Medical Neuroscience Department Theses and Dissertations

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Browsing Medical Neuroscience Department Theses and Dissertations by Author "Apostolova, Liana G."

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    Characterization of Cerebral Blood Flow in Older Adults: A Potential Early Biomarker for Alzheimer's Disease
    (2022-04) Swinford, Cecily Gwinn; Risacher, Shannon L.; Saykin, Andrew J.; Apostolova, Liana G.; Wu, Yu-Chien; Gao, Sujuan
    Over 5 million older adults have Alzheimer's disease (AD) in the US, and this number is projected to double by 2050. Clinical trials of potential pharmacological treatments for AD have largely shown that once cognitive decline has occurred, targeting AD pathology in the brain does not improve cognition. Therefore, it is likely that the most effective treatments for AD will need to be administered before cognitive symptoms occur, necessitating a biomarker for the early, preclinical stages of AD. Cerebral blood flow (CBF) is a promising early biomarker for AD. CBF is decreased in individuals with AD compared to their normally aging counterparts, and it has been shown that CBF is altered in mild cognitive impairment (MCI) and earlier stages and may occur prior to amyloid or tau aggregation. In addition, CBF can be measured using arterial spin labeled (ASL) MRI, a noninvasive imaging technique that can be safely repeated over time to track prognosis or treatment efficacy. The complex temporal and spatial patterns of altered CBF over the course of AD, as well as the relationships between CBF and AD-specific and -nonspecific factors, will be critical to elucidate in order for CBF to be an effective early biomarker of AD. Here, we begin to characterize the relationships between CBF and risk factors, pathologies, and symptoms of AD. Chapter 1 is a systematic review of published literature that compares CBF in individuals with AD and MCI to CBF in cognitively normal (CN) controls and assesses the relationship between CBF and cognitive function. Chapter 2 reports our original research assessing the relationships between CBF, hypertension, and race/ethnicity in older adults without dementia from the the Indiana Alzheimer’s Disease Research Center (IADRC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI). Chapter 3 reports our original research assessing the relationships between CBF and amyloid beta and tau aggregation measured with PET, as well as whether hypertension or APOEε4 positivity affects these relationships, in older adults without dementia from the IADRC. Chapter 4 reports our original research assessing the relationship between the spatial distribution of tau and subjective memory concerns.
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    Imaging Genetics and Biomarker Variations of Clinically Diagnosed Alzheimer's Disease
    (2020-08) Stage, Edwin Carl Jr.; Yoder, Karmen K.; Apostolova, Liana G.; Risacher, Shannon L.; Gao, Sujuan; Saykin, Andrew J.
    Neuroimaging biomarkers play a crucial role in our understanding of Alzheimer’s disease. Beyond providing a fast and accurate in vivo picture of the neuronal structure and biochemistry, these biomarkers make up a research framework, defined in a 2018 as the A(amyloid)/T(tau)/N(neurodegeneration) framework after three of the hallmarks of Alzheimer’s disease. I first used imaging measures of amyloid, tau and neurodegeneration to study clinically diagnosed Alzheimer’s disease. After dividing subjects into early (onset younger than 65) and late-onset (onset of 65 and older) amyloid-positive (AD) and amyloid-negative (nonAD) groups, I saw radically differing topographical distribution of tau and neurodegeneration. AD subjects with an early disease onset had a much more severe amyloid, tau and neurodegeneration than lateonset AD. In the nonAD group, neurodegeneration was found only in early-onset FDG PET data and in a nonAlzheimer’s-like MRI and FDG pattern for late-onset. The late-onset nonAD resembled that of limbic-predominant age-related TDP-43 encephalopathy. I next utilized an imaging genetics approach to associate genome-wide significant Alzheimer’s risk variants to structural (MRI), metabolic (FDG PET) and tau (tau PET) imaging biomarkers. Linear regression was used to select variants for each of the models and included a pooled sample, cognitively normal, mild cognitive impairment and dementia groups in order to fully capture the cognitive spectrum from normal cognition to the most severely impaired. Model selected variants were replicated using voxelwise regression in an exploratory analysis of spatial associations for each modality. For each imaging type, I replicated some associations to the biomarkers previously seen, as well as identified several novel associations. Several variants identified with crucial Alzheimer’s biomarkers may be potential future targets for drug interventions.
