Microstructural changes in gray and white matter in aging and AD

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PROJECT SUMMARY Accumulating neuropathological and animal studies suggest that AD pathology impacts brain microstructure years before clinical manifestation of the disease. Various processes involved including alterations in dendritic arborization and spines, neurite morphology, synaptic density, and axonal transport and packing. Until recently, the evaluation of these microstructural properties and their association with AD pathology has been mainly limited to postmortem tissue. Recent advances in MRI techniques have provided us with the ability to measure cortical and white matter microstructural properties such as neurite morphology and macromolecular tissue content in human in vivo. In the proposed study, we will employ a set of advanced quantitative MRI sequences and analytical approaches to measure changes in cortical and white matter neurite morphology and macromolecular content in preclinical AD and will examine their association with cognitive outcomes, and amyloid and tau pathology measured by PET. We have recently demonstrated the utility of these measures in detecting alterations in cortical and white matter neurite and macromolecular content in a sample of healthy older adults and patients with amnestic mild cognitive impairment. We have also tested the association between these measures and AD pathology in a small sample of older adults with confirmed AD pathology. Teaming up with experts in early AD characterization and AD pathology and leveraging Stanford ADRC PET- MR and deep phenotyping resources, we will study the following aims on a sample of 120 older adults who have a clinical consensus diagnosis of either cognitively normal controls (HC) or mild cognitive impairment (MCI), and will be confirmed to be Aβ- or Aβ+ based on ADRC amyloid PET data. We will examine cross- sectional and longitudinal changes in cortical microstructural properties including neurite density (NDI) and orientation dispersion index (ODI) (Aim 1), and in white matter microstructural and macromolecular tissue properties including NDI, ODI and macromolecular tissue volume (MTV) (Aim 2), along with their association with cognitive outcomes and AD pathology identified by PET. Taking a network-neuroscience approach, we will also examine connectome-level microstructural changes in preclinical AD and will test the utility of a multi-layer network framework for integrating measures across modalities (microstructural, molecular, PET, cognition) to capture the heterogeneity of AD. The proposed systematic investigation of microstructural and molecular changes in cortical and white matter in preclinical AD and their association with AD pathology and cognitive outcomes in a well-characterized preclinical AD sample can provide unique insight regarding AD development in early stages of the disease and can significantly improve our mechanistic understanding of AD. The outcomes also have the potential to inform development of experimental treatments, monitoring their effectiveness, and predicting cognitive and clinical trajectories of preclinical AD patients.