De Pablo Fernández, Eduardo; (2019) Pathophysiological mechanisms of non-motor features and their role on the pathogenic process in Parkinson’s disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In the first section, clinical and neuropathological studies were conducted to evaluate the underlying pathophysiological mechanisms of non-motor features in Parkinson’s disease (PD) including hypothalamic dysfunction, circadian abnormalities and constipation. A clinico-pathological study showed an early and progressive involvement by Lewy pathology of the paraventricular, infundibular and supraoptic nuclei of the hypothalamus. Neuropathological involvement spared dopaminergic structures and did not correlate with non-motor clinical features potentially associated to hypothalamic dysfunction. A neuropathological study of the circadian system demonstrated direct histological involvement of the suprachiasmatic nucleus of the hypothalamus likely responsible for circadian dysfunction in PD. Similar neuropathological involvement was seen in progressive supranuclear palsy whilst no neuropathological abnormalities were found in the suprachiasmatic nucleus and pineal gland in multiple system atrophy. A comprehensive assessment of constipation in PD using clinical, radiological and electrophysiological techniques revealed heterogeneous multiple overlapping pathophysiological abnormalities involving slow colonic motility and anorectal dysfunction (rectal hyposensitivity and defecatory dyssynergia) with important clinical implications. The second part of the thesis evaluated the influence of non-motor features on the pathogenic process and disease progression in PD through epidemiological and clinico-pathological studies. A large retrospective record-linkage cohort study showed an increased risk of subsequent PD in individuals with type 2 diabetes, greater in younger participants or those with diabetic complications. Autonomic dysfunction was independently associated with faster disease progression and reduced survival in a retrospective large cohort of autopsy-confirmed PD patients although these findings were not associated with more diffuse or severe neuropathology at post-mortem. Finally, PD subtyping based on a combination of motor and non-motor features at diagnosis predicted disease progression and survival in a large cohort of pathology-proven patients with PD. Lewy pathology and Alzheimer’s neuropathological changes showed different rates of progression among subtypes and, in addition to age, they constitute important determinants of clinical heterogeneity.

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