Klinički i morfološki korelati napredovanja i heterogenosti atipičnih parkinsonizama

Abstract

Progresivna supranuklearna paraliza (PSP) i multipla sistemska atrofija parkinsonog tipa (MSA‐P) predstavljaju, posle Parkinsonove bolesti (PB), dve najčešće forme neurodegenerativnih parkinsonizama. Nedavna istraživanja ukazuju da postoji velika klinička heterogenost unutar pojedinih entiteta iz grupe atipičnih parkinsonizama (AP), koja je praćena i heterogenošću njihovih patoloških nalaza, čime se problem diferencijalne dijagnoze parkinsonizama, dalje usložnjava i komplikuje. Stoga, pored dobrog poznavanja kliničkih razlika koje proizilaze iz prirodnog toka AP, savremeni dijagnostički algoritmi teže ka uvođenju sofisticiranih, novih dijagnostičkih procedura kojima će se ubrzati postavljanje dijagnoze, definisati subtipovi bolesti, pratiti progresija bolesti i efikasnost terapijskih tretmana. Izučavanje MSA‐P i dva najčešća fenotipa PSP (klasični fenotip (PSP‐RS) i parkinsoni fenotip (PSP‐P)), pruža jedinstvenu priliku za ispitivanje kliničkih i morfoloških korelata heterogenosti i napredovanja atipičnih parkinsonizama, čime se stvaraju dobri modeli za razumevanje patofizioloških procesa koji su u osnovi ovih oboljenja. Ciljevi. Osnovni ciljevi studije su: a) ispitivanje heterogenosti kliničkog ispoljavanja i napredovanja različitih formi AP; b) ispitivanje i kvantifikovanje specifičnih motornih obrazaca u AP; c) ispitivanje profila psihijatrijskih i bihejvioralnih poremećaja kod obolelih od PSP i dinamike njihovih promena tokom jednogodišnjeg perioda praćenja; d) ispitivanje specifičnosti obrazaca nepredovanja moždane atrofije u dva osnovna fenotipa PSP, multimodalnim metodama magnetne rezonance (MR); e) ispitivanje kvaliteta života i determinanti koje utiču na njegovo pogoršanje u AP. Metode. U studiju je uključen 121 bolesnik kod kojih je dijagnoza postavljena na osnovu važećih kriterijuma za PSP‐RS, PSP‐P i MSA‐P. Istraživanje je podeljeno u više celina i jednim delom je imalo karakteristike studije preseka, dok je drugim delom predstavljalo prospektivnu kohortnu studiju. Za prikupljanje podataka o sociodemografskim i fenotipskim karakteristikama bolesnika sa AP, korišćen je unapred dizajniran semistrukturisani upitnik. Praćenje miljokaza progresije bolesti bazirano je na kriterijumima preporučenim u literaturi. U istraživanju je korišćena opsežna baterija testova i upitnika za procenu težine motornih simptoma i stadijuma bolesti, kognitivnog i bihejvioralnog statusa bolesnika, procenu kvaliteta života. Za ispitivanje i kvantifikovanje specifičnih motornih obrazaca u AP, korišćen je posebno dizajniran multisenzorni sistem za objektivnu analizu motornog obrasca metodom „finger tapping“‐a. U studiju neurovizuelizacionih ispitivanja progresije moždane atrofije uključen je 31 bolesnik sa dijagnozom PSP i 36 zdravih kontrola. Za analizu topografske distribucije izmena na nivou sive i bele mase mozga, kao i stepena njihove progresije, korišćene su nekonvencionalne metode MR: procena debljine korteksa vertex‐by‐vertex analizom; volumetrijsko ispitivanje srednjeg mozga; difuziona tenzorska (DT) MR. Rezultati. Prospektivna studija prirodnog toka bolesti. Procenjeno srednje vreme preživljavanja iznosilo je 11,2 godine kod obolelih od PSP‐P, 6,8 godina kod obolelih od PSP‐RS i 7,9 godina kod obolelih od MSA‐P. Onesposobljavajući tok bolesti u PSP‐RS u poređenju sa PSP‐P, se dodatno može sagledati i kroz postizanje većeg broja miljokaza unutar prve tri godine trajanja bolesti (p˂0,001), kao i kroz tendenciju ranijeg javljanja svih definisanih miljokaza tokom vremena progresije bolesti. Tokom celog perioda praćenja, učestali padovi, teška disfagija i kognitivno oštećenje su se javljali značajno češće u oba fenotipa PSP, nego u MSA‐P, dok za učestalost javljanja poremećaja govora, potrebe za urinarnom katetrizacijom i invalidskim kolicima, nisu uočene razlike između ispitivanih grupa. Specifičnosti motornih obrazaca u AP. Motorni obrazac „hipokinezije bez dekrementa”, predstavlja nalaz specifičan za PSP‐RS, dok bolesnici sa PB i MSAP ispunjavaju kriterijum bradikinezije sa smanjenjem amplitude i brzine repetitivnih pokreta. Obrazac i dinamika psihijatrijskih poremećaja u PSP. Opšti obrazac neuropsihijatrijskih poremećaja ukazuje da su apatija (92%), depresija (76%) i dezinhibicija (64%), najčešći simtptomi u PSP...

