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Hypothesis: Chronic inflammation in Long COVID reduces dopamine levels, and contributes to fatigue and brain fog

Liz Moore1

1Disability Rights Advocate

Cite as Moore, L. (2024). Hypothesis: Chronic inflammation in Long COVID reduces dopamine levels, and contributes to fatigue and brain fog. Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 2, 10-16

Abstract

Some of the most debilitating symptoms of Long COVID include brain fog and extreme fatigue. Cytokine storms and chronic inflammation are well-documented in SARS-COV-2 infections. Chronic inflammation, in turn, may impact central dopamine signaling. Lowered dopamine and/or dopamine dysfunction could be the underlying mechanism behind the brain fog and fatigue associated with Long COVID.

Introduction

Dopamine is a natural substance found in the body. It is part of a group of chemical messengers called catecholamines, which act as signaling molecules both within and outside the nervous system. In the central nervous system, dopamine signaling plays a crucial role in several important processes such as motor coordination, attention, and motivation. Dopamine dysfunction can cause numerous symptoms, many of which are seen in Long COVID. These symptoms include: fatigue, motor difficulties, executive dysfunction, and cognitive dysfunction.1 One cause of dopamine dysfunction is chronic inflammation. 

Both chronic inflammatory diseases and central nervous system (CNS) disorders are associated with (1) dopamine dysfunction, and (2) a post-viral onset. Parkinson’s Disease (PD) is a neurodegenerative disorder in which the progressive loss of dopamine neurons in the substantia nigra drives motor and cognitive difficulties. Post-viral PD and Parkinsonism have been documented in historic epidemics, such as the 1918 flu epidemic and more recent flu outbreaks,2,3 as well as in some cases of Long COVID.4,5 

Multiple sclerosis (MS) is another neurodegenerative condition that causes fatigue and cognitive dysfunction similar in presentation to Long COVID. Notably, recent research suggests MS may be a long- term complication of Epstein-Barr virus infections.6 The “dopamine imbalance hypothesis” has also been proposed as an underlying mechanism of fatigue in MS.7 

To date, there have been at least 20 documented cases of “post-COVID-19 Parkinsonism.”4 Although these numbers are currently low, it is possible that the inflammatory damage from acute COVID infection may constitute a neurological “hit and run” that leads to a subsequent increased incidence of PD and/or Parkinsonism.5

Hypothesis

SARS-CoV-2-induced neuroinflammation may impact dopamine signaling in the nervous system. Impaired dopamine signaling may contribute to the debilitating cognitive symptoms some Long COVID patients experience.

How inflammation affects dopamine

Acute inflammation can have profound effects on dopamine signaling, with studies demonstrating that vaccination or interferon-alpha treatment increase dopamine activity.8,9 In the acute phase of an infection, this response may promote rest and recovery (i.e., “sickness behaviors”).10 However, chronic inflammation and exposure to inflammatory cytokines can cause pathological impairment of dopamine neurons and dopamine signaling via a number of mechanisms.11,12

In mouse models, inflammatory stimuli can cause dopamine neuron degeneration and behavioral phenotypes similar to what is seen in PD.13,14 Dopamine neurons are particularly sensitive to metabolic stress and can express major histocompatibility complex class I (MHC-I) in response to inflammation, which in turn can directly recruit cytotoxic T-cells to attack these neurons.15 As dopamine signaling itself suppresses inflammation, the death of dopamine neurons can further feed into systemic inflammation.16  

Adapting to brain hypometabolism

Metabolic changes in the brain may occur after an acute inflammatory event.17 Brain hypometabolism refers to a localized decrease in glucose consumption, typically inferred by decreased blood supply. Brain hypometabolism occurs in several CNS disorders, such as Alzheimer’s and PD.18 Notably, regional brain hypometabolism has also been documented in Long COVID via positron emission tomography (PET) imaging techniques.19 Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which can present similarly to Long COVID, is also associated with a hypometabolic state.20 Dopamine dysfunction could be an adaptation to metabolic changes frequently seen in Long COVID; alternatively, neuroinflammation or damage to dopamine neurons could precipitate a hypometabolic state in limbic structures.21

Pro-inflammatory immune signaling

Additional inflammatory processes can also affect dopamine synthesis. Cytokines are chemical messengers in the immune system that regulate immune functions such as inflammation.22 Pro-inflammatory cytokines induced by infections like SARS-COV-2 and influenza, can impact brain dopamine levels in a number of ways. For example, inflammation can prevent dopamine synthesis by limiting the availability of tetrahydrobiopterin (BH4), an enzyme cofactor required to convert tyrosine into dopamine.11

Microglia are the brain’s resident immune cells with several functions. Under baseline conditions, microglia quietly patrol the nervous system for signs of trouble. Once activated, microglia undergo a dramatic shift in behavior and begin secreting proinflammatory cytokines, which further fuels the neuroinflammation process.23 Inflammation can cause microglia to become activated and engage in pro-inflammatory signaling. Additionally, inflammation can block dopamine receptors via striatal adenosine A24 receptors.24 This immune signaling may be an effort to decrease the brain’s energy demands.

