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Title: NEUROPSYCHOBIOLOGICAL MECHANISMS OF AFFECTIVE AND COGNITIVE DISORDERS IN THE CHORNOBYL CLEAN-UP WORKERS TAKING INTO ACCOUNT THE SPECIFIC GENE POLYMORPHISMS.
Author: Loganovsky KN, Bomko MO, Abramenko IV, Kuts KV, Belous NI, Masiuk SV, Gresko MV, Loganovska TK, Antypchuk KY, Perchuk IV, Kreinis GY, Chumak SA.
Journal: Probl Radiac Med Radiobiol; 2018 Dec; 23():373-409. PubMed ID: 30582858.
Abstract:
Relevance of the present work is determined by the considerable prevalence of both affective and cognitive disor-ders in the victims due to the Chornobyl accident, the pathogenesis of which is insufficiently studied.Objective is to identify the neuropsychiobiological mechanisms of the formation of the remote affective and cog-nitive disorders following exposure to ionizing radiation taking into account the specific gene polymorphisms.Design, object and methods of research. The retrospective and prospective cohort study with the external andinternal control groups. The randomized sample of the male participants in liquidation of the consequences of theaccident (Chornobyl clean-up workers, liquidators) at the Chornobyl nuclear power plant (ChNPP) in 1986-1987(n = 198) recruited from the Clinico-epidemiological registry (CER) of NRCRM aged 39-87 (M ± SD: 60.0-8.5 years)with the external irradiation dose ranged 0.6-5900.0 mSv (M ± SD: 456.0 ± 760.0 mSv) was examined. The compar-ison group (n = 110) consisted of the unexposed patients of the Radiation Psychoneurology Department with thecorresponding age and sex (the external control group). The internal control group included the liquidators irradi-ated at doses < 50.0 mSv (n = 42). The standard diagnostic neuropsychiatric scales, psychodiagnostic questionnairesand tests, neuropsychological methods (including the Wechsler Adult Intelligence Scale (WAIS) with premorbid IQ(pre-IQ) assessment), neuropsychiatric and psychophysiological methods (quantitative EEG (qEEG) and the audito-ry cognitive evoked potentials (Event-Related Potentials, ERP) were applied. The genotypes of the serotonin trans-porter gene SLC6A4 were determined by the 5_HTTLPR and rs25531 polymorphisms. The methods of descriptive and vari-ation statistics, non-parametric criteria, regression-correlation analysis, survival analysis by Kaplan - Meier and riskanalysis were used.Results. Cerebrovascular diseases, organic mental and depressive disorders, mainly of radiation-stress-relatednature, prevail among the liquidators. The overall risk of neuropsychiatric pathology increases (Pv < 0.001) with theirradiation dose. The verbal memory and learning are impaired, as well as the full IQ is reduced at the expense of theverbal one. The frequency of both mild cognitive impairment and dementia is risen. The cognitive impairment atdoses > 0.3 Sv is dose-dependent (r = 0.4-0.7; p = 0.03-0.003). Affective disorders (depression) and neurocogni-tive deficit are more severe at higher doses of irradiation (> 50 mSv). In the left posterior temporal region(Wernicke's area) the qEEG indices changes become dose-dependent at doses greater than 0.25-0.3 Sv. The dis-turbed brain information processes lateralized to the Wernicke's area are observed even at doses > 50 mSv. The car-riers of intermediate and low-level genotypes (LА/S, LА/LG, LG/LG, LG/S, S/S) of the serotonin transporter gene SLC6A4have more depressive disorders, especially severe ones, and tend to have more frequent and severe cognitive andstress-related disorders.The debut of depressive disorders in the carriers of the intermediate and low-activity genotypes occurs much earli-er (Log-Rank Test = 4.43, p = 0.035) in comparison with the carriers of the high-performance genotype LА/ LА.Conclusions. The radiation-induced dysfunction of the cortico-limbic system in the left dominant hemisphere ofthe human brain with a specific involvement of the hippocampus is considered to