covid-associated neuroinflammation in covid-noninfected

 Another article recently found profound neuroinflammatory increases during the Covid pandemic, this time in never-infected persons (see covid neuroinflam in noninfected BrainBehavImmun2022 in dropbox, or doi.org/10.1016/j.bbi.2022.02.018 )

Details (see the article for many more details):

-- 57 "pre-pandemic" and 15 "pandemic" patients were compared, based on data sets from other studies

-- multimodal PET/MRI imaging was used to investigate brain levels of two inflammatory markers: 18 kDa translocator protein (TSPO) and myoinositol (mIns), comparing levels in subjects scanned post-pandemic versus scanned pre-pandemic

-- assessment of the link between neuroinflammatory signals (and their localization in the brain) from the scans and scores on a questionnaire assessing mental and physical impacts of the pandemic

-- serum levels of cytokines and chemokines were measured from venous blood measurements to evaluate possible links between neural and circulating inflammatory markers

-- all of the subjects had confirmed negative tests for SARS-CoV-2 antibodies, as a means to decrease the likelihood that they had been or were infected

-- in the brain they assessed a priori regions-of-interest, those areas previously associated with stress or depression:

    -- hippocampus

    -- thalamus

    -- anterior cingulate cortex

-- the pandemic cohort experienced the following symptoms: mood alterations (54%), mental (36%) and physical (27%) fatigue, and dyscognition/brain fog (18%)

Results (again, I did not include most of the specifics):

-- the pandemic group had higher levels of neuroinflammation in cortical and subcortical regions, including sensory, motor, and higher-order association areas

    -- the area of the brain involved were quite disparate, involving the above-mentioned regions-of-interest as well as both grey and white matter regions (precentral, postcentral, amygdala, putamen, supplementary motor cortex, cingulates.... see their table 2)

    -- white matter signal elevations were positively associated with physical fatigue, mental fatigue, and mood alterations, as well as with pro-inflammatory peripheral blood markers (IL-16 and MCP-1)

-- there was low inter-subject variability in the findings (ie, pretty much all post-covid findings were the same in all of the people assessed, though the intensity of the signals did vary)

-- one single subject was scanned during both the pre-pandemic and pandemic periods, finding similar results to the group findings (widespread PET signal in all brain regions found in the overall group analysis)

-- overall, there were specific imaging changes in the post-pandemic group that reflected the anticipated brain connections, and tracked with their symptom burden (higher vs lower):

    -- physical fatigue and PET signal changes were associated with the intraparietal sulcus and precuneus regions

    -- mental fatigue and mood alterations with the hippocampal area

    -- though for brain fog, there was no clear association (but very small sample)

Commentary:

-- exposure to social stressors as found in pre-pandemic times have been linked with elevations of pro-inflammatory cytokines and of brain glial /immune cell expression and enrichment

-- this article found significant neural changes in uninfected people during the pandemic (likely from the pandemic-associated intense social isolation), reflecting neuroinflammation in areas of the brain associated with the individuals' deficits, and providing support for neuroimmune responses as the underlying mechanism

--this is not so surprising, given that we do know that depression and other mental health issues have been much more common during Covid throughout society (eg, see http://gmodestmedblogs.blogspot.com/2020/08/covid-severe-psych-substance-use.html)

    -- the prevalence of fatigue and brain fog, for example, have been reported in increased frequency in noninfected individuals

    -- it has been suggested that chronic stress can trigger the sympathetic nervous system to release catecholamines and glucocorticoids; and microglia can respond to these elevated hormones by altering their density and triggering up-regulation of pro-inflammatory molecules, making people feel ill

        -- microglia are the resident immune cells of the brain, and, among other things, express TSPO (one of the inflammatory markers assessed above, though TSPO can also be expressed peripherally in immune cells and then could possibly migrate to the brain, so more research is needed here)

-- and, we do know that depression itself is associated with neuroinflammation

-- but, the relevance of this study is that it ties in specific physiologic neural changes in non-infected people with their symptoms during the pandemic

-- and, this is important both for providers as well as the patients

    -- for providers: many may not understand that there are these impressive physiologic changes associated with mental and physical symptoms, and perhaps not take the depression or other symptoms so seriously

    -- for patients: many may feel that they are being diminished by a healthcare system which often focuses on "organic" disease instead of the increasingly evident integrated biopsychosocial model, since they do not have an obvious physical ailment

-- one interesting sideline is the role of statins in neuroinflammation

    -- a study in older adults having a concussion found that the long-term incidence of dementia was decreased in those who were on a statin both before and after the concussion: http://gmodestmedblogs.blogspot.com/2019/05/statins-dec-dementia-after-concussion.html

    -- another found that statins were more effective than placebo in decreasing depressive symptoms: http://gmodestmedblogs.blogspot.com/2019/08/simvastatin-for-depression.html

    -- and, another found that the combo of simvastatin and vitamin D together led to decreased migraine recurrences: http://gmodestmedblogs.blogspot.com/2016/01/migraine-prophylaxis-with.html

Limitations:

-- small sample size, limiting generalizability and completeness of our understanding. However, these results were internally consistent across individuals, scanners used, age groups, genotypes, and sexes

-- a more robust study would assess the same people before and during the pandemic to check for changes. There was one person who was scanned both times, finding results similar to the group overall, but would be useful to see the results of many more such people

-- the information from the symptom questionnaire was not obtained at the time of the scans, making it difficult to be sure that the symptoms in question correlated specifically with the scans done

-- there was no information on the specifics of the individual circumstances; they did not have the data to isolate specific factors associated with the symptoms, such as social isolation, financial strain, overall changes in lifestyle

-- they had to very few specimens of cytokine/chemokines (five patients), to enable them to evaluate effectively the extent of circulatory inflammatory markers that could be linked to neuroinflammatory processes

so, the point of these last few blogs is that SARS-CoV-2 has profound society-wide effects. There has been lots of information on "long Covid"/PASC in the literature (and in my prior blogs...), detailing the potentially disabling long-term effects on people who may have even asymptomatic or mild infections. In addition, there seems to be important adverse effects on non-infected family members: eg, PTSD in those involved with patients who are in the ICU (see http://gmodestmedblogs.blogspot.com/2022/03/covid-ptsd-in-family-members.html ), or on noninfected people who have significant psychological problems likely from Covid-related social isolation, as in the above study. so, there are an array of profound effects, both in those infected and those non-infected with SARS-CoV-2 but living in this awful pandemic time.

Again, I am just a bit concerned that we need to figure out how to adjust appropriately to our "new normal" of long-term coronavirus endemicity by avoiding the extremes of social isolation/lockdown/working and schooling at home/economic disruption, as well as avoiding the opposite and treating the current covid-decreasing time as if we were pre-pandemic. I think it really is so important to be vaccinated fully and up to date (including boosters, now and in the future), and may well make sense to use masks and some continued distancing in high-risk Covid situations. And this continues to be so important, especially since 1 in 4 people in the US live with a disability and 16% are over 65yo...

geoff

 

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