Introduction. Progressive supranuclear palsy (PSP) and parkinsonian subtype of multiple system atrophy (MSA‐P) are, after Parkinson’s disease (PD), the most common forms of neurodegenerative parkinsonism. Recent advances in this field suggests that there is a high clinical heterogeneity of certain entities within the group of atypical parkinsonisms (AP), as well as heterogeneity of their pathological findings, which makes diferential diagnosis of parkinsonism more complex and challenging. Therefore, in addition to a good knowledge of clinical differences arising from the natural course of AP, new diagnostic algorithms strive to introduce sophisticated diagnostic procedures to speed up diagnosis, define disease subtypes, monitor progression of disease and the effectiveness of therapeutic treatments. The study of MSA‐P and the two most common PSP phenotypes (classic phenotype (PSP‐RS) and parkinsonian phenotype (PSP‐P)), provides a unique opportunity to examine clinical and morphological correlates of heterogeneity and progression of atypical parkinsonisms, creating good models for understanding the pathophysiological processes underlying these diseases. Objectives. The main objectives of our research are: a) exploring the heterogeneity of clinical manifestation and progression of various forms of AP; b) testing and quantification of specific motor patterns in AP; c) examining the profile of psychiatric and behavioural disorders in patients with PSP and the dynamics of their changes over a one‐year follow‐up; d) tracking the brain atrophy and its progression in two main PSP phenotypes, with multimodal magnetic resonance imaging (MRI); e) to estimate which demographic and clinical factors were the main contributors to the health‐related quality of life (HRQoL) and how did the HRQoL change over a follow‐up period of 1 year in these patients. Methods. The study included 121 patients diagnosed according to the current clinical criteria for PSP‐RS, PSP‐P and MSA‐P. The research partly had the characteristics of the cross‐section study, while the other part was a prospective cohort study. In order to collect data on sociodemographic and phenotypic characteristics of patients with AP, a pre‐designed semi‐structured questionnaire was used. Defining the clinical milestones of progression was based on the criteria recommended in the literature. An extensive battery of scales and questionnaires were used for assessing the severity of motor symptoms and stages of the diseases, cognitive and behavioral status of patients, and assessment of quality of life. For the testing and quantification of specific motor patterns in the AP, a specially designed multisensor system for the objective analysis of the motor pattern using the "finger tapping" method, was used. The MRI study of progression of brain atrophy included 31 PSP patients and 36 healthy controls. The topographic distribution of gray matter and white matter (WM) atrophy, as well as the degree of their progression, were assessed by unconventional MRI methods: cortical thickness (vertex‐by‐vertex analysis), midbrain volumetric examination, diffusion tensor (DT) MRI analysis. Results: Prospective natural history study of AP. The estimated mean survival time was 11.2 years in PSPP, 6.8 years in PSP‐RS and 7.9 years in MSA‐P. More disabling course of PSP‐RS compared to PSP‐P was also highlighted through the higher number of milestones reached in the first 3 years of the disease (p˂0.001), as well as in the trend to reach all clinical milestones earlier. During the entire follow‐up period, frequent falls, severe dysphagia, and cognitive impairment were significantly more frequent in both PSP phenotypes than in MSA‐P, while there were no differences in the frequency of speech disturbances, need for urinary catheterization, and wheelchair dependence, between the investigated groups . Specificity of motor “finger tapping” patterns in AP. The motor pattern of "hypokinesia without decrement" is a PSPRS‐ specific finding, while patients with PD and MSA‐P fulfill the criteria of bradykinesia with a reduction in amplitude and velocity of repetitive movements. Pattern and dynamics of neuropsychiatric disorders in PSP. A general pattern of neuropsychiatric disorders indicates that apathy (92%), followed by depression (76%) and disinhibition (64%), were the most common symptoms in PSP...