Клиничке, генетске и морфолошке карактеристике болесника са деменцијом раног почетка : докторска дисертација
Мандић-Стојменовић, Горана, 1980- 21482343
Стефанова, Елка, 1959- 12534375
Костић, Владимир, 1953- 12148839
Новаковић, Ивана, 1961- 12576359
Семниц, Марија, 1968- 13311591
Alzheimerova bolest (AB) i frontotemporalna demencija (FTD) predstavljaju dve najčešće forme degenerativnih demencija ranog početka (DRP). DRP se definiše kao demencija čiji kognitivni i/ili bihejvioralni simptomi počinju pre 65. godine života. Uprkos značajnom napretku na polju neuropsihologije, neuroimidžinga, genetike, biomarkera iz cerebrospinalne tečnosti, DRP je još uvek nedovoljno prepoznat entitet čija se konačna dijagnoza često pogrešno ili prekasno postavlja predstavljajući izazov kliničarima čak i u tercijarnim centrima. Novija istraživanja ukazuju na veliku kliničku heterogenost, značajan procenat atipičnih prezentacija na početku bolesti (bihejvioralni simptomi, depresija, psihotični simptomi ili neamnestički kognitivni deficiti), ali i preklapanje simptoma u okviru pojedinih entiteta spektra AB i FTD ranog početka čime se problem dijagnoze i diferencijalne dijagnoze degenerativnih DRP značajno komplikuje. Stoga, pored dobrog poznavanja kliničkih, neuropsiholoških i psihijatrijskih razlika koje proizilaze iz prirodnog toka AB i FTD, savremeni dijagnostički algoritmi teže ka uvođenju sofisticiranih, novih dijagnostičkih procedura kojima će se ubrzati postavljanje adekvatne dijagnoze, definisati subtipovi bolesti, pratiti progresija bolesti i efikasnost terapijskih tretmana. Ciljevi. Osnovni ciljevi studije su: a) ispitivanje heterogenosti kliničkog, kognitivnog i neuropsihijatrijskog ispoljavanja spektra AB i FTD ranog početka (ABrp) i (FTDrp); b) ispitivanje učestalosti različitih izoformi apolipoproteina E (APOE) u spektru ABrp i FTDrp; c) ispitivanje obrasca nasleđivanja i mutacija u genima za amiloidni prekusorski protein (APP), presenilin 1 (PSEN1), progranulin (GRN), tau protein (MAPT), chromosome 9 open reading frame 72 (C9ORF72) u spektru ABrp; d) ispitivanje obrasca nasleđivanja i mutacija u genima za GRN, MAPT, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG) u spektru FTDrp; e) ispitivanje učestalosti heksanukleotidne ekspanzije u C9ORF72 genu u grupi konsekutivnih bolesnika sa degenerativnom DRP (ABrp, FTDrp, DLT); f) ispitivanje morfoloških specifičnosti mozga multimodalnim metodama magnetne rezonance (MR) u bolesnika sa amnestičkom ABrp i bihejvioralnom varijantom FTD Metode. U studiju je uključeno 207 bolesnika kojima je u periodu od 01.04.2012. do 01.04.2017. godine na Klinici za neurologiju KCS postavljena dijagnoza na osnovu važećih kriterijuma za spektar AB i FTD kao i 3 bolesnika sa DLT (za potrebe genetske pilot studije). Istraživanje jednim delom predstavlja studiju slučajeva i kontrola, a drugim delom studiju preseka. U okviru spektra ABrp i FTDrp bolesnici su podeljeni prema kliničkoj