COVID-19 Update [October '22]

By B. Jeanne Billioux, MD and Avindra Nath, MD

For this update, we present some pertinent updates in the literature and news, including new insights into long-term COVID-19 neurologic outcomes and links between COVID-19 and Alzheimer’s Disease.

This month, a study published in Nature Medicine looked at incident neurologic sequelae in COVID-19 survivors over a one-year period using US Department of Veterans Affairs (VA) health care databases (Xu 2022). This is a well-designed study with appropriate controls, which shows an increase in neurological complications in hospitalized and non-hospitalized patients with COVID-19 at 12 months after onset of infection. The long follow up, the large sample size and the syndromic approach as opposed to symptom-based characterization of patients makes this a unique study. In this study, 154,068 individuals with COVID-19 were compared to two large control cohorts (a contemporary control cohort of 5,638,795 individuals, and a historical control cohort of 5,859,621 individuals) to assess the risks and burdens of incident neurologic disorders at 12 months after COVID-19 infection. In the post-acute phase, the COVID-19 cohort had a higher risk of a multitude of neurologic disorders, including cerebrovascular disorders like ischemic (hazard ratio (HR) 1.50) or hemorrhagic (HR 2.19) stroke, memory issues (HR 1.77), Alzheimer’s disease (HR 2.03), epilepsy and seizures (HR 1.80), dysautonomia (HR 1.30), Parkinson-like disease (HR 1.50), and Guillain-Barré syndrome (GBS) (HR 2.16), among others.  When examining the risk of any neurologic disorder after COVID-19, the hazard ratio was 1.42.  Over all, 42% had increased risk for developing neurological sequela in the year after the infection. Although the risks were greatest in patients who had been in the ICU, these risks of neurologic disorders were still elevated in patients who were not hospitalized for their COVID-19 (Xu 2022).  Similarly, a retrospective cohort study in Lancet Psychiatry analyzed the health care records of nearly 1,300,000 deidentified patients who had had COVID-19 and compared them to a matched cohort of patients with another respiratory infection, and identified the risk trajectories for a number of neurologic and mental health diagnoses over a two year period.  There was an increased risk of developing a new neurologic or psychiatric issues at 6 months, including cognitive issues (HR 1.36), dementia (HR 1.33), epilepsy or seizures (HR 1.14), GBS (HR 1.12), ischemic stroke (HR 1.11), myoneural junction or muscle disease (HR 1.89), anxiety (HR 1.13) or psychotic disorder (HR 1.27).  Over a 2-year period, this risk came to normalize for disorders such as stroke and anxiety, but persisted for others including cognitive issues, dementia, epilepsy and seizures, and psychotic disorders (Taquet 2022).  

Another study published this month used a similar approach, looking at deidentified data from medical records of over 6 million older patients (³65 years), specifically targeting new diagnoses of Alzheimer’s Disease in patients who had COVID-19 compared to controls.  They found that patients who had had COVID-19 (n=410,748) had an increased risk of receiving a new diagnosis of Alzheimer’s disease in the year following their infection, with a hazard ratio of 1.82; this risk was increased in patients over age 85 years (HR 1.89) (Wang 2022).  Complementing these findings, another recent study looked at brain gene expression in deceased patients with severe COVID-19 patients compared to controls and patients with Alzheimer’s Disease, with a focus on gene expression profiles implicated in Alzheimer’s Disease.  The authors found several common pathways affected in both diseases, with the brains of severe COVID-19 patients showing increased expression in a number of genes implicated in the pathogenesis of AD, notably including genes related to neuroinflammatory pathways such as the Wnt signaling pathway (Green 2022).  To further understand the potential link between Alzheimer’s Disease and COVID-19, this month the Alzheimer’s Association Global Consortium released a review on the subject, including potential mechanisms as well as methodology to systematically address the issues described, accessed at www.ncbi.nlm.nih.gov/pmc/articles/PMC9494609/ ⧉  (de Erausquin 2022). 

Though we are still in the early stages of understanding neuropsychiatric sequelae of Sars-CoV-2 infection, the findings of the above studies are intriguing and sobering; moreover, studies such as these reinforce the need for more ongoing research to continue unfolding the potential links between COVID-19 and neurologic and cognitive sequelae. Most concerning is that many of these conditions are chronic illnesses which will require life-long care with major implications for the health care systems, the economy and the well-being of society.

References

• Xu E, Xie Y, Al-Aly Z. Long-term neurologic outcomes of COVID-19. Nat Med. 2022 Sep 22. doi: 10.1038/s41591-022-02001-z. https://www.nature.com/articles/s41591-022-02001-z#MOESM1 ⧉

• Taquet M, Sillett R, Zhu L, Mendel J, Camplisson I, Dercon Q, Harrison PJ. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients. Lancet Psychiatry. 2022 Oct;9(10):815-827. doi: 10.1016/S2215-0366(22)00260-7. Epub 2022 Aug 17. PMID: 35987197; PMCID: PMC9385200.  https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(22)00260-7/fulltext ⧉

• Wang, Lindsey et al. Association of COVID-19 with New-Onset Alzheimer’s Disease. 1 Jan. 2022 : 411 – 414. https://content.iospress.com/articles/journal-of-alzheimers-disease/jad220717 ⧉

• Green R, Mayilsamy K, McGill AR, Martinez T, Chandran B, Blair LJ, Bickford PC, Mohapatra SS, Mohapatra S. SARS-CoV-2 Infection Increases the Gene Expression Profile for Alzheimer's Disease Risk. Mol Ther Methods Clin Dev. 2022 Sep 24. doi: 10.1016/j.omtm.2022.09.007. Epub ahead of print. PMID: 36187720; PMCID: PMC9508696. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508696/ ⧉

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