Significance of brain lesions in Parkinson disease dementia and Lewy body dementia.
ABSTRACT Dementia is increasingly recognized as a common feature in patients with Parkinson disease (PD)and dementia with Lewy bodies (DLB), both sharing many clinical and morphological features and believed to form a continuum within the spectrum of Lewy body diseases. Based on a large autopsy series of parkinsonism (31-37% with dementia) and review of the recent literature, the pathological changes underlying cognitive impairment in PD with dementia (PDD) and DLB are discussed. PD cases with Lewy body stages 3-5, i.e. only mild to moderate cortical alpha-synuclein (alphaSyn) depositions,and no additional pathologies, are rarely associated with cognitive impairment, which is frequently seen in PD and DLB cases with considerable cortical and limbic alphaSyn load (increasing Lewy body densities) and/or associated widespread Alzheimer-type pathology. Clinicopathological studies show a negative relation between cognitive impairment and both cortical Lewy body pathology and Alzheimer type changes, suggesting that these either alone or in combination are major causes of cognitive dysfunction, while others related them to presynaptic alphaSyn aggregates. The neuropathology of PDD and DLB is similar, without significant differences between cortical and subcortical Lewy bodies and the pattern of synuclein pathology in the brainstem, but there are topographic differences in nigral lesions, more frequent affection of the hippocampal CA 2/3 subareas and more severe diffuse amyloid plaque load in the striatum of DLB. In conclusion, the pathology underlying cognitive impairment in PDD and DLB is heterogeneous, but there are some differences in the topography and severity of lesions between both phenotypes that need further evaluation.
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ABSTRACT: Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson’s disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson’s disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.Translational Neuroscience. 06/2012; 3(2).
- Molecular Aspects Of Neurodegeneration and Neuroprotection, Edited by AA Farooqi, 01/2011: chapter 7: pages 72-89; Betham Science Publishers.
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ABSTRACT: Synaptic dysfunction is thought to have an important role in the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease (AD) and Lewy body disease (LBD). To improve our understanding of synaptic alterations in health and disease, we investigated synaptosomes prepared from post-mortem human cerebral cortex, putamen (PT), and two regions of the caudate nucleus, dorso-lateral (DL) and ventro-medial (VM), regions commonly affected in AD and LBD. We observed that the fraction of synaptosomal particles with reactivity for dopamine transporter (DAT) was significantly reduced in the PT and VM caudate of patients with neuropathological diagnosis of LBD. As expected, these differences also were reflected in direct measurements of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in caudate and PT of LBD patients. The fraction of synaptosomal particles positive for amyloid β (Aβ) was significantly increased in frontal cortical samples of patients with the neuropathological diagnosis of severe AD, and was positively correlated with disease progression. We also prepared synaptosomes from the striatum of mice with severe loss of DA neurons (Slc6a3-DTR mice) and wild-type littermate controls. We observed markedly reduced levels of DAT-positive synaptosomes in Slc6a3-DTR mice following exposure to diphtheria toxin (DT). Striatal levels of DA and DOPAC in Slc6a3-DTR mice also were reduced significantly following DT exposure. We conclude that flow cytometric analysis of synaptosomes prepared from human or mouse brain provides an opportunity to study expression of pathology-associated proteins and also the specific loss of dopaminergic nerve terminals. Hence, we believe it is a valid method to detect pathological changes at the level of the synapse in LBD as well as AD.Laboratory Investigation advance online publication, 28 July 2014; doi:10.1038/labinvest.2014.103.Laboratory Investigation 07/2014; 94(10). · 3.83 Impact Factor