prezentaciji na početku bolesti. Za prikupljanje podataka o sociodemografskim i kliničkim karakteristikama bolesnika sa DRP, korišćen je unapred dizajniran semistrukturisani upitnik. U istraživanju je korišćena opsežna baterija testova i upitnika za procenu kognitivnog i bihejvioralnog statusa bolesnika. Bolesnicima je posle pismenog pristanka uziman uzorak krvi za molekularno-genetske analize: ispitivanje profila APOE kao i postojanje mutacija u genima za APP, PSEN1, GRN, TAU, C9ORF72, a u određenim slučajevima i za VCP i ANG. Kod 62 bolesnika sa amnestičkom formom ABrp, 28 bolesnika sa FTDbv i 48 zdravih kontrolnih ispitanika pregled mozga je obavljen na MR aparatu jačine 1,5 T. Na snimcima je analizirana debljina korteksa, mikrostrukture promene bele mase i aksonalnih puteva mozga pomoću difuzionog tenzorskog imidžinga (DTI) kao i promene u fukcionalnoj povezanosti delova mozga na „sekvencama bazičnog stanja mirovanja“ (resting) sekvencama. Rezultati: Demografske i kliničke karakteristike:Bolesnici iz spektra ABrp i FTDrp nisu se međusobno razlikovali po godinama starosti, godinama starosti na početku bolesti, trajanju bolesti, polu kao ni u obrazovanju. Bolesnici iz spektra ABrp imali su značajno manja dostignuća na testovima verbalnog i vizuelnog epizodičkog pamćenja, vizuoprostornih i egzekutivnih funkcija, dok su ispitanici spektra FTDrp značajno češće ispoljavali agitaciju, euforiju, apatiju, dezinhibiciju, iritabilnost, aberantno motorno ponašanje i izmene na planu ishrane. Parkinsonizam, motorne stereotipije, ataksija i disfagija su bili značajno češći u spektru FTDrp, dok je jedino u ovih ispitanika verifikovana BMN, klinička slika PSP-a i distonija. Iako je amnestička prezentacija bila najčešća forma našeg spektra ABrp, čak trećina ovih bolesnika prezentovala se atipično- posteriornom kortikalnom atrofijom, potom frontalnom varijantom i jezičkom formom AB. Bolesnici sa FTDrp očekivano su najčešće ispunjavali kriterijume za FTDbv, posle čega je sledila nfvPPA, FTD sindromi preklapanja (FTD-BMN, FTD-PSP, FTD-KBS) i PPAsv. Genetske karakteristike: Familijarnu formu bolesti imala je trećina bolesnika sa ABrp (najveći broj ispitanika je ispunio kriterijume za amnestičku, potom frontalnu varijantu ABrp) i FTDrp (najveći broj bolesnika ispunio je kriterijume za FTDbv, potom PNFA), dok je autozomno dominantan (AD) obrazac nasleđivanja postojao u 4.7% i 7.7% probanada sa ABrp i FTDrp redom. Genske mutacije su dokazane u 4 bolesnika sa ABrp (3.1% svih ABrp): 2 bolesnika su imala mutacije u PSEN1 genu (mutacija Tyr159Cys u egzonu 5 do sada nije objavljena), a 2 bolesnika u APP genu. Nijedan bolesnik sa ABrp nije bio nosilac mutacija u MAPT, GRN i C9ORF72 genima. Navedene mutacije su identifikovane u 7.3% ABrp ispitanika sa familijarnom ABrp (trećina ABrp bolesnika sa AD obrascem nasleđivanja) i 1.2% ispitanika bez obolelih srodnika...
Medicina - Neurologija / medicine - neurology Datum odbrane: 25.03.2019.
