Do Activated Glia Contribute to Long COVID?

Some people become depressed after COVID-19. The cause remains a mystery, but now a small PET study hints that glia might be involved. In the May 31 JAMA Psychiatry, scientists led by Jeffrey Meyer at the University of Toronto reported high levels of the glial translocator protein, a marker for gliosis, in 20 people two years after COVID. The TSPO signal in their putamen correlated with slow movement. The authors believe lingering neuroinflammation due to micro- or astrogliosis might help explain some long COVID symptoms. In contrast, nationwide studies of 8 million adults in England and 3.5 million in Denmark published in the same journal found equal risks of mental disorders after hospitalization from COVID or a severe bout of flu, suggesting that disease severity drove the risk of psychiatric problems. The studies add to the mystery that is post-COVID syndrome (May 2023 conference news).

  • People with long COVID have persistent depression and/or cognitive symptoms.
  • Gliosis is seen in their putamina and striata.
  • However, nationwide studies found but weak links between SARS-COV2 infection and mental disorders.

“The PET pilot study provides evidence that COVID-19 leads to sustained, and potentially deleterious, microglial activation after acute symptoms, which can be a potential target for trials designed to alleviate long-lasting neuropsychiatric symptoms,” wrote Tharick Pascoal at the University of Pittsburgh (comment below).

In some people, COVID whips peripheral cytokines into a “storm,” stirring neuroinflammation in the brain. At postmortem, half of the people who died of severe COVID had micro- and astrogliosis (Cosentino et al., 2021). Microgliosis has also been linked to depression, a symptom of long COVID (Gritti et al., 2021; Hashioka 2011). 

To see if microglia were stirring in people living with post-COVID syndrome, first author Joeffre Braga turned to TSPO PET. The translocator protein is predominately expressed by activated microglia but can also be overexpressed by activated astrocytes (Boche et al., 2019; Rizzo et al., 2017). Braga compared scans from 20 people who never had COVID to scans from 20 who had developed depression, for the first time in their life, within three months of mild to moderate COVID. Scans were taken a few months to two years after COVID diagnosis. Participants ranged from 18 to 72 years old, average age 33. Cases and controls were matched based on whether they carried a single nucleotide variant in TSPO that weakens binding to PET ligands, in this case FEPPA (Mizrahi et al., 2012). 

Compared to controls, people with long COVID had 1.7-fold more TSPO in their dorsal putamen and twice the amount in their ventral striatum (see image below). Aberrant function in these areas has been tied to low energy or motivation, and to apathy—all symptoms of depression (Liljeholm and O’Doherty et al., 2012; Heron et al., 2018). TSPO expression in the hippocampus and cortex also trended higher in COVID cases.

Gliosis After COVID. TSPO levels in the striata and putamina of people with long COVID (navy triangles) were higher on average (orange bars) than in the same brain regions in controls (blue triangles). A similar trend held in the hippocampus and cortex. Closed triangles represent people carrying a TSPO variant that increases ligand binding. [Courtesy of Braga et al., JAMA Psychiatry, 2023.]

High TSPO in the putamen also correlated with slow motor speed on a finger-tapping task. The putamen helps control movement speed, and slowed movements are a sign of depression (Bennabi et al., 2013). However, FEPPA binding did not correlate with depression or cognition, as measured by the Hamilton Depression Rating Scale and the self-reported Cognitive Failures Questionnaire, perhaps because gliosis was negligible in areas associated with these traits—i.e. the cortex and hippocampus, respectively.

The authors speculate that injury to the putamen or striatum, or to neighboring regions, may cause the gliosis. The substantia nigra and ventral tegmental areas project to the striatum and are hot spots for expression of angiotensin converting enzyme, a receptor for SARS-CoV2. Others had found that SARS-CoV2 inflames the choroid plexus, a structure near the putamen and striatum, which then stirs up microglia and astrocytes (Jun 2021 news).

This paper is based on a single PET scan. Alexander Gerhard of the University of Manchester, U.K., suggested following participants to track neuroinflammation and compare its symptoms and peripheral inflammatory markers over time. “These lines of investigation might ultimately allow us to modulate neuroinflammatory changes after COVID-19 and other neuropsychiatric disorders,” he wrote in a JAMA Psychiatry editorial.

Despite ubiquitous reports of mental health problems after COVID, researchers led by Daniel Kondziella and Michael Benros at the University of Copenhagen caution against reading too much into the currently available data. In the May 24 JAMA Psychiatry, they reported that for most people the likelihood of being diagnosed with a mental health disorder was no higher within two years of testing positive for COVID than it was among people who had tested negative. Among almost 527,000 Danish adults who tested positive and 3.1 million who tested negative, first author Vardan Nersesjan found that the former were 25 percent likelier to develop new neuropsychological problems only if they were over 70.

This age discrepancy might be partially due to disease severity, since older adults have a higher risk of severe COVID. Indeed, people hospitalized with COVID were 2.5 times likelier to develop mental health issues than people not needing hospitalization, the authors found. This trend was also true for people hospitalized for non-COVID respiratory tract infections or pneumonia. “Deterioration of mental health after hospitalization for COVID-19 is common but no more frequent than after other infections with similar severity,” the authors concluded.

Similarly, scientists led by Peter Watkinson at the University of Oxford reported from a nationwide survey of electronic health records in England, that among 32,500 adults hospitalized with COVID and 16,700 hospitalized with other respiratory infections, the likelihood of subsequent mental illness was the same. In the May 11, 2022, issue of JAMA Psychiatry, first author Ashley Kieran Clift reported that both groups were two to three times likelier to develop depression, anxiety, psychosis, bipolar disorder, or dementia in the year after hospital discharge than were 8.3 million people who were never hospitalized.

