Prerpints.org logo
Preprint
Review

Proposing Bromo-Epi-Androsterone for Neurologic Long-COVID

This is a preprint, it has not been peer-reviewed.

Submitted:

30 June 2024

Posted:

01 July 2024

You are already at the latest version

Abstract
The neurologic effects of long-COVID are a therapeutic challenge. This article discusses the immunologic manifestations of long-COVID and proposes a non-androgenic, synthetic analog of dehydroepiandrosterone (DHEA), bromo-epi-androsterone (BEA), as a candidate for clinical trials for this exigent collection of neurologic conditions. Moreover, because there is an association between long-COVID and Alzheimer’s disease, the evaluation of BEA in long-COVID may serve as a proxy for its effect on neuroinflammatory biomarkers of Alzheimer’s disease that are shared with long-COVID.
Keywords: 
  -  
Preprints on COVID-19 and SARS-CoV-2

1. Introduction

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the pathogen responsible for COVID-19 disease; when COVID symptoms persist, the condition is commonly referred to as long-COVID. Multiple mechanisms are thought to contribute to the multisystem manifestations and prolonged symptoms experienced in long-COVID cases. This article addresses neurologic aspects of long-COVID and how immune dysregulation is thought to participate in these manifestations. Moreover, the article proposes the utility of the synthetic dehydroepiandrosterone (DHEA) analog, bromo-epi-androsterone (BEA), as a multi-faceted intervention to promote immune homeostasis and reduce non-productive inflammation resulting in a favorable outcome to this disease.
Current research suggests the pathogenic mechanisms underlying long-COVID include the persistent presence of SARS-CoV-2 virus [1], formation of microscopic blood clots [2], dysregulation of the immune system [3], disruption of normal mitochondrial function including mitochondrial “storms” [4], reactivation of latent viral pathogens such as the Epstein-Barr virus and human herpesvirus-6 [5], extension of ongoing inflammatory processes [6], triggering of autoimmune responses [7], as well as impairment of brainstem signal transduction pathways and dysfunction of vagus nerve signaling [8,9].

2. COVID and Cognitive Dysfunction

COVID-19 infection frequently leads to persistent cognitive dysfunction commonly known as "brain fog." This condition involves impairments in attention, processing speed, memory, and executive functioning [10]. Symptoms including fatigue, sleep problems, language difficulties, and loss of smell/taste frequently accompany brain fog [11]. Meta-analyses indicate that around 22% of COVID-19 patients experience cognitive dysfunction 19 weeks after infection, with nearly 20% still affected at 9 months [12,13]. Both mild and severe COVID-19 cases can result in prolonged cognitive impairment, which worsens the longer the symptoms persist [14].
The apparent primary driver of COVID-19-related cognitive decline is the extended inflammation triggered by SARS-CoV-2 infection. This inflammation can increase blood-brain barrier permeability, activate brain immune cells like microglia and astrocytes, and ultimately lead to neuronal damage [15,16]. The virus can also invade and damage dopamine neurons in the midbrain, which is implicated in Parkinson's disease [17]. Chronic inflammation reduces neurogenesis and impairs synaptic plasticity in the hippocampus resulting in memory deficits. Furthermore, inflammatory factors can disrupt mood regulation, causing depression and other mood issues in survivors [18].

3. COVID and Immune Dysregulation

SARS-CoV-2 infection triggers both the innate and adaptive immune responses to clear the viral pathogen [19]. However, in patients with long COVID, there are observed changes in immune cells, increased autoantibody levels, and reactivation of latent viruses [20–22]. The long-term effects of COVID-19 on the immune system are evident through epigenetic and transcriptional alterations in monocytes, which can lead to chronic inflammation, excessive autoimmune activity, and persistent consequences throughout the body [23].
Recovering COVID-19 patients exhibit abnormalities in intermediate monocytes and T-cell activation, associated with ongoing endothelial cell activation and coagulation dysfunction [24,25]. Long COVID patients show a decline in CD4+ and CD8+ effector memory cells [26], while pro-inflammatory cytokines like IFN-β and IFN-λ1 remain elevated for several months after infection [27]. The persistent SARS-CoV-2 presence also leads to dendritic cell deficiency [28] and reductions in non-classical monocyte and lymphocyte subsets [29].
This aberrant and sustained immune activation produces a broad spectrum of self-targeting antibodies hypothesized to contribute to various long COVID symptoms [30]. Long-COVID patients exhibit abnormally high levels of functional autoantibodies targeting G protein-coupled receptors linked to both persistent neurological and cardiovascular issues [31]. SARS-CoV-2-induced autoimmunity can cause immune blood disorders, antiphospholipid syndrome, systemic lupus erythematosus, vasculitis, acute arthritis and Kawasaki-like syndromes [32].
Neurological complications of long COVID are also associated with changes in inflammatory cytokines. Interleukin-6 (IL-6) levels are significantly increased in patients with Long-COVID compared to those without post-Covid symptoms [33,34]. Indeed, high IL-6 levels are associated with both development and severity of Long Covid neurological manifestations [35].
Although not looking at neurologic complications specifically, Long-COVID patients have elevated IL-1β, TNF and IP-10 cytokines [36]. Interferon-alpha (IFN-α) levels are also elevated in Long-COVID patients, particularly those with neurological symptoms [34]. Activation of the cGAS-STING pathway, which induces IFN-α production, may contribute to neurodegenerative processes in Long-COVID [34]. The anti-inflammatory cytokines IL-4 and IL-10 are reduced in Long-Covid patients compared to those without post-Covid symptoms, suggesting an imbalance that favors a pro-inflammatory state that could drive neurological complications [33,36].