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    The Role of Microglial-Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) in Neuronal Homeostasis and Tau Pathogenesis
    (2021-06) Jadhav, Vaishnavi Sunil; Landreth, Gary E.; Lamb, Bruce T.; Oblak, Adrian L.; Apostolova, Liana G.; Lasagna Reeves, Cristian A.
    The importance of microglia in neurodegeneration has been highlighted by recent identification of microglial genes associated with increased risk for dementia. Among these, several variants of ‘Triggering Receptor expressed on myeloid cells 2’ (TREM2), confer higher risk for different types of dementia including Alzheimer’s disease and frontotemporal-like dementia with early onset. The mechanism by which alterations in TREM2 predisposes individuals to early dementia and how TREM2 influences proteinopathies, especially tauopathy remains unclear. The first part of this thesis focused on the role of TREM2 in neuronal homeostasis using a novel Trem2 p.Y38C mouse model (Trem2Y38C/Y38C) and mice lacking Trem2 (Trem2-/-). Young adult Trem2Y38C/Y38C and Trem2-/- mice exhibited synaptic impairments with reduced long-term potentiation accompanied by oligodendrocyte/myelin impairments. These pathologies are reminiscent of the clinical manifestation in patients with TREM2 p.Y38C mutation and functional loss of TREM2. Since these alterations were detected in wildtype Trem2Y38C/Y38C and Trem2-/- mice in the absence of any pathological insults, these results demonstrate that TREM2 directly impacts neuronal functions and homeostasis independent of the triggers such as pathological tau. In the second part of the thesis, we addressed the role of TREM2 in tau pathogenesis using aforementioned Trem2Y38C/Y38C and Trem2-/- mouse models crossed to human wildtype tau expressing ‘htau’ mice. Loss of functional TREM2 does not alter the overall phosphorylated tau burden but shifts localization of tau to the interstitial fluid in a tau species and sex-dependent manner. Female htau mice lacking functional TREM2 showed lower insoluble tau (largely intracellular) but higher tau levels in the interstitial fluid (extracellular). Transcriptomic analysis reveal alterations in genes associated with neuroinflammation and microglial phagocytic pathways in htau;Trem2Y38C/Y38C and htau;Trem2-/- mice . These alterations likely suggest compromised uptake and/or clearance of extracellular tau leading to the accumulation of tau in the ISF, which has been shown to be detrimental to the synapses. These results demonstrate that TREM2 is important for microglial, neuronal, and white matter functions and provides unique insights on the aspects of tau pathogenesis impacted by TREM2.
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    Transcriptomic Profiling in Mild Cognitive Impairment and Alzheimer's Disease Using Neuroimaging Endophenotypes
    (2022-12) Bharthur Sanjay, Apoorva; Yoder, Karmen K.; Apostolova, Liana G.; Risacher, Shannon L.; Gao, Sujuan; Nudelman, Kelly
    Alzheimer’s disease (AD) is a devastating neurodegenerative disease affecting more than 6 million Americans and 50 million people worldwide currently. It is an irreversible neurodegenerative disease which causes decline in memory, cognition, personality, and other functions which eventually lead to death due to complete brain failure. Recently there has been a lot of research that has focused on enabling early intervention and disease prevention in AD which could have a significant impact on this disease, be crucial for life management, assessment of risk for future generations, and assistance in end-of-life preparation. For a late-life complex multifactorial disease, such as AD, where both genetic and environmental factors are involved, integrating multiple layers of genetic, imaging, and other biomarker data is a critical step for therapeutic discovery and building predictive risk assessment tools. The multifactorial nature of AD suggests that multiple therapeutic targets need to be identified and tested together. Hence, we need a systems-level approach to build biomarker profiles which can be used for drug discovery and screening/risk assessment. The research presented in this dissertation focuses on utilizing a systems level approach to identify promising imaging genetics biomarkers that provide insight into dysregulated biological pathways in AD pathogenesis and identify critical mRNA measures that can be investigated further within the scope of novel therapeutics, as well as input variables in predictive models for AD risk, screening, and diagnosis. The overall research goal was the development of systems level, imaging genetics biomarker signatures to serve as tools for risk analysis and therapeutic discovery in AD. The specific outcomes of the analyses were characterization of patterns in gene expression at systems level using neuroimaging endophenotypes, and identification of specific driver genes and genotypic variants, which can inform predictive modeling for diagnosis, risk, and pathogenic profiling in AD.