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Principal Investigator: Aivi Thanh Nguyen
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2024
Award: $155,520
Funding agency: National Institute on Aging
PROJECT DESCRIPTION/ABSTRACT
This NIH K08 proposal describes a five-year career development plan for Dr. Aivi T. Nguyen to obtain the
necessary research and professional skills and serve as transition to become a successful, independently
funded physician-scientist. Dr. Nguyen completed her clinical training in Anatomic Pathology and
Neuropathology at the Hospital of the University of Pennsylvania, after which she pursued post-doctoral
training under the mentorship of Dr. Edward B. Lee in the Translational Neuropathology Research Laboratory,
University of Pennsylvania. Currently, Dr. Nguyen is an assistant professor at Mayo Clinic Rochester, MN and
contributing neuropathologist to the Alzheimer’s Disease Research Center (ADRC) and Mayo Clinic Study of
Aging (MCSA). Dr. Nguyen’s long-term research focus is examining the role of microglia in cognitive resilience,
normal aging, and aging-related CNS diseases through integration of neuropathology and translational
research approaches to better understand neuroinflammation in human disease. This K08 award will provide
protected time to acquire expertise in integrating antemortem Alzheimer’s disease (AD) biomarkers and
neuropsychiatric data with postmortem neuropathology and to obtain expertise in two-photon in vivo imaging of
microglia in AD mouse models. Research will be performed under the mentorship of Dr. Prashanthi Vemuri, an
expert in cognitive resilience and neuroimaging, and Dr. LongJun Wu, an expert in microglial dynamics and
neuroimmune interactions using two photon in vivo imaging. This award will also provide protected time for Dr.
Nguyen to gain expertise through formal coursework, scientific seminars, and scientific meetings.
AD, neuropathologically defined by β-amyloid plaques and neurofibrillary tangles, progresses in a spatio-
temporally distinct fashion that can be studied in vivo by recent advances in neuroimaging and fluid
biomarkers. Several ante- and postmortem studies have shown a discrepancy between AD pathology extent
and cognition, forming the basis of cognitive resilience. A potentially protective microglial subpopulation termed
amyloid-responsive microglia (ARM) was previously described in a single-nuclei RNA sequencing study of
human AD brain. Whether microglial heterogeneity, specifically ARM, contribute to resilience is unclear. This
proposal leverages antemortem AD biomarkers, cognitive data, and postmortem tissue from MCSA
participants to address these specific aims: (1) Determine postmortem ARM tissue expression association with
antemortem fluid and neuroimaging biomarkers, and whether ARM may be predicted by biomarkers; (2)
Evaluate differential ARM tissue expression in cognitively resilient individuals versus not, and test antemortem
predictors; and (3) Examine ARM phagocytosis and effects on downstream neuronal dystrophy in the setting of
AD genetic risk. These studies will drive the development of an independent research program to study
microglial heterogeneity and its role in resilience and AD and provide better understanding of cognitive aging.
