein could be detected within the foci of inflammation in both the brain and the heart, particularly in the endothelial cells of small blood vessels. Since no nucleocapsid protein could be detected, the presence of spike protein must be ascribed to vaccination rather than to viral infection. The findings corroborate previous reports of encephalitis and myocarditis caused by gene-based COVID-19 vaccines.”

11 OCT 2022: Social communication skill attainment in babies born during the COVID-19 pandemic: a birth cohort study (BMJ Archive of Disease in Childhood)
“Parentally reported developmental outcomes in a birth cohort of babies born into lockdown during the COVID-19 pandemic may indicate some potential deficits in early life social communication. It must be noted that milestones are parentally reported and comparison is with a historical cohort with associated limitations. Further studies with standardised testing is required to validate these findings.”

1 SEP 2023: SARS-CoV-2 Spike amyloid fibrils specifically and selectively accelerates amyloid fibril formation of human prion protein and the amyloid β peptide (bioRxiv preprint)
“Albeit purely in vitro, our data suggest that cross-seeding by Spike-amyloid fibrils can be implicated in the increasing number of reports of CJD, AD, and possibly other NDs in the wake of COVID-19.”