SJEZD PSYCHIATRICKE SPOLECNOSTI CLS JEP BUDOUCNOST PECE 0 DUSEVNE NEMOCNE V SOUVISLOSTECH
12.-15. CERVNA 2014 HOTEL HARMONY, SPINDLERUV MLYN
Poradatele: Martin Holly, Pavel Doubek, Marek Pav
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MUDr. Martin Holly MUDr. Pavel Doubek, Ph.D. MUDr. Marek Pav, Ph.D. Psychiatricka lecebna Bohnice, Psychiatricka klinika, a Vseobecna fakultni nemocnice, Praha
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lekarska fakulta UK
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GUARANT International spol. s r. o. Na Pankraci 17, 140 21 Praha 4
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Za odbornou a jazykovou stranku tohoto sborniku odpovidaji autori jednotliv}'ch pfispevku. ISBN 978-80-263-0702-0
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BUDOUCNOST PECE O DUSEVNE NEMOCNE V SOUVISLOSTECH
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SYMPOSIUM PSYCHIATRICKE KLINIKYVFN A 1. LF UK: BIOLOGICKA DIAGNOSTIKAA LECBA DUSEVNiCH PORUCH garant prof. Jili Raboch ENERGETIC.KY METABOLISMUS U PACIENTC- S DEPRESi A ALZHEIMEROVOU DEMENCi
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J. Hroudova 1 , Z. FiSar1 , R. Jirak 1 , H. Hansikova 2, L. Wenchich2, J. Raboch1 1 Psychiatricka klinika, 1. lekafskafakulta, Univerzita Karlova v Praze a VSeobecnafakultnf riemocnice v Praze, Praha, Ceska Republika 2 Klinika detskeho a dorostoveho lekafstvf, Univerzita Karlova v Praze a Vseobecnafakultnf nemocnice v Praze, Praha, Ceska Republika Summary ENERGY METABOLISMUS IN PATIENTS WITH DEPRESSION AND ALZHEIMER'S DISEASE Mitochondrial dysfunctions are concerned in a range of diseases, neurodegenerative and psychiatric disorders included. We examined effects of depressive disorder and/or Alzheimer's disease (AD) on both mitochondrial enzyme activities (citrate synthase, complexes of electron transport chain) and cellular respiration in blood platelets. Enzyme activities were measured spectrophotometrically, kinetics of oxygen consumption by mitochondria was measured electrochemically. Physiological respiration, maximal capacity of electron transport system (ETS) and respiratory rate after complex I inhibition were decreased in intact platelets of depressive patients, compared to controls. Complex II activity was significantly decreased in depressive patients. In AD, we found decreased physiological respiration and ETS capacity; whereas respiratory rate after complex I inhibition was increased. Unchanged respiratory rate was observed in permeabilized platelets. Significant decrease of citrate synthase and complex N activities were observed in AD patients. Complex I was significantly increased in AD patients, complex II was increased in subgroup of AD patients with depression. Results suggest that insufficient substrate availability, rather than ETS functional disturbances, is responsible for decreased mitochondrial respiration. It can be concluded that changes of mitochondrial functions participate in the pathophysiology of depression and AD. Their modulation can contribute to therapeutic and/ or adverse effects of antidepressants and mood stabilizers. Keywords: depression; Alzheimer's disease, electron transport chain complexes, cellular respiration, high resolution respirometry Cile Nan'.istajid dukazy, ze mitochondrialni dysfunkce souvisi s narusenim energetickeho metabolismu a jsou zahrnuty v patogenezi Alzheimerovy choroby (AD) [1, 2]. Narusena funkce mitochondrii vede nejen ke snizeni produkce ATP, ale take ke zv}'sene produkci volnych radikalU, ke zmenam nitrobuneeneho kalcia, oxidaenimu stresu a apopt6ze. 66
Pfodpokladame, ze zmeny energetickeho metabolismu hunky se podili na patofyziologii AD, poruch nalady a na terapeutick}'ch nebo vedlejsich ucincich antidcpresiv [3]. Sledovali jsme respiraeni rychlost a aktivity mitochondrialnich cmzymu v krevnich destickach u pacientu s AD, u pacientu s depresivni epizodou 11 v remisi, u zdrav}'ch kontrol. Cilem prace bylo zjistit, zda je aktivita citratsynthazy, komplexu elektronoveho transportniho fetezce a buneena respirace ovlivnena pfi depresi a pfi AD. Snahou studie je nalezeni biologick}'ch parametril, ktere by mohly hYt vhodn}'mi markery onemocneni a ktere by mohly bYt diem leCby psychofarmaky.
