Study Indicates That Even Those With Mild Or Asymptomatic COVID-19 Can Develop Brain Inflammation And Other Neurological Conditions In Long Term
A new study from the Netherlands involving medical scientists from the Biomedical Primate Research Centre (BPRC), Amsterdam UMC, Utrecht University, , Leiden University Medical Center and the University of Twente have confirmed that that the SARS-CoV-2 coronavirus is neuroinvasive as shown by viral RNA and inflammation in the brain.
The SARS-CoV-2 coronavirus may cause acute respiratory disease, but the infection can also initiate neurological symptoms. In this study, the researchers show that SARS-CoV-2 infection causes brain inflammation in the macaque model. An increased metabolic activity in the pituitary gland of two macaques was observed by longitudinal positron emission tomography-computed tomography (PET-CT). Post-mortem analysis demonstrated infiltration of T-cells and activated microglia in the brain, and viral RNA was detected in brain tissues from one animal. The team observed Lewy bodies in brains of all rhesus macaques. These data emphasize the virus’ capability to induce neuropathology in this nonhuman primate model for SARS-CoV-2 infection. As in humans Lewy body formation is an indication for the development of Parkinson’s disease, this data represents a warning for potential long-term neurological effects after SARS-CoV-2 infection even if individuals merely had mild or asymptomatic conditions of the disease. Long COVID or PASC (Post-acute sequelae of SARS-CoV-2 infection)
is becoming a serious concern to many medical practitioners and experts.
The study findings were published in a preprint server and are currently pending peer review. https://www.biorxiv.org/content/10.1101/2021.02.23.432474v1
The COVID-19 pandemic has claimed well over 2.5 million lives, but its long-term sequelae are still being identified.
The SARS-CoV-2 produces an infection that may be associated with a wide spectrum of disease, from asymptomatic to critical or terminal respiratory failure or multi-organ dysfunction.
The new study findings describe the results of a macaque study that showed the development of neurological features of inflammation, following infection by SARS-CoV-2.
Although the SARS-CoV-2 virus typically primarily affects the respiratory organs, in about a third of hospitalized COVID-19 patients, neurological manifestations are present. These include anosmia or dysgeusia, delirium, impaired consciousness, seizures, or psychosis. Some patients also develop Parkinsonism.
These neurological symptoms may be due to brain infection by the virus or because of virus-induced immune cell activation. More evidence is required to arrive at a conclusion on this matter in human SARS-CoV-2 infection.
Importantly the long-term effects on the central nervous system (CNS) following this infection, even with mild or moderate COVID-19, are poorly understood, though they are probably present in most patients.
The study team in order to explore this performed a study in a controlled design on two macaque species, the rhesus macaques and cynomolgus macaques.
Interestingly after inoculation with SARS-CoV-2 into the monkeys by a combination of intratracheal and intran
asal routes, the researchers found that viral RNA was found in both tracheal and nasal swabs for up to ten days. All the monkeys had mild to moderate disease.
The study team also followed up the animals with weekly tracer PET-CT scans of the brains after the virus was no longer found in the respiratory samples.
The team found that two of four monkeys showed increased tracer uptake in the pituitary gland at many points.
Typically tracer uptake is a proxy for metabolic activity. The metabolic activity of the pituitary is typically similar to brain background metabolism.
Significantly in one animal, tracer uptake increased from day 8 to the last scan at day 35. This indication of higher metabolic activity could have been due to direct infection of the pituitary gland, or an indirect effect of pituitary inflammation, or the result of hypothalamic-pituitary dysfunction.
To date however no COVID-19 patient with active infection has been found to have low cortisol levels indicative of low pituitary function.
Upon euthanizing the animals at 5-6 weeks post-infection, the researchers found that viral RNA was detectable (using real-time quantitative polymerase chain reaction, RT-qPCR) in many parts of the right brain in the cynomolgus macaques during autopsy studies.
Overview of CNS effects by SARS-CoV-2 exposure in a macaque brain. Presence of viral RNA was investigated in multiple regions of the brain as indicated by the numbers. Viral RNA-positive regions in cynomolgus macaque C3 are indicated by a yellow background. The analysed brain regions are indicated with a number. Brain areas with T-cells (CD3+) and activated microglia (Mamu-DR+) are shown in light blue (mild expression) and dark blue (moderate expression), respectively. Brain areas with Lewy bodies (a-synuclein+) are shown in orange.
Importantly these included the cerebellum, the medial motor cortex, sensory cortex, and the basal ganglia. The pituitary, olfactory bulb, substantia nigra, medulla oblongata, pons, nucleus caudatus, and putamen did not show immunological markers for the viral RNA.
However subgenomic RNA was not present, indicating that viral replication was not occurring in the brain at that point. Viral antigens were also not detected in any animal.
Significantly though, inflammation was observed in the brains of all infected macaques. T cell infiltration was also present in the brain parenchyma, which may indicate that T cells crossed the blood-brain barrier following infection.
Microglial activation was also present in different brain areas, notably the pituitary and the olfactory bulb, but at a low level. B lymphocytes were not found, neither was there any evidence of brain ischemia or necrosis.
Alarmingly the macaque brain tissue also contained Lewy bodies, or a-synuclein deposits, which, in humans, is linked to Parkinson’s disease or Lewy body dementia. These were found in the midbrain of all rhesus macaques and one aged cynomolgus macaque, but none of the controls.
The study findings have numerous implications. This shows that SARS-CoV-2 drives inflammation in the macaque brain. The presence of viral RNA also indicates that the virus is neuroinvasive.
So far critically ill COVID-19 patients have shown some signs of neuropathology. In contrast, the macaques in this study had only mild or moderate infection symptoms, but brain involvement was present.
The study team propose that the route of entry of the virus to the brain could be the olfactory bulb or other neuronal pathways, such as infected sensory or motor neurons, thus reaching the pituitary, which has the entry receptor for the virus, the angiotensin-converting enzyme 2 (ACE2).
Just as significant is the fact that in all the infected macaques, there was evidence of immune activation in the olfactory bulb, as shown by the presence of activated microglia or T cells.
It should be noted that if the virus is transported within neurons, it could also explain the development of Parkinson-like symptoms. The virus could also reach the substantia nigra, connected to Parkinson’s disease, by retrograde transport. This region is in the ventral midbrain, where Lewy bodies were found in the macaques. These accumulations of misfolded protein within inclusion bodies are associated with Parkinson’s disease or Lewy body dementia in humans.
From their study findings, the researchers ask whether they have predictive value for the long-term development of these disorders in COVID-19 patients, even if the infection was mild or even asymptomatic.
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