Structural and functional brain changes of cognitive and other non-motor dysfunctions in idiopathic and genetic Parkinson’s disease

Resumen

Parkinson’s disease (PD) is the second most frequent neurodegenerative disease in our environment, affecting more than 300.000 people in Spain, more than 8.000 in the Basque Country, and 4.500 people approximately in Biscay. In addition, several studies have shown the socio-health impact of PD, both in terms of lower labor productivity and lower quality of life. PD is characterized by motor symptoms mainly, however, it also entails other alterations, such as visual hallucinations, mood disorders, sleep disturbances and cognitive dysfunction. In 30% of patients with PD, a deterioration of certain cognitive functions can be observed from the initial stages of the disease. These symptoms increase as the disease progresses, damaging many aspects of patients' daily lives and reducing their quality of life. Studies also show that 80% of PD patients with cognitive impairment develop dementia. In 2004, the team led by Dr. Zarranz and Dr. Gómez-Esteban described for the first time a mutation in the alpha-synuclein gene (E46K-SNCA) in a family from the Basque Country. This mutation induces a disease in the brain by Lewy bodies (the pathological paradigm of idiopathic PD) and also has a clinical phenotype superposable to more aggressive forms of PD, including early cognitive impairment and visuospatial disorders, therefore, is an excellent genetic model of idiopathic PD. This thesis is composed by five scientific contributions, and is an attempt to characterize the pattern of brain damage underlying cognitive impairments and other non-motor dysfunctions in PD through advanced neuroimaging techniques. Firstly, the first study aimed to investigate the neuroanatomical and neurofunctional correlates of verbal memory deficit in PD patients. The second study assessed the functional connectivity within the default mode network (DMN), and the cognitive and brain correlates of the disrupted DMN functional connectivity in PD. The third study evaluated frontal, striatal and limbic brain changes and correlates of apathy in PD patients. The fourth study investigated the classification of Lewy body diseases with a comprehensive set of non-motor features including an extensive cognitive evaluation. Finally, the fifth study assessed structural and resting-state functional connectivity brain differences in Lewy body diseases based on severity of non-motor symptoms. Results revealed verbal memory deficit in PD that was related to white matter alterations in anterior cingulate and to lower brain activation in orbitofrontal regions. Structural-functional relationship underlying verbal memory deficit was also found in PD. In addition, a disruption between posterior and temporal regions within the DMN was exhibited in PD patients, even after controlling for grey matter atrophy. The disrupted DMN functional connectivity is accompanied by lower performance in verbal and visual memory, and visual abilities. Moreover, PD patients with high apathy symptoms showed fronto-striatal and fronto-limbic disruption, while PD patients with low apathy symptoms showed fronto-limbic disruption but fronto-striatal hyperconnectivity. Finally, the clinical picture of severe Lewy body diseases and most affected idiopathic PD patients is characterized by a rapidly evolving cognitive impairment that initiates in the early phase of the development of motor symptoms, and by grey matter atrophy in temporal and parietal areas, white matter alterations in corpus callosum and anterior thalamic radiation, and functional connectivity reductions between language network and dorsal-attentional and salience networks. The characterization of the pattern of brain damage of cognitive and other nonmotor features by neuroimaging and the comparison with those observed in idiopathic forms of Lewy body diseases has an invaluable utility to improve our understanding of the pathophysiology of nervous system in PD. Moreover, it could help clinicians and researchers to identify prognostic biomarkers in this disease when tested longitudinally, which in turn may support the development of effective and more personalized treatment strategies and the accuracy of diagnosis for PD patients.