Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies

• Published in: Nature reviews. Neuroscience Vol. 14; no. 9; pp. 626 - 636
• Main Authors: Irwin, David J., Lee, Virginia M.-Y., Trojanowski, John Q.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2013; Nature Publishing Group
• Subjects: 631/378/1689/364; 692/698/1688/1366/64; 692/699/375/365/1283; 692/699/375/365/1718; alpha-Synuclein - physiology; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - physiology; Amyloid beta-protein; Animal Genetics and Genomics; Behavioral Sciences; Biological Techniques; Biomedicine; Brain - pathology; Brain - physiology; Development and progression; Diagnosis; Genetic aspects; Humans; Neurobiology; Neurons - pathology; Neurons - physiology; Neurosciences; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Physiological aspects; review-article; Risk factors; tau Proteins - physiology; United States
• ISSN: 1471-003X; 1471-0048; 1471-0048
• DOI: 10.1038/nrn3549

Key Points Notable heterogeneity exists in the neuropathological substrates that underlie dementia in the setting of Parkinson's disease dementia (PDD). Nevertheless, the presumptive caudal-to-rostral spread of Lewy body and neurite pathology from the lower brainstem to telencephalic regions, which culminates in a heavy burden of this α-synuclein (α-syn) pathology in limbic and neocortical structures, is the most characteristic pathological finding in most PDD cases. Up to 50% of patients with PDD can have sufficient amyloid-β (Aβ) plaque and tau neurofibrillary tangle (NFT) pathology for the diagnosis of a second neurodegenerative dementia — that is, Alzheimer's disease (AD) — and this co-morbid pathology is more common in PDD than PD. Tau NFT and Aβ plaque pathology may act synergistically with Lewy body and neurite pathology to confer a worse prognosis and a higher burden of cortical Lewy body and neurite pathology in PDD. Clinical phenotypes of PD may help to identify neuropathological subtypes of PD that exhibit differing propensities for developing dementia. For example, non-tremor-dominant or postural gait instability PD phenotypes may often be associated with greater Aβ plaque pathology and shorter times to dementia in patients with PDD than in patients with PD exhibiting less co-morbid AD neuropathology and a tremor-dominant phenotype. Genetic variations may contribute to the heterogeneity in the neuropathology and the time-of-onset of dementia in PD. For example, the apolipoprotein E ( APOE ) ε4 genotype may increase both Lewy body and neurite pathology and AD neuropathology and result in an increased risk of dementia in PD. Moreover, heterozygous mutations in β-glucocerebrosidase ( GBA ) may increase the severity of Lewy body and neurite patholgy in 'pure' synucleinopathies. Further biomarker and detailed clinicopathological correlation studies of prospective patients will help to further elucidate the inter-relationships of AD and α-syn pathology in PD and the development of dementia in patients with PD. These discoveries will be crucial in the development of meaningful disease-modifying therapies for PDD. Many cases of Parkinson's disease (PD) are characterized by not only deficits in movement but also cognitive dysfunction, which can develop into dementia. Here, Irwin et al . review the complex connections between the neuropathological aetiologies that underlie the cognitive deficits associated with PD. Dementia is increasingly being recognized in cases of Parkinson's disease (PD); such cases are termed PD dementia (PDD). The spread of fibrillar α-synuclein (α-syn) pathology from the brainstem to limbic and neocortical structures seems to be the strongest neuropathological correlate of emerging dementia in PD. In addition, up to 50% of patients with PDD also develop sufficient numbers of amyloid-β plaques and tau-containing neurofibrillary tangles for a secondary diagnosis of Alzheimer's disease, and these pathologies may act synergistically with α-syn pathology to confer a worse prognosis. An understanding of the relationships between these three distinct pathologies and their resultant clinical phenotypes is crucial for the development of effective disease-modifying treatments for PD and PDD.