4. DHEA and Cortisol

DHEA (dehydroepiandrosterone) and its sulfate (DHEA-S) are the most abundant steroids of the metabolome and play essential roles in physiological processes such as metabolism, immune function and the stress response [37]. The DHEA secretory rate changes throughout an individual’s lifespan; after attainment of adulthood levels that plateaus until the late 20’s, DHEA levels start a steady decline such that by 70-80 years of age, peak concentrations of DHEAS are only 10-20% of those in young adults [38].
DHEA and cortisol have opposite hormonal actions and the balance between DHEA and cortisol levels is important for multiple and diverse physiologic functions [39]. DHEA is known as the “youth hormone” [41]; and cortisol is commonly known as the “stress hormone” [42]. A lower DHEA to cortisol ratio is associated with stress, metabolic syndrome, immune dysfunction including susceptibility to infection, frailty and all-cause mortality [43,44,45,46,47]. While the adrenal glands are the primary site for these steroids, they are also locally synthesized in other tissues including primary lymphoid organs, intestine, gonads, skin, brain and the heart [48]. The age-related decrease in the DHEA/cortisol ratio is associated the with immunological changes observed during ageing, immunosenescence [49,50] along with the paradoxical concurrent upregulation of inflammation, inflammaging [51].

5. BEA – (16 Alpha-bromoepiandrosterone)

BEA (16 alpha-bromoepiandrosterone) is a synthetic DHEA analog that lacks DHEA's androgenic and estrogenic actions. A primary mechanism of DHEA is as a potent inhibitor of mammalian glucose-6-phosphate dehydrogenase (G6PDH); and in this regard, BEA is about 60 times as potent as DHEA [52]. A previous formulation of BEA was developed over 20 years ago as a treatment for a range of human infections; in 9 clinical trials, that formulation treated 228 participants for varying infections: HIV, malaria and hepatitis [53–55].
In March of 1999, the FDA issued an IND (investigational new drug) status for this formulation to be investigated in patients with HIV/AIDS [56,57] for which it showed efficacy [58]. Since BEA limits non-productive inflammation [59] and exhibits broad immune support, it has been proposed as a treatment for the world’s greatest pathogen Mycobacterium tuberculosis [60,61].
Like DHEA, BEA promotes a T1 response [62] and rebalances the Th1/Th2 ratio that naturally decreases with age; this offsets the consequences of a Th2 shift: increased susceptibility to infections, reduced response to vaccines, and higher incidence of autoimmune disorders in the elderly [63–65].

