Neuroinflammatory Part of the Systemic Inflammatory Process in the Development of Neurodegenerative Conditions

Background: neurodegenerative processes are prognostically dramatic conditions. They are actively studied by both neurologists and psychiatrists. Nosological forms are diverse and include regressive autism, dementia, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, progressive epilepsy of infancy and childhood, generalized hyperkinesis, Tourette’s syndrome and many other conditions that are common to progressive neurological deficit, loss of cognitive functions, the appearance of nonspecific symptoms of brain irritation (epileptic seizures, hyperkinesis, dystonic states, stereotypes, psychotic episodes and other symptoms). Despite many ongoing studies the treatment of the described conditions is limited to temporary, incomplete and pharmacologically dependent relief of symptoms, since the problem of the etiopathogenesis of these conditions remains open. 
The aim of review is to present current immunological concepts of pathogenesis of neurodegenerative diseases. 
Material and method: using keywords “neuroinflammation, neurodegeneration, multiple sclerosis, Parkinson disease, epilepsy, parasitosis, microbiota” selected relevant scientific publications in domestic and international databases. 
Conclusion: recent advances in neuroimmunology show a significant role of neuroinflammation in the triggering and development of neurodegenerative processes, some of which are autoimmune in nature, which is confirmed by the indicators of immunity intensity introduced into clinical practice and by the detected antibody titers to brain tissues. In recent decades in a series of scientific works attention has been paid to the study of infectious agents detected in the immunological screening of patients with neurodegeneration, however, these data are fragmented and contradictory, and therefore are ignored by the medical community. This review presents a modern view of the etiopathogenesis of neurodegenerative diseases from the point of view of the summative antigenic burden, assessment of the immunological potential, homeostatic resource, and compensatory capabilities of the human body, which as a result can become a starting point for proposing new therapeutic strategies for the treatment of these intractable diseases. 

1. Cova I, Markova A, Campini I, Grande G, Mariani C, Pomati S. Worldwide trends in the prevalence of dementia. J NeurolSci. 2017;379:259–260. doi: 10.1016/j.jns.2017.06.030

2. Adler CH, Beach TG, Hentz JG, Shill HA, Caviness JN, Driver-Dunckley E, Sabbagh MN, Sue LI, Jacobson SA, Belden CM, Dugger BN. Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology. 2014;83(5):406–412. doi: 10.1212/WNL.0000000000000641

3. Alafuzoff I, Ince PG, Arzberger T, Al-Sarraj S, Bell J, Bodi I, Bogdanovic N, Bugiani O, Ferrer I, Gelpi E, Gentleman S, Giaccone G, Ironside JW, Kavantzas N, King A, Korkolopoulou P, Kovács GG, Meyronet D, Monoranu C, Parchi P, Parkkinen L, Patsouris E, Roggendorf W, Rozemuller A, Stadelmann-Nessler C, Streichenberger N, Thal DR, Kretzschmar H. Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium. Acta Neuropathol. 2009;117(6):635–652. doi: 10.1007/s00401-009-0523-2

4. Alafuzoff I, Thal DR, Arzberger T, Bogdanovic N, Al-Sarraj S, Bodi I, Boluda S, Bugiani O, Duyckaerts C, Gelpi E, Gentleman S, Giaccone G, Graeber M, Hortobagyi T, Höftberger R, Ince P, Ironside JW, Kavantzas N, King A, Korkolopoulou P, Kovács GG, Meyronet D, Monoranu C, Nilsson T, Parchi P, Patsouris E, Pikkarainen M, Revesz T, Rozemuller A, Seilhean D, Schulz-Schaeffer W, Streichenberger N, Wharton SB, Kretzschmar H. Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathol. 2009;117(3):309–320. doi: 10.1007/s00401-009-0485

5. Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease--a double-edged sword. Neuron. 2002;35(3):419–432. doi: 10.1016/s0896-6273(02)00794-8

6. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918–934. doi: 10.1016/j. cell.2010.02.016

7. Stephenson J, Nutma E, van der Valk P, Amor S. Inflammation in CNS neurodegenerative diseases. Immunology. 2018;154(2):204–219. doi: 10.1111/imm.12922

8. Subhramanyam CS, Wang C, Hu Q, Dheen ST. Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin Cell Dev Biol. 2019;94:112–120. doi: 10.1016/j.semcdb.2019.05.004

9. Fields RD, Araque A, Johansen-Berg H, Lim SS, Lynch G, Nave KA, Nedergaard M, Perez R, Sejnowski T, Wake H. Glial biology in learning and cognition. Neuroscientist. 2014;20(5):426–431. doi: 10.1177/1073858413504465

10. Clarke LE, Barres BA. Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci. 2013;14(5):311–321. doi: 10.1038/nrn3484