be the key cerebral basis of post-radiation organic brain damage. The association of genotypes by 5_HTTLPR and rs25531 polymorphisms of the SLC6A4gene with affective and cognitive disorders suggests the presence of neuropsychobiological features of these dis-orders associated with ionizing radiation depending on the certain gene polymorphisms. Aktual'nist' roboty zumovlena znachnoiu poshyrenistiu u postrazhdalykh vnaslidok Chornobyl's'koï katastrofyafektyvnykh i kognityvnykh rozladiv, patogenez iakykh vyvcheno nedostatn'o.Meta doslidzhen' – vyznachyty neĭropsykhobiologichni mekhanizmy formuvannia afektyvnykh i kognityvnykh rozladivviddalenogo periodu pislia vplyvu ionizuiuchogo vyprominiuvannia z urakhuvanniam spetsyfichnykh gennykhpolimorfizmiv.Dyzaĭn, ob’iekt i metody doslidzhennia – retrospektyvno-prospektyvne kogortne doslidzhennia iz zovnishnim tavnutrishnim kontrolem. Obstezhena randomizovana vybirka uchasnykiv likvidatsiï naslidkiv avariï (ULNA) na Chorno-byl's'kiĭ AES (ChAES) 1986-1987 rr. cholovichoï stati (n = 198) z Kliniko-epidemiologichnogo reiestru NNTsRM u vitsi39–87 rokiv (M -#177; SD: 60,0 -#177; 8,5 roku), dozy zovnishn'ogo oprominennia – 0,6–5900,0 mZv (M -#177; SD: 456,0 -#177; 760,0 mZv).Grupa porivniannia (n = 110) – neeksponovani patsiienty viddilu radiatsiĭnoï psykhonevrologiï vidpovidnogo viku istati (zovnishniĭ kontrol'). Vnutrishniĭ kontrol' – ULNA, opromineni v dozakh -#060; 50,0 mZv (n = 42). Vykorystanistandartni diagnostychni neĭropsykhiatrychni shkaly, psykhodiagnostychni opytuval'nyky i testy, neĭropsykhologichnimetody (vkliuchaiuchy shkalu intelektu Vekslera dlia doroslykh (WAIS) z premorbidnoiu otsinkoiu), neĭro- i psy-khofiziologichni metody (komp’iuterna EEG ta kognityvni slukhovi vyklykani potentsialy). Vyznacheni genotypy genatransportera serotoninu SLC6A4 za polimorfizmamy 5_HTTLPR ta rs25531. Vykorystani metody deskryptyvnoï ivariatsiĭnoï statystyky, neparametrychni kryteriï, regresiĭno-koreliatsiĭnyĭ analiz, analiz vyzhyvanosti za Kep-lenom-Meĭerom, ryzyk-analiz.Rezul'taty. v ULNA dominuiut' tserebrovaskuliarni zakhvoriuvannia, organichni psykhichni ta depresyvni rozlady pe-revazhno radiatsiĭno-stresornogo kharakteru. Zagal'nyĭ ryzyk neĭropsykhiatrychnoï patologiï zrostaie (Pv -#060; 0,001)z dozoiu oprominennia. Porushena verbal'na pam’iat' ta navchannia, zmenshenyĭ IQ za rakhunok verbal'nogo. Zbil'-shena chastota legkogo kognityvnogo rozladu i dementsiï. Kognityvni porushennia pry dozakh -#062; 0,3 Zv zalezhat'(r = 0,4–0,7; p = 0,03– 0,003) vid dozy oprominennia. Afektyvni rozlady (depresiia) i neĭrokognityvnyĭ defitsytvyshchi pry bil'shykh dozakh oprominennia (-#062; 50 mZv). U liviĭ zadniĭ skroneviĭ diliantsi (zona Vernike) parametry EEGzalezhat' vid dozy pry oprominenni v dozakh ponad 0,25–0,3 Zv. Porusheni informatsiĭni protsesy golovnogo moz-ku z lateralizatsiieiu do zony Vernike vzhe pry dozakh -#062; 50 mZv. Nosiï promizhnykh ta nyz'koaktyvnykh genotypiv (LA/S,LA/LG, LG/LG, LG/S, S/S) genu transportera serotoninu SLC6A4 maiut' bil'she depresyvnykh rozladiv, osoblyvo, tiazh-kykh ta tendentsiiu do bil'shoï chastoty i vyrazhenosti kognityvnykh i stresovykh rozladiv. Debiut depresyvnykh roz-ladiv u nosiïv promizhnykh ta nyz'kofunktsional'nykh genotypiv vidbuvaiet'sia znachno ranishe (Log-Rank Test = 4,43,p = 0,035) porivniano z nosiiamy vysokofunktsional'nogo genotypu LA/LA.Vysnovky. Radiatsiĭno-indukovana dysfunktsiia kortyko-limbichnoï systemy livoï dominantnoï pivkuli golovnogomozku z osoblyvym zaluchenniam gipokampu, ie kliuchovym tserebral'nym bazysom organichnogo urazhennia mozkupislia oprominennia. Asotsiatsiia genotypiv z polimorfizmamy 5_HTTLPR i rs25531 gena SLC6A4 z afektyvnymy ikognityvnymy rozladamy svidchyt' pro naiavnist' neĭropsykhobiologichnykh osoblyvosteĭ tsykh rozladiv, pov’iazanykhz diieiu ionizuiuchoï radiatsiï, zalezhno vid pevnykh gennykh polimorfizmiv.

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