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The Neurological Renaissance: Elucidating the Complex Relationship between Syphilis and Neurodegenerative Disorders in the Contemporary Era

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Article Type Research Article
Subject Medicine Group
OCLC JBRES Record
Catarina Rodrigues Gomes, Arun Kumar Jaiswal, Aline Ferreira Maciel de Oliveira and Vasco Azevedo
Issue: Volume7-Issue4
Pages: 1-6
Received: 2026-03-24
Accepted: 2026-04-13
Published: 2026-04-14

Abstract

The global resurgence of syphilis has coincided with increasing evidence of complex interactions between Treponema pallidum infection and neurological disorders, extending beyond classical neurosyphilis manifestations. This perspective article synthesizes recent clinical and translational evidence on syphilis-associated neurological complications, focusing on (i) putative mechanisms linking infection to neurodegenerative trajectories (molecular mimicry and persistent neuroinflammation), (ii) clinical phenotypes that mimic autoimmune disease, and (iii) diagnostic challenges arising from atypical presentations and evolving biomarker strategies. Recent studies indicate that spirochetal infections may contribute to neuroinflammatory cascades associated with dementia, movement disorders, and psychiatric manifestations through molecular mimicry and persistent neuroinflammation. The increase in syphilis incidence, from 39.6 to 62.5 per 100,000 in the United States between 2019 and 2023, necessitates urgent reconsideration of screening protocols, particularly for populations presenting with unexplained neurological symptoms. We advocate for a paradigm shift toward comprehensive neurological evaluation in syphilis cases, enhanced surveillance for atypical presentations, and integration of advanced diagnostic biomarkers, including Cerebrospinal Fluid (CSF) CXCL13 and other emerging neuroinflammatory markers, with explicit attention to implementation barriers that limit global adoption.

FullText HTML FullText PDF DOI: 10.37871/jbres2291 Crossmark

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Copyright

© 2026 Gomes CR, et al. Distributed under Creative Commons CC-BY 4.0 Creative CommonsAttribution

How to cite this article

Gomes CR, Jaiswal AK, Oliveira AFM, Azevedo V. The Neurological Renaissance: Elucidating the Complex Relationship between Syphilis and Neurodegenerative Disorders in the Contemporary Era. J Biomed Res Environ Sci. 2026 Apr 14; 7(4): 6. Doi: 10.37872/jbres2291

Subject area(s)

