Free water imaging in PD

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PROJECT SUMMARY/ABSTRACT Dysfunction in protein clearance mechanisms is thought to underlie many neurodegenerative disorders, and specifically those with multi-etiology cognitive impairment and dementia. Abnormal protein accumulation of α- synuclein with aggregates in the form of Lewy bodies (LB) are found in Parkinson’s disease (PD) and β-amyloid (Aβ) and tau protein accumulations in Alzheimer’s disease (AD). However, multi-etiology dementia with mixed LB/AD pathology has been observed at autopsy in up to 80% of patients with Lewy Body Dementias, which includes PD Dementia (PDD) and the closely related Dementia with Lewy Bodies (DLB). For patients who first present with motor symptoms, Aβ and tau aggregation likely occurs somewhere between motor symptom onset and dementia. Understanding mechanisms of proteins clearance from brain tissue is critical to developing interventions prior to dementia onset, but these mechanisms remain controversial. Animal studies show evidence for several brain waste clearance pathways removing Aβ and tau from extracellular spaces in the brain, and for sleep playing a key role, during which an expansion of extracellular spaces appears to facilitate protein clearance. There are limited means of non-invasively evaluating the brain waste clearance system in vivo in human brains. We propose use of diffusion magnetic resonance imaging (dMRI) of free water (FW) and intra voxel incoherent motion (IVIM) that will be acquired during simultaneous PET-MR imaging, to identify the association of brain FW fraction (f) and flow measures with the accumulation of Aβ and tau proteins in patients across the Lewy Body Disease spectrum (PD/PDD/DLB). This high-risk R21 proposal requests funding for dMRI FW/IVIM sequence application and analysis of FW f and flow. These data will be integrated with the Aβ and tau PET, cognitive data, and sleep biomarkers, which are collected through the Stanford Alzheimer’s disease Research Center (ADRC). Leveraging the deeply phenotyped PD and DLB patient data with pure LB pathology and with mixed LB/AD pathology, through the Stanford ADRC, we propose two Specific Aims: 1. Determine associations of FW f and flow (dMRI) with Aβ and tau co-pathology (PET), and cognitive function, in PD and DLB 2. Determine associations of FW fraction and flow with sleep disturbance in PD and DLB. This proposal addresses a critical gap in understanding the role of FW diffusion within the context of Aβ and tau protein accumulation, disrupted sleep-wake behavior, and cognitive decline across the Lewy Body Disease spectrum.