In the past few months, we have learned that COVID-19 can cause a wide range of neurocognitive anomalies and even damage. From the beginning, people affected with the disease have complained of anosmia (altered sense of smell), ageusia (altered sense of taste), “brain fog”, similar to what has been reported in chronic fatigue syndrome and during chemotherapy, and now even such symptoms as ataxia (altered gait) and psychosis (disordered thinking and/or behavior, possibly coupled with hallucinations or paranoid/persecutory ideations).
RELATED: COVID-19 reduces grey matter volume in areas related to memory, executive function: Nature Magazine
Now, a study from Tulane has come out that strongly suggest that, even in mild forms or onsets of the disease, even with asymptomatic presentation, the brain may experience diffuse yet profound insult in the form of “innumerable” microbleeds throughout the brain.
The brain is made up of neurons as well as glia (deriving from the Latin for glue). Making up around 80% of the brain, glial cells are the support cells and can be classified according to shape and function.
- Astrocytes are star-shaped and provide scaffolding for neurons. They help nourish the neurons and also can attend to the synapse, cleaning up molecules such as neurotransmitters so that the synapse is ready to receive new electrochemical information.
- Oligodendrocytes are cells that extend along the axon (the long tail-like extension) of the neuron and sheathe it in myelin, a fatty substance that gives white matter its characteristic color. Myelin coats the neuron and enables quicker conduction of neuronal activity. Without myelin, the impulses of a neuron could take up one hundred times longer to conduct, or even longer. Oligodendrocytes serve many neurons at once, sometimes providing this critical support at a 30:1 ratio.
- Microglia are also star-shaped, but they are much smaller than the other glial cells. Microglia are the resident phagocytes. They monitor the brain and clean up any extraneous debris in the intercellular space. Any cells that have undergone damage or cell death (apoptosis) will attract the attention of microglia, which converge on the site in order to engulf the matter.
Microglia are especially active in terms of disease, where they secrete cytokines, chemokines, and other chemical signals that can produce neuroinflammation. Depending on the situation, this release of chemicals can be beneficial but it can also simultaneously worsen a situation, as microglia have the ability to release reactive oxygen species (ROS), which we know of as free radicals, and these can wreak havoc on cells themselves. This damage from ROS can cause more microglial activity, creating the vicious cycle known as cytokine storm.
Polish study: Neurologia
In late 2021, researchers from Poland compiled a comprehensive review of information, drawing not only upon analyzed data sets but also case studies, to give a broad perspective of how COVID-19 affects the brain. The authors indicated then that SARS-CoV-2 most likely entered the brain through one or more sites, probably through docking with the ACE2 receptor; these receptors can be found in multiple various sites in the central nervous system. Possibly the virus could travel via peripheral nerve systems, such as the vagus nerve; alternatively, it could become introduced in the brain directly, through the olfactory bulb (routing through the nose). Other avenues include infecting endothelial cells as well as breaching the blood-brain barrier through leukocytes.
Since the Polish paper was released, it appears more and more likely that direct neuroinvasion occurs at the site of the olfactory bulb, although the other routes remain possible methods of entry.
The authors additionally noted:
Among patients who displayed abnormal neuroimaging findings, territorial acute/subacute infarction, multiple ischaemic foci, evidence of thrombus in large intra- and extra-cranial vessels, cerebral venous thrombus complicated by haemorrhagic infarcts, and cortical/subcortical microhaemorrhages have been reported frequently invarious observational studies.
Thrombi are blood clots, a known complication of COVID-19. In the lungs and in the body’s periphery, they can cause embolism and deep vein thrombosis; in the brain, they can lead to stroke and other vascular conditions or deterioration. A recent review subsequent to the Polish study found that COVID-19 is associated with a 33-fold increase in pulmunary embolism and five-fold increase in deep vein thrombosis due to blood clotting abnormalities, and that “[e]ven those people with mild symptoms who do not need to be hospitalised might have a small increase in the risk of [blood clots].”
Tulane study
Earlier this month (April 2022), researchers from Tulane University released a paper that studied the effects of COVID-19 on non-human primates (NHPs), specifically Rhesus monkeys and African green monkeys. The aim was to track neurological manifestations of COVID in the parenchyma (functional brain tissue; that is, the neurons and glia, everything we have been talking about up until now). They found that
This work reveals neuroinflammation, brain hypoxia, microhemorrhages, and pathology consistent with hypoxic-ischemic injury with rare infection of brain vasculature in SARS-CoV-2 infected NHPs and provides key insights into SARS-CoV-2-associated neuropathogenesis. Our findings are consistent with those reported on autopsied brain of human subjects who died with SARS-CoV-2 infection.
In other words, in addition to a type of vascular infection that strikes only rarely, in the main the researchers found widespread evidence of microhemorrhages, inflammation, cell death due to lack of oxygen, and injury reminiscent of stroke.
Moreover, they found that this damage tended to center in very particular parts of the brain: the basal ganglia, cerebellum, and brainstem. All of these structures comprise the oldest parts of the brain, responsible not only for physiological regulation and maintenance (such as heart rate and muscle tone) but also integration of sensory impulses and information, as well as coordination of movement with intention. The cerebellum, for example, has been shown to interact with the frontal lobe when movement is initiated; the two sections “converse” on a regular basis.
This study is highly important in that it explored changes in the brainstem, an area of the brain that often escapes scanning in MRI or other live imaging. It also regularly escapes histological staining post-mortem, as the apparatus used to capture the information has to be specifically calibrated to look in just those areas before any data collection is performed. In other words, the pathologists must program in the parameters to include the neuroarchitectural sites, and most simply do not include these parameters unless specifically searching for anomalies.
