Browsing by Subject "Alzheimer’s disease"

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    Advanced methodologies for neuromodulation and quantitative MRI with MB-SWIFT
    (2023) WU, Lin
    Introduction: Deep Brain Stimulation (DBS) treatment for Alzheimer’s disease (AD) is becoming increasingly evident. In this study, we exploited a novel orientation-selective (OS) strategy recently introduced by our group for DBS, entitled orientation-selective DBS (OS-DBS). This strategy entails that, by using multiple contacts with independent current sources within a multi-electrode array, the electric field can be oriented along any desired orientation in space. Therefore, axons parallel to the electric field spatial gradients are preferentially activated. Moreover, we applied the OS methodology to epidural spinal cord stimulation. In order to detect pathological processes of AD non-invasively with magnetic resonance imaging (MRI) technology, an alternating Look-Locker (aLL) method was developed to study novel MRI biomarkers such as T1? based on rotating frame MRI methods tailored to reveal neurodegeneration. Objectives and Methods: 1) For OS-ESCS, we introduced a similar OS approach for ESCS, and demonstrated orientation dependent brain activations as detected by brain fMRI. 2) To study OS-DBS of the subthalamic nucleus (STN), AD related targets including the entorhinal cortex (EC) and medial septal nucleus (MSN), to demonstrate the basic principle of OS and prove its feasibility and advantage in optimizing the stimulation of the target. Here, OS-DBS with a three-channel electrode was utilized to stimulate the rat STN, EC, and MSN to modulate the activation of brain networks connected to the stimulation sites. The induced brain activity was monitored with fMRI by Multi-Band Sweep Imaging with Fourier Transformation (MB-SWIFT) readout at 9.4 T. 3) The aLL method was proposed to perform simultaneous quantitative T1 and T1?, or T1 and B1 3D MRI mapping. Look-Locker scheme that alternates magnetization from the laboratory frame’s +Z and -Z axes is combined with a