Metody J)o studie byli zafazeni pacienti s depresivni epizodou; tiZe jejich deprese byla ohodnocena pomod Hamiltonovy skaly deprese (HRSD-21), kontrolni skupina byla tvofena zdrav}'mi dobrovolniky. Byli zarazeni pacienti s AD a vekove odpovfdajid kontroly. Kognitivni postizeni bylo ohodnoceno pomod skaly minimental state examination (MMSE), deprese u AD byla identifikovana geriatrickou skalou deprese (GDS); diagn6za AD byla potvrzena v}'pocetni tomografii mozku nebo magnetickou rezonanci. Zmeny buneeneho dychani byly mefeny v krevnich destickach pacientu v depresivni epizode, v remisi au pacienru s AD, a byly porovnavany se zdrav}'mi kontrolami. Dychani mitochondrii, tj. celkova aktivita systemu oxidaeni fosforylace (OXPHOS), bylo mefeno s pouZitim oxygrafu s Clarkov}'mi elektrodami. Respirometricka mefeni s vysok}'m rozlisenim byla provadena v intaktnich a take v permeabilizovanych bunkach (v pfitomnosti substratu a inhibitoru OXPHOS). Rychlost spotfeby kysliku byla hodnocena v nekolika respiracnich stavech. Aktivita citratsyntazy a komplexu elektronoveho transportniho fetezce byla mefena spektrofotometricky. Statisticka v}'znamnost byla hodnocena pomod MannovaWhitneyova U testu. Vysledky Fyziologicka respirace v krevnich destickach depresivnich pacientu se nelisila od kontrol; ke statisticky v}'znamnemu sniZeni doslo po leCbe antidepresivy. Respiracni rychlost po inhibici komplexu I a maximalni kapacita elektronoveho transportniho systemu byla rovnez snizena statisticky v}'znamne po lecbe antidepresivy. U osob s depresi jsme zjistili statisticky v}'znamne sniZeni aktivity komplexu II v porovnani s kontrolami. U pacientu s AD byla v}'znamne sniZena fyziologicka respirace i max. kapacita clektronoveho transportniho systemu. U pacientu s AD bylo v}'znamne sniZeni aktivity citratsyntazy a komplexu N . U pacientu s AD (bez deprese) byla zv}'sena aktivita komplexu I v porovnani s kontrolami. U podskupiny AD pacientu se symptomy deprese byla navic v}'znamne zv}'sena aktivita komplexu II oproti kontrolam i ve srovnani s AD pacienty bez deprese. Nepozorovali jsme v}'znamnou souvislost mezi aktivitami mitochondrialnich enzymu a stupnem kognitivniho poskozeni nebo tizi deprese. Zavery V patofyziologii depresivni poruchy i AD muze b}'t zahrnuta zmenena aktivita komplexu II a N dychaciho fetezce. Symptomy deprese pfi AD mohou mit jiny 67
patofyziologicI
Podporeno vyzkumnym z6:merem Ministerstva skolstvi, ml6:deze a telovychovy MSM0021620849 a projektem PRVOUK-P26/ LF1/ 4.
