Neuroinflammation, white matter integrity, AD biomarkers and pathology in corticobasal syndrome - PROJECT SUMMARY Corticobasal syndrome (CBS) is a neurodegenerative disorder characterized by impaired motor and higher cortical function. Pathologies underlying CBS are heterogeneous; ~60% have a 4-repeat (4R) tauopathy (CBS- 4R) and 20-30% have Alzheimer’s disease (CBS-AD). It has been shown that molecular pathology influences patterns of brain atrophy in CBS, yet little is known about biological disease mechanisms underlying CBS and how mechanisms are related to molecular pathology. This R01 will focus on assessing the biological mechanism of neuroinflammation in CBS. Neuroinflammation plays a key role in the pathogenesis of different neurodegenerative diseases, including AD and 4R tauopathies, and has been linked mechanistically to damage of the white matter which is a key feature of CBS. The first aim of the grant will use the PET ligand 1C-ER176 to assess the distribution of neuroinflammation in the brain and Neurite Orientation Dispersion and Density Imaging (NODDI) to measure white matter microstructure. The second aim will measure biomarkers of neuroinflammation from blood plasma, such as plasma glial fibrillary acidic protein and proinflammatory cytokines. We will prospectively recruit 80 CBS patients, with each participant undergoing clinical testing, MRI diffusion tensor imaging, ER176, Aβ and tau-PET, and a blood draw. The Aβ and tau PET will be used to classify CBS patients with (CBS-AD) and without (CBS-4R) biomarker-confirmed AD. We will determine whether patterns of ER176 uptake, NODDI abnormalities, and blood plasma metrics differ between CBS-AD and CBS-4R and whether they differ compared to 30 healthy controls and 30 patients with amnestic AD. We will also assess relationships between these different outcome measures and determine whether they are related to markers of disease severity. These first two aims will determine the role of neuroinflammation and white matter microstructure damage in CBS and whether neuroimaging and plasma metrics can be used as indirect biomarkers of AD in CBS. Forty CBS patients will be brought back after two years to allow for the assessment of longitudinal relationships. As we are unable to determine the exact molecular pathology underlying CBS-4R during life, we will further this work in aim 3 by assessing our disease mechanisms of interest in an autopsy cohort of 90 CBS patients with known pathology. We will measure burden of activated microglia and astrocytes, myelin and tau proteins from brain tissue and determine whether burden differs across the three most common pathologies underling CBS-4R (corticobasal degeneration n=30, progressive supranuclear palsy n=30) and CBS-AD (n=30). Findings from aim 3 will complement and help validate findings from our clinical cohort in aims 1&2. This grant is highly significant as results will help elucidate the mechanistic role of neuroinflammation and white matter damage in CBS and determine the value of neuroimaging and plasma measures as biomarkers of disease and pathology. This work may also provide potential mechanistic treatment targets for CBS and biomarkers to help in the selection/stratification of patients for clinical trials.
