Multiscale and multimodal brain network changes causing Parkinson's dementia

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.