Long-term prospective study of contribution of vascular, metabolic and inflammatory co-morbidities to cognitive and motor impairment in Parkinson's disease

MUDr. Branislav Veselý, Ph.D.

Doctoral thesis

Abstract:

Dizertačná práca je zložená zo 4 rukopisov prác publikovaných v impaktovaných časopisoch hodnotených podľa Web Of Science v Q1 a Q2. Piaty rukopis, ktorý sumarizuje výsledky longitudinálnej štúdie je aktuáln v recenznom konaní v magazíne Movement Disorders Journal. Celkovo práca pozostáva z dvoch prehľadových prác a troch originálnych publikácií. Prvé tri práce sú zamerané na vaskulárne komorbidity, hlavne na zmeny bielej hmoty mozgu zobrazené na MRI. Prvé dve práce sú prehľadové články o literatúre o negatívnom vplyve zmien bielej hmoty mozgu na motorické a kognitívne príznaky Parkinsonovej choroby (PCH). Tretia práca je o negatívnom vplyve zmien bielej hmoty mozgu na progresiu z normálneho kongitívneho stavu na mierny kognitívny deficit. Štvrtá práca je zameraná na negatívny vplyv zápalových markerov na kognitívny status pacientov s PCH. Piata práca sumarizuje výsledky longitudinálnej štúdie o negatívnom vplyve vaskulárnych, metabolických a zápalových faktorov na pokles kognitívnych funkcií pacientov s PCH. Dôležitým faktom tejto časti výskumu je že komorbidity sú potenciálne liečiteľné a ich eliminácia môže v pozitívnom zmysle zlepšiť priebeh PCH. Moja práca nadväzuje na dlhodobý výskum prof. Rektora a jeho tímu ohľadne vaskulárnych a zápalových komorbidít a ich vplyvu na PCH. Na základe výsledkov našich štúdii môžeme potvrdiť klinický dôležitý negatívny vplyv vaskulárnej, metabolickej a zápalovej patológie na progresiu zhoršovanie symptómov PCH. Väčšina vaskulárnych, metabolických a zápalových faktorov je liečitelná a preto navrhujeme dôsledné detekovanie patologických vaskulárnych a metabolických zmien a tým možné predídenie deteriorácie PCH resp. zlepšenie priebehu PCH. Taktiež sme navrhli jednoduchý nástroj pozostávajúci s použitia QRISK2 nástroja, dotazníka kvality života a hladiny kyseliny močovej, ktorý sa dá použiť s pomerne vysokou senzitivitou a špecificitou na predikciu progresie kognitívnych funkcií s normálneho stavu do mierneho kognitívneho deficitu. Samozrejme na validizáciu sú potrebné ďalšie štúdie s dostatočným počtom pacientov.

Abstract:

In my dissertation thesis, I present four manuscripts published in journals evaluated as Q1 and Q2 according to Web of Science (WOS) ranking. A fifth manuscript, which summarizes the results of a longitudinal study, is under revision with Movement Disorders journal. Altogether, this thesis contains two reviews and three original manuscripts. The first three papers were focused on vascular co-morbidity, in particular on white matter lesions in the MRI. The first two of these manuscripts reviewed the literature regarding the contribution of white matter lesions to PD motor and gait impairment and cognitive impairment. The third manuscript described the contribution of white matter lesions to the transition from CN to MCI. The fourth paper focused on the relationship between inflammatory markers and cognitive impairment in PD. The last manuscript provides the results of a two-year longitudinal study on the contribution of vascular, metabolic, and inflammatory comorbidities to cognitive decline in PD, in particular to the transition from CN to MCI. The importance of this research area is underlined by the fact that co-morbidities are potentially treatable and that their treatment might influence the clinical course of PD. My work continues in the line of the long-term research of Ivan Rektor’s team on vascular and inflammatory contribution to PD. In our studies, we focused on the status and progression of clinically relevant cognitive and motor impairment in PD. Based on the results of a long-term prospective study, we can conclude that the vascular, metabolic, and inflammatory pathology significantly influences the cognitive and motor status in PD. The results of our studies confirm a clinically important role of vascular impairment in cognitive and motor decline in PD. The cumulative index of vascular risk factors and white matter lesions are associated with clinically important cognitive impairment in PD, i.e. the transition from normal cognition to mild cognitive impairment. Our results indicate an impact of inflammation on non-motor signs and quality of life in PD. The increase of levels of serum inflammatory biomarkers may indicate the progression of non-motor impairment in PD. As most of the investigated co-morbidities are potentially treatable, we suggest that by treating the co-morbidities we could positively influence and possibly slow the development of cognitive decline in PD and ultimately even improve patient quality of life in PD. As we were able to demonstrate a sensitivity of non-motor symptoms to the elevation of inflammatory markers, we suggest that these symptoms, in particular cognition and mood disturbances, should be given more attention in further testing of the therapeutic potential of anti-inflammatory agents. Our results and other cited studies make it increasingly clear that potentially treatable co-morbidities are clinically relevant for important cognitive decline in PD. We propose that a careful evaluation of the general health status (not only from a strict neurological perspective) of patients with PD should performed and effectively managed in routine clinical practice. We constructed a simple cognitive risk predictor model (using QRISK2, the ADL questionnaire, and the level of uric acid) that could be easily used in clinical practice to predict the progression from NC to MCI. However, independent prospective validation of this model is needed. Further prospective long-term studies on larger populations should be encouraged to confirm the role of co-morbidities in PD progression.

Keywords

vascular risk factors, inflammation, metabolic factors, cognitive impairment, Parkinson’s disease, white matter lesions

Language used: English

Date on which the thesis was submitted / produced: 10. 10. 2018

Thesis defence

• Date of defence: 17. 12. 2018
• Supervisor: prof. MUDr. Ivan Rektor, CSc.
• Reader: doc. MUDr. Kateřina Menšíková, Ph.D., doc. MUDr. Matej Škorvánek, PhD., MUDr. Hana Brožová, Ph.D.

Masaryk University

Faculty of Medicine

Doctoral programme / field:
Neurology (4-years) / Neurology