Immune Markers in the Blood of Patients with Frontotemporal Dementia

The aim: to identify a number of markers of inflammation in the blood of patients with frontotemporal dementia (FTD).

Material and methods: 34 patients with FTD were examined. The diagnosis of FTD was established according to the diag-nostic criteria of the International consortium 2011. The control group consisted of 35 people, comparable in age and sex with patients with FTD. Blood plasma was used for immunological studies. The enzymatic activity of leukocyte elastase (LE) and the functional activity of D1-proteinase inhibitor (D1-PI) were determined by spectrophotometric method, the concentration of interleukin-6 (IL-6), C-reactive protein (CRP) and the level of autoantibodies to S100b and myelin basic protein (MBP) were determined by enzyme immunoassay.

Results: patients with FTD showed a significant increase in the activity of D1-PI compared with the control (p < 0,001). Other indicators did not differ from the control ones. However, a significant variation of all studied parameters was revealed,both the excess of values and their decrease relative to the control. For example, the scatter of LE activity was from 127 to 276,5 nmol/min u ml. According to the level of LE activity, two immunophenotypes were identified: 47% of patients with FTD are characterized by a proinflammatory immunophenotype with an increase in inflammatory marker values, and 53% of patients with FTD are characterized by a proinflammatory immunophenotype with insufficient neutrophil activity, similar to Alzheimer's disease.

Conclusion: the findings indicate the involvement of inflammatory reactions in the development of FTD and the heterogeneity of this dementia in terms of immunological parameters.

1. Emelin AYu, Lobzin VYu, Vorobyov SV. Cognitive impairment: a guide for doctors. Moscow. 2019;416. (In Russ.).

2. Teichmann M, Daigmorte C, Funkiewiez A et al. Moral emotions in frontotemporal dementia. J. Alzheimers Dis. 2019;69(3):887–896. DOI:10.3233/JAD-180991.

3. Blass DM. V kn.: Psixiatricheskie aspekty` nevrologicheskix zabolevanij: Podxody` k vedeniyu bol`ny`x. pod red. KG Liketsosa, PV Rabinsa, DzhR Lipsi, FR Sle`vni: per. s angl. pod red. NN Yaxno. 2-e izd. M.: MEDpress-in-form, 2019;328].

4. Bang J, Spina S, Miller BL. Frontotemporal demen-tia. Lancet. 2015;386:1672–82. DOI: http://dx.DOI.org/10.1016/S0140-6736(15)00461-4.

5. Rosness TA, Engedal K, Chemali Z. Frontotempo-ral dementia: An Updated Clinician’s Guide. J. Geriatr. Psychiatry Neurol. 2016;29(5):271–280. DOI:10.1177/089198871665498.

6. Hodges JR, Piguet O. Progress and challenges in fron-totemporal dementia research: a 20-year review. J. Alzheimers Dis. 2018;62(3):1467–1480. DOI:10.3233/JAD-171087.

7. Gil MJ, Manzano MS, Cuadrado ML et al. Frontotem-poral lobar degeneration: Study of a clinicopatho-logical cohort. J. Clin. Neurosci. 2018;58:172–180. DOI:10.1016/j.jocn.2018.10.024.

8. Androsova LV, Mikhaylova NM, Zozulya SA i dr. Immunobiokhimich-eskie markery vospaleniya pri dementsiyakh, assot-siirovannykh s vozrastom. Rossiiskii psikhiatricheskii zhurnal. 2017;4:61–66. (In Russ.).

9. Klyushnik TP, Androsova LV, Mikhaylova NM i dr. Systemic inflammatory markers in age-associated cognitive impairment and Alzheimer’s disease. Zhurnal nevrologii i psihiatrii im. S.S. Korsako-va. 2017;117(7):74–79. ht tps: //DOI.org/10.17116/jnevro20171177174-79. (In Russ.).

10. Androsova L, Mikhaylova N, Zozulya S, Dupin A, Kly-ushnik T. A comparative study of innate immunity markers in Alzheimer's disease, Mixed dementia and Vascular dementia. International Journal of Clini-cal Neurosciences and Mental Health. 2016;3(Sup-pl.1):S03. DOI: http://dx.doi.org/10.21035/ijcn-mh.2016.3(Suppl.1).S03.

11. McCauley ME, Baloh RH. Inflammation in ALS/FTD pathogenesis. Acta Neuropathol. 2019:137(5);715–730. DOI:10.1007/s00401-018-1933-9.

12. Öijerstedt L, Chiang HH, Björkström J, Forsell C, Lili-us L, Lindström AK, Thonberg H, Graff C. Confirmation of high frequency of C9orf72 mutations in patients with frontotemporal dementia from Sweden Neurobi ol Aging. 2019;Mar 27. pii: S0197-4580(19)30087-9. DOI:10.1016/j.neurobiolaging.2019.03.

13. Galimber ti D, Scarpini E. Genetics and biology of Alz-heimer's disease and frontotemporal lobar degenera-tion. Int. J. Clin. Exp. Med. 2010;3(2):129–143.

14. Foiani MS, Woollacott IO, Heller C et al. Plasma tau is increased in frontotemporal dementia. J. Neurol. Neu-rosurg. Psychiatry. 2018;89(8):804–807. DOI:10.1136/jnnp-2017-317260.

