Prevalence of Concomitant Pathologies in Parkinson's Disease: Implications for Prognosis, Diagnosis, and Insights into Common Pathogenic Mechanisms

Abstract

Pathologies characteristic of Alzheimer's disease (i.e., hyperphosphorylated tau and amyloid-β (Aβ) plaques), cardiovascular disease, and limbic predominant TDP-43 encephalopathy (LATE) often co-exist in patients with Parkinson's disease (PD), in addition to Lewy body pathology (α-synuclein). Numerous studies point to a putative synergistic relationship between hyperphosphorylation tau, Aβ, cardiovascular lesions, and TDP-43 with α-synuclein, which may alter the stereotypical pattern of pathological progression and accelerate cognitive decline. Here we discuss the prevalence and relationships between common concomitant pathologies observed in PD. In addition, we highlight shared genetic risk factors and developing biomarkers that may provide better diagnostic accuracy for patients with PD that have co-existing pathologies. The tremendous heterogeneity observed across the PD spectrum is most likely caused by the complex interplay between pathogenic, genetic, and environmental factors, and increasing our understanding of how these relate to idiopathic PD will drive research into finding accurate diagnostic tools and disease modifying therapies.

Keywords: Parkinson’s disease; TDP-43; amyloid-β; cerebrovascular disease; co-pathology; tau; α-synuclein.

Fig. 1

Schematic illustrating stereotypical progression for (a) tau pathology: Neurofibrillary Braak stages (9); (b) amyloid-β pathology: Thal phases (10); (c) α-syn: Braak stages (1), dark blue arrows, Lewy pathology consensus criteria, light blue arrows (12); and (d) Limbic predominant age-related TDP-43 (11).

Fig. 2

Overview of potential mechanisms illustrating how co-pathologies may arise and interact. (1) Tau and α-syn monomers assemble into oligomers followed by larger aggregates. Intracellular tau and α-syn have been shown to interact and promote the fibrilization of each other. (2) Genetics can play a role in the relationship between tau and α-syn as both protein aggregates have been observed in LRRK2 carriers. In addition, genome wide association studies have revealed the MAPT locus is associated with increased risk in Alzheimer’s disease (AD) and Parkinson’s disease (PD). APOE ɛ4 is a well-known risk factor for AD; however, when APOE ɛ4 is expressed in α-syn mice motor dysfunction and general neurodegeneration is observed. TARDBP mutations are associated with motor neuron disease; however, the presence of a TDP-43 mutation (p.N267S substitution) has been found in a patient clinically diagnosed with PD. (3) Aβ and α-syn exist in different subcellular compartments; however, in pathological states both have been detected in mitochondria, lysosomes, and autophagosomes. (4) Failing cellular mechanisms can also contribute to the increased accumulation of pathologies observed in neurodegenerative diseases such as PD, as disrupted autophagy has been shown to impact α-syn, Aβ, and tau metabolism and clearance from the brain. (5) α-syn and tau are thought to propagate in a manner reminiscent of prions increasing the likelihood of aggregating in the same cell. Methods associated with this include exocytosis (5a), formation of tunnelling nanotubes (5b) and via synapses (5c). (6) Oligomeric species of tau and α-syn are capable of eliciting and inflammatory response from astrocytes and microglia resulting in an increase in proinflammatory cytokines. This in turn has a feed-forward affect where the upregulated immune system can lead to further protein aggregation and neuronal damage.

Fig. 3

Photomicrograph demonstrating the presence of multiple pathologies in CA1 region of the hippocampus in a PD case. (a) Neurofibrillary tangles (black arrowhead) and neuropil threads (black arrows), (b) amyloid-β plaque, (c) Lewy body, and (d) TDP-43 neuronal intranuclear inclusion (blue arrowhead) and dystrophic neurites (blue arrows). Scale bar represents 100μm.