Browsing by Subject "Alzheimer's disease"

Hypoxia is a profound stressor of the central nervous system implicated in numerous neurodegenerative diseases. While it is increasingly evident that the early effects of hypoxia cause impairment at the level of the axon, the precise mechanisms through which hypoxia compromises axonal structure and function remain unclear. However, links between hypoxia-induced axonopathic disease and the amyloid cascade, as well as the upregulation of amyloid precursor protein (APP) and amyloid beta (Aβ) by hypoxic stress, give rise to the hypothesis that proteolytic cleavage of APP into Aβ may be specifically responsible for axonopathy under conditions of hypoxia.

The goal of this dissertation was thus to understand dependence of hypoxia-induced axonal morphological and functional impairment on APP cleavage and the production of Aβ. I have developed a model of hypoxia-induced axonopathy in retinal explants. Using this model, I have experimentally addressed the core hypothesis that APP cleavage, and in particular the formation of Aβ, is necessary and sufficient to mediate morphological and functional axonopathy caused by hypoxia. I have found that there is a dissociation between the mechanisms responsible for hypoxia-induced morphological and functional impairment of the axon in the explanted retina, with the former being dependent on APP-to-Aβ processing and the latter likely being dependent on cleavage of a non-APP substrate by the enzyme BACE1. These findings shed light on mechanisms of hypoxia-induced axonopathy.

Brain Positron emission tomography (PET) has been widely employed for the clinic diagnosis of Alzheimer's disease (AD). Studies have shown that PET imaging is helpful in differentiating healthy elderly individuals, mild cognitive impairment (MCI) individuals, and AD individuals (Nordberg, Rinne, Kadir, & Långström, 2010). However, PET image quality and quantitative accuracy is degraded from partial volume effects (PVEs), which are due to the poor spatial resolution of PET. As a result, the compensation of PVEs in PET may be of great significance in the improvement of early diagnosis of AD. There are many different approaches available to address PVEs including region-based methods and voxel-based methods. In this study, a voxel-based PVE compensation technique using high-resolution anatomical images was investigated. The high-resolution anatomical images could be computed tomography (CT) or magnetic resonance imaging (MRI) images. Such methods have been proposed and investigated in many studies (Vunckx et al., 2012). However, relatively little research has been done on comparing the effects of different MRI images on voxel-based PVE correction methods. In this study, we compare the effect of 6 different MRI image protocols on PVE compensation in PET images. The MRI protocols compared in this study are T1-, T2-, proton-density (PD)-weighted and 3 different inversion recovery MRI protocols.

Results: OSEM and MAP/ICD images with isotropic prior are blurry and/or noisy. Compared with the OSEM and MAP/ICD images obtained by using an isotropic prior, the PET image reconstructed using anatomical information show better contrast and less noise. Visually, the PET image reconstructed with the ZeroCSF prior gave the PET image that visually appears to match best with the PET phantom. PET images reconstructed with T2, PD and ZeroWM image are similar to one another in image quality, but relative to the PET phantom and the ZeroCSF PET image, these images have poor contrast between CSF pockets and surrounding GM tissue, and they have less contrast between GM and WM. PET image reconstructed with T1 image had a better GM and CSF contrast, some of the CSF pockets in GM were reconstructed, but the WM region was very noisy. PET images reconstructed with ZeroGM image had noticeably worse performance on the GM reconstruction. Analysis suggest that these effects are caused by differences in tissue contrast with different MRI protocols

Keywords: PET, MRI, partial volume effect, image reconstruction, SPECT, Alzheimer's disease.

