The NET-PDD study: defining the roles of NEuroinflammation and Tau aggregation in Parkinson's Disease Dementia

Parkinson's disease (PD) causes problems with walking and movement, but around half of patients will also develop dementia within the first 10 years of their disease course. The primary goal of this study is to better understand the earliest changes in the brain that lead to memory problems and dementia in PD. These early changes would be the best targets for new treatments to prevent or slow dementia, and may be relevant not just to PD dementia but to other forms of dementia (including Alzheimer's disease), because a number of these conditions share similar features when brains are examined after death. In most conditions involving dementia, it is difficult to study the earliest brain changes before symptoms emerge, but this is possible in PD because the dementia comes later than the movement problems. In addition, my previous work has identified a method of determining whether an individual with early PD is at high risk or low risk of going on to develop a dementia within the next few years (based on performance on thinking tests and genetic variation). This means that we can look specifically at what brain changes are occurring in high dementia risk patients before the dementia actually becomes apparent.

My previous research has contributed to the theory that 2 processes - build-up of a protein called tau, and inflammation within the brain - might be particularly important in the development of PD dementia. The main aim of this study is to investigate this theory by comparing markers of these processes in 2 groups of patients: a group at high dementia risk, and a group at low dementia risk (20 per group). Healthy volunteers of similar age will also be included for comparison. Inflammation and tau deposits will be measured using a special type of brain scanning (PET imaging), as well as in the fluid that bathes the brain and spinal cord (cerebrospinal fluid), and in the blood. Participants will undergo PET scanning at the beginning of the study, as well as a lumbar puncture to collect a cerebrospinal fluid sample, a blood test, and clinical and memory assessments. They will be seen again at 18 months to assess changes in their clinical condition and memory, and have a blood test. Scans, lumbar punctures and blood tests will then be repeated at 3 years to look at how measures of inflammation and build-up of tau protein have changed, and how they relate to the development of memory problems and dementia. As well as measuring markers of inflammation and tau on the scans and in the fluid samples, immune cells will be extracted from blood and used in experiments in the laboratory to look at how they respond to tau and other key proteins. Finally, the most promising of the inflammation and tau-related markers identified in cerebrospinal fluid and blood will be measured in a separate large group of approximately 200 patients and 100 healthy individuals to confirm their value in tracking progression to dementia.

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?

Answering these questions will bring us much closer to developing new treatments to prevent or slow the onset of the dementia which has such devastating consequences for patients with PD. It will also allow us to work out which combination of the tools we are studying (brain imaging, blood and spinal fluid tests) is most useful for tracking progression to dementia and the effect of treatments on this over time, which will be critical for future clinical trials of these treatments.

BACKGROUND
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 following groups will gain benefit from this research.

1. Patients and carers
Parkinson's disease (PD) affects around 2% of those over 65, with the number of UK cases predicted to rise to 162,000 by 2020 (Parkinson's UK). My own work has shown that 50% of these individuals will develop dementia within 10 years of diagnosis, for which no effective treatment is available. Dementia has a devastating effect on quality of life of patients, their families and their carers. The impact on these individuals who are at risk of PD dementia, and on those who will care for them, will be twofold:
i. It will provide an opportunity to acquire understanding of this research and take an active role in providing feedback to shape both this study and our future work. This is an immediate benefit facilitated through the involvement of patients and carers in discussion forums at our 6-monthly open days at the John Van Geest Centre for Brain Repair. In addition, our PD-Patient and Public Involvement (PD-PPI) panel will take an active advisory role on both the conduct of the study and the dissemination of research findings to the public, as outlined in more detail in the 'Pathways to Impact' statement.
ii. In the longer term (within 5 years of project completion), this work has the potential to facilitate clinical trials of therapies targeting neuroinflammation and/or tau aggregation to prevent or slow the development of dementia in PD. If the findings are positive, the study will both confirm the relevance of inflammation and tau as therapeutic targets, and establish the utility of imaging/CSF/blood-based markers of these 2 processes as biomarkers for tracking response to therapy. This will benefit the PD community, but may also benefit those with other dementias such as Alzheimer's disease in which neuroinflammation and tau may play a common pathogenic role.

2. Drug discovery organizations
This work will benefit such organizations (both non-commercial and commercial) within the timespan of the project by providing definitive evidence for (or against) a critical contribution of tau aggregation and/or neuroinflammation in the early stages of PD dementia which will guide development of new therapies. Specific examples include the ARUK Drug Discovery Institute which seeks to develop anti-tau therapies for dementia, and Medimmune, a Cambridge-based subsidiary of Astra Zeneca which seeks to develop immunotherapies for neurological disease.

3. Pharmaceutical industry
The work will benefit commercial organisations (within 5 years of project completion) by informing clinical trial design and optimizing the likelihood of positive trial outcomes through:
i. establishing a strategy for identifying individuals with early evidence of neuroinflammation and tau aggregation so that enriched cohorts can be selected for trials;
ii. identifying the optimal imaging/CSF/blood markers of inflammation and tau aggregation for tracking disease progression and response to therapy over time.

4. National Health Service and Social Care
Through its capacity to accelerate the development of new treatment options to prevent dementia, this research is in line with the key priorities of the government as outlined in the Prime Minister's Challenge on Dementia 2020 and supported by the NIHR's expanding dementia research programme and the establishment of a national Dementia Research Institute. PD dementia is an untreatable problem affecting around 39000 individuals in the UK and has major socioeconomic implications. It is a significant risk factor for hospital admissions and for nursing home placement. Indeed costs of care in PD are estimated to be over 3 times greater for those with dementia than those without. This research will help accelerate progress along therapeutic pathways to slow PD progression and delay the onset of dementia, thus ultimately resulting in significant savings for the NHS and social care within an estimated 10-20 years.