6. Discussion

Significant immune differences between individuals with long-COVID and controls are distinguished by circulating immune cell populations [22]; this gives reason to believe that restoring immune homeostasis with an agent such as BEA would benefit the inflammatory state associated with this immune dysregulation and lead to improvement in long-COVID symptoms. Identifying and implementing tools for neuropsychologic assessment will be imperative to accurately assess a treatment effect for BEA or other proposed therapeutic interventions for neuro-long-COVID [66–68].
Brain changes seen in Alzheimer’s disease (AD) overlap with those observed in COVID-19 patients with the conditions sharing similar biologic pathways [69]. Cognitive changes associated with long-COVID are also associated with Alzheimer’s disease [70,71] with common processes of neuroinflammation and cerebral microvascular injury [72]. Interferon 1 (IFN-1) signaling has been offered as a plausible mechanism of cognitive impairment in both long-COVID and AD [73]. In 2022, a collaborative international task force formed by the WHO and the Alzheimer’s Association published a protocol to systematically investigate the neuropsychiatric aftereffects of COVID infection. Noting that the SARS-CoV-2 virus can directly infect the brain, they also provided a review of the evidence connecting those COVID manifestations to Alzheimer’s disease and related dementias (ADRD). Their specific hypothesis is that “SARS-CoV-2 induces ADRD-like pathology along the extended olfactory cortical network (EOCN) in older individuals with certain genetic susceptibilities;” the involvement of the olfactory cortical network in early AD is well established, and olfactory dysfunction is a strong clinical correlate of mild cognitive impairment (MCI) in AD and other dementias [74]. Theories supportive of a causative role for infectious agents in AD are not novel [75]. A molecular mechanism for SARS-CoV-2 cerebral involvement involves human angiotensin-converting enzyme 2 (ACE2) receptors, abundantly expressed in the brain and olfactory bulb [76,77], are sites of the SARS-CoV-2 invasion [71].
Anticipating a clinical trial of BEA for the neurologic complications of long-COVID with the understanding that this disease may be considered a surrogate for AD, a range of traditional and novel inflammatory markers could be employed as outcomes to assess BEA intervention as it relates to both diseases. Monitoring BEA’s influence on the neurologic effects long-COVID may provide insights into AD management with BEA’s impact on neuroinflammation in long- COVID serving as a proxy for AD treatment efficacy. The range of blood-based markers would include CRP, IFN, TNF, IL-1b, IL-2, IL-5, IL-6, IL-10, IL-17, NLRP3, GM-CSF, CXCL9, CCL-11, Klotho, MCP-1, BDNF, GFAP, LPC, NFL, HGS, 5-CSt, Lumican, Cortisol, LTL (leukocyte telomere length) and CD38.

7. Summary

The manifestations of post-acute sequelae of SARS-CoV-2 virus infection in a large database of the US Department of Veterans Affairs identified over 150,000 neurologic long-COVID cases from a cohort of over 5 million contemporary controls and over 5 million historical controls [78]. An abundant database such as this with a well characterized population may provide ample opportunity for assessing the value of BEA in neurologic long-COVID and, by extension, Alzheimer’s disease.

Conflicts of Interest

The author serves as the Chief Medical Officer for Protibea Therapeutics, Inc.

