Solo or Trio: What is the protein-pathology underpinning Parkinson’s Disease Dementia?

Guest writer: Yuanxi Zhang, MD, MS

Parkinson’s Disease Dementia(PPD)

Parkinson’s disease (PD) is a neurodegenerative, movement disorder, which is characterized by motor symptoms and non-motor symptoms. Classic motor symptoms include resting tremor, muscle rigidity, slow movements, postural and balancing issues. Among all non-motor manifestations, dementia is one of the most common symptoms. Parkinson’s disease patients have a 3.5-6.1 times higher risk of developing dementia compared to general population 1 .The prevalence of Parkinson’s Disease Dementia (PDD) among Parkinson’s Disease patients is estimated to be 30-75% 2 . On average it takes about 10 years after PD diagnosis 3 to develop PDD.

Neuropathology of PPD

The pathological hallmarks of PDD are dopaminergic neuron loss in midbrain and the formation of ɑ-synuclein Lewy body and Lewy neurites across multiple brain regions from brain stem, limbic system, sub-cortex to cortex. Misfolded ɑ-synuclein aggregates and forms insoluble filaments (Lewy neurites) or sphere-shaped bodies(Lewy bodies). A multitude of studies have revealed that ɑ-synuclein contained Lewy bodies or neurites are the most compelling factors that contribute to PDD and directly correlated with PDD. A study 4 from 45 PD cases has shown that the cognitive impairment correlates with Lewy bodies especially with cortical Lewy bodies. Besides, a comparison study 5 conducted with 92 PDD and 48 non-demented PD cases has revealed recently that the severity of cortical Lewy bodies or neurites is the factor that correlates with PDD. Heiko Braak 6 and colleagues even revealed a staging map of Parkinson’s disease based on topography of ɑ-synuclein neuropathology from brainstem to limbic and neocortical regions in the brain.

Synergy between ɑ-synuclein, Amyloid-β and tau

All the evidence mentioned above points towards ɑ-synuclein contained Lewy bodies as culprit

for PDD. However, more and more studies on neuropathology of PDD have shown that ɑ-

synuclein is not working solo. One of the studies 7 recently has found that up to 50% patients with

PDD also presented neuropathology of Amyloid-β plaques and tau neurofibrillary tangles along

with ɑ-synuclein Lewy bodies or Lewy neurites. There is an increasing amount of evidence

collected from both clinical and experimental data that substantiates a synergistical feature

between ɑ-synuclein, Amyloid-β and tau underlying neuropathology of PDD.

Clinical data

First of all, data 8 collected and analyzed from 57 patients with PDD or dementia with Lewy Bodies (DLB) has shown an association between a longer duration of parkinsonism prior to dementia and less severe cortical a-synuclein pathology and lower Amyloid-β plaque scores. The results revealed a synergistical collaboration between these two proteins behind developmental curve of PDD. Furthermore, a recent study 9 from Europe has analyzed 56 PD cases, 29 of which were diagnosed with PDD, using quantitative and semi quantitative assessments on all three protein pathologies: a-synuclein, tau and Amyloid-β. The study has found a significant positive correlation to each other. More importantly, the study findings also revealed that a combination of all three protein pathologies is a better predictor of dementia than any single protein pathology. Another study 10 from same region conducted with a total of 89 patients with DLB or PDD has revealed similar findings abovementioned, that is, not one, but combined pathologies of Amyloid β-plague and phosphorylated tau tangles, and ɑ-synuclein Lewy bodies or neurites has become a major determining factor in the development of dementia of PD patients and indicating that the combination of all three protein pathologies contributed to cognitive decline in patients with DLB and PDD.

Frequency of pathology scores in (A) control, (B) Parkinson's disease dementia, (C) dementia with Lewy bodies and (D) Alzheimer's disease. The frequency of each pathology score, by brain region, was calculated as described in “Materials and Methods” section. The left‐hand y‐axis represents the percentage of cases with a particular score. BA9, BA21, BA24 and BA40 refer to the Brodmann areas, as defined in Materials and Methods section. “α‐Syn” is α‐synuclein labeling of Lewy bodies and neurites; “tangles” refer to phosphorylated tau labeling of neurofibrillary tangle and neurites; “plaques” is labeling of senile plaques with an antibody to Aβ.

Experimental data

Besides, the collaboration between these proteins have also been corroborated on animal model

or cellular level. Utilizing human ɑ-synuclein/human Amyloid-β protein precursor(APP)

transgenic mice, the study 11 has found that “Amyloid-β peptides enhance a-synuclein

accumulation and neuronal deficits”. In another study 12 , Lani K. Clinton and colleagues

generated a triple transgenic mouse line with human Amyloid-β, human tau, and mutant human

a-synuclein, which would develop Alzheimer’s disease(AD) and DLB. The study illustrated that

not only did both Amyloid-β plaque pathology and tau pathology deteriorated dementia in these

triple transgenic mice, but also pathological changes in a-synuclein and Lewy body-like deposits

accelerated dementia in DLB-AD mice.

In addition, the synergistic features of between ɑ-synuclein and tau or Amyloid-β were also observed on cellular level. In the study 13 , Elisa A. Waxman and her colleague have demonstrated that a-synuclein is able to promote the formation of neurofibrillary tangle-like aggregates using human-derived cellular model, and that the promotion of a-synuclein is affected by status of tau Howlett DR, et al. Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias Brain Pathology.2014. mutation and the phosphorylation. Furthermore, another study 14 conducted with cell line PC12 by Anna Kazmierczak and her colleagues has also revealed that “a-synuclein enhances the release and toxicity of Amyloid-β”.

In conclusion

Although the synergistical feature of Amyloid-β, tau and ɑ-synuclein pathology in PDD have

become manifest, there are some pitfalls that also are imperative to be pointed out: first of all,

not all PD patients with cortical ɑ-synuclein pathology will develop dementia, a small

percentage 15 of PD cases with ɑ-synuclein pathology has shown no any signs, symptoms of

dementia. Secondly, not all PDD patients present cortical ɑ-synuclein pathology, there are PDD

patients that didn’t show cortical ɑ-synuclein pathology from post-mortem examination.

Methodology employed to assess clinical symptoms may explain this exception to some extent.

More data or studies are needed to interpret this issue.

In the future molecular mechanisms of how three proteins work together in the development of

PDD needs to be explored so that effective treatments can be developed accordingly.

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Keywords: Parkinson’s disease, Parkinson’s disease dementia, Neuropathology, ɑ-synuclein,

synergy, neurodegeneration, movement disorder.