Chemo Brain and Long COVID

PART 7: The long COVID tsunami – what are the neurological implications?

What could be causing this puzzling war on the brain in the absence of viral infection?  As we go through this blog series, we will explore why the Brain is being battered in Long Covid. 

Dr. Michelle Monje’s team at Stanford has spent two decades studying cognitive impairment after cancer.  They uncovered key details in how chemotherapy impairs the function of the brain’s white matter, regions of the brain normally rich in well-insulated nerve fibers that quickly transmit signals from one place to another. Myelin, the fatty coating insulating the long arms of the neurons, helps speed the transmission of nerve signals. In chemo brain, damage to myelin slows their transmission. Now they are looking at brain findings after COVID.
 
Their work was published in June 2022 in "Cell."  
Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain  https://www.cell.com/cell/fulltext/S0092-8674(22)00713-9
 
Dr. Monje and her colleagues examined brain changes in mice in which the researchers had induced SARS-CoV-2 infections confined to the respiratory system. Mice lack the cellular receptors that the SARS-CoV-2 virus uses to invade human cells, but animals in the study were genetically engineered to express the necessary receptors in the respiratory tract. After exposure to SARS-CoV-2, the mice had mild infections they did not lose weight or behave as though they were ill, and the virus was not found in their brains.

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Credit CELL: Volume 185, ISSUE 14, P2452-2468.e16, July 07, 2022

Their findings included:

1. Increased CNS cytokines (cytokines are small, secreted proteins that are key modulators of inflammation). One of the elevated cytokines they found was CCL11 which is a factor that can decrease the generation of new neurons and impair learning or memory.  CCL11 can directly cause microglial reactivity specifically in the hippocampus. Beyond their role in innate immunity, recent studies have shown that CCL11 and related molecules may directly contribute to degenerative processes in the central nervous system (CNS). CCL11 levels increase in the plasma and cerebrospinal fluid  In humans, altered CSF and plasma levels of CCL11 have been observed in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and secondary progressive multiple sclerosis (SPMS) when compared to age-matched, healthy controls.  A recent study published June 2022, discussed the role of CCL11 inducing  neuronal cytotoxicity effects by inducing the production of reactive oxygen species (ROS) in microglia cells and neurological outcomes post COVID. 
2. Increased microglial activity in the brain. Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. They act as the central ‘housekeepers’ to maintain homeostasis. Microglia account for 10–15% of all cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS).  If activated, in an inflammatory state, the microglia modify synaptic connections and synaptic plasticity required for learning and memory especially in critical areas like the hippocampus sometimes called the ‘primary memory center.” The researchers found that microglial activity was ‘very high’ in the hippocampus.  This overenthusiastic cleanup effort in the hippocampus can deter the creation of new neurons, which are linked to maintaining healthy memory.

Credit: CELL Volume 185, ISSUE 14, P2452-2468.e16, July 07, 2022

Microglial cell activation was also very high in the subcortical white matter of the brain White matter is found in the deeper tissues of the brain (subcortical). It contains nerve fibers (axons), which are extensions of nerve cells (neurons).
 
Scientists found decreased oligodendrocytes, and myelin loss. Oligodendrocytes are the myelinating cells of the central nervous system (CNS). Myelin gives the white matter its color and it also protects the nerve fibers from injury. When the myelin sheath is damaged, nerve impulses slow or even stop, causing neurological problems.  These diagrams are taken from the Monje article. 

Credit: CELL Volume 185, ISSUE 14, P2452-2468.e16, July 07, 2022

The most common demyelinating disease is multiple sclerosis (MS), an autoimmune disorder in which the immune system attacks myelin of the brain, spinal cord, and/or eyes. Scientists have long regarded the brain's white matter as passive infrastructure, but new work shows that it actively affects learning and mental illness. 

Credit: CC BY creativecommons.org

1. After mild COVID-19, analysis of gene activity in single cells uncovered more microglia with high levels of pro-inflammatory molecules called chemokines and more activity in genes involved in inflammation. The genes expressed in microglia after COVID-19 overlapped closely with those expressed by microglia in other disease contexts, including cognitive decline in aging and in neurological conditions such as Alzheimer’s disease. This finding lines up with prior work linking microglial reactivity to poor cognitive function.
2. The study results illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection, which may contribute to cognitive impairment following even mild COVID.

 
Although the researchers at Stanford did not say what was driving these findings, but in this research published Feb 2022 in Brain Behavior Immunity, it was the spike protein that drove neuroinflammation and microglial cell activation.   
The brain is in big trouble and may help explain why we saw alarming brain atrophy in the UK Biobank study.
 
The U.K. Biobank Study Showed Shrinking Brains post COVID 
 
The findings, published in Nature, reveal tissue damage and greater shrinkage in brain areas. The U.K. Biobank is a large-scale biomedical database and research resource that is enabling new scientific discoveries to be made that improve public health and represents data from more than 500,000 study participants.
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• Using the UK Biobank resource, scientists looked at changes that took place in the brain following mild—as opposed to moderate or severe—SARS-CoV-2 infection.  Despite the infection being mild for 96% of our participants, we saw a greater loss of grey matter volume, and greater tissue damage in the infected participants, on average 4.5 months after infection.  They showed a greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex (OFC) and parahippocampal gyrus (PHG)   The PHG surrounds the hippocampus and is important for memory encoding.  The OFC is involved in the cognitive process of decision-making and is a key brain area for emotion and identifying stimuli.  They also showed greater tissue damage in regions connected with the primary olfactory cortex, an area linked to smell.
• There was greater decline in their mental abilities to perform complex tasks, and this mental worsening was partly related to these brain abnormalities. 

 Top, the main analysis shows that the strongest, localized reductions in grey matter thickness in the 401 infected participants compared with the 384 controls are bilaterally in the parahippocampal gyrus, anterior cingulate cortex and temporal pole, as well as in the left orbitofrontal cortex, insula and supramarginal gyrus. 

The overlapping olfactory- and memory-related functions of the regions shown to alter significantly over time in SARS-CoV-2—including the parahippocampal gyrus/perirhinal cortex, entorhinal cortex and hippocampus in particular raise the possibility that longer-term consequences of SARS-CoV-2 infection might in time contribute to Alzheimer’s disease or other forms of dementia. 

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