11. Luo XG, Chen SD. The changing phenotype of microglia from homeostasis to disease. Transl Neurodegener. 2012;1(1):9. doi: 10.1186/2047-9158-1-9

12. Bachiller S, Jiménez-Ferrer I, Paulus A, Yang Y, Swanberg M, Deierborg T, Boza-Serrano A. Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response. Front Cell Neurosci. 2018;12:488. doi: 10.3389/fncel.2018.00488

13. Liddelow SA, Barres BA. Reactive Astrocytes: Production, Function, and Therapeutic Potential. Immunity. 2017;46(6):957–967. doi: 10.1016/j.immuni. 2017.06.006

14. De Biase LM, Schuebel KE, Fusfeld ZH, Jair K, Hawes IA, Cimbro R, Zhang HY, Liu QR, Shen H, Xi ZX, Goldman D, Bonci A. Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia. Neuron. 2017;95(2):341–356.e6. doi: 10.1016/j. neuron.2017.06.020

15. Уранова НА, Вихрева ОВ, Рахманова ВИ, Орловская ДД. Ультраструктурная патология олигодендроцитов в белом веществе при непрерывнотекущей параноидной шизофрении: роль микроглии. Журнал неврологии и психиатрии имени С.С. Корсакова. 2017;117(9):76–81. doi: 10.17116/jnevro20171179176-81 Uranova NA, Vikhreva OV, Rakhmanova VI, Orlovskaia DD. Ultrastructural pathology of oligodendrocytes in the white matter in continuous paranoid schizophrenia: a role for microglia. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2017;117(9):76–81. (In Russ.). doi: 10.17116/jnevro20171179176-81

16. Takahashi N, Sakurai T, Davis KL, Buxbaum JD. Linking oligodendrocyte and myelin dysfunction to neurocircuitry abnormalities in schizophrenia. Prog Neurobiol. 2011;93(1):13–24. doi: 10.1016/j.pneurobio. 2010.09.004

17. Nave KA. Myelination and support of axonal integrity by glia. Nature. 2010;468:244–252. doi: 10.1038/nature09614

18. Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1988;51(6):745–752. doi: 10.1136/jnnp.51.6.745.

19. Dugger BN, Hentz JG, Adler CH, Sabbagh MN, Shill HA, Jacobson S, Caviness JN, Belden C, Driver-Dunckley E, Davis KJ, Sue LI, Beach TG. Clinicopathological outcomes of prospectively followed normal elderly brain bank volunteers. J Neuropathol Exp Neurol. 2014;73(3):244–252. doi: 10.1097/NEN.0000000000000046

20. Adler CH, Connor DJ, Hentz JG, Sabbagh MN, Caviness JN, Shill HA, Noble B, Beach TG. Incidental Lewy body disease: clinical comparison to a control cohort. Mov Disord. 2010;25(5):642–646. doi: 10.1002/mds.22971

21. Frigerio R, Fujishiro H, Ahn TB, Josephs KA, Maraganore DM, DelleDonne A, Parisi JE, Klos KJ, Boeve BF, Dickson DW, Ahlskog JE. Incidental Lewy body disease: do some cases represent a preclinical stage of dementia with Lewy bodies? Neurobiol Aging. 2011;32(5):857–863. doi: 10.1016/j.neurobiolaging. 2009.05.019

22. Ghaziuddin M, Al-Khouri I, Ghaziuddin N. Autistic symptoms following herpes encephalitis. Eur Child Adolesc Psychiatry. 2002;11(3):142–146. doi: 10.1007/s00787-002-0271-5

23. Cornford ME, McCormick GF. Adult-onset temporal lobe epilepsy associated with smoldering herpes simplex 2 infection. Neurology. 1997;48(2):425–430. doi: 10.1212/wnl.48.2.425

24. Simmons A. Herpesvirus and multiple sclerosis. Herpes. 2001;8(3):60–63. PMID: 11867021.

25. Camacho-Soto A, Faust I, Racette BA, Clifford DB, Checkoway H, Searles Nielsen S. Herpesvirus Infections and Risk of Parkinson’s Disease. Neurodegener Dis. 2020;20(2–3):97–103. doi: 10.1159/000512874

26. Steiner I, Kennedy PG, Pachner AR. The neurotropic herpes viruses: herpes simplex and varicella-zoster. Lancet Neurol. 2007;6(11):1015–1028. doi: 10.1016/S1474-4422(07)70267-3

27. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H. Diabetes, smoking, and other medical conditions in relation to Parkinson’s disease risk. Parkinsonism Relat Disord. 2006;12(3):185–189. doi: 10.1016/j.parkreldis. 2005.09.004