NeurologyNeurological Disorders

References

  1. Rankin E, Forrest A, Maharjan L, Wei G, Blavo C, Chawla J. Epidemiological analysis of syphilis trends, disparities, and public health implications in the United States, 2018-2022. BMC Infect Dis. 2025 Sep 12;25(1):1106. doi:10.1186/s12879-025-11332-4. PMID:40940657; PMCID:PMC12427103.
  2. GBD 2021 Nervous System Disorders Collaborators. Global, regional, and national burden of disorders affecting the nervous system, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024 Apr;23(4):344-381. doi:10.1016/S1474-4422(24)00038-3. Epub 2024 Mar 14. Erratum in: Lancet Neurol. 2024 May;23(5):e9. doi:10.1016/S1474-4422(24)00114-5. Erratum in: Lancet Neurol. 2024 Jul;23(7):e11. doi:10.1016/S1474-4422(24)00231-X. PMID:38493795; PMCID:PMC10949203.
  3. Horton M, Whiley DJ, Mayhew M, McLean S. Association between spirochaetal infection and neurodegenerative diseases: a systematic review and quantitative synthesis of observational studies. J Med Microbiol. 2026 Mar;75(3):002136. doi:10.1099/jmm.0.002136. PMID:41790564; PMCID:PMC12967094.
  4. Marra CM. Neurosyphilis. Brain. 2025 Dec 4;148(12):4222-4240. doi:10.1093/brain/awaf329. PMID:40911405.
  5. Minter DJ, Chow FC. Neurosyphilis. Ann Neurol. 2025 Nov;98(5):1070-1076. doi:10.1002/ana.78016. Epub 2025 Sep 2. PMID:40891640.
  6. Garg RK, Pandey S, Agrawal MK, Mahdi RA, Singhal S. The spectrum of movement disorders in neurosyphilis: a systematic review. Neurol Sci. 2026 Jan 6;47(1):110. doi:10.1007/s10072-025-08687-6. PMID:41493643.
  7. Sanpei Y, Hanazono A, Funasaka M, Yasuda K, Takahashi Y, Sugawara M. Markedly elevated IgG index: a key to differentiating neurosyphilis from autoimmune limbic encephalitis. Intern Med. 2025 Jun 15;64(12):1906-1910. doi:10.2169/internalmedicine.4625-24. Epub 2024 Nov 28. PMID:39603625; PMCID:PMC12241774.
  8. Kanakaraj L, Mamtani H, Dahale AB, M N, S N, Sinha S, Thippeswamy H. Psychiatric manifestations of neurosyphilis over past two decades: findings from a tertiary care neuropsychiatric hospital in south India. Asian J Psychiatr. 2024 Apr;94:103952. doi:10.1016/j.ajp.2024.103952. Epub 2024 Feb 3. PMID:38364749.
  9. Gao YS, Li Q, Zhou H, Zhang ZQ, Feng H, Liu GF, Shen Y. Enhancing clinical awareness: retrospective analysis of neurosyphilis cases and diagnostic predictors for early recognition and treatment. Neurol Sci. 2024 Jun;45(6):2825-2833. doi:10.1007/s10072-023-07285-8. Epub 2024 Jan 4. PMID:38177969.
  10. Chevalier FJ, Bacon O, Johnson KA, Cohen SE. Syphilis: a review. JAMA. 2025 Dec 2;334(21):1927-1940. doi:10.1001/jama.2025.17362. Erratum in: JAMA. 2025 Dec 2;334(21):1955. doi:10.1001/jama.2025.21028. PMID:41100079.
  11. Tang H, Hu J, Wu Y, Gao J, Wang W, Zheng X, Zhang R, Liang B, Zhou F, Guo Z. Cerebrospinal fluid proteome reveals dysregulation of lysosomal and axonal proteins in neurosyphilis. J Proteome Res. 2026 Feb 6;25(2):713-722. doi:10.1021/acs.jproteome.5c00689. Epub 2026 Jan 23. PMID:41576922; PMCID:PMC12887999.
  12. Kotani R, Hatano K, Ishibashi K, Iwata A. 18F-THK5351 PET is superior to conventional MRI in identifying inflammatory lesions by imaging astrogliosis in 2 cases of neurosyphilis. Clin Nucl Med. 2024 Dec;49(12):e677-e679. doi:10.1097/RLU.0000000000005494. Epub 2024 Oct 10. PMID:39390647.
  13. Du FZ, Zhang X, Zheng XL, Zhang RL, Wang QQ. Cerebrospinal fluid CXCL13 concentration for diagnosis of neurosyphilis: a systematic review and meta-analysis. BMJ Open. 2024 May 31;14(5):e078527. doi:10.1136/bmjopen-2023-078527. PMID:38821573; PMCID:PMC11149136.