References

  1. Vibholm LK, Nielsen SSF, Pahus MH, Frattari GS, Olesen R, Andersen R, Monrad I, et al. SARS-CoV-2 persistence is associated with antigen-specific CD8 T-cell responses. EBioMedicine. 2021 Feb;64:103230. Epub 2021 Jan 30. [CrossRef] [PubMed] [PubMed Central]
  2. Ahamed J, Laurence J. Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches. J Clin Invest. 2022 Aug 1;132(15):e161167. [CrossRef] [PubMed] [PubMed Central]
  3. Glynne P, Tahmasebi N, Gant V, Gupta R. Long COVID following mild SARS-CoV-2 infection: characteristic T cell alterations and response to antihistamines. J Investig Med. 2022 Jan;70(1):61-67. Epub 2021 Oct 5. [CrossRef] [PubMed] [PubMed Central]
  4. Noonong K, Chatatikun M, Surinkaew S, Kotepui M, Hossain R, Bunluepuech K, Noothong C, et al. Mitochondrial oxidative stress, mitochondrial ROS storms in long COVID pathogenesis. Front Immunol. 2023 Dec 22;14:1275001. [CrossRef] [PubMed] [PubMed Central]
  5. Zubchenko S, Kril I, Nadizhko O, Matsyura O, Chopyak V. Herpesvirus infections and post-COVID-19 manifestations: a pilot observational study. Rheumatol Int. 2022 Sep;42(9):1523-1530. Epub 2022 Jun 1. [CrossRef] [PubMed] [PubMed Central]
  6. Talla A, Vasaikar SV, Szeto GL, Lemos MP, Czartoski JL, MacMillan H, Moodie Z, et al. Persistent serum protein signatures define an inflammatory subcategory of long COVID. Nat Commun. 2023 Jun 9;14(1):3417. [CrossRef] [PubMed] [PubMed Central]
  7. Su Y, Yuan D, Chen DG, Ng RH, Wang K, Choi J, Li S, Hong S, et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell. 2022 Mar 3;185(5):881-895.e20. Epub 2022 Jan 25. [CrossRef] [PubMed] [PubMed Central]
  8. Matschke J, Lütgehetmann M, Hagel C, Sperhake JP, Schröder AS, Edler C, Mushumba H, et al. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 2020 Nov;19(11):919-929. Epub 2020 Oct 5. [CrossRef] [PubMed] [PubMed Central]
  9. Spudich S, Nath A. Nervous system consequences of COVID-19. Science. 2022 Jan 21;375(6578):267-269. Epub 2022 Jan 20. [CrossRef] [PubMed]
  10. Matias-Guiu JA, Herrera E, González-Nosti M, Krishnan K, Delgado-Alonso C, Díez-Cirarda M, Yus M, et al. Development of criteria for cognitive dysfunction in post-COVID syndrome: the IC-CoDi-COVID approach. Psychiatry Res. 2023 Jan;319:115006. Epub 2022 Dec 10. [CrossRef] [PubMed]
  11. Premraj L, Kannapadi NV, Briggs J, Seal SM, Battaglini D, Fanning J, Suen J, Robba C, Fraser J, Cho SM. Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis. J Neurol Sci. 2022 Mar 15;434:120162. Epub 2022 Jan 29. [CrossRef] [PubMed] [PubMed Central]
  12. Ceban F, Ling S, Lui LMW, Lee Y, Gill H, Teopiz KM, Rodrigues NB, et al. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022 Mar;101:93-135. Epub 2021 Dec 29. [CrossRef] [PubMed] [PubMed Central]
  13. Zeng N, Zhao YM, Yan W, Li C, Lu QD, Liu L, Ni SY, et al. A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action. Mol Psychiatry. 2023 Jan;28(1):423-433. Epub 2022 Jun 6. [CrossRef] [PubMed] [PubMed Central]
  14. Cheetham NJ, Penfold R, Giunchiglia V, Bowyer V, Sudre CH, Canas LS, Deng J, et al. The effects of COVID-19 on cognitive performance in a community-based cohort: a COVID symptom study biobank prospective cohort study. EClinicalMedicine. 2023 Jul 21;62:102086. [CrossRef] [PubMed] [PubMed Central]
  15. Wang P, Jin L, Zhang M, Wu Y, Duan Z, Guo Y, Wang C, Guo Y, Chen W, Liao Z, Wang Y, Lai R, Lee LP, Qin J. Blood-brain barrier injury and neuroinflammation induced by SARS-CoV-2 in a lung-brain microphysiological system. Nat Biomed Eng. 2023 Jun 22. Epub ahead of print. Erratum in: Nat Biomed Eng. 2023 Oct 31. [CrossRef] [PubMed]
  16. Soung AL, Vanderheiden A, Nordvig AS, Sissoko CA, Canoll P, Mariani MB, Jiang X, Bricker T, Rosoklija GB, Arango V, Underwood M, Mann JJ, Dwork AJ, Goldman JE, Boon ACM, Boldrini M, Klein RS. COVID-19 induces CNS cytokine expression and loss of hippocampal neurogenesis. Brain. 2022 Dec 19;145(12):4193-4201. [CrossRef] [PubMed] [PubMed Central]