15. Logroscino G, Imbimbo BP, Lozupone M et al. Prom-ising therapies for the treatment of frontotemporal dementia clinical phenotypes: from symptomatic to disease-modifying drugs. Expert Opin. Pharmacother. 2019;(4)19:1–17. DOI:10.1080/14656566.2019.1598377.

16. Foiani MS, Cicognola C, Ermann N et al. Searching for novel cerebrospinal fluid biomarkers of tau patholo-gy in frontotemporal dementia: an elusive quest. J. Neurol. Neurosurg. Psychiatry. 2019;90(7):740–746. DOI:10.1136/jnnp-2018-319266.

17. Broce I, Karch CM, Wen N et al. Immune-related ge-netic enrichment in frontotemporal dementia: An analysis of genome-wide association studies PLoS Med. 2018;15(1):1002487. DOI:10.1371/journal.pmed.1002487.

18. Baugh RJ, Travis J. Human leukocyte granule elas-tase: rapid isolation and characterization. Biochem-istry. 1976;15(4):836–841.

19. Thake CD, Mian T, Garnham AW, Mian R. Leukocyte counts and neutrophil activity during 4 h of hypo-capnic hypoxia equivalent to 4000 m. Aviat Space Environ Med. 2004;75(9):811–817.

20. Majanskij A.N. Lekcii po immunologii. Izd-vo Nizhe-gorodskoj gos. med. akademii. 2003;272. (In Russ.).

21. Ionescu CV, Cepinskas G, Savickiene J, Sandig M, Kvi-etys PR. Neutrophils induce sequential focal changes in endothelial adherens junction components: role of elastase. Microcirculation. 2003;10(2):205–220.

22. Topham MK, Carveth HJ, McIntyre TM et al. Human endothelial cells regulate polymorphonuclear leu-kocyte degranulation. FASEB J. 1998;12(9):733–746.

23. Jarovaja GA,Docenko VL, Neshkova EA. Patogeneticheskaja rol' lejkocitarnoj jelastazy. Novyj spektrofotometricheskij metod ee opredelenija v plazme krovi cheloveka. Informa-cionnyj bjulleten'. Moskva. 1995;1:16–18. (In Russ.).

24. Jarovaja GA. Bioreg-ulirujushhie funkcii i patogeneticheskaja rol' pro-teoliza. Laboratornaja medicina. 2000;(3):19–22. (In Russ.).

25. Stockley RA. Alpha-1-antitrypsin review. Clin. Chest. Med. 2014;35(1):39–50. DOI:10.1016/j.ccm.2013.10.001.

26. Kuta AE, Baum LL. C-reactive protein is produced by a small number of normal human peripheral blood lymphocytes. J. Ex. Med. 1986;164(1):321–326.

27. Kushner I, Jiang SL, Zhang D et al. Do post-transcrip-tional mechanisms participate in induction of C-re-active protein and serum amyloid A by IL-6 and IL-1? Ann. N. Y. Acad. Sci. 1995;762(1):102–107.

28. Coil J, Tam E, Waterfield JD. Proinflammatory cy-tokine profiles in pulp fibroblasts stimulated with lipopolysaccharide and methyl mercaptan. J. Endod. 2004;30:(2):88–91.

29. Soderquist B, Kallman J, Holmberg H et al. Secretion of IL-6, IL-8 and G-CSF by human endothelial cells in vi-tro in response to Staphylococcus aureus and staphy-lococcal exotoxins. APMIS. 1998;106(12):1157–1164.

30. Azzolina A, Bongiovanni A, Lampiasi N. Substance P induces TNF-alpha and IL-6 production through NF kappa B in peritoneal mast cells. Biochim. Biophys. Acta. 2003;1643(1–3):75–83.

31. Hoenstein R., Admon D., Solomon A. et al. Interleu-kin-2 activates human peripheral blood eosinophils. Cell. Immunol. 2001;210(2):116–124.

32. Inoue K. Microglial activation by purines and pyrim-idines. Glia. 2002;40(2):156–163.

33. Rascovsky K, Hodges JR, Knopman D et al. Sensitivity of diagnostic criteria in autopsy-confirmed patients with behavioural variant frontotemporal dementia. (by FTD). First Report of the International by FTD Criteria Consortium (FTDC), Neurology. 2011;76:262–263.

34. Teichmann M, Daigmorte C, Funkiewiez A et al. Moral Emotions in Frontotemporal Dementia. J. Alzheimers Dis. 2019;69(3):887–896. DOI:10.3233/JAD-180991.

35. Gorno-Tempini ML, Hillis AE. Weintraub S. et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006–1014. DOI:10.1212/WNL.0b013e31821103e6.

36. Dotsen-ko VL, Neshkova EA, Yarovaya GA. Detection of leuko-cyte elastase from complex with plasma D1-protease inhibitor by it enzymatic activity with a synthetic substrate. Vopr. med. khim.1994;40(3):20–25. (In Russ.).

37. Nartikova VF, Paskhina TS. A unified method for assay of alpha-1-antitrypsin and alpha-2-macroglob-ulin activity in human serum (plasma). Vopr. med. khim. 1979;25(4):494–499. (In Russ).

38. Zozulja S.A., Olejchik I.V., Androsova L.V. i dr. Monitoring techenija jendog-ennyh psihozov po immunologicheskim pokaza-teljam. Psihicheskoe zdorov'e . 2017;1:11–18. (In Russ.).