28. Wang H, Liu X, Tan C, Zhou W, Jiang J, Peng W, Zhou X, Mo L, Chen L. Bacterial, viral, and fungal infection-related risk of Parkinson’s disease: Meta-analysis of cohort and case-control studies. Brain Behav. 2020;10(3):e01549. doi: 10.1002/brb3.1549

29. Koyuncu OO, Hogue IB, Enquist LW. Virus infections in the nervous system. Cell Host Microbe. 2013;13(4):379– 393. doi: 10.1016/j.chom.2013.03.010

30. Kennedy PG, Rovnak J, Badani H, Cohrs RJ. A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation. J Gen Virol. 2015;96(Pt 7):1581–1602. doi: 10.1099/vir.0.000128

31. Schmutzhard E, Pohl P, Stanek G. Borrelia burgdorferi antibodies in patients with relapsing/remitting form and chronic progressive form of multiple sclerosis. J Neurol Neurosurg Psychiatry. 1988;51(9):1215–1218. doi: 10.1136/jnnp.51.9.1215

32. Vendrik KEW, Ooijevaar RE, de Jong PRC, Laman JD, van Oosten BW, van Hilten JJ, Ducarmon QR, Keller JJ, Kuijper EJ, Contarino MF. Fecal Microbiota Transplantation in Neurological Disorders. Front Cell Infect Microbiol. 2020;10:98. doi: 10.3389/fcimb.2020.00098

33. Hasegawa S, Goto S, Tsuji H, Okuno T, Asahara T, Nomoto K, Shibata A, Fujisawa Y, Minato T, Okamoto A, Ohno K, Hirayama M. Intestinal Dysbiosis and Lowered Serum Lipopolysaccharide-Binding Protein in Parkinson’s Disease. PLoS One. 2015;10(11):e0142164. doi: 10.1371/journal.pone.0142164

34. Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, Youn E, Summanen PH, Granpeesheh D, Dixon D, Liu M, Molitoris DR, Green JA 3rd. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16(4):444–453. doi: 10.1016/j.anaerobe.2010.06.008

35. Cosorich I, Dalla-Costa G, Sorini C, Ferrarese R, Messina MJ, Dolpady J, Radice E, Mariani A, Testoni PA, Canducci F, Comi G, Martinelli V, Falcone M. High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv. 2017;3(7):e1700492. doi: 10.1126/sciadv.1700492

36. Singh A, Dawson TM, Kulkarni S. Neurodegenerative disorders and gut-brain interactions. J Clin Invest. 2021;131(13):e143775. doi: 10.1172/JCI143775

37. Burgdorf KS, Trabjerg BB, Pedersen MG, Nissen J, Banasik K, Pedersen OB, Sørensen E, Nielsen KR, Larsen MH, Erikstrup C, Bruun-Rasmussen P, Westergaard D, Thørner LW, Hjalgrim H, Paarup HM, Brunak S, Pedersen CB, Torrey EF, Werge T, Mortensen PB, Yolken RH, Ullum H. Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders. Brain Behav Immun. 2019;79:152–158. doi: 10.1016/j. bbi.2019.01.026

38. Fan CK, Holland CV, Loxton K, Barghouth U. Cerebral Toxocariasis: Silent Progression to Neurodegenerative Disorders? Clin Microbiol Rev. 2015;28(3):663– 686. doi: 10.1128/CMR.00106-14

39. Alloo J, Leleu I, Grangette C, Pied S. Parasite infections, neuroinflammation, and potential contributions of gut microbiota. Front Immunol. 2022;13:1024998. doi: 10.3389/fimmu.2022.1024998

40. Lombard F, Basset D, Cambonie G, Bastien P, Jeziorski E. Pediatric angiostrongyliasis. Med Sante Trop. 2018;28(1):76–81. doi: 10.1684/mst.2018.0756

41. Wu Y, Duffey M, Alex SE, Suarez-Reyes C, Clark EH, Weatherhead JE. The role of helminths in the development of non-communicable diseases. Front Immunol. 2022;13:941977. doi: 10.3389/fimmu.2022.941977

42. Jackson H. Infestations, with particular reference to hydatid cysts of the brain. Proc R Soc Med. 1964;57(1):15–22. PMID: 14114170; PMCID: PMC1897287.

43. Лабораторная диагностика в мониторинге пациентов с эндогенными психозами («Нейро-иммуно-тест»): Медицинская технология. 2-е изд., испр. и доп. М.: ООО «Издательство «Медицинское информационное агентство», 2016:32 с. ISBN 978-5-9986-0279-5 Laboratornaja diagnostika v monitoringe pacientov s jendogennymi psihozami (“Nejro-immuno-test”): Medicinskaja tehnologija. 2-e izd., ispr. i dop. M.: Medical Informational Agency, 2016:32 s. (In Russ.). ISBN 978-5-9986-0279-5