  17. Yang L, Kim TW, Han Y, Nair MS, Harschnitz O, Zhu J, Wang P, et al. SARS-CoV-2 infection causes dopaminergic neuron senescence. Cell Stem Cell. 2024 Feb 1;31(2):196-211.e6. Epub 2024 Jan 17. [CrossRef] [PubMed] [PubMed Central]
  18. Kavanagh E. Long Covid brain fog: a neuroinflammation phenomenon? Oxf Open Immunol. 2022 Sep 27;3(1):iqac007. [CrossRef] [PubMed] [PubMed Central]
  19. Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell. 2021 Feb 18;184(4):861-880. Epub 2021 Jan 12. [CrossRef] [PubMed] [PubMed Central]
  20. Su Y, Yuan D, Chen DG, Ng RH, Wang K, Choi J, Li S, Hong S, et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell. 2022 Mar 3;185(5):881-895.e20. Epub 2022 Jan 25. [CrossRef] [PubMed] [PubMed Central]
  21. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023 Mar;21(3):133-146. Epub 2023 Jan 13. Erratum in: Nat Rev Microbiol. 2023 Jun;21(6):408. [CrossRef] [PubMed] [PubMed Central]
  22. Klein J, Wood J, Jaycox JR, Dhodapkar RM, Lu P, Gehlhausen JR, Tabachnikova A, et al. Distinguishing features of long COVID identified through immune profiling. Nature. 2023 Nov;623(7985):139-148. Epub 2023 Sep 25. [CrossRef] [PubMed] [PubMed Central]
  23. Cheong JG, Ravishankar A, Sharma S, Parkhurst CN, Grassmann SA, Wingert CK, Laurent P, et al. Epigenetic memory of coronavirus infection in innate immune cells and their progenitors. Cell. 2023 Aug 31;186(18):3882-3902.e24. Epub 2023 Aug 18. [CrossRef] [PubMed] [PubMed Central]
  24. Fogarty H, Ward SE, Townsend L, Karampini E, Elliott S, Conlon N, Dunne J, et al.; Irish COVID-19 Vasculopathy Study (iCVS) Investigators. Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction. J Thromb Haemost. 2022 Oct;20(10):2429-2438. Epub 2022 Aug 4. [CrossRef] [PubMed] [PubMed Central]
  25. Townsend L, Dyer AH, Naughton A, Kiersey R, Holden D, Gardiner M, Dowds J, et al. Longitudinal Analysis of COVID-19 Patients Shows Age-Associated T Cell Changes Independent of Ongoing Ill-Health. Front Immunol. 2021 May 7;12:676932. [CrossRef] [PubMed] [PubMed Central]
  26. Glynne P, Tahmasebi N, Gant V, Gupta R. Long COVID following mild SARS-CoV-2 infection: characteristic T cell alterations and response to antihistamines. J Investig Med. 2022 Jan;70(1):61-67. Epub 2021 Oct 5. [CrossRef] [PubMed] [PubMed Central]
  27. Phetsouphanh C, Darley DR, Wilson DB, Howe A, Munier CML, Patel SK, Juno JA, Burrell LM, Kent SJ, Dore GJ, Kelleher AD, Matthews GV. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol. 2022 Feb;23(2):210-216. Epub 2022 Jan 13. [CrossRef] [PubMed]
  28. Sumi T, Harada K. Immune response to SARS-CoV-2 in severe disease and long COVID-19. iScience. 2022 Aug 19;25(8):104723. Epub 2022 Jul 4. [CrossRef] [PubMed] [PubMed Central]
  29. Gruber CN, Patel RS, Trachtman R, Lepow L, Amanat F, Krammer F, Wilson KM, et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell. 2020 Nov 12;183(4):982-995.e14. Epub 2020 Sep 14. Erratum in: Cell. 2023 Jul 20;186(15):3325. [CrossRef] [PubMed] [PubMed Central]
  30. Wang EY, Mao T, Klein J, Dai Y, Huck JD, Jaycox JR, Liu F, et al. Diverse functional autoantibodies in patients with COVID-19. Nature. 2021 Jul;595(7866):283-288. Epub 2021 May 19. [CrossRef] [PubMed]
  31. Wallukat G, Hohberger B, Wenzel K, Fürst J, Schulze-Rothe S, Wallukat A, Hönicke AS, Müller J. Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms. J Transl Autoimmun. 2021;4:100100. Epub 2021 Apr 16. [CrossRef] [PubMed] [PubMed Central]
  32. Novelli L, Motta F, De Santis M, Ansari AA, Gershwin ME, Selmi C. The JANUS of chronic inflammatory and autoimmune diseases onset during COVID-19 - A systematic review of the literature. J Autoimmun. 2021 Feb;117:102592. Epub 2020 Dec 14. [CrossRef] [PubMed] [PubMed Central]