Alzheimer's disease (AD) accounts for 60%-80% of dementia. AD patients start by having mild memory, language, and thinking difficulties, then gradually lose more critical abilities, such as dressing, bathing, or walking. AD not only degrades patients’ life quality but also burdens caregivers and the health system. Specifically, there are 6.5 million AD cases in the U.S. today, and the annual health costs for 2022 are estimated to be $321 billion. AD diagnosis has been evolving in the past 30 years. The criteria established in 1984 recommended that AD cannot be identified until a post-mortem neuropathological test is performed. Recently, more biomarkers have gradually been discovered, such as brain atrophy, Positron Emission Tomography (PET) measures of glucose hypometabolism, and cerebrospinal fluid (CSF) and PET measures of pathological amyloid-beta and tau. However, these biomarkers lack the specificity to probe the damage in the neuronal microstructure that directly causes the disease, and they only provide late diagnoses when the AD progression is no longer reversible. Since the neuronal damages are believed to begin 20 years or more before symptoms start, biomarkers that can detect abnormalities in the neuronal microstructure would enable the diagnosis of AD at the very early stage of neurodegeneration, years before the onset of symptoms, and they could thus potentially enable better treatment outcomes since neuronal damage at the early stage could be reversible.Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that can noninvasively probe the microstructure of the human brain in vivo. Some regions in the cortical gray matter and hippocampus are known to experience early neurodegeneration in AD, and changes in DTI metrics in these regions could reflect the early stage of AD. However, the cortex is folded and is made of different cortical layers and cortical regions and the hippocampus is made of different subfields that have distinct neuronal populations with a specific microstructure. Additionally, neurodegeneration does not necessarily occur at the same time across different cortical depths or regions in the cortex or across different subfields in the hippocampus. As such, the development of early diagnostic biomarkers would require the ability to probe the neuronal microstructure at specific cortical depths and in specific cortical regions and hippocampal subfields in vivo. However, doing so with DTI has been challenging because the average cortical thickness is only 2.5 mm and the average hippocampal volume is only 2.84 mL. Therefore, a high-resolution DTI acquisition within a reasonable scan time is needed. In this dissertation, we first aim to develop DTI acquisition and reconstruction methodologies to acquire high-resolution (0.9-mm to 1.0-mm isotropic) whole-brain DTI images. Specifically, we used an efficient multi-band multi-shot echo-planar imaging sequence and a multi-band multiplexed sensitivity-encoding reconstruction. Furthermore, we aim to develop a data analysis pipeline that can quantitatively probe the microstructure and capture characteristic features: 1) in the cortex by performing a column-based cortical depth analysis of the diffusion anisotropy and radiality; and 2) in the hippocampus by investigating intra-hippocampal fiber tracts and connectomes, with the long-term goal of enabling the early diagnosis of AD. In the cortex, a column-based cortical depth analysis that samples the fractional anisotropy (FA) and radiality index (RI) along radially oriented cortical columns was performed to quantitatively analyze the FA and RI dependence on the cortical depth, cortical region, cortical curvature, and cortical thickness across the whole brain. We first studied young healthy subjects to optimize the data acquisition and analysis pipeline and to investigate the consistency of the results. The results showed characteristic FA and RI vs. cortical depth profiles, with an FA local maximum and minimum (or two inflection points) and a single RI maximum at intermediate cortical depths in most cortical regions, except for the postcentral gyrus where no FA peaks and a lower RI were observed. These results were consistent between repeated scans from the same subjects and across different subjects. They were also dependent on the cortical curvature and cortical thickness in that the characteristic FA and RI peaks were more pronounced i) at the banks than at the crown of gyri or at the fundus of sulci and ii) as the cortical thickness increases. We then performed a preliminary clinical study in a small cohort of AD patients and age-matched healthy controls (HC) to further examine if this methodology could be applied to detect differences in the FA and RI vs. cortical depth profiles between the AD and HC groups. The FA and RI at each cortical depth and in different regions of interest (ROIs) were sampled and compared between these two groups to look for any significant differences. Additionally, based on the results from the young healthy subjects, we minimized the dependence of these DTI metrics (FA and RI) on structural metrics such as cortical thickness and cortical curvature. The results showed significant differences (p < 0.05) in the FA and RI profiles between the AD and HC groups for specific cortical depths, curvature subsets, and ROIs. To generate intra-hippocampal fiber tracts and connectomes, the hippocampus of all subjects was registered to a common template and deterministic fiber tracking was performed. The fiber orientations across hippocampal subfields were investigated, and the connectivity among subfields was quantified. The results showed characteristic fiber orientations in different hippocampal subfields that were generally consistent between repeated scans and across all subjects: right/left in the middle of the CA4/dentate gyrus subfield and the inferior part of the subiculum; anterior/posterior in CA2/CA3; superior/inferior in the medial and inferior parts of the molecular layer and subiculum. These in vivo fiber orientations aligned with those obtained from an ex vivo specimen scanned over 21 hours at a 0.2-mm isotropic resolution. However, the ex vivo scan delineated the C-shaped molecular layer, which was not shown in the in vivo scans. The in vivo connectomes were generally consistent between repeated scans and across all subjects. The in vivo and ex vivo connectomes both showed more connectivity within the head than within the body of the hippocampus; however, the in vivo and ex vivo connectivity ranking across pairs of subfields was not exactly the same, which could be explained by altered diffusion properties in the ex vivo sample due to fixation or by the higher resolution in the ex vivo scan. In conclusion, the proposed high-resolution whole-brain DTI acquisition, column-based cortical depth analysis of the diffusion anisotropy and radiality, and intra-hippocampal fiber tracking captured characteristic features of FA and RI vs. cortical depth profiles in the cortex and characteristic fiber orientations and connectivity strengths across different subfields of the hippocampus, which were consistent between repeated scans from the same subjects and across different subjects. In addition, the cortical analysis applied in a preliminary clinical study of AD patients vs. HC showed significant differences in the FA and RI profiles between these two groups, showing the potential of this methodology to generate biomarkers for the early diagnosis of AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects over 5 million people in the United States alone. This number is predicted to triple to by the year 2050 due to both increasing life expectancies and the absence of disease-attenuating drugs. The etiology of AD remains unclear, and although there are multiple theories implicating everything from oxidative stress to protein misfolding, misregulated metal ions appear as a common thread in disease pathology.