Long COVID symptoms such as brain fog and fatigue could be caused by dopamine dysfunction driven by chronic inflammation. After establishing whether dopamine dysfunction is present in Long COVID, further research could establish precise pathways and treatment options.

How to test the hypothesis 

Researchers have used PET scans and dopaminergic radioligands such as Carbon-11-FLB 457 to study dopamine in vivo in PD.25 PET scans of Long COVID patients and healthy controls could provide insight into dopamine dysfunction in Long COVID.

Testing recommendations

  1. Use screening questions and clinical measures to identify Long COVID patients who have symptoms consistent with dopamine dysfunction. In addition to self-reported symptoms, consider clinical measures such as the Mini Mental Status Exam, Mini Cog, Computerized Continuous Performance Test, and basic neurological and motor exams.26, 27,28
  2. Account for medications or comorbidities known to affect dopamine levels. Since many people with Long COVID take these medications and have relevant comorbidities, excluding them may not be feasible. Consider asking participants to discontinue dopaminergic medications prior to testing.
  3. Select participants who live close to the testing facility and use a quiet, low-light waiting room to limit external variables and minimize post-exertional malaise (PEM).29 
  4. Consider testing two groups of Long COVID patients (in addition to a control group) based on the presence or absence of symptoms potentially related to dopamine dysfunction.
  5. Perform all PET scans at the same time of day because circadian rhythm can affect dopamine levels.30

Unanswered questions

  1. Is chronic inflammation the cause of dopamine dysfunction in Long COVID?
  2. Is dopamine dysfunction in Long COVID a way to protect the brain during metabolic stress?
  3. How does PEM affect dopamine synthesis in Long COVID?
  4. Can dopaminergic medications used to treat PD, such as levodopa/carbidopa or pramipexole, reduce brain fog and fatigue in people with Long COVID?31
  5. Cholamine-O-methyltransferase (COMT) inhibitors are sometimes used to increase dopamine levels in patients with PD.32 Could drinking natural COMT inhibitors, such as those found in green tea,33 reduce cognitive symptoms of Long COVID?
  6. Green tea contains polyphenols that may be neuroprotective against PD.33 Does drinking green tea during acute COVID infection have a neuroprotective effect against Long COVID?34
  7. How does gut microbiome dysbiosis affect dopamine levels in Long COVID?
  8. Dopamine synthesis requires adequate intake and absorption of dopamine cofactors and precursors (e.g., vitamin B6, L-tyrosine, L-DOPA). Many biopsychosocial aspects of LC impact dietary intake and absorption, ranging from anosmia to food insecurity. Could supplemental L-tyrosine, L-DOPA, and/or vitamin B6 help alleviate symptoms of dopamine dysfunction in Long COVID?

References

1. Franco R, Reyes-Resina I, Navarro G. Dopamine in Health and Disease: Much More Than a Neurotransmitter. Biomedicines. 2021;9(2):109. doi:10.3390/biomedicines9020109

2. Cocoros NM, Svensson E, Szépligeti SK, et al. Long-term Risk of Parkinson Disease Following Influenza and Other Infections. JAMA Neurology. 2021;78(12):1461-1470. doi:10.1001/jamaneurol.2021.3895

3. Leta V, Urso D, Batzu L, et al. Viruses, parkinsonism and Parkinson’s disease: the past, present and future. J Neural Transm (Vienna). 2022;129(9):1119-1132. doi:10.1007/s00702-022-02536-y

4. Leta V, Boura I, van Wamelen DJ, Rodriguez-Violante M, Antonini A, Chaudhuri KR. Chapter Four – Covid-19 and Parkinson’s disease: Acute clinical implications, long-COVID and post-COVID-19 parkinsonism. In: Chaudhuri KR, Rodríguez-Violante M, Antonini A, Boura I, eds. International Review of Neurobiology. Vol 165. Covid-19 and Parkinsonism. Academic Press; 2022:63-89. doi:10.1016/bs.irn.2022.04.004

5. Brandão PRP, Grippe TC, Pereira DA, Munhoz RP, Cardoso F. New-Onset Movement Disorders Associated with COVID-19. 2021;11(1):26. doi:10.5334/tohm.595

6. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222

7. Dobryakova E, Genova HM, DeLuca J, Wylie GR. The Dopamine Imbalance Hypothesis of Fatigue in Multiple Sclerosis and Other Neurological Disorders. Frontiers in Neurology. 2015;6. Accessed December 27, 2023. https://www.frontiersin.org/articles/10.3389/fneur.2015.00052

8. Capuron L, Pagnoni G, Drake DF, et al. Dopaminergic Mechanisms of Reduced Basal Ganglia Responses to Hedonic Reward During Interferon Alfa Administration. Archives of General Psychiatry. 2012;69(10):1044-1053. doi:10.1001/archgenpsychiatry.2011.2094

9. Brydon L, Harrison NA, Walker C, Steptoe A, Critchley HD. Peripheral Inflammation is Associated with Altered Substantia Nigra Activity and Psychomotor Slowing in Humans. Biological Psychiatry. 2008;63(11):1022-1029. doi:10.1016/j.biopsych.2007.12.007

10. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56. doi:10.1038/nrn2297

11. Felger JC, Miller AH. Cytokine effects on the basal ganglia and dopamine function: The subcortical source of inflammatory malaise. Frontiers in Neuroendocrinology. 2012;33(3):315-327. doi:10.1016/j.yfrne.2012.09.003

12. Felger JC, Treadway MT. Inflammation Effects on Motivation and Motor Activity: Role of Dopamine. Neuropsychopharmacol. 2017;42(1):216-241. doi:10.1038/npp.2016.143

13. Imbriani P, Martella G, Bonsi P, Pisani A. Oxidative stress and synaptic dysfunction in rodent models of Parkinson’s disease. Neurobiology of Disease. 2022;173:105851. doi:10.1016/j.nbd.2022.105851

14. Qin L, Wu X, Block ML, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55(5):453-462. doi:10.1002/glia.20467

15. Cebrián C, Zucca FA, Mauri P, et al. MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun. 2014;5(1):3633. doi:10.1038/ncomms4633

16. Yan Y, Jiang W, Liu L, et al. Dopamine Controls Systemic Inflammation through Inhibition of NLRP3 Inflammasome. Cell. 2015;160(1):62-73. doi:10.1016/j.cell.2014.11.047

17. Shinjyo N, Kita K. Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia. Frontiers in Cellular Neuroscience. 2021;15. Accessed December 27, 2023. https://www.frontiersin.org/articles/10.3389/fncel.2021.765217

18. Zilberter Y, Zilberter M. The vicious circle of hypometabolism in neurodegenerative diseases: Ways and mechanisms of metabolic correction. Journal of Neuroscience Research. 2017;95(11):2217-2235. doi:10.1002/jnr.24064

19. Verger A, Kas A, Dudouet P, Goehringer F, Salmon-Ceron D, Guedj E. Visual interpretation of brain hypometabolism related to neurological long COVID: a French multicentric experience. Eur J Nucl Med Mol Imaging. 2022;49(9):3197-3202. doi:10.1007/s00259-022-05753-5

20. Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proceedings of the National Academy of Sciences. 2016;113(37):E5472-E5480. doi:10.1073/pnas.1607571113

21. Menezes DC de, Lima PDL de, Lima IC de, et al. Metabolic Profile of Patients with Long COVID: A Cross-Sectional Study. Nutrients. 2023;15(5):1197. doi:10.3390/nu15051197

22. Zhang JM, An J. Cytokines, Inflammation, and Pain. International Anesthesiology Clinics. 2007;45(2):27. doi:10.1097/AIA.0b013e318034194e

23. Colonna M, Butovsky O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annual Review of Immunology. 2017;35(1):441-468. doi:10.1146/annurev-immunol-051116-052358

24. Dantzer R. Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiological Reviews. 2018;98(1):477-504. doi:10.1152/physrev.00039.2016

25. Niccolini F, Su P, Politis M. Dopamine receptor mapping with PET imaging in Parkinson’s disease. J Neurol. 2014;261(12):2251-2263. doi:10.1007/s00415-014-7302-2

26. Computerized Test for ADHD. Psych Central. Published September 5, 2013. Accessed December 27, 2023. https://psychcentral.com/adhd/computerized-testing-for-adhd-is-it-useful

27. Mini-Mental State Examination. Physiopedia. Accessed December 3, 2023. https://www.physio-pedia.com/Mini-Mental_State_Examination

28. Mini-Cog. Physiopedia. Accessed December 3, 2023. https://www.physio-pedia.com/Mini-Cog

29. Post-exertional malaise. In: MEpedia. Accessed December 3, 2023. https://me-pedia.org/wiki/Post-exertional_malaise

30. Verwey M, Dhir S, Amir S. Circadian influences on dopamine circuits of the brain: regulation of striatal rhythms of clock gene expression and implications for psychopathology and disease. F1000Res. 2016;5:F1000 Faculty Rev-2062. doi:10.12688/f1000research.9180.1

31. List of Dopaminergic antiparkinsonism agents. Drugs.com. Accessed December 27, 2023. https://www.drugs.com/drug-class/dopaminergic-antiparkinsonism-agents.html

32. Schapira AH, Obeso JA, Olanow CW. The place of COMT inhibitors in the armamentarium of drugs for the treatment of Parkinson’s disease. Neurology. 2000;55(11 Suppl 4):S65-68; discussion S69-71.

33. Li C, Lin J, Yang T, Shang H. Green Tea Intake and Parkinson’s Disease Progression: A Mendelian Randomization Study. Frontiers in Nutrition. 2022;9. Accessed December 27, 2023. https://www.frontiersin.org/articles/10.3389/fnut.2022.848223

34. AL Mughram MH, Ghatge MS, Kellogg GE, Safo MK. Elucidating the Interaction between Pyridoxine 5′-Phosphate Oxidase and Dopa Decarboxylase: Activation of B6-Dependent Enzyme. International Journal of Molecular Sciences. 2023;24(1):642. doi:10.3390/ijms24010642

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