Impact of Tau Protein Deposition in Parkinson s Disease
Abstract
Rationale: Dementia is a common and devastating problem in Parkinson s disease (PD) and the closely related illness dementia with Lewy bodies (DLB), affecting an estimated 80% of clinical PD patients and all DLB patients. Recently, DLB has been reconsidered as a kind of PD, because in both diseases the hallmark change in the brain is accumulation of the protein alpha-synuclein into Lewy bodies inside brain cells. However, brain changes of Alzheimer s disease (AD) in the form of tau protein aggregates inside brain cells and beta-amyloid plaques outside brain cells are commonly observed in these diseases at autopsy, and both tau and amyloid have been increasingly linked to cognitive impairment in these diseases. Although much is known about amyloid and tau in the brains of PD and DLB patients after they die, little is known about how tau and amyloid accumulate over time in these diseases, whether they impact alpha-synuclein pathology in life, and whether the accumulation of tau and amyloid causes cognitive impairment. The answers to these questions will reveal whether tau and amyloid should be considered primary targets for the treatment of PD and DLB. Recently developed Positron Emission Tomography (PET) imaging ligands permit tau and amyloid to be measured in the brains of living patients. In clinical research approved by institutional review boards covering safety and ethics in the USA and the world, we and others have already used these tools to show that both amyloid and tau are seen in many patients with PD and DLB who have trouble thinking, but whether amyloid and tau increase in amount as PD and DLB brain disease worsens is unknown. For example, tau and/or amyloid could accumulate early in the course of PD or DLB, setting the stage for future problems in thought and memory (cognition), or only later, causing cognitive problems in real time as they accumulate. Furthermore, spinal fluid measures of alpha-synuclein are known to fall in PD, but whether tau and amyloid worsen this reduction is also unknown. Objective: In this study, we will use tau PET and amyloid PET to study how tau and amyloid accumulate over time in cognitively normal PD, and also in PD dementia and DLB patients. This will allow us to assess whether these protein aggregates drive alpha-synuclein pathology, each other s aggregation, and also cognitive impairment. This research in patients with PD and DLB will be conducted after approval with regard to both safety and ethics by the institutional review committees at our institution. Aims: The Aims of the proposed study are to determine whether tau and amyloid accumulate over time within PD and DLB subjects, whether the presence of tau or amyloid at baseline increases the other protein s deposition and drives down alpha-synuclein levels in spinal fluid, and whether the deposition of tau or amyloid over time accelerates cognitive decline. Relationship of Proposed Work to the Focus Area: In addressing these questions, the proposed work directly addresses the Focus Area of pathophysiological implications of tau protein in PD. Ultimate Applicability of This Research: Successful completion of this work will reveal how tau and amyloid change over time in patients living with clinical PD and DLB, will determine whether they impact alpha-synuclein, a key protein whose aggregation underlies PD and DLB, and will show whether accumulation of tau and/or amyloid drives dementia or other clinical changes in PD and DLB. This knowledge will have many implications for PD and DLB. If tau and amyloid accumulation prove to be major factors that drive progressive cognitive impairment in these diseases, or that drive alpha-synuclein pathology in life, this work will prove important in identifying them as targets for PD and DLB therapies. In this regard, several drugs targeting tau and amyloid are under development for AD, and this work would justify testing these new treatments in PD and DLB. Furthermore, tau and amyl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810516
Entities
People
- Stephen Gomperts
Organizations
- Massachusetts General Hospital
- United States Army