  33. Queiroz MAF, Neves PFMD, Lima SS, Lopes JDC, Torres MKDS, Vallinoto IMVC, Bichara CDA, et al. Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome. Front Cell Infect Microbiol. 2022 Jun 30;12:922422. [CrossRef] [PubMed] [PubMed Central]
  34. Queiroz MAF, Brito WRDS, Pereira KAS, Pereira LMS, Amoras EDSG, Lima SS, Santos EFD, et al. Severe COVID-19 and long COVID are associated with high expression of STING, cGAS and IFN-α. Sci Rep. 2024 Feb 29;14(1):4974. [CrossRef] [PubMed] [PubMed Central]
  35. Yin JX, Agbana YL, Sun ZS, Fei SW, Zhao HQ, Zhou XN, Chen JH, Kassegne K. Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis. Infect Dis Poverty. 2023 Apr 24;12(1):43. [CrossRef] [PubMed] [PubMed Central]
  36. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023 Mar;21(3):133-146. Epub 2023 Jan 13. Erratum in: Nat Rev Microbiol. 2023 Jun;21(6):408. [CrossRef] [PubMed] [PubMed Central]
  37. Storbeck KH, Schiffer L, Baranowski ES, Chortis V, Prete A, Barnard L, Gilligan LC, et al. Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism. Endocr Rev. 2019 Dec 1;40(6):1605-1625. [CrossRef] [PubMed] [PubMed Central]
  38. Genazzani AD, Lanzoni C, Genazzani AR. Might DHEA be considered a beneficial replacement therapy in the elderly? Drugs Aging. 2007;24(3):173-85. [CrossRef] [PubMed]
  39. Suh E, Cho AR, Haam JH, Gil M, Lee YK, Kim YS. Relationship between Serum Cortisol, Dehydroepiandrosterone Sulfate (DHEAS) Levels, and Natural Killer Cell Activity: A Cross-Sectional Study. J Clin Med. 2023 Jun 13;12(12):4027. [CrossRef] [PubMed] [PubMed Central]
  40. Hauray B, Dalgalarrondo S. Incarnation and the dynamics of medical promises: DHEA as a fountain of youth hormone. Health (London). 2019 Nov;23(6):639-655. Epub 2018 Apr 13. [CrossRef] [PubMed]
  41. Seddon JA, Chiang SS, Esmail H, Coussens AK. The Wonder Years: What Can Primary School Children Teach Us About Immunity to Mycobacterium tuberculosis? Front Immunol. 2018 Dec 13;9:2946. [CrossRef] [PubMed] [PubMed Central]
  42. Vignesh V, Castro-Dominguez B, James TD, Gamble-Turner JM, Lightman S, Reis NM. Advancements in Cortisol Detection: From Conventional Methods to Next-Generation Technologies for Enhanced Hormone Monitoring. ACS Sens. 2024 Apr 26;9(4):1666-1681. Epub 2024 Mar 29. [CrossRef] [PubMed] [PubMed Central]
  43. Forti P, Maltoni B, Olivelli V, Pirazzoli GL, Ravaglia G, Zoli M. Serum dehydroepiandrosterone sulfate and adverse health outcomes in older men and women. Rejuvenation Res. 2012 Aug;15(4):349-58. Epub 2012 Apr 23. [CrossRef] [PubMed]
  44. Ohlsson C, Labrie F, Barrett-Connor E, Karlsson MK, Ljunggren O, Vandenput L, Mellström D, Tivesten A. Low serum levels of dehydroepiandrosterone sulfate predict all-cause and cardiovascular mortality in elderly Swedish men. J Clin Endocrinol Metab. 2010 Sep;95(9):4406-14. Epub 2010 Jul 7. [CrossRef] [PubMed]
  45. Zhang S, Otsuka R, Shimokata H, Nishita Y, Tange C, Takemura M, Satake S. Serum levels of dehydroepiandrosterone sulfate are associated with a lower risk of mobility-subtype frailty in older Japanese community-dwellers. Arch Gerontol Geriatr. 2023 Feb;105:104846. Epub 2022 Oct 23. [CrossRef] [PubMed]
  46. Leng SX, Cappola AR, Andersen RE, Blackman MR, Koenig K, Blair M, Walston JD. Serum levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone sulfate (DHEA-S), and their relationships with serum interleukin-6, in the geriatric syndrome of frailty. Aging Clin Exp Res. 2004 Apr;16(2):153-7. [CrossRef] [PubMed]
  47. Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Schölmerich J, Falk W, Lang B. Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab. 1998 Jun;83(6):2012-7. [CrossRef] [PubMed]
