Ispitivanje funkcionalnih i morfoloških poremećaja centralnog nervnog sistema kod bolesnika sa miotoničnom distrofijom tipa 1

Abstract

Uvod: Miotonična distrofija tipa 1 (MD1) je autozomno-dominantno nasledno oboljenje, koje pored mišića, zahvata mnoga druga tkiva i organe, uključujući i mozak. Zahvaćenost centralnog nervnog sistema (CNS) u MD1 podrazumeva neuropsihološke i bihevioralne poremećaje. Razvoj savremenih neurovizualizacionih tehnika i molekularne medicine omogućava bolje sagledavanje uzroka moždanih poremećaja. Ciljevi: Određivanje neuropsihološkog i bihevioralnog profila bolesnika sa MD1, ispitivanje morfoloških specifičnosti njihovog mozga i analiza nivoa biomarkera neurodegeneracije u likvoru. Materijal i metode: Ispitivano je 66 bolesnika kod kojih je dijagnoza MD1 potvrđena molekularno-genetskom analizom. Stepen mišićne slabosti određivan je prema MIRS (Muscular Impairment Rating Scale). U istraživanju je korišćena opsežna baterija klasičnih neuropsiholoških testova, kao i obiman set kompjuterskih testova iz baterije CANTAB (Cambridge Neuropsychological Test Automated Battery). U studiji su korišćene sledeće skale: Hamiltonove skale za procenu depresije i anksioznosti, Milonov multiaksijalni klinički upitnik (MMCI) za poremećaje ličnosti, DSS skala za merenje prekomerne dnevne pospanosti (PDP) i Kruppova skala za težinu zamora (FSS). Kod bolesnika i 38 zdravih kontrola pregled mozga je obavljen na aparatu za magnetnu rezonanciju (MR) jačine 1,5 T. Na snimcima je određivano ukupno opterećenje hiperintenznim lezijama bele mase (HLBM), zapremina sive mase mozga pomoću morfometrije zasnovane na vokselu (VBM) i analiza puteva bele mase metodom difuzionog tenzorskog imidžinga (DTI). Transkranijalna sonografija mozga (TCS) korišćena je za analizu struktura srednje linije moždanog stabla kod bolesnika i 55 zdravih kontrola. Nivo ukupnog i fosforilisanog tau proteina (T-tau i P-tau) i beta amiloida 42 (Aβ42) u likvoru bolesnika i 26 neurološki zdravih kontrola određivan je metodom sendvič ELISA. Rezultati: Vizuospacijalna disfunkcija je uočena kod 80 %, egzekutivna disfunkcija kod 67 %, a oštećenje jezičke funkcije imenovanja kod 62 % obolelih. Značajna depresivnost je registrovana kod 15 %, anksioznost kod 11 %, PDP kod 44 %, a zamor kod 52 % bolesnika. Klinički značajan poremećaj ličnosti je imalo 60 % obolelih (zavisan tip ličnosti 52 %, a paranoidan 39 %). Lošiji rezultati na pojedinim neuropsihološkim i bihevioralnim testovima bili su u korelaciji sa većim brojem CTG ponovaka (p<0,05). MD1 bolesnici su imali veće opterećenje HLBM u odnosu na zdrave kontrole (0,30 ± 0,80 prema 0,04 ± 0,10; p<0,01)...

Background: Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease, that besides muscle affects many other tissues and organs, including the central nervous system. Brain manifestations in DM1 include neuropsychological and behavioral impairment. Development of modern neuroimaging and molecular medicine enables better insight in possible causes of the central nervous system involvement in DM1. Aims: Assessment of neuropsychological and behavioral profile of DM1 patients, structural analysis of their brain and investigation of cerebrospinal fluid biomarkers of neurodegeneration. Material and methods: Study comprised 66 genetically confirmed DM1 patients. Severity of muscle weakness was assessed using the Muscular Impairment Rating Scale (MIRS). Extensive battery of classic pen and pencil tests and Cambridge Neuropsychological Test Automated Battery (CANTAB) were used. Following measures were also administered: Hamilton depression and anxiety scales, Millon Multiaxial Clinical Inventory (MMCI) for personality pattern, Daytime Sleepiness Scale (DSS) and Krupp’s Fatigue Severity Scale (FSS). Magnetic resonance imaging on 1.5 T equipment was performed in patients and 38 healthy controls (HCs). Images were used for analysis of the white matter hyperintense lesions (WMHL) load, grey matter volume using voxel-based morphometry (VBM) and assessment of white matter tracts with diffusion tensor imaging (DTI). Transcranial sonography (TCS) was used for analysis of the brainstem midline structures in patients and 55 HCs. Cerebrospinal fluid levels of total and phosphorylated tau protein (T-tau and P-tau) as well as beta amyloid 42 (Aβ42) were analyzed in patients and 26 HCs using sandwich ELISA. Results: Visuospatial dysfunction was observed in 80 % of DM1 patients, executive dysfunction in 67 % and naming was impaired in 62 %. Significant depressiveness was registered in 15 % and anxiety in 11 % of patients, excessive daytime sleepiness in 44 % and fatigue in 52 %. Clinically significant personality impairment was registered in 60 % of patients (dependent personality in 52 % and paranoid in 39 %). Worse results on certain neuropsychological and behavioral tests correlated with longer CTG expansion (p<0.05). DM1 patients had higher WMHL load compared to HCs (0.30 ± 0.80 vs. 0.04 ± 0.10; p<0.01). VBM showed decrease in grey matter volume in almost all parts of the brain, including cerebral cortex, cerebellum, basal ganglia and thalami (p<0.05)...