Chelation therapy has shown some effectiveness in clinical trials, but to date, there are no FDA-approved metal chelators for the treatment of AD. One of the biggest problems with general chelators is their inability to differentiate between the metal ions involved in disease progression verses those involved in normal metabolic function. To address this problem, we have developed a prochelator approach whereby the prochelator (SWH) does not bind metals with significant biological affinity. However, once activated to the chelator (CP) via enzymatic hydrolysis, the molecule is able to bind copper and reduce its toxicity both in vitro and in a cellular model of Alzheimer's Disease.

Central to this strategy is the site-specificity provided by enzymatic activation of the prochelator. In our system, SWH to CP conversion is mediated by beta-secretase, an enzyme involved in A-beta generation. However, in order to render SWH capable of hydrolysis in cells, we modified the prochelator to contain a dihydrocholesterol membrane anchor attached via a polyethylene glycol linker. From this construct, we created beta-MAP, which is an SWH-based FRET probe to demonstrate beta-secretase-mediated conversion of SWH to CP. beta-MAP was also used to confirm the efficacy of a known beta-secretase inhibitor without the need to for mutated cells lines or expensive antibodies. beta;-MAP and the associated microscopy method represent a significant advancement to the currently available ELISA assays for beta-secretase activity.

While activation of the prochelator by an enzyme in cells is encouraging, non-specific hydrolysis of the peptide prevents significant accumulation of the chelator on the cell membrane. Furthermore, attachment of the polyethylene glycol and sterol units induce cell toxicity not seen with the native CP peptide. These drawbacks prevent the current prochelator from effectively protecting cells from AD conditions. Structural modifications to overcome these problems, including implementation of a new peptide sequence are planned for future experiments.

