title: Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson's disease.
abstract: The neuropathological substrate of dementia in patients with Parkinson's disease is still under debate, particularly in patients with insufficient alternate neuropathology for other degenerative dementias. In patients with pure Lewy body Parkinson's disease, previous post-mortem studies have shown that dopaminergic and cholinergic regulatory projection systems degenerate, but the exact pathways that may explain the development of dementia in patients with Parkinson's disease remain unclear. Studies in rodents suggest that both the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways may functionally interact to regulate certain aspects of cognition, however, whether such an interaction occurs in humans is still poorly understood. In this study, we performed stereological analyses of the A9 and A10 dopaminergic neurons and Ch1, Ch2 and Ch4 cholinergic neurons located in the basal forebrain, along with an assessment of α-synuclein pathology in these regions and in the hippocampus of six demented and five non-demented patients with Parkinson's disease and five age-matched control individuals with no signs of neurological disease. Moreover, we measured choline acetyltransferase activity in the hippocampus and frontal cortex of eight demented and eight non-demented patients with Parkinson's disease, as well as in the same areas of eight age-matched controls. All patients with Parkinson's disease exhibited a similar 80-85% loss of pigmented A9 dopaminergic neurons, whereas patients with Parkinson's disease dementia presented an additional loss in the lateral part of A10 dopaminergic neurons as well as Ch4 nucleus basalis neurons. In contrast, medial A10 dopaminergic neurons and Ch1 and Ch2 cholinergic septal neurons were largely spared. Despite variable Ch4 cell loss, cortical but not hippocampal cholinergic activity was consistently reduced in all patients with Parkinson's disease, suggesting significant dysfunction in cortical cholinergic pathways before frank neuronal degeneration. Patients with Parkinson's disease dementia were differentiated by a significant reduction in hippocampal cholinergic activity, by a significant loss of non-pigmented lateral A10 dopaminergic neurons and Ch4 cholinergic neurons (30 and 55% cell loss, respectively, compared with neuronal preservation in control subjects), and by an increase in the severity of α-synuclein pathology in the basal forebrain and hippocampus. Overall, these results point to increasing α-synuclein deposition and hippocampal dysfunction in a setting of more widespread degeneration of cortical dopaminergic and cholinergic pathways as contributing to the dementia occurring in patients with pure Parkinson's disease. Furthermore, our findings support the concept that α-synuclein deposition is associated with significant neuronal dysfunction in the absence of frank neuronal loss in Parkinson's disease.
authors: 1 Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden helene.hall@mail.mcgill.ca.
authors: Hélène
authors: H
authors: Hall
authors: 2 Neuroscience Research Australia and the University of New South Wales, Randwick, 2031 New South Wales, Australia.
authors: Stefanie
authors: S
authors: Reyes
authors: 1 Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
authors: Natalie
authors: N
authors: Landeck
authors: 3 Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3010 Victoria, Australia.
authors: Chris
authors: C
authors: Bye
authors: 4 Basic Research and Integrative Neuroscience, Centre for Neuroscience, Department of Life Sciences, University of Trieste, Trieste, Italy.
authors: Giampiero
authors: G
authors: Leanza
authors: 2 Neuroscience Research Australia and the University of New South Wales, Randwick, 2031 New South Wales, Australia5 Discipline of Biomedical Science, School of Medical Sciences, Sydney Medical School, University of Sydney, Lidcombe, 1825 New South Wales, Australia.
authors: Kay
authors: K
authors: Double
authors: 3 Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3010 Victoria, Australia.
authors: Lachlan
authors: L
authors: Thompson
authors: 2 Neuroscience Research Australia and the University of New South Wales, Randwick, 2031 New South Wales, Australia.
authors: Glenda
authors: G
authors: Halliday
authors: 1 Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
authors: Deniz
authors: D
authors: Kirik
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000201:enzymology / Q000473:pathology*; D005260:Female; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D020961:Lewy Body Disease / Q000175:diagnosis* / Q000201:enzymology / Q000523:psychology; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000175:diagnosis* / Q000201:enzymology / Q000523:psychology
chemical_list: D002795:Choline O-Acetyltransferase
keywords: Lewy bodies; Parkinson’s disease; cholinergic neurons; dementia; dopaminergic neurons