Parkinson’s disease and cerebrovascular changes: a clinico-epidemiological and neuroimaging study. Summary of the Habilitation Thesis in Medicine. 321.05 - Clinical neurology

Abstract

Relevance of the Topic. Parkinson’s disease (PD), which is experiencing a global increase in prevalence [1], is frequently associated with vascular risk factors (hypertension, diabetes mellitus, dyslipidemia) that contribute not only to cerebrovascular morbidity but also potentially to the initiation or progression of neurodegenerative processes [2-4]. Evidence supporting the interaction between subclinical cerebral ischemia, vascular dysfunction, and dopaminergic degeneration underpins the hypothesis of a vasculo-neurodegenerative co-evolution [5-6]. Investigating these shared mechanisms may facilitate the identification of common biomarkers and enable early differential diagnosis between idiopathic PD and vascular parkinsonism [7-8]. Clinically, the association of PD with vascular lesions correlates with cognitive impairment, more severe motor symptoms, and reduced responsiveness to levodopa, suggesting a significant functional and prognostic impact [9-13]. Incorporating the vascular profile into the evaluation of PD patients provides a foundation for personalized therapies and secondary prevention interventions, thereby mitigating disability progression and socio-economic burden [13-14]. In a transitioning healthcare system such as that of the Republic of Moldova, local clinicalepidemiological research is essential for adapting screening policies, treatment approaches, and interdisciplinary management of PD [2], [14]. Description of the Study Field and Identification of Research Problems. Despite progress in recent decades, the relationship between Parkinson’s disease (PD) and cerebrovascular disease (CVD) remains incompletely understood, with multiple unresolved issues: (1) common pathogenic mechanisms — evidence for the involvement of microcirculatory impairment, chronic inflammation, and oxidative stress remains indirect [4,15-16]; (2) the role of chronic subclinical cerebral ischemia and its impact on PD progression and therapeutic response is still insufficiently studied; advanced methods such as diffusion-weighted imaging (DWI) and MRI perfusion may aid in early detection [4], [17]; (3) there remains a lack of specific biological or imaging markers for mixed PD–CVD forms, limiting differential diagnosis; (4) characterization of micro- and macrostructural vascular lesions through comparative studies between PD patients and the general population is needed [18], [11]; (5) particularities of vascular risk factors remain unclear — the extent to which the expression of hypertension, diabetes mellitus, or dyslipidemia differs in PD patients compared to the general population is unknown [8], [19]; (6) the influence of therapeutic adherence on PD progression in the context of vascular risk is poorly documented; (7) the impact of CVD on non-motor symptoms of PD — including cognitive impairment, depression, and apathy — requires further investigation to clarify causal relationships [9], [20]; (8) knowledge, attitudes, and practices (KAP) studies on patient and physician perceptions regarding PD–CVD comorbidity could provide a basis for educational and organizational intervention strategies [21]; (9) the absence of clear integrated management guidelines at both international and regional levels complicates treatment of patients with PD and cerebrovascular comorbidities. Approaches to addressing the issues outlined above include longitudinal clinicalepidemiological studies, multimodal brain imaging (advanced MRI, PET), analysis of 5 inflammatory and genetic markers, KAP surveys, and the development of composite risk scores for PD–CVD. In the Republic of Moldova, the lack of epidemiological and clinical-imaging data concerning PD and vascular comorbidities justifies the need for an integrative study to guide public health policies and enable treatment personalization [14, 22-23]. Research Aim: To investigate the clinical-epidemiological, imaging, and management characteristics of patients with Parkinson’s disease in the population of the Republic of Moldova, through analysis of the association between vascular risk factors and cerebral vascular neuroimaging changes, evaluation of imaging heterogeneity to assess its clinical impact, and development of personalized and systemic management recommendations tailored to the specific needs of this patient group. Research Objectives: 1. To conduct a clinical-epidemiological evaluation of patients with Parkinson’s disease in the population of the Republic of Moldova to identify an integrative clinical-epidemiological profile and the medico-social particularities of these patients. 2. To phenotype Parkinson’s patients based on the nature of the association (comorbidity or causality) with cerebrovascular disease, as well as according to the dominant clinical-evolutionary syndrome, to develop personalized management recommendations tailored to patient needs. 