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

Lead Research Organisation: University of Cambridge
Department Name: Clinical Neurosciences

Abstract

Parkinson's disease (PD) causes problems with movement and walking, but half of patients also develop dementia within the first 10 years after diagnosis. This is very difficult to treat and has a major impact on quality of life and care needs. The goal of my fellowship is investigate early biological changes that predict and drive dementia in PD. We already know that abnormal protein deposits (alpha-synuclein and tau) are found in the brain in PD at post-mortem and seem to be linked to dementia, but precisely how they cause dementia is unclear. I am exploring the theory that small clumps of these proteins form early in the disease and cause inflammation in the brain which leads to an earlier dementia. Protein clumps may also leak out of the brain into the blood and activate the body's immune system - which can further drive brain inflammation.
To investigate this, I am measuring inflammation and protein deposits in the brain in PD patients using PET scans, as well as measuring immune markers and protein clumps in the fluid that bathes the brain and spinal cord (cerebrospinal fluid), and in the blood. In order to determine whether these processes predict and drive dementia, I am studying newly-diagnosed PD patients who have not yet developed dementia, and comparing a group at high dementia risk with a group at low dementia risk (with risk determined by thinking and genetic tests), and a group of healthy volunteers ('controls') of similar age.
40 patients (20 high risk, 20 low risk) and 40 controls have been recruited as planned. PET scanning has shown that there is more inflammation in certain brain regions in PD patients at higher dementia risk, and that inflammation and deposition of tau protein is linked across the brain in high risk cases. I have also found evidence of activation of immune cells in the blood in PD, particularly in those at high dementia risk. Furthermore, my results show more infiltration of immune cells from blood into the cerebrospinal fluid in PD compared to controls. I have also been working in collaboration with my colleagues in Chemistry to develop new techniques to visualise very small protein clumps in fluid samples. We have found differences in the composition of these small protein clumps in blood samples from PD patients compared to controls, and shown that similar-sized protein clumps extracted from PD brain samples cause inflammation when mixed with immune cells in the lab.
A critical part of my project involves following study participants over time with repeated assessments at 18 months and 3 years to look at whether early markers of immune activation and protein clumping predict memory decline and dementia, and to see how these markers change alongside changes in thinking and memory. However, my study has encountered delays due to technical problems with PET scanning, availability of certain test kits, and the COVID pandemic and so I will not be able to complete the 3 year assessments by the end of my fellowship. During the delays, I have set up other studies to help answer my research question, including a clinical trial to test whether an immunosuppressant drug azathioprine) has any impact on the progression of early PD.
Extending my fellowship with a 2 year transition award would ensure that I can complete the long-term assessments planned in my original project, and thereby identify the immune and protein markers which are most closely related to developing dementia in PD. These markers are critical for future clinical trials. By the end of the 2 years, I will also have completed the clinical trial of azathioprine in PD, which, if successful, will provide the first evidence that immune suppression can alter disease course in PD. I will also be able to complete my work investigating precisely how protein clumps interact with immune cells in the lab. This will help identify molecules to target with new treatments in future trials aiming to slow progression to dementia in PD.

Technical Summary

My early research showed that half of people with Parkinson's disease (PD) develop dementia within 10 years of diagnosis (Williams-Gray JNNP 2013), which represents a major therapeutic challenge. My CS fellowship aims to understand mechanisms driving progression to PD dementia, with a focus on the role of neuroinflammation. I hypothesize that early soluble aggregates of alpha-synuclein and tau protein: (i)provoke a neuroinflammatory response in the brain through activation of microglial Toll-like receptors (TLRs), and (ii)trigger immune activation in the periphery; immune activation and neuroinflammation in turn drive neurotoxicity and widespread neurodegeneration, with an accelerated progression to dementia in those with a more aggressive immune response. The NET-PDD study is investigating this by comparing newly-diagnosed PD cases at 'high risk' and 'low risk' of dementia and healthy controls, and tracking cognitive progression alongside PET, cerebrospinal fluid and blood markers of protein aggregation and immune activation over time. Baseline data has yielded supportive results but progress with longitudinal data collection has been hampered by several factors including technical issues with PET scanning and COVID-related delays. In mitigation, historic stored biosamples have been used to generate additional data to address my hypothesis, and a complimentary 'proof of concept' trial has been established (AZA-PD - separately funded) to investigate whether peripheral immunosuppression impacts on early PD progression. A transition support award would enable me to: (i)complete collection of critical NET-PDD longitudinal data; (ii)complete the AZA-PD trial; and (iii)develop in-vitro studies with patient monocytes, mechanistically exploring the role of TLRs in mediating protein aggregate-immune interactions. This work will facilitate development of critically needed biomarkers and inform future experimental medicine studies focusing on immune-based therapeutic targets

Publications

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Brown GC (2023) The Endotoxin Hypothesis of Parkinson's Disease. in Movement disorders : official journal of the Movement Disorder Society

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Gonzalez MC (2023) Cognitive and Motor Decline in Dementia with Lewy Bodies and Parkinson's Disease Dementia. in Movement disorders clinical practice

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Holbrook J (2023) Natural killer cells have an activated profile in early Parkinson's disease in Journal of Neuroimmunology

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Kouli A (2024) Neuroinflammation is linked to dementia risk in Parkinson's disease. in Brain : a journal of neurology

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Ye R (2023) Locus Coeruleus Integrity Is Linked to Response Inhibition Deficits in Parkinson's Disease and Progressive Supranuclear Palsy. in The Journal of neuroscience : the official journal of the Society for Neuroscience