Vagus nerve stimulation (VNS) is an effective treatment for epilepsy, depression, and stroke rehabilitation with ongoing studies of additional clinical applications including rheumatoid arthritis and heart failure. Acute VNS alleviates inflammation caused by infection, and clinical studies of VNS treatment for immune dysregulation are promising. However, more widespread use of VNS is limited by surgical implantation, and risks associated with surgery are deleterious in patients with pre-existing neurocognitive impairment. Non-invasive methods of VNS (e.g., transcutaneous VNS) produce inconsistent results and lack a robust biomarker to confirm nerve stimulation. There is a need for a method of VNS that provides targeted stimulation with reduced invasiveness. As well, side effects limit therapy. Reduced heart rate (HR) during stimulation is associated with therapy for heart failure, but stimulation frequency and amplitude are limited by patient tolerance. An understanding of physiological responses to parameter adjustments would allow control of therapeutic and side effects. The purpose of this dissertation was to develop novel methods of VNS, investigate new applications of VNS for post-operative treatment, and conduct parametric studies to increase the dynamic range between therapeutic effects and side effects.First, we developed a minimally invasive, targeted, percutaneous vagus nerve stimulation approach (pVNS). We stimulated the cervical vagus nerve in mice using an ultrasound-guided needle electrode under sevoflurane anesthesia. The concentric bipolar needle electrode was placed adjacent to the carotid sheath, and nerve stimulation was verified in real-time using bradycardia as a biomarker. Activation of vagal fibers was also confirmed by immunohistochemical quantification of c-Fos and choline acetyltransferase expression in relevant brainstem structures, including the dorsal motor nucleus and nucleus tractus solitarius. Following lipopolysaccharide (LPS) administration, pVNS reduced plasma levels of tumor necrosis factor at 3 h post-injection. pVNS also prevented LPS-induced hippocampal microglial activation as analyzed by changes in Iba-1 immunoreactivity, including cell body enlargement and shortened ramifications. LPS injection reduced memory function at 24 and 48 h but not when pVNS was delivered post-injection. These results provide a novel therapeutic approach using VNS to modulate neuro-immune interactions that affect cognition. Second, we assessed pVNS efficacy in prevention of surgery-induced delirium superimposed on dementia in Alzheimer’s Disease-like (CVN-AD) mice. Orthopedic surgery increased hippocampal microglia activation, amyloid-beta (AB) accumulation, and neuronal loss as measured by histology. At 24 h post-operation, neural pathologies were absent in animals that received post-operative pVNS. We quantified blood-brain barrier (BBB) permeability with intracardial tracer injection to investigate vessel integrity. Following surgery, pVNS reduced tracer concentration in the hippocampus indicating improved BBB integrity. We paired 5x familial autosomal dominant (5xFAD) AD mice and wild type (C57) mice using parabiosis to evaluate the contribution of circulating factors from sterile surgery on post-operative pathologies. AB accumulation and microglia activation increased in 5xFAD mice when the C57 parabiosis partner received orthopedic surgery. Thus, post-operative pVNS protects against surgery-induced increases in dementia pathology driven by systemic inflammation. Finally, we measured the effect of the temporal pattern of VNS on HR (a proxy to therapy) and laryngeal EMG (a side effect) in anesthetized mice. Amplitude, intra-burst frequency, and mean pulse rate (MPR) modulated HR while only MPR modulated EMG. Neither outcome was sensitive to stimulation pattern at clinical frequencies. However, stimulation modulated HR to a greater degree than EMG at an amplitude and frequency above those used clinically. We leveraged collected data to construct computational models of HR and laryngeal muscle activity that reproduced VNS responses for amplitudes and patterns. To model HR, we incorporated a mechanism for frequency-dependent filtering of vagal pulses by cardiac ganglia, and the model overestimated HR changes at a high intra-burst frequency when filtering was removed. The experiment outcomes indicate concurrent increases of stimulation amplitude and MPR modulate HR more than laryngeal EMG, and the model outcomes indicate that ganglia fidelity contributes to stimulation frequency effects on HR. The results impact the field of VNS through the invention of a minimally invasive method of stimulation to modulate neuroinflammation, demonstration of protective effects of VNS on delirium superimposed on dementia, and identification of stimulation adjustments to maximize a proxy for therapy over side effects.

Cellular damage due to oxidative stress is implicated in a wide variety of conditions including degenerative diseases like Alzheimer's and Parkinson's Diseases. One source of oxidative stress is the interaction of redox-active metals such as copper and iron with hydrogen peroxide to produce hydroxyl radicals. Preventing metal-induced oxidative stress by metal chelation is one potential approach to treat some of these diseases, but there remain significant challenges in designing chelators that target damaging metals while not disturbing healthy metal ion distribution.

