The NET-PDD study: defining the roles of NEuroinflammation and Tau aggregation in Parkinson’s Disease Dementia
Study Code / AcronymNET-PDD
Status / StageActive
Dates1 February 2018 -
31 January 2023
Duration (calculated)04 years 11 months
Funder/Grant study pageMRC UKRI
Contracted CentreUniversity of Cambridge
Contracted Centre Webpage
Principal InvestigatorCaroline Williams-Gray
WHO CatergoriesUnderstanding Underlying Disease
Disease TypeParkinson's Dementia
CPEC Review Info
|Study Code / Acronym
|Status / Stage
|04 years 11 months
|Funder/Grant study page
|University of Cambridge
|Contracted Centre Webpage
Dementia affects half of Parkinson’s disease patients within 10 years of diagnosis with a major impact on quality of life. Whilst cortical a-synuclein pathology has been linked to PD dementia (PDD), other factors are implicated. I hypothesize that PDD is driven by oligomeric forms of tau as well as a-synuclein, which provoke a neuroinflammatory response through activation of microglial Toll-like receptors (TLRs), in turn catalyzing the disease process. AIMS 1. to establish that neuroinflammation and tau aggregation are critical early events in PDD; 2. to demonstrate that oligomers of tau and a-synuclein are quantifiable in CSF and blood and are reliable biomarkers of PDD risk; 3. to show that these oligomers play a critical role in driving an inflammatory response in PD through activation of TLRs. METHODS I will compare 2 groups with newly-diagnosed PD, at ‘high risk’ (n=20) or ‘low risk’ (n=20) of dementia, and age-matched controls (n=40). Participants will undergo PET scans, lumbar puncture and blood sampling at baseline and 3 years, with interim clinical assessment. Specifically: 1. [11C]PK11195 and [18F]AV1451 PET will be used to measure microglial activation and tau deposition in the brain respectively; 2. CSF and serum samples will be analyzed for inflammatory cytokines, a-synuclein and tau using multiplex immunoassays; 3. novel methods will be used to quantify oligomers in CSF and blood including single molecule fluorescence spectroscopy and proximity ligation assays; 4. the inflammatory response of participant monocytes to tau and a-synuclein oligomers will be measured in vitro, with and without TLR inhibition. Candidate CSF and blood biomarkers will be validated in an independent cohort (200 PD, 100 controls). IMPORTANCE This will provide definitive evidence to support clinical trials of immunotherapeutic and anti tau-aggregation therapies to delay the onset of dementia in PD, and establish optimal biomarkers for these trials.
The research will specifically address these key questions:
1. Are inflammation and tau deposition important early events in the brain as Parkinson’s dementia is developing?
2. Can we measure small clumps (‘oligomers’) of tau and other related proteins (such as alpha synuclein) in the spinal fluid and blood of Parkinson’s patients at high risk of dementia, and is this a useful tool to help predict and track development of dementia?
3. Do these abnormal clumps of tau protein drive an inflammatory response in patients’ immune cells?