α-Synuclein strain properties are associated with diagnosis of and progression to Parkinson's disease with dementia

点击翻译按钮获取中文摘要

Dementia with Lewy Bodies (DLB) is the 2nd most common dementia illness after Alzheimer’s disease, by definition is associated with deposition of aggregated alpha-synuclein in the cortex and is identified as a research priority under the Alzheimer’s Disease Related Dementia’s program. Parkinson’s disease dementia (PDD) is one of the DLB’s and is diagnosed when an individual develops dementia more than a year after onset of the motor symptoms of Parkinson’s disease (PD). Up to 1/3 PD patients will have cognitive impairment (PD-CI) at the time of diagnosis and more than 80% become demented over the course of their disease, having progressed from PD-normal cognition (PD-NC), to PD-MCI (Mild CI) and then PDD. This progression, however, is variable with 20% of individuals with PD-NC or PD-MCI after 15 years and the rate of PDD, amongst those who do develop dementia, is highly variable. PDD is particularly debilitating because patients can also suffer from delusions and hallucinations, together leading to significant cost in quality of life and increased mortality over PD alone. Determining the association between pathological markers and PDD clinical presentation is crucial for understanding the pathogenesis and developing more effective symptomatic and disease-modifying therapies. Pathogenic α‐syn transmission has been strongly implicated in mediating pathology spread in a stereotyped fashion from the gut to the brain, with α‐syn pathology in the cortex driving development of dementia. Recent studies support the notion that pathogenic α‐syn may behave in manner similar to strain-specific prions that exhibit distinct biochemical and pathologic phenotypes. These different strains may underlie the heterogeneity in α‐synucleinopathies, and perhaps the variability observed in the onset and progression of cognition impairment (CI) in PD. However, the association between the properties of α‐syn strains and CI in PD is significantly limited. We propose to use an established protocol to amplify α‐syn aggregates by using the template of pathological α‐syn from the CSF samples of our PD-NC and PDD patients, and identify, define and segregate different α‐syn strains by biophysical and biochemical methods and cellular and animal assays. We will compare the strain properties between different cognitive strata in both a cross-sectional (Aim 1) and longitudinal (Aim 2) analysis, to evaluate the extent to which α‐syn strains change with and predict development of PD-MCI and PDD. We will then apply these same methods to gut and brain autopsy tissue from individuals with PD and a gut-brain alpha-synucleinopathy mouse model (Aim 3). We will determine the association between the properties of characterized α‐syn strains and CI in PD. The overarching goal of this project is to determine if PD-MCI and PDD strains and the strain conversion can be developed as biomarkers for the onset and progression of CI in PD. Successful completion of our Aims will mainly identify new markers for predicting the onset and progression of CI in PD, but also uncover the pathogenesis of dementia in PD, discover promising targets for disease modifying and generating novel experimental models.