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Principal Investigator: Hadi Hosseini
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $745,073
Funding agency: National Institute on Aging
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.
Terms: <AD dementia><AD pathology><Affect><Aging><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease pathology><Alzheimer's disease patient><Alzheimer's pathology><Alzheimer's patient><Alzheimers Dementia><Ammon Horn><Amyloid><Amyloid (Aβ) plaques><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Plaques><Amyloid Protein A4><Amyloid Substance><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Animals><Autopsy><Axonal Transport><Axoplasmic Transport><Aβ><Behavior><Body Tissues><Brain><Brain Nervous System><Cell Communication and Signaling><Cell Signaling><Clinical><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Communities><Consensus><Cornu Ammonis><Data><Detection><Development><Diagnosis><Diffusion><Disease><Disease Outcome><Disorder><Disturbance in cognition><Effectiveness><Encephalon><Evaluation><Heterogeneity><Hippocampus><Human><Image><Impaired cognition><Intracellular Communication and Signaling><Investigation><Investigators><Knowledge><Link><MR Imaging><MR Tomography><MRI><MRI biomarker><MRI marker><MRIs><MT-bound tau><Magnetic Resonance Imaging><Maps><Measurement><Measures><Medial><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Modality><Modeling><Modern Man><Molecular><Monitor><Morphology><Myelin><NMR Imaging><NMR Tomography><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurites><Neuritic Plaques><Neurobiology><Neurocyte><Neurofibrillary Tangles><Neuron Degeneration><Neurons><Neurosciences><Nuclear Magnetic Resonance Imaging><Outcome><PET><PET Scan><PET imaging><PETSCAN><PETT><Parietal Lobe><Pathology><Phenotype><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Primary Senile Degenerative Dementia><Process><Property><Prospective Studies><Rad.-PET><Reproducibility><Research Personnel><Research Resources><Researchers><Resources><Sampling><Senile Plaques><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Synapses><Synaptic><Techniques><Testing><Tissues><Zeugmatography><a beta peptide><abeta><amnestic mild cognitive impairment><amyloid beta><amyloid beta plaque><amyloid-b plaque><amyloid-b protein><aβ plaques><beta amyloid fibril><biological signal transduction><brain morphology><brain tissue><cognitive defects><cognitive dysfunction><cognitive loss><compare effectiveness><connectome><cored plaque><density><developmental><diffuse plaque><diffused><diffuses><diffusing><diffusions><disease heterogeneity><elderly patient><extracellular><gray matter><hippocampal><histologic studies><histological studies><imaging><improved><in vivo><indexing><insight><magnetic resonance imaging biomarker><magnetic resonance imaging marker><microtubule bound tau><microtubule-bound tau><mild cognitive disorder><mild cognitive impairment><necropsy><neural degeneration><neural imaging><neuro-imaging><neurobiological><neurodegeneration><neurodegenerative><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neuroimaging><neurological degeneration><neurological imaging><neuronal><neuronal degeneration><neuropathologic><neuropathological><neuropathology><novel><older adult><older adulthood><older patient><parietal cortex><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><postmortem><pre-clinical><preclinical><predictive biomarkers><predictive marker><predictive molecular biomarker><primary degenerative dementia><prodromal AD><prodromal Alzheimer's><prodromal Alzheimer's disease><senile dementia of the Alzheimer type><soluble amyloid precursor protein><substantia alba><substantia grisea><synapse><tangle><tau><tau Proteins><tau factor><white matter><τ Proteins>