  48. Taves MD, Gomez-Sanchez CE, Soma KK. Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function. Am J Physiol Endocrinol Metab. 2011 Jul;301(1):E11-24. Epub 2011 May 3. [CrossRef] [PubMed] [PubMed Central]
  49. Bauer ME, Jeckel CM, Luz C. The role of stress factors during aging of the immune system. Ann N Y Acad Sci. 2009 Feb;1153:139-52. [CrossRef] [PubMed]
  50. Buoso E, Lanni C, Molteni E, Rousset F, Corsini E, Racchi M. Opposing effects of cortisol and dehydroepiandrosterone on the expression of the receptor for Activated C Kinase 1: implications in immunosenescence. Exp Gerontol. 2011 Nov;46(11):877-83. Epub 2011 Jul 27. [CrossRef] [PubMed]
  51. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014 Jun;69 Suppl 1:S4-9. [CrossRef] [PubMed]
  52. Henderson E, Schwartz A, Pashko L, Abou-Gharbia M, Swern D. Dehydroepiandrosterone and 16 alpha-bromo-epiandrosterone: inhibitors of Epstein-Barr virus-induced transformation of human lymphocytes. Carcinogenesis. 1981;2(7):683-6. [CrossRef] [PubMed]
  53. Frincke JM, Stickney DR, Onizuka-Handa N, Garsd A, Reading C, Krudsood S, Wilairatana P, Looareesuwan S. Reduction of parasite levels in patients with uncomplicated malaria by treatment with HE2000. Am J Trop Med Hyg. 2007 Feb;76(2):232-6. [PubMed]
  54. Freilich D, Ferris S, Wallace M, Leach L, Kallen A, Frincke J, Ahlem C, Hacker M, Nelson D, Hebert J. 16alpha-bromoepiandrosterone, a dehydroepiandrosterone (DHEA) analogue, inhibits Plasmodium falciparum and Plasmodium berghei growth. Am J Trop Med Hyg. 2000 Nov-Dec;63(5-6):280-3. [PubMed]
  55. Ayi K, Giribaldi G, Skorokhod A, Schwarzer E, Prendergast PT, Arese P. 16alpha-bromoepiandrosterone, an antimalarial analogue of the hormone dehydroepiandrosterone, enhances phagocytosis of ring stage parasitized erythrocytes: a novel mechanism for antimalarial activity. Antimicrob Agents Chemother. 2002 Oct;46(10):3180-4. [CrossRef] [PubMed] [PubMed Central]
  56. Frincke J. HE2000 begins clinical trials: interview with James Frincke, Ph.D. Interview by John S. James. AIDS Treat News. 1999 Jun 4;(No 320):4-7. [PubMed]
  57. Starving the virus. Res Initiat Treat Action. 1999 Apr;5(2):32-3. [PubMed]
  58. Reading C, Dowding C, Schramm B, Garsd A, Onizuka-Handa N, Stickney D, Frincke J. Improvement in immune parameters and human immunodeficiency virus-1 viral response in individuals treated with 16alpha-bromoepiandrosterone (HE2000). Clin Microbiol Infect. 2006 Nov;12(11):1082-8. [CrossRef] [PubMed]
  59. Nicoletti F, Conrad D, Wang A, Pieters R, Mangano K, van Heeckeren A, White SK, Frincke J, Reading CL, Auci DL, Stickney D. 16alpha-Bromoepiandrosterone (HE2000) limits non-productive inflammation and stimulates immunity in lungs. Clin Exp Immunol. 2009 Dec;158(3):308-16. Epub 2009 Sep 30. [CrossRef] [PubMed] [PubMed Central]
  60. Seddon JA, Chiang SS, Esmail H, Coussens AK. The Wonder Years: What Can Primary School Children Teach Us About Immunity to Mycobacterium tuberculosis? Front Immunol. 2018 Dec 13;9:2946. [CrossRef] [PubMed] [PubMed Central]
  61. López-Torres MO, Marquina-Castillo B, Ramos-Espinosa O, Mata-Espinosa D, Barrios-Payan JA, Baay-Guzman G, Yepez SH, et al. 16α-Bromoepiandrosterone as a new candidate for experimental diabetes-tuberculosis co-morbidity treatment. Clin Exp Immunol. 2021 Aug;205(2):232-245. Epub 2021 Jun 1. [CrossRef] [PubMed] [PubMed Central]
  62. Hernández-Pando R, Aguilar-Leon D, Orozco H, Serrano A, Ahlem C, Trauger R, Schramm B, Reading C, Frincke J, Rook GA. 16alpha-Bromoepiandrosterone restores T helper cell type 1 activity and accelerates chemotherapy-induced bacterial clearance in a model of progressive pulmonary tuberculosis. J Infect Dis. 2005 Jan 15;191(2):299-306. Epub 2004 Dec 9. [CrossRef] [PubMed]
  63. Targonski PV, Jacobson RM, Poland GA. Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine. 2007 Apr 20;25(16):3066-9. Epub 2007 Jan 16. [CrossRef] [PubMed]