The basal ganglia, too, are extremely important structures to have implicated in the course of this disease. The basal ganglia is the basis of the limbic system, one of the most ancient mammalian centers of the brain. It consists of the dorsal striatum (comprised of the caudate nucleus, globus pallidus, and putamen), substantia nigra (the site of dopamine production), subthalamic nuclei, nucleus accumbens (part of the reward system), the ventral striatum and the olfactory tubercle.
The olfactory tubercle links immediately with the olfactory bulb, which is hypothesized to be a direct route of COVID-19 neuroinvasion.
See also that the caudate, putamen and globus pallidus (elements of the dorsal striatum) lie directly adjacent and are connected to the internal capsule, a highly interwoven and integrated structure of white matter (that is, highly myelinated). Damage to this structure can cause loss of communication of various brain centers—especially motor areas—to other parts of the central nervous system.
When you look at where the basal ganglia is situated, it becomes clear as to the implications of COVID-19 damage in the brain.
And keep in mind that these structures do not exist in isolation. They are adjacent to the hippocampus, the amygdala, the thalamus (the central relay system of the brain), and the hypothalamus, which includes the pituitary gland. They also abut the cingulate gyrus which mediates the reward system of the brain and which has connections to the frontal cortex. The cingulate gyrus includes the caudate nucleus.
In short, the limbic system surrounds the basal ganglia. The two share interworkings.
The researchers conclude (with my emphasis):
In our two models of aged NHPs infected with SARS-CoV-2, we found evidence of prominent neuroinflammation, microhemorrhages with and without associated microthrombi, and neuronal injury and death consistent with hypoxic-ischemic injury but without substantial virus detection in brain. Our findings are largely in line with those reported in autopsy studies of individuals who died from infection. Like human disease, reactive astrocytes and microglia were a common feature, seen throughout the entirety of the brain in infected animals. This appeared greater in basal ganglia, brainstem, and cerebellum[.]
What are microbleeds?
As the term itself implies, microbleeds are “small chronic brain hemorrhages which are likely caused by structural abnormalities of the small vessels of the brain.” They can be imaged with various techniques such as MRI. A paper in April 2021 examined the cases of two women who eventually were diagnosed with hemorrhagic necrotizing encephalopathy associated with COVID. I cite these cases not to say that their fate will be the fate of those with mild disease, but rather to demonstrate visually what microbleeds associated with COVID-19 look like.
Microbleeds are minute injuries that can lead to profound injury if the bleed is not halted. The blood naturally will begin to clot, unless there is some underlying dysfunction. We already know that COVID-19 disrupts normal blood clotting. In the parenchymal tissue, microbleeds with clotting would create debris in the tissue itself, which would attract the attention of microglia, the sentinel macrophages of the brain. They will activate, then converge on the site of the injury to seal it from expanding and doing further damage.
Considering the Tulane study, one begins to get an idea for the extensive problem this may pose for individual patients. The seal created by the microglia is known as a scar; this glial scar is the functional equivalent of a brain lesion. Axons that normally would travel through that area are not able to communicate any longer.
This damage is profound and distributed diffusely throughout the entire brain.
Microglia when active converge upon the site of a disturbance or injury very rapidly.
The following video should be cued to 3:19 where Beth Stevens, a researcher at Boston Children’s Hospital, describes and demonstrates how microglia respond to injury. The relevant information extends through 5:13, where you can clearly see how microglia converge upon an acute injury (in Stevens’ example, created by a laser).
Covid-19 in Human tissue
The Tulane study is critical for our understanding of how COVID advances in the brain because we cannot confirm such processes in the human brain until autopsy. Non-human primates are probably the closest we will get to having concrete evidence of these injuries until more people with COVID-19, unfortunately, pass away. In the meantime, we do have a handful of evidence provided in the two-plus years of combatting COVID where human remains have been histologically stained and studied.
In January 2022, Anthony Fernández-Castañeda and associates published a study in BioRxIV detailing myelin loss in COVID-19 in a mouse study, and they used histological staining images of COVID-19 found in humans for comparison. These are images of human tissue, detailing damage of both gray matter and white matter.
Compare that to the Tulane study, where the NHPs had their brains histologically examined (see right, pink-shaded image).
Why is this important?
In an article overviewing cerebral microbleeds in general, Sergi Martinez-Ramirez and associates relate how these microbleeds [MBs] can impact cognitive function:
One of the initial studies assessing the cognitive impact of MBs compared the performance on multiple cognitive domains between patients with and without MBs from a neurovascular clinic [44]. The two subgroups were matched for age, gender, intelligence quotient, extent of WMH [white-matter hyperintensities], and type and location of ischemic stroke. Individuals with MBs had a much higher prevalence of executive dysfunction than those without MBs (60% versus 30%, P = 0.03).
Exceptionally notable was this summation (emphasis mine):
In logistic regression analyses, the presence of MBs was the only independent predictor of executive dysfunction. Interestingly, in individuals with executive dysfunction, MBs were predominantly located in the frontal lobes and basal ganglia, areas classically considered the neuroanatomical substrate for executive function. These results suggested that (a) MBs may actually have a negative effect on cognition, independently of other concurrent vascular lesions, and (b) there seems to be an anatomical correlation between the distribution of MBs and the cognitive domains affected, suggesting a direct damage of MBs over the tissue as the pathogenic mechanism.
This reinforces findings from earlier this year showing that COVID-19 can lead to dysexecutive syndrome.
Indeed, this may portend terrible implications for those with neurological COVID symptoms. Some doctors have already expressed concerns that what we are colloquially calling “brain fog” may later lead to dementia resembling Alzheimer’s disease. If the virus concentrates in the basal ganglia, as has been suggested by the Tulane study, we may see a dramatic increase in corticobasal dementia as the years progress, with symptoms resembling that of CTE.