Terms: <2-photon><AD dementia><AD pathology><Address><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 biomarker><Alzheimer's brain><Alzheimer's disease biological marker><Alzheimer's disease brain><Alzheimer's disease pathology><Alzheimer's pathology><Alzheimers Dementia><Alzheimer’s biological marker><Alzheimer’s disease biomarker><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><Anatomic Sites><Anatomic structures><Anatomy><Astroprotein><Autopsy><Award><Aβ><Biological Markers><Blood Plasma><Body Tissues><CNS Diseases><CNS disorder><Central Nervous System Diseases><Central Nervous System Disorders><Cessation of life><Clinic><Clinical Data><Cognition><Cognitive><Cognitive aging><Complex><Data><Death><Deposit><Deposition><Development><Development Plans><Disease Progression><Funding><GFA-Protein><GFAP><Gene Transcription><Genetic><Genetic Risk><Genetic Transcription><Glial Fibrillary Acid Protein><Glial Fibrillary Acidic Protein><Glial Intermediate Filament Protein><Heterogeneity><Histologic><Histologically><Hortega cell><Human><Image><Individual><Infrastructure><Laboratory Research><Ligand Binding><Liquid substance><LysoTracker><MR Imaging><MR Tomography><MRI><MRI biomarker><MRI marker><MRIs><MT-bound tau><Magnetic Resonance Imaging><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Membrane><Mentorship><Mice><Mice Mammals><Microglia><Modern Man><Murine><Mus><NIH><NMR Imaging><NMR Tomography><National Institutes of Health><Nerve Cells><Nerve Unit><Neural Cell><Neuritic Plaques><Neurocyte><Neurofibrillary Tangles><Neuroimmune><Neurons><Neuropsychologies><Neuropsychology><Nuclear Magnetic Resonance Imaging><PET><PET Scan><PET imaging><PETSCAN><PETT><Participant><Pathologic><Pathology><Pennsylvania><Phagocytosis><Phenotype><Physicians><Plasma><Plasma Serum><Play><Population><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Prefrontal Cortex><Primary Senile Degenerative Dementia><RNA Expression><Rad.-PET><Receptor Protein><Reporter><Research><Reticuloendothelial System, Serum, Plasma><Risk-associated variant><Role><Scientist><Senile Plaques><Single-Nucleus Sequencing><Subgroup><TREM2><TREM2 gene><Tauopathies><Testing><Time><Tissues><Transcription><Transgenic Mice><Translational Research><Translational Science><Triggering Receptor Expressed in Myeloid Cells 2><Triggering Receptor Expressed on Myeloid Cells 2><United States National Institutes of Health><Universities><University Hospitals><Visualization><Work><Zeugmatography><a beta peptide><abeta><abeta deposition><abnormally aggregated tau protein><age group><aged><aging associated><aging related><aging resilience><amyloid beta><amyloid beta deposition><amyloid beta plaque><amyloid β deposition><amyloid-b plaque><amyloid-b protein><awake><aβ deposition><aβ plaques><beta amyloid fibril><bio-markers><biologic marker><biomarker><career development><clinical training><coping><cored plaque><demographics><developmental><diffuse plaque><filamentous tau inclusion><fluid><gitter cell><glial activation><glial cell activation><human RNA sequencing><human RNA-seq><human disease><imaging><in vivo><in vivo two-photon imaging><liquid><longitudinal imaging><magnetic resonance imaging biomarker><magnetic resonance imaging marker><meeting><meetings><membrane structure><mesoglia><microglial cell><microgliocyte><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><mouse model><murine model><natural aging><necropsy><nerve cell death><nerve cell loss><neural imaging><neural inflammation><neuro-imaging><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neuroimaging><neuroimaging biomarker><neuroimaging marker><neuroinflammation><neuroinflammatory><neurological imaging><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neuropathologic><neuropathologic tau><neuropathological><neuropathological tau><neuropathology><neuroprotection><neuroprotective><neuropsychiatric><neuropsychiatry><neuropsychologic><normal aging><normative aging><p-tau><p-τ><paired helical filament of tau><perivascular glial cell><phospho-tau><phospho-τ><phosphorylated tau><population based><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><post-doctoral training><post-translational modification of tau><postdoctoral training><postmortem><posttranslational modification of tau><predictive biomarkers><predictive marker><predictive molecular biomarker><primary degenerative dementia><professor><programs><receptor><resilience><resilience during aging><resilience in aging><resilience in normal aging><resilience to aging><resilient><resilient aging><resilient to aging><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><sNuc-Seq><self-aggregate tau><senile dementia of the Alzheimer type><serial imaging><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><skills><snRNA sequencing><snRNA-seq><social role><soluble amyloid precursor protein><spatiotemporal><tangle><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><tau factor><tau fibrillization><tau filament><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neurofibrillary tangle><tau neuropathology><tau oligomer><tau paired helical filament><tau phosphorylation><tau polymerization><tau posttranslational modification><tau-1><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><translation research><translational investigation><two-photon><τ Proteins><τ aggregation><τ phosphorylation>