3. To investigate the presence and extent of vascular involvement in patients with Parkinson’s disease and its impact on the clinical manifestations of Parkinson’s disease. 4. To assess vascular risk factors in Parkinson’s disease patients, their pharmacological management, and their influence on clinical manifestations of Parkinson’s disease, as well as to study the correlation between these factors and cerebral neurovascular imaging lesions. 5. To evaluate the association of Parkinson’s disease with neurovascular imaging lesions and to investigate their role in the clinical manifestations of Parkinson’s disease. 6. To study the management of Parkinson’s disease patients within the healthcare system of the Republic of Moldova through Knowledge, Attitudes, and Practices (KAP) analysis and to identify existing barriers. 7. To develop institutional and national recommendations regarding the comprehensive diagnosis of Parkinson’s disease and the interdisciplinary management of these patients. Summary of Research Methodology and Justification of Chosen Methods. Fundamental research and clinical studies in the field of Parkinson’s disease have served as the theoretical and scientific methodological foundation, demonstrating that Parkinson’s disease is a pathology with considerable impact on the patient, their immediate entourage, and society [24], as well as a condition that demands significant involvement of the healthcare system [25]. The selection of research methods and interpretation of results were guided by recent studies indicating associations between Parkinson’s disease and cardiovascular and cerebrovascular pathology, which 6 negatively affect the progression and clinical manifestations of Parkinson’s disease [26]. The current research considered neuroimaging studies from recent years highlighting the presence and role of cerebral vascular lesions in the onset and evolution of Parkinson’s disease [27]. Cerebral vascular lesions and vascular risk factors are investigated from the perspective of potential aggravating factors for Parkinson’s disease [4]. The study’s aim and objectives were addressed through clinical and neuroimaging methods, as well as through interviews with physicians and patients to elucidate their knowledge, attitudes, practices, and encountered barriers. Data collection was performed both qualitatively and quantitatively via questionnaires and assessment scales covering epidemiological, medico-social, motor and non-motor clinical aspects, as well as psycho-affective and cognitive domains. Additionally, internationally approved neuroimaging protocols for evaluating patients with Parkinson’s disease were applied, in accordance with international recommendations aimed at optimizing Parkinson’s disease research [28]. Novelty and Scientific Originality: • The novelty of the conducted research lies in the complex, multidimensional, and interdisciplinary innovative approach to patients with Parkinson’s disease in the Republic of Moldova — a neurodegenerative disorder potentially strongly influenced by vascular pathophysiological mechanisms. • The study provides an integrative concept of Parkinson’s disease within the population of the Republic of Moldova, highlighting the clinical heterogeneity of PD and presenting the patient’s profile in relation to family, society, and healthcare services. • The in-depth investigation of neurovascular imaging changes identified greater severity of vascular impairment and specific patterns of cerebral vascular lesion localization in PD patients. • The research found that cerebrovascular changes impact the progression and severity of Parkinson’s disease, functional disability caused by both conditions, quality of life, development of neuropsychiatric symptoms, and cognitive impairments, which consequently affect family and societal integration through reduced work capacity, disability, workforce dropout, and increased burden on healthcare systems. • The study emphasizes the necessity of early detection of vascular risk factors to enable comprehensive, multidisciplinary, early, and proactive management. Significant Problem Addressed in the Field. This study is the first and only research in the Republic of Moldova to phenotype the medico-social aspects and clinical particularities of patients with Parkinson’s disease from the country, as well as to map the barriers to specialized medical care for these patients. The study’s findings identified an aggravating effect of the association and burden of vascular risk factors and cerebrovascular lesions on the clinical severity of Parkinson’s disease. These results enable the optimization of personalized management for patients with Parkinson’s disease in the Republic of Moldova. 