and/or behavioral symptoms before the age of 65. Despite significant advances in neuropsychology, neuroimaging, genetics and biomarkers from cerebrospinal fluid, uncertainties regarding the early and correct diagnosis of EOD even at the level of tertiary referral centres still exist. Recent studies indicate a high clinical heterogeneity, a significant percentage of atypical presentations at disease onset (behavioral symptoms, depression, psychotic symptoms or non-cognitive cognitive deficits), as well as overlap of symptoms within individual entities of the AD and FTD which further complicate early diagnosis and differential diagnosis of degenerative EOD. Therefore, in addition to a good knowledge of clinical, neuropsychological and psychiatric differences arising from the natural course of AD and FTD, new diagnostic algorithms tend to introduce sophisticated diagnostic procedures that will speed up making the adequate diagnosis, define dementia subtypes, monitor progression of the disease and the effectiveness of therapeutic treatments. Objectives. The main objectives of the study are: a) investigating the heterogeneity of clinical, cognitive and neuropsychiatric manifestations of the early onset AD (EOAD) and FTD (EOFTD) spectrum; b) testing the frequency of the different isoforms of apolipoprotein E (APOE) in the EOAD and EOFTD spectrum c) examination of the inheritance pattern and mutations in the genes for the amyloid precursor protein (APP), presenilin 1 (PSEN1), progranulin (GRN), tau protein (MAPT), chromosome 9 open reading frame 72 (C9ORF72) in the EOAD spectrum; d) examining the inheritance pattern and mutations in the genes for GRN, MAPT, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG) in the EOFTD spectrum; e) testing the frequency of hexanucleotide repeat expansion in the C9ORF72 gene in a group of consecutive patients with degenerative DRP (EOAD, EOFTD, Dementia with Lewy bodies (DLT)); f) examining the morphological specificity of the brain with multimodal magnetic resonance imaging (MR) in amnestic EOAD and the behavioral variant of FTD patients (FTDbv). Methods. Two hundred and seven consecutive patients diagnosed according to the current clinical criteria for AD and FTD spectrum were recruited from the Neurology Clinic, Clinical Centre of Serbia from 01.04.2012. until 01.04.2017. We also included 3 patients with DLB (for the needs of the genetic pilot study). The research partly had characteristics of case-control study and partly was cross-section study. Within the spectrum of EOAD and EOFTD, patients were divided according to the clinical presentation at the disease onset. In order to collect data on sociodemographic and clinical characteristics of patients with EOD, a pre-designed semi-structured questionnaire was used. We used an extensive battery of tests and questionnaires to evaluate the cognitive and behavioral status of patients. The blood sample for molecular-genetic analysis was taken: (after the written consent) for testing of the APOE profile as well as mutations in the genes for APP, PSEN1, GRN, TAU, C9ORF72, and in certain cases for VCP and ANG. In 62 patients with amnestic EOAD, 28 patients with FTDbv and 48 healthy control subjects brain scan was performed on a 1.5 T MRI. The topographic distribution of gray matter and white matter (WM) atrophy were assessed by unconventional MRI methods: cortical thickness and diffusion tensor (DT) MRI analysis. We also investigated functional connectivity of different brain networks by resting state functional MRI (RS fMRI). Results: Demographic and clinical features: EOAD and EOFTD patients did not differ in age, age at the disease onset, duration of the disease, gender and education. Patients in the EOAD spectrum had significantly lower achievements in verbal and visual episodic memory tests, visuospatial and executive functions, while patients in the EOFTD spectrum more frequently expressed agitation, euphoria, apathy, disinhibition, irritability, aberrant motor behavior and dietary changes. Parkinsonism, motor stereotyping, ataxia, and dysphagia were significantly more common in the EOFTD spectrum, while MND, clinical picture of PSP and dystonia were only seen in EOFTD patients. Although the amnesic presentation was the most common form in our EOAD spectrum, a third of these patients presented atypicaly- posterior cortical atrophy, following frontal variant and language form of AD. As expected, the majority of FTD patients met criteria for FTDbv, followed by non-fluent progressive aphasia (nfvPPA), FTD-overlap syndroms (FTD-BMN, FTD-PSP, FTD-CBS) and semnatic variant of primary progressive aphasia (svPPA). Genetic analysis: In our cohort, one third of EOAD (majority of patients with amnestic and frontal variant) and EOFTD (majority of patients with FTDbv then nfvPPA) patients had familial form of dementia, while the autosomal dominant (AD) inheritance pattern existed in 4.7% and 7.7% of probands with EOAD and EOFTD, respectively. There were 4 gene mutations carriers within our EOAD cohort (3.1% of all EOAD patients): 2 patients had mutations in the PSEN1 gene (the mutation Tyr159Cys in exon 5was reported for the first time) and 2 patients in the APP gene...
srpski
2018
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OSNO - Opšta sistematizacija naučnih oblasti, Neurologija. Neuropatije
early onset dementia, early onset Alzheimer's disease, early onset frontotemporal dementia, neuropsychological characteristics, neuropsychiatric characteristics, genetics, cerebral atrophy, multimodal magnetic resonance imaging
OSNO - Opšta sistematizacija naučnih oblasti, Neurologija. Neuropatije
demencija ranog početka, alzheimerova bolest ranog početka, frontotemporalna demencija ranog početka, neuropsihološke karakteristike, neuropsihijatrijske karakteristike, genetika, moždana atrofija, multimodalna magnetna rezonanca
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