To overcome this challenge, prochelators that are responsive to conditions of oxidative stress have been introduced. By designing ligands that only bind metal ions in the presence of oxidants, damaging metals can be bound and removed while not perturbing the metals necessary for cell function. Masking the phenol of a chelator with a boronic ester creates a prochelator that has little to no affinity for metal ions until exposure to H₂O₂ converts the prochelator to the chelator, which is then available to bind metal ions. Described here is the development of boronate-based prochelators that react with H₂O₂ to produce chelating agents of variable denticity, ranging from 2 to 6.

Quinoline boronic acid pinanediol ester, or QBP, is a new bidentate prochelator introduced here that reacts with H₂O₂ with a rate of 0.22 M-1s-1 to produce 8-hydroxyquinoline, a known metal-binding agent. Results in Chapter 2 show that QBP can be activated in vitro under conditions that mimic early Alzheimer's Disease pathology where copper, amyloid beta peptide, and ascorbic acid exacerbate formation of reactive oxygen species. QBP does not bind metal ions, nor does it disaggregate metal-promoted amyloid beta peptide aggregates. However, the released 8-hydroxyquinoline sequesters copper from amyloid beta and both diminishes further formation of reactive oxygen species and inhibits further aggregation of amyloid-beta.

The syntheses and crystal structures of hexadentate prochelators are described in Chapter 3, along with their rates of oxidation in response to hydrogen peroxide exposure and their ability to protect against hydroxyl radicals formed in vitro by iron (or copper), ascorbic acid, and hydrogen peroxide. The hexadentate chelators are based on a tripodal architecture in which three phenol moieties are linked via nitrogens on three alkyl arms to a central nitrogen to provide an N₃O₃ donor set for metal complexation. Of three prochelator/chelator pairs prepared, the pair (trenBsalam/trensalam) with amine linkages was deemed most suitable for potential biological studies. The prochelator trenBsalam oxidizes at a rate of 0.72 M-1s-1 to produce the chelator trensalam in the presence of hydrogen peroxide. The transition metal coordination chemistry and metal ion affinities of trensalam were further studied in Chapter 4 by x-ray crystallography, UV/Vis spectroscopy and cyclic voltammetry.

The response of a series of bidentate prochelators to various oxidants, including hydrogen peroxide, superoxide, peroxynitrite and hypochlorite, was evaluated by UV/Vis spectroscopy in Chapter 5. Varying the diol that is appended to the boronic ester results in hydrogen peroxide oxidation rates ranging from 0.018 to 1.27 M-1s-1. Lastly, the stability of different boronic acid and diol combinations was probed by spectroscopic techniques and indicate that boronic esters formed with pinanediol form the most stable prochelators under physiological conditions.

Background: Increasing evidence suggests that early diagnosis of Alzheimer’s disease and related diseases (ADRD) offers opportunities for access to supportive services and disease management. However, most cases of ADRD are diagnosed in the later stages of the disease limiting the benefits of supportive services and increasing challenges related to the disease. This study aimed to understand facilitators and barriers to early ADRD diagnosis among Black and White individuals seeking racial differences in this process. Methods: Our sample included 21 racially diverse caregivers (n= 21) of older adults with ADRD, including Black caregivers (n=11) and White caregivers (n= 10). Semi-structured interviews were conducted individually with participants. Duke University Health System (DUHS). Data were coded for emerging themes and analyzed through the lens of the life course framework using NVIVO analysis software. Results: Facilitators and barriers along the diagnosis process were shaped by the individual, family/caregiver, and interactions with the healthcare system. Racial differences were particularly evident regarding family/caregiver's lower knowledge about ADRD, care approach offered to the care recipient, and prevalent negative interactions with the healthcare system among Black caregivers. Conclusions: The diagnosis process pathways were lengthy, characterized by caregivers' persistence, challenges to receiving an adequate cognitive assessment, and limited access to supportive services. Black caregivers experienced a more prolonged process, lower knowledge about ADRD, and challenging interactions with the healthcare system.