7 Theoretical Significance. The results of this research extend and deepen the existing knowledge regarding the role of vascular mechanisms in the neurodegenerative processes of Parkinson’s disease and their impact on the clinical-evolutionary severity of the disease. The study identified an aggravating effect of the presence and burden of vascular risk factors, as well as the presence and severity of cerebral vascular lesions, on the severity of motor and non-motor symptoms of Parkinson’s disease, patients’ functional status, and their quality of life. Applied Value. The importance of a multidisciplinary approach to patients with Parkinson’s disease was established, emphasizing early and proactive detection of vascular risk factors—key mediators of the relationship between Parkinson’s disease and cerebrovascular disease. This study is the first in the Republic of Moldova to evaluate the management of Parkinson’s disease patients from both the perspective of healthcare service beneficiaries and providers. Barriers to access specialized medical services for Parkinson’s disease patients were identified, aiming to improve patientcentered access to care. Preferences of both patients and healthcare providers regarding Parkinson’s disease management were assessed to formulate tailored recommendations. Main Results Submitted for Defense: 1. The clinical-epidemiological and medico-social pattern of patients with Parkinson’s disease in the Republic of Moldova varies according to biological criteria and disease progression. 2. The nature of the association — comorbidity or causality — between cerebrovascular disease and parkinsonism results in particular clinical-evolutionary phenotypes of the disease, necessitating differentiated management for these patients. 3. The dominant clinical syndrome of Parkinson’s disease may be indicative of a specific clinical-evolutionary phenotype, which determines the specific needs for personalized patient management. 4. Vascular risk factors are more prevalent in the population of patients with Parkinson’s disease. 5. The presence and burden of vascular risk factors are associated with greater severity of motor and non-motor symptoms. 6. Cerebrovascular lesions are more prevalent in the population of patients with Parkinson’s disease and exhibit a specific pattern of localization. 7. The presence and severity of cerebrovascular lesions are associated with distinct clinical features, onset, and progression of Parkinson’s disease. 8. Barriers exist in the management of Parkinson’s disease within the healthcare system of the Republic of Moldova, both at the level of patients and specialized service providers. Approval of the Study Results. The main results of the research were communicated and discussed at various national and international scientific forums, including the European Academy of Neurology Day in the Republic of Moldova, held jointly with the Congress of Neurologists of the Republic of Moldova (Chișinău, 16– 18 September 2021); the National Alzheimer’s Disease Conference (CNALZ) (Iași, 8 Romania, 23–26 February 2022, invited lecturer); the 4th Edition of the National Conference on Modern Neurosciences “Parkinson’s Disease & Other Movement Disorders” (Iași, Romania, 6–8 April 2023, invited lecturer); the 6th International Conference on Nanotechnologies and Biomedical Engineering (Chișinău, Republic of Moldova, 20–23 September 2023, invited lecturer); the 6th National Congress of Neurosciences (Iași, Romania, 9–12 October 2024, invited lecturer); the National Conference on Modern Neurosciences "Parkinson’s Disease and Other Movement Disorders" (Iași, Romania, 11–13 April 2024 and 11–13 April 2025, invited lecturer); the 26th World Congress on Parkinson’s Disease and Related Disorders (Amsterdam, Netherlands, 1–4 May 2021); the European Academy of Neurology Congress MDS (Copenhagen, Denmark, 27–31 August 2023); and the International Headache Congress (on-line, audio presentation, 8-12.09.2021). The thesis was discussed and approved at the joint meeting of the Functional Neurology Laboratory of the INN, Neurology Departments 1 and 2 of the Nicolae Testemițanu State University of Medicine and Pharmacy, and the Brain Health Center on 22 May 2025 (Minutes No. 7); as well as at the Scientific Seminar of specialties 312 Physiology; 321 General/Specialized Medicine: 312.02 Neurosciences (including Psychophysiology), 321.05 Clinical Neurology, 321.21 Neurosurgery, minutes dated 1 July 2025. Publications on the Thesis Topic. A total of 42 publications have been produced on the thesis topic, including: 1 national monograph, 1 chapter in an international monograph (SCOPUS indexed), 1 chapter in a national monograph, 5 SCOPUS-indexed articles, 1 article in other international journals, 1 national article category A, 4 national articles category B+, 3 national articles category B, 4 national articles category C, 4 other articles from the Republic of Moldova, 8 national abstracts, 11 international abstracts, as well as 4 innovations, 4 implementation acts, and 3 copyrights. Volume and Structure of the Thesis: The thesis contains an introduction, six chapters of original results and discussions, conclusions and recommendations, a bibliography of 455 titles, 24 appendices, 265 pages of main text, 74 figures, and 42 tables. The research results have been published in 42 scientific works.