For recovered individuals, COVID-19 is likely to contribute to a higher long-term risk of cognitive decline, including Alzheimer’s and dementia, according to a new journal article published in Alzheimer's & Dementia.
In the article, the researchers review some 100 years of literature regarding the long-term neurological impact of different coronaviruses, including what we know—and don’t know—about the current SARS-CoV-2 pandemic. The article is authored by scientists associated with the Alzheimer's Association, which is funding the initial work of a consortium of experts from more than 30 countries to understand how COVID-19 increases the risk, severity, pace and progression of neurodegenerative diseases.
The study will enroll participants selected from a pool of millions of confirmed COVID-19 cases documented in hospitals worldwide. A second group of enrollees will comprise people participating in existing international research studies. Participants will be evaluated on a host of measures at their initial appointment and again 6, 9 and 18 months later. These measures include cognition, behavior and, when possible, brain volumes measured by MRI. The study is expected to continue throughout 2024, but initial results are expected in early 2022.
“The under-recognized medical history of these viruses over the last century suggests a strong link to brain diseases that affect memory and behavior," said Maria Carrillo, chief science officer of the Alzheimer's Association coauthor of the paper. "In this difficult time, we can create a 'silver lining' by capitalizing on the Alzheimer's Association's global reach and reputation to bring the research community together to illuminate COVID-19's long-term impact on the brain."
From the nose to the brain
Neurotropic respiratory viruses have long been known to result in chronic brain pathology. In fact, previous studies have suggested the 1918 influenza pandemic—the last pandemic before COVID-19—was and is still the underlying cause of encephalitis lethargica (or sleeping sickness), movement disorders, sleep cycle abnormalities and even psychotic illnesses.
Coronaviruses have been shown to invade the central nervous system, and SARS-CoV-2 is no different. While there are several possible transmission routes, one of the most common is through a person’s olfactory bulb. From there, SARS-CoV-2—which binds to the many ACE2 receptors found in the nose—can target deeper parts of the brain, such as the thalamus, brain stem and hippocampus. The virus can also migrate from tissue to blood and lymphatic vessels, eventually crossing the blood brain barrier (BBB).
“In some individuals, SARS‐CoV‐2 infection triggers a massive release of cytokines, chemokines and other inflammation signals leading to BBB dysfunction, injury to astrocytes, activation of microglia and astrocytes promoting neuroinflammation and neuronal death,” the authors explain in their paper. “Immune response and excessive inflammation in COVID‐19 may accelerate the progression of brain inflammatory neurodegeneration; elderly individuals are more susceptible to severe outcomes.”
In a separate BBB study, researchers, led by Tetyana P. Buzhdyganviral, showed spike proteins cause blood‐brain barrier damage in vitro. Additionally, in post mortem brain tissue, they found ACE2 expressed in the frontal cortex vasculature.
Neuropsychiatric disorders
Brain inflammation accompanies the majority of common neurodegenerative disorders, and is suspected of contributing to major psychiatric disorders as well.
Given that the risk factors of dementia include stroke, coronary heart disease and carotid stenosis, and atrial fibrillation, the study authors say they expect COVID‐19-related cardiovascular and cerebrovascular disease to contribute to a higher long‐term risk of cognitive decline and dementia.
Additionally, multiple lines of evidence suggest viral infections of the brain can impact a person's risk of developing Alzheimer’s or Parkinson's disease. In the case of SARS‐CoV‐2, the researchers expect the virus’s effect on glial reactivity, neuronal function and survival, exaggerated cytokine responses, and/or the formation of anti‐neuronal antibodies to all contribute to a higher risk of neurodegeneration.
“The present pandemic provides a unique—if unwelcome—opportunity to test the role of neurotropic viruses in a prospective fashion in individuals that have recovered from COVID‐19,” the researchers’ paper reads. “The mechanisms by which neurological abnormalities result from COVID‐19 remains to be fully established.”
To make matters worse, the lasting cognitive effects of COVID-19 are expected to move beyond neurodegenerative disorders. This team of researchers, from the Alzheimer’s Association and The Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, anticipate a bidirectional relationship between psychiatric distress and COVID-19.
“Impaired cognitive abilities may cause poor occupational and functional outcomes that precipitate or exacerbate mental health concerns, and poor mental health may likewise contribute to cognitive dysfunction,” they write.
A systematic review published in July 2020 in The Lancet found that recovering COVID‐19 patients presented with high levels of PTSD and depressive symptoms. Patients with preexisting psychiatric disorders reported worsening of their symptoms.