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Alzheimer’s Disease (AD) disproportionately impacts women; and the loss of ovarian hormones during the perimenopausal transition has been identified as a sex-specific risk factor. Previous studies have shown that the ovarian hormone, estrogen, utilizes its neuroprotective effects on tissues in the brain by aiding in cognitive function, exerting anti-inflammatory effects, promoting neuronal synaptic activity, and regulating energy biosynthesis. These effects are lost when circulating ovarian hormones are decreased. Additionally, during the perimenopausal transition women are experiencing similar neurological deficits found in AD patients such as reduced verbal acuity, memory deficits, delayed speech, etc. making early diagnosis of AD, if present, difficult. As a result, the window for therapeutic intervention is limited. Studies have shown that long-term physical exercise has been associated with a reduction in the rates of cognitive decline, dementia, and other related-neurodegenerative diseases. However, despite the strong evidence for greater female vulnerability, studies aiming to unravel the mechanisms that influence female susceptibility and the potential beneficial effects of exercise on cognitive function, menopause, and AD, are lacking.Here we sought to identify how hormonal changes during the perimenopausal transition influences the susceptibility of females to age-related cognitive decline and the effectiveness of physical exercise during this period in mouse models of AD. Based on a well-characterized neuropathological progression of the CVN-AD (APPSwDI/mNos2-/-) mouse model, we assessed mice at 24 weeks of age (WoA; mid AD-neuropathology) and at 36 WoA (late AD-neuropathology). Mice were treated with either the oil vehicle or 4-vinylcyclohexene diepoxide (VCD) to induce gradual ovarian failure. All mice were given pre- and post-cardiovascular tests at two timepoints, to assess the effects of exercise or being sedentary for 12 weeks. All 24 WoA mice remained sedentary throughout the study. Half of the 36 WoA CVN-AD mice remained sedentary while the other half were exercised with both voluntary wheel running and treadmill training for 12 weeks beginning at 24 WOA. Additionally, all mice were given a novel object recognition test (NOR) 1 week prior to sacrifice to assess short-term episodic memory. After sacrifice, uterine weights, body weights and total follicular counts were assessed. We found that VCD-treatment was effective in reducing uterine weights in all CVN-AD mouse models. Additionally, we found that at 36 WoA CVN-AD have a natural gradual loss in ovarian function. Exercise prior to the exacerbation of AD neuropathology and during the perimenopausal transition increased cardiovascular fitness, improved memory function, and increased the number of healthy ovarian follicles in comparison to sedentary 36 WoA CVN-AD mice. We then investigated the changes in forebrain metabolite levels in 36 WoA CVN-AD mice to identify whether metabolic changes in menopause-like ovarian failure were linked to AD progression and if exercise intervention could modify these effects. As a control, we used forebrain homogenates of sedentary 36 WoA NOS-/- (mNos2-/-) mice that were subjected to the same timelines of VCD- or oil-treatment. Forebrain samples were analyzed using the Biocrates MxP Quant 500 kit, 3 Flow-Injection-Analysis (FIA-MS) and 2 Ultra-High-Pressure Liquid Chromatography (UPLC). The CVN-AD genotype had significantly lower metabolite levels in comparison to NOS-/- mice and this effect was exacerbated by VCD-treatment. When evaluating the effects of exercise on the CVN-AD genotype we found that exercise significantly shifted the brain metabolome and increased metabolite levels in comparison to sedentary CVN-AD and NOS-/- mice. We then compared the interaction between exercise and VCD-treatment and found that exercise was able to reduce some of the negative effects associated with VCD. Within the sedentary CVN-AD treatment group, we found that VCD-treatment significantly increased the number of metabolite changes in comparison to Oil-treated mice. Whereas in the exercise CVN-AD treatment and NOS-/- control groups, VCD’s effects were dampened. These findings indicate that exercise was effective in reducing the effects of VCD-treatment, so much so, there was no difference in the number of metabolite changes between exercised CVN-AD and NOS-/- mice. We then sought to examine the potential role of menopause-like ovarian failure on the neuroinflammatory response and β-amyloid plaque deposition through the evaluation of overall microglial expression, homeostatic microglial expression, and β-amyloid plaque deposition in subregions of the hippocampus. We performed a triple immuno-fluorescence stain (Iba1, Tmem119 and β-amyloid) on brain slices through CA1, CA3 and dentate gyrus (DG) regions of sedentary and exercised 36 WoA CVN-AD mice and 36 WoA NOS-/- control mice. We used confocal microscopy to image the subregions of the hippocampus. Images were then analyzed in the ilastik software program to output cell and area counts of Iba1, Tmem119 and β-amyloid. VCD-treatment in sedentary CVN-AD mice significantly increased microglial proliferation in all subregions of the hippocampus. In comparison, exercise significantly reduced this effect. When evaluating Tmem119 expression, we found that in the CA1 region the CVN-AD genotype has significantly fewer healthy microglia in comparison to sedentary Oil-treated NOS-/- mice. When evaluating Tmem119 expression in the exercised CVN-AD mice we found that in the CA1 region, exercise was able to stave off some of the effects of the genotype and VCD-treatment, however, these effects did not occur in the CA3 and DG. Lastly, when evaluating how microglial expression coupled with exercise intervention and VCD-treatment affected β-amyloid plaque deposition in the CVN-AD mice we found no significant differences within any of the subregions. Taken together, these findings indicate that Aβ plaque deposition may occur independently from microglial expression and that regardless of exercise intervention and VCD-treatment, once Aβ plaques in the CVN-AD pathology occurs they will continue to persist. Collectively these data suggest that the CVN-AD neuropathology drastically impacts cognitive function, the brain metabolome and microglial response. Additionally, exercise as an early intervention during the perimenopausal transition period can prevent some, but not all the deleterious effects of the loss of estrogens and AD neuropathology. Overall, these findings will be significant in contributing to the AD field, especially in evaluating AD as a multiomic disease with sex-specific risk factors that can be modulated by early non-invasive exercise intervention.