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Literatura 1. Parker, W.D., Jr., et al., Electron transport chain defects in Alzheimer's disease brain. Neurology, 1994. 44(6): p. 1090-6. 2. Bosetti, F., et al., Cytochrome c oxidase and mitochondrial F1Fo-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease. Neurobiol Aging, 2002. 23(3): p. 371-6. 3. Hroudova, J ., et al., Mitochondrial respiration in blood platelets of depressive patients. Mitochondrion, 2013. 13(6): p. 795-800. 4. Hroudova, J . and Z. Fisar, Activities of respiratory chain complexes and citrate synthase influenced by pharmacologically different antidepressants and mood stabilizers. Neuro Endocrinol Lett, 2010. 31(3): p. 336-42. vYzNAM KORTIZOLU A HOMOCYSTEINU V DIAGNOSTICE ALZHEIMEROVY DEMENCE - vYSLEDKY Z vYzKUMNEHO zAMERU M. Zvefova, z. Fi.Sar, R. Jirak, J. Hroudova, E. Kitzlerova, J. Raboch Psychiatrick6: klinika, 1. lekafsk6:fakulta, Univerzita Karlova v Fraze a VSeobecn6:fakultni nemocnice v Fraze, Praha, Cesk6: republika Summary MEANING OF CORTISOL AND HOMOCYSTEINE IN DETECTION OF ALZHEIMER'S DEMENTIA - RESULTS OF THE RESEARCH PLAN Background: Cortisol and homocysteine are presumed to be risk factors for stress- and age-related disorders, such as Alzheimer's disease (AD). The aim of this study was to investigate the association of plasma cortisol or homocysteine concentration with AD. Materials and Methods: Plasma cortisol and homocysteine concentration were measured in 80 AD patients, and 37 elderly healthy controls. Patients were recruited from the Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague. 68
Results: Plasma cortisol was positively correlated with cognitive impairment in AD patients. We confirmed significant correlation between homocysteine concentration and the degree of cognitive impairment in AD patients. Conclusions: The association of high cortisol and high homocysteine with degree of cognitive impairment or stage of dementia in AD indicate potential role of high plasma cortisol and homocysteine as biomarkers of the disease und/or indicators of brain damage during the progression of AD dementia. Keywords: Alzheimer's disease, biochemical markers, cortisol, homocysteine Ovod a cile V soueasnosti jsou hledana dalSi diagnosticka kriteria a dalSi biologicke markery, ktere by byly specificke pro Alzheimerovu nemoc. Zatim vsak nebyla nalezena zadna nova metoda, ktera by byla vice prii.kazna a pro pacienty mene zateZujici nez je odber mozkomisniho moku. Mezi biochemicke markery, zjistitelne v periferni krvi a podilejici se na patofyziologii neurodegenerativnich poruch, lze zafadit uptake serotoninu do krevnich desticek, aktivitu monoaminooxidazy a plazmaticke koncentrace kortizolu a homocysteinu. Krome maieho procenta geneticky podminenych pnpadii neni pncina AD znama. Mezi zname hypotezy vzniku AD provazene neurodegeneraci a kognitivnim postiZenim pam hypoteza cholinergni (snizena synteza acetylcholinu), amyloidova (abnorma.Ini akumulace amyloidu-~) a tau (patologicka agregace tau proteinu). Pozornost je vsak venovana fade dalSich faktorii, ktere mohou b:Yt zahrnuty v etiologii AD, pfedevsim mechanismiim vedoucim k poskozeni neuroplasticity a neurogeneze, jako jsou mitochondrialni dysfunkce a dalsi. Imunoneuroendokrinni a neurochemicke cesty vedouci k neurodegeneraci jsou propojeny pres vzajemne ovlivrfovani funkci neurotransmiterov}'ch systemii a osy hypotalamus - hypofyza - kiira nadledvin (HPA). Patofyziologicke mechanismy AD zahrnuji zv}'senou aktivitu osy HPA, chronicke zanetlive procesy, zv}'seny oxidacni a nitrosaeni stres, narusenou neuroplasticitu a neurogenezi. Biologicky aktivnimi molekulami studovan}'mi pfi AD jsou proto glukokortikoidy, prozanetlive cytokiny transkripcni faktor aktivovany v odezve na zv}'seni hladin cAMP (CREB), mozkov}' neurotrofni faktor (BDNF), glykogensyntazakinaza-3 (GSK-3) a dalSi. Mezi biochemicke markery, ktere jsou zjistitelne z periferni krve, a ktere se podileji na patofyziologii neurodegenerativnich poruch, pam kortizol a homocystein. Kortizol (hydrokortizon) je jednim ze steroidnich hormonii syntetizovanych z cholesterolu v zona fasciculata kiiry nadledvin. Produkce je regulovana prostfednictvim HPA osy (CRH~ ACTH~ kortizol). Hlavnimi stimuly pro uvolnenijsou stres (teplo, zima, fyzicka zatez), adrenalin, vasopresin, pyrogeny, bolest a hypoglykemie. Kortizol je v plazme transportovan pfevazne ve vazbe na transcortin (90%), albumin (7%), asi 3 % plazmatickeho poolu tvon volny, biologicky aktivni hormon. Mezi hlavni fyziologicke funkce patn regulace intermediarniho metabolismu bilkovin, gluk6zy a lipidii, regulace krevniho tlaku a imunomodulaeni vliv. BiologicI
