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Current Concepts and Controversies in the Pathogenesis of Parkinson's Disease Dementia and Dementia With Lewy Bodies

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Review

Current Concepts and Controversies in the Pathogenesis of Parkinson's Disease Dementia and Dementia With Lewy Bodies

Rimona S Weil et al. F1000Res.

Abstract

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are relentlessly progressive neurodegenerative disorders that are likely to represent two ends of a disease spectrum. It is well established that both are characterised pathologically by widespread cortical Lewy body deposition. However, until recently, the pathophysiological mechanisms leading to neuronal damage were not known. It was also not understood why some cells are particularly vulnerable in PDD/DLB, nor why some individuals show more aggressive and rapid dementia than others. Recent studies using animal and cell models as well as human post-mortem analyses have provided important insights into these questions. Here, we review recent developments in the pathophysiology in PDD/DLB. Specifically, we examine the role of pathological proteins other than α-synuclein, consider particular morphological and physiological features that confer vulnerabilities on some neurons rather than others, and finally examine genetic factors that may explain some of the heterogeneity between individuals with PDD/DLB.

Keywords: DLB; Dmentia with Lewy Bodies; PDD; Parkinson's disease dimentia; neurodegeneration.

Conflict of interest statement

Competing interests: RSW, TL and JB declare that they have no competing interests. AES has consulted for AstraZeneca, Medtronic and Grunenthal, Novartis Pharmaceuticals, Merck Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals and Medtronic; has served on the advisory boards of Boehringer Ingelheim Pharmaceuticals and Osmotica; received honoraria from Boehringer Ingelheim Pharmaceuticals; holds stock in AstraZeneca and received royalties from Oxford University Press. JMS has received research funding and positron emission tomography tracer from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly and Company); has consulted for Roche, Eli Lilly and Company, and MSD; given education lectures sponsored by Eli Lilly and Company and serves on a data safety monitoring committee for Axon Neuroscience SE.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Alpha-synuclein pathology.
( a) Lewy body found in the dopaminergic cells of the substantia nigra (double arrow) along with Lewy neurites (arrows). ( b) Lewy bodies observed in the cingulate gyrus (arrows). ( c) A dense network of Lewy neurites in the CA2 subregion of the hippocampus. Bar = 50 µm ( a) and 100 µm ( b, c).

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    2. F1000 Recommendation

Grant support

RSW has received grants from the Academy of Medical Sciences and the National Institute for Health Research Biomedical Research Centre and is supported by a fellowship from University College London and the Wellcome Trust. TL is funded by an Alzheimer’s Research UK senior fellowship. JB is funded by a fellowship from the Alzheimer’s Society. AES acknowledges support from the EU Commission, Parkinson’s UK, GE Healthcare, ESRC, Amgen Pharmaceuticals and the Movement Disorders Society. JMS acknowledges the support of the National Institute of Health Research Biomedical Research Centre and has received grants from the Wolfson Foundation, Medical Research Council, Alzheimer’s Research UK, Brain Research Trust, Engineering and Physical Sciences Research Council, and European Union’s Horizon 2020 research and innovation programme.

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