An aging global population and accompanying increases in the prevalence of age-related disorders are leading to greater financial, social, and health burdens. Alzheimer’s disease and related dementias are one such category of age-related disorders that are associated with progressive loss of physical and cognitive ability. One proposed preventative measure against risk for such dementias is improving cardiovascular fitness, which may help reverse or buffer age-related brain atrophy associated with worse aging-related outcomes and cognitive decline. However, research into this potential of cardiovascular fitness has suffered from extreme heterogeneity in study design methodology leading to a lack of cohesion in the field and undermining any potential causal evidence that may exist. In addition, while direct measures of cardiovascular fitness (e.g., VO2Max) and healthy lifestyle behaviors typically associated with better cardiovascular fitness (e.g., exercise, diet, smoking status) are not necessarily highly correlated, they are often conflated in existing research. This has contributed to a lack of clarity in generalizing and comparing results.

This dissertation presents results from four original research projects addressing open empirical questions about possible links between cardiovascular fitness, healthy lifestyle behaviors, and structural brain integrity in midlife, which has become a target of intervention research seeking to stave off cognitive decline and risk for dementia before irreversible damage has accrued. Each section of the dissertation builds on increasingly complex aspects of these links with the goal of providing supporting evidence that may aid future biomarker research and clinical trials design. All studies involved were conducted using behavioral data, physiological data, and structural MRI data from the Dunedin Study, which has followed a population-representative birth cohort to midlife.

Across four empirical sections, results collectively suggest that there is a modest association between cardiovascular fitness and both grey and white matter structural integrity as well as between healthy lifestyle behaviors and grey matter structural integrity. Further, results indicate that these associations may extend beyond cross-sectional data and have relevance for measures capturing the extent of age-related atrophy in the brain. In addition, the results reinforce prior findings that cardiovascular fitness and healthy lifestyle behaviors are independent constructs and suggest that the differentially mapping of these constructs onto specific features of brain integrity in midlife may be useful in directing the search for risk biomarkers and designing clinical trials.