  14. Wang C, Zhang Y, Wang X, Zhou J, Wang X, Song G, Sun Y, Gu K, Xu A, Huang J. Neutrophil-associated proteins as novel biomarkers elevated in cerebrospinal fluid of patients with neurosyphilis. J Infect Dis. 2024 Sep 23;230(3):558-568. doi:10.1093/infdis/jiae078. PMID:38427829.
  15. Mostaghimi D, Mehta S, Yoon J, Kosana P, Marra CM, Corley MJ, Farhadian SF. Epigenetic changes in cerebrospinal fluid and blood of people with neurosyphilis. J Infect Dis. 2025 Apr 15;231(4):883-893. doi:10.1093/infdis/jiae476. PMID:39356164; PMCID:PMC11998562.
  16. Zhao W, Luo H. Investigation of the role of interleukin-27 in the immune regulation of Treg and Th17 cells in neurosyphilis patients. Folia Neuropathol. 2023;61(4):387-395. doi:10.5114/fn.2023.132099. PMID:38174681.
  17. Weng W, Song B, Zhang M, Zhu W. Untargeted metabolomics in a prospective cross-sectional observational study reveals differences in plasma and cerebrospinal fluid between asymptomatic neurosyphilis and serofast syphilis. Medicine (Baltimore). 2025 Oct 17;104(42):e45361. doi:10.1097/MD.0000000000045361. PMID:41189184; PMCID:PMC12537089.
  18. Du F, Lu Z, Wu Q, Zhang X, Zheng X, Zhang R, Wang Q. Treponema pallidum flagellin FlaB3 activates inflammation and inhibits autophagy in HMC3 cells via the TLR4 pathway. ACS Infect Dis. 2025 Mar 14;11(3):773-783. doi:10.1021/acsinfecdis.4c01064. Epub 2025 Mar 4. PMID:40036177.
  19. Yang Y, Gu X, Zhu L, Cheng Y, Lu H, Guan Z, Shi M, Ni L, Peng R, Zhao W, Wu J, Qi T, Long F, Chai Z, Gong W, Ye M, Zhou P. Clinical parameter-based prediction model for neurosyphilis risk stratification. Epidemiol Infect. 2024 Jan 15;152:e21. doi:10.1017/S0950268824000074. PMID:38224151; PMCID:PMC10894895.
  20. Guan H, Peng J, Xia Z, Di X, Wang Q, Zou C, Cai R, Chen C, Wei H. The diagnostic and prognostic value of CXCL13, CXCL10, and CXCL8 in patients with neurosyphilis. Front Immunol. 2025 Oct 27;16:1654251. doi:10.3389/fimmu.2025.1654251. PMID:41221293; PMCID:PMC12597757.
  21. Sethi V, Marks M. Neurosyphilis in 2025. Curr Opin Neurol. 2025 Aug;38(4):397-405. doi:10.1097/WCO.0000000000001404. Epub 2025 Jul 3. PMID:40605685.
  22. Peng RR, Wu J, Zhao W, Zhu L, Guan Z, Gu X, Shi M, Yu J, Cheng Y, Zhou P. An observational prospective study based on a large cohort of HIV-negative neurosyphilis patients with particular reference to the Jarisch-Herxheimer reaction. Eur J Clin Microbiol Infect Dis. 2024 Jun;43(6):1073-1080. doi:10.1007/s10096-024-04810-1. Epub 2024 Apr 1. PMID:38557924; PMCID:PMC11178573.
  23. Zhang RL, Zhang X, Du FZ, Zhou QY, Wu MZ, Ren JJ, Zhou Z, Li AL, Li DD, Li HX, Yang LG, Feng WL, Yang TC, Li YY, Zhang J, Wang SP, Luo Y, Gu MS, Yu XY, Hu LH, Zhao JB, Ma YN, Ma XW, Zeng TX, Gao Y, Wang QQ. The performance of a novel diagnostic criteria for neurosyphilis in HIV-negative patients. Sci Rep. 2024 Dec 28;14(1):31171. doi:10.1038/s41598-024-82477-6. PMID:39732770; PMCID:PMC11682042.
  24. Wudel B, Purewal R, Hatchette TF, Stein D, Morshed M, Minion J, Vallée M, Hayden K, Hamula C. Canadian Public Health Laboratory Network (CPHLN) diagnostic recommendations for neurosyphilis in Canada. J Assoc Med Microbiol Infect Dis Can. 2024 Dec 19;9(4):219-228. doi:10.3138/jammi-2024-0022. PMID:40672717; PMCID:PMC12258648.
  25. Wei W, Li W. Global research trends in neurosyphilis: a bibliometric analysis from 2010 to 2024. Front Immunol. 2025 Oct 2;16:1649106. doi:10.3389/fimmu.2025.1649106. PMID:41112265; PMCID:PMC12528085.
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