Ziyad Al-Aly at the Veterans Affairs St. Louis Health Care System disagreed that hospitalization alone explains the link between mental health problems and COVID. “The huge body of evidence that we have amassed over the past three years is compelling, and irrefutably demonstrates an increased risk of neuropsychiatric disorders after any COVID infection,” he wrote to Alzforum. “I think we need to focus more on understanding how to best prevent and treat these conditions.”—Chelsea Weidman Burke

Comments

  1. Braga et al. conducted an interesting study to test if microglial activation, measured by a TSPO PET tracer, is linked to persistent depressive and cognitive symptoms presented by some patients after acute COVID-19 infection.

    The authors performed gold-standard PET arterial input function quantification and their regional total distribution volume (VT) results appear robust despite the small sample size. The inclusion of actual brain images and binding potentials (k3/k4) would have provided a better understanding of the role of off-target and non-displaceable tracers on the groups. The clinical impact of the PET results was supported by an association between TSPO VT in the basal ganglia and a motor performance test.

    In summary, this pilot study suggests that COVID-19 may cause sustained and potentially harmful microglial activation after acute symptoms. I concur with the authors that further study of this as a target for alleviating COVID-related long-lasting neuropsychiatric symptoms could be beneficial. If the authors had access to the patients’ CSF, it would increase the likelihood of identifying specific proteins involved in the microglial activation process as potential therapeutic targets.

    View all comments by Tharick Pascoal

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References

News Citations

  1. Long COVID and Dementia: The Link Is Still Elusive
  2. COVID-19 Prompts Choroid Plexus to Ring Alarm Bell

Paper Citations

  1. Cosentino G, Todisco M, Hota N, Della Porta G, Morbini P, Tassorelli C, Pisani A. Neuropathological findings from COVID-19 patients with neurological symptoms argue against a direct brain invasion of SARS-CoV-2: A critical systematic review. Eur J Neurol. 2021 Nov;28(11):3856-3865. Epub 2021 Aug 17 PubMed.
  2. Gritti D, Delvecchio G, Ferro A, Bressi C, Brambilla P. Neuroinflammation in Major Depressive Disorder: A Review of PET Imaging Studies Examining the 18-kDa Translocator Protein. J Affect Disord. 2021 Sep 1;292:642-651. Epub 2021 Jun 5 PubMed.
  3. Hashioka S. Antidepressants and neuroinflammation: Can antidepressants calm glial rage down?. Mini Rev Med Chem. 2011 Jun;11(7):555-64. PubMed.
  4. Boche D, Gerhard A, Rodriguez-Vieitez E, MINC Faculty. Prospects and challenges of imaging neuroinflammation beyond TSPO in Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2019 Dec;46(13):2831-2847. Epub 2019 Aug 8 PubMed.
  5. Rizzo G, Veronese M, Tonietto M, Bodini B, Stankoff B, Wimberley C, Lavisse S, Bottlaender M, Bloomfield PS, Howes O, Zanotti-Fregonara P, Turkheimer FE, Bertoldo A. Generalization of endothelial modelling of TSPO PET imaging: Considerations on tracer affinities. J Cereb Blood Flow Metab. 2017 Jan 1;:271678X17742004. PubMed.
  6. Mizrahi R, Rusjan PM, Kennedy J, Pollock B, Mulsant B, Suridjan I, De Luca V, Wilson AA, Houle S. Translocator protein (18 kDa) polymorphism (rs6971) explains in-vivo brain binding affinity of the PET radioligand [(18)F]-FEPPA. J Cereb Blood Flow Metab. 2012 Jun;32(6):968-72. Epub 2012 Apr 4 PubMed.
  7. Liljeholm M, O'Doherty JP. Contributions of the striatum to learning, motivation, and performance: an associative account. Trends Cogn Sci. 2012 Sep;16(9):467-75. Epub 2012 Aug 10 PubMed.
  8. Le Heron C, Apps MA, Husain M. The anatomy of apathy: A neurocognitive framework for amotivated behaviour. Neuropsychologia. 2017 Jul 8; PubMed.
  9. Bennabi D, Vandel P, Papaxanthis C, Pozzo T, Haffen E. Psychomotor retardation in depression: a systematic review of diagnostic, pathophysiologic, and therapeutic implications. Biomed Res Int. 2013;2013:158746. Epub 2013 Oct 30 PubMed.

External Citations

  1. mental health disorder

Further Reading

Primary Papers

  1. Braga J, Lepra M, Kish SJ, Rusjan PM, Nasser Z, Verhoeff N, Vasdev N, Bagby M, Boileau I, Husain MI, Kolla N, Garcia A, Chao T, Mizrahi R, Faiz K, Vieira EL, Meyer JH. Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms. JAMA Psychiatry. 2023 Aug 1;80(8):787-795. PubMed.
  2. Gerhard A. Does Microglial Activation Lead to Cognitive Changes After COVID-19 Infection?. JAMA Psychiatry. 2023 Aug 1;80(8):767. PubMed.
  3. Nersesjan V, Christensen RH, Kondziella D, Benros ME. COVID-19 and Risk for Mental Disorders Among Adults in Denmark. JAMA Psychiatry. 2023 May 24; PubMed.
  4. Clift AK, Ranger TA, Patone M, Coupland CA, Hatch R, Thomas K, Hippisley-Cox J, Watkinson P. Neuropsychiatric Ramifications of Severe COVID-19 and Other Severe Acute Respiratory Infections. JAMA Psychiatry. 2022 Jul 1;79(7):690-698. PubMed.

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