  64. Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, Witkowski JM, Franceschi C. Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Front Immunol. 2018 Jan 10;8:1960. [CrossRef] [PubMed] [PubMed Central]
  65. Briceño O, Lissina A, Wanke K, Afonso G, von Braun A, Ragon K, Miquel T, et al. Reduced naïve CD8(+) T-cell priming efficacy in elderly adults. Aging Cell. 2016 Feb;15(1):14-21. Epub 2015 Oct 15. [CrossRef] [PubMed] [PubMed Central]
  66. Ellingjord-Dale M, Brunvoll SH, Søraas A. Prospective Memory Assessment before and after Covid-19. N Engl J Med. 2024 Feb 29;390(9):863-865. [CrossRef] [PubMed]
  67. Delgado-Alonso C, Delgado-Alvarez A, Díez-Cirarda M, Oliver-Mas S, Cuevas C, Montero-Escribano P, Ramos-Leví AM, et al. Cognitive profile in multiple sclerosis and post-COVID condition: a comparative study using a unified taxonomy. Sci Rep. 2024 Apr 29;14(1):9806. [CrossRef] [PubMed] [PubMed Central]
  68. Nami M, Thatcher R, Kashou N, Lopes D, Lobo M, Bolanos JF, Morris K, et al. A Proposed Brain-, Spine-, and Mental- Health Screening Methodology (NEUROSCREEN) for Healthcare Systems: Position of the Society for Brain Mapping and Therapeutics. J Alzheimers Dis. 2022;86(1):21-42. [CrossRef] [PubMed]
  69. Pszczołowska M, Walczak K, Misków W, Antosz K, Batko J, Karska J, Leszek J. Molecular cross-talk between long COVID-19 and Alzheimer's disease. Geroscience. 2024 Jun;46(3):2885-2899. Epub 2024 Feb 23. [CrossRef] [PubMed] [PubMed Central]
  70. Ciaccio M, Lo Sasso B, Scazzone C, Gambino CM, Ciaccio AM, Bivona G, Piccoli T, Giglio RV, Agnello L. COVID-19 and Alzheimer's Disease. Brain Sci. 2021 Feb 27;11(3):305. [CrossRef] [PubMed] [PubMed Central]
  71. Pulliam L, Sun B, McCafferty E, Soper SA, Witek MA, Hu M, Ford JM, et al. Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer's Disease. Int J Mol Sci. 2024 Mar 29;25(7):3830. [CrossRef] [PubMed] [PubMed Central]
  72. Zhou Y, Xu J, Hou Y, Leverenz JB, Kallianpur A, Mehra R, Liu Y, Yu H, Pieper AA, Jehi L, Cheng F. Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment. Alzheimers Res Ther. 2021 Jun 9;13(1):110. [CrossRef] [PubMed] [PubMed Central]
  73. Vavougios GD, Tseriotis VS, Liampas A, Mavridis T, de Erausquin GA, Hadjigeorgiou G. Type I interferon signaling, cognition and neurodegeneration following COVID-19: update on a mechanistic pathogenetic model with implications for Alzheimer's disease. Front Hum Neurosci. 2024 Mar 18;18:1352118. [CrossRef] [PubMed] [PubMed Central]
  74. de Erausquin GA, Snyder H, Brugha TS, Seshadri S, Carrillo M, Sagar R, Huang Y, et al. Chronic neuropsychiatric sequelae of SARS-CoV-2: Protocol and methods from the Alzheimer's Association Global Consortium. Alzheimers Dement (N Y). 2022 Sep 22;8(1):e12348. [CrossRef] [PubMed] [PubMed Central]
  75. Whitson HE, Banks WA, Diaz MM, Frost B, Kellis M, Lathe R, Schmader KE, Spudich SS, Tanzi R, Garden G. New approaches for understanding the potential role of microbes in Alzheimer's disease. Brain Behav Immun Health. 2024 Feb 21;36:100743. [CrossRef] [PubMed] [PubMed Central]
  76. Bostanciklioğlu M. Severe Acute Respiratory Syndrome Coronavirus 2 is Penetrating to Dementia Research. Curr Neurovasc Res. 2020;17(4):342-343. [CrossRef] [PubMed]
  77. Singal CMS, Jaiswal P, Seth P. SARS-CoV-2, More than a Respiratory Virus: Its Potential Role in Neuropathogenesis. ACS Chem Neurosci. 2020 Jul 1;11(13):1887-1899. Epub 2020 Jun 18. [CrossRef] [PubMed]
  78. Xu E, Xie Y, Al-Aly Z. Long-term neurologic outcomes of COVID-19. Nat Med. 2022 Nov;28(11):2406-2415. Epub 2022 Sep 22. [CrossRef] [PubMed] [PubMed Central]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.d
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Alerts
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

© 2024 MDPI (Basel, Switzerland) unless otherwise stated