Active Brain & Nervous System Psychology & Behaviour

Multiscale and multimodal brain network changes causing Parkinson’s dementia

Funder Wellcome Charity-funded
Recipient organisation University College London
Funding £4.1M
Period Sept 2023 — Sept 2031

In plain English

AI plain-English summary

More than half of all Parkinson’s patients will eventually develop dementia, yet doctors cannot predict who will or why. Current treatments for Parkinson’s focus on movement problems, leaving dementia largely unaddressed because its biological roots remain unknown. This project aims to uncover those roots by tracking how brain networks break down in early Parkinson’s dementia. The researcher will combine advanced MRI, PET scans that detect abnormal proteins such as tau and alpha-synuclein, blood-based markers, and drugs that alter neurotransmitter levels to map the sequence of events leading to cognitive decline. If successful, this work could identify which patients are at highest risk of dementia years before symptoms appear, allowing earlier intervention. It may also reveal specific targets—such as faulty feedback circuits or depleted acetylcholine—for new drugs designed to slow or prevent dementia, not just treat motor symptoms. The computational models developed here could eventually help clinicians test treatment strategies virtually before trialling them in people. This is fundamental science aimed at understanding a poorly understood disease mechanism. While no immediate clinical tool will emerge, similar brain-network research has already reshaped how we diagnose Alzheimer’s and multiple sclerosis. A clearer picture of Parkinson’s dementia could do the same.

View original technical description
Dementia affects more than half of patients with Parkinson’s disease (PD) but the underlying mechanisms are not understood. I have previously shown that PD dementia is linked to changes in brain networks, but the causes of network dysfunction are not known. Specific gaps are: the link between network dysfunction and accumulation of pathological proteins such as alpha-synuclein, amyloid and tau; relative importance of feedback versus feedforward signaling within circuits; the role of neurotransmitters such as acetylcholine and noradrenaline on PD dementia; and the sequence of events leading to PD dementia. In this proposal I will use advanced MRI combined with PET imaging, plasma markers and pharmacological manipulation to transform our understanding of PD dementia. My goals are to: - Relate network changes in early PD dementia to underlying neural pathology using tau and amyloid PET and fluid biomarkers - Characterise changes in feedback and feedforward brain networks in early PD dementia using high-field MRI and magnetoencephalography - Understand the link between neurotransmitters and network changes in PD dementia through pharmacological manipulation - Determine the sequence of events leading to Parkinson’s dementia using computational modelling This will shed light onto pathological mechanisms, provide targets for intervention and guide development of effective biomarkers for PD dementia.

View the original record at the funder ↗

Researchers

Rimona Weil (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Exploring the pathways through which amyloid/tau co-pathology impacts dementia in Parkinson's Disease
Multiscale modelling of progression in Parkinson's disease
The NET-PDD study: defining the roles of NEuroinflammation and Tau aggregation in Parkinson's Disease Dementia
Using neuroimaging data to map dysfunctional brain networks and predict symptom severity in Parkinson's disease progression.
Multimodal PET/MRI and 31-Phosphorus magnetic resonance spectroscopy to mechanistically stratify sporadic Parkinson's disease

Original classification

Career Development Award

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