Cholinergic and dopaminergic aspects of dementia in Parkinson's disease: postmortem neuropathological findings and modeling of cognitive dysfunction in rodents

Sammanfattning: Motor symptoms are currently considered the first clinical hallmark of Parkinson’s disease (PD). They develop as a result of dopamine loss in the striatum, subsequent to the progressive neurodegeneration of dopamin- ergic neurons in the substantia nigra. However, non-motor symptoms are frequent in PD patients and can greatly affect their quality of life. Among these, cognitive impairment affects primarily executive functions, as well as memory and attention. The diagnosis of dementia is made when the cognitive decline has progressed to a stage where the activities of daily living are severely affected. Although Lewy bodies containing alpha-synuclein may be a key neuropathological feature of dementia in Parkinson’s disease, the exact neurochemical deficits responsible for the development of cognitive decline are less clear. In fact, studies have shown separately that the dopaminergic and cholinergic systems can be affected in cognitively impaired and demented PD patients. The aim of this thesis was to investigate how the dopaminergic and cholinergic deficits contribute to the emergence of cognitive impairment in PD. To this end, detailed histological and stereological analyses of both neuronal populations were performed on postmortem brains from PD patients with and without dementia and suggested that concomitant degeneration of a subpopula- tion of non-nigral midbrain dopaminergic and basal forebrain cholinergic neurons could be an important factor in the development of dementia in PD. This study also demonstrated that the Lewy pathology was more severe in the basal forebrain and hippocampus in demented individuals compared with non-demented patients. To further elucidate the involvement of these particular deficits in dementia, we then attempted to model cognitive dysfunction in rats via targeted alpha-synuclein overexpression in the ventral tegmental area and the medial septum/vertical limb of the diagonal band of Broca, two structures rich in dopaminergic and cholinergic neurons, respectively. The animals displayed a unique impairment in spatial learning and memory, as assessed by the Morris water maze. The behavioral impairment appeared to be mediated by the alpha-synuclein pathology in the surviving neurons, thus suggesting a possible cellular dysfunction. Finally, this thesis describes a novel method to monitor the activity of choline acetyltransferase, the enzyme mediating acetylcholine synthesis, based on magnetic resonance spectroscopy. Future develop- ment of this method for in vivo applications could help discern the nature and the role of the cholinergic dysfunction in PD more precisely.