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

Nature Reviews Neuroscience volume 14, pages 626–636 (2013)Cite this article

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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.

Abstract

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.

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Figure 1: Hypothetical model of α-syn toxicity and spread of pathology in PD and PDD.
Figure 2: Neuropathology of PDD.

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Acknowledgements

We thank the patients and their families who have contributed to the research reviewed here, which has led to meaningful developments in our understanding of Parkinson's disease and related disorders. Funding for our research was provided by the US National Institutes of Health grants P30 AG10124, AG17586, P50 NS53488 and T32-AG000255.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Alzheimer's Disease Core Center, Institute on Aging, University of Pennsylvania Perelman School of Medicine, HUP, Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, 19104–4283, Pennsylvania, USA

    David J. Irwin, Virginia M.-Y. Lee & John Q. Trojanowski

  2. Department of Neurology, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia, 19104–6021, Pennsylvania, USA

    David J. Irwin

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  1. David J. Irwin
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Glossary

Executive functioning

Abilities in mental flexibility, planning and working memory that are mediated by striatal–frontal networks.

Semantic memory

Memory for the meaning and context of objects and concepts that is mediated by the temporal lobe and its connections throughout the neocortex.

Mild cognitive impairment

(MCI). MCI comprises subjective cognitive complaints with objective findings of cognitive impairment in one or more cognitive domains that does not interfere with the patient's ability to perform tasks of daily living. MCI is thought to represent a prodromal state to Alzheimer's disease and other dementias. Recently, clinical criteria have been defined for MCI in the setting of Parkinson's disease.

Bradykinesia

Symptoms of slowed movement seen in Parkinson's disease and other disorders involving nigral–striatal dopaminergic pathways.

Constructional praxis

The ability to draw or copy a figure (such as clock-drawing or drawing intersecting pentagons), which relies on attention, planning and organization skills (executive function) and visuospatial perceptual abilities.

Verbal memory

Short-term memory for words and verbal information that is partially mediated by language function (for example, memory for words tested through a list-learning task).

Transmission

The spread of a pathological protein in an altered conformation (for example, PrPSc) between neurons within an individual; transmission does not necessarily imply that the disease protein is infectious (that is, it can be spread between individuals).

Amyloid fibrils

Insoluble filamentous structures composed of polymerized protein monomers with notable β-sheet conformation, which can be detected with amyloid-binding dyes (for example, thioflavin S).

Cognitive reserve

This refers to the notion of relative resistance to clinical symptoms of neurodegeneration and other CNS insults that is thought to be mediated by neuroplasticity or an ability to recruit additional brain networks to compensate for the disease state; such plasticity may be influenced by education or other environmental or genetic factors.

Cerebrovascular disease

(CVD). Damage to intracerebral blood vessels from atherosclerosis and lipohyalinosis, which are caused by systemic cardiovascular risk factors (for example, hypertension, diabetes and hyperlipidaemia) and result in ischaemic damage to the brain parenchyma (for example, lacunar infarcts).

Amyloid angiopathy

A form of cerebral vasculopathy that is caused by fibrillar amyloid-β deposition in blood vessel walls.

Tauopathies

A family of neurodegenerative disease proteinopathies that are characterized by inclusions composed primarily of the microtubule-associated protein tau.

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Irwin, D., Lee, VY. & Trojanowski, J. Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat Rev Neurosci 14, 626–636 (2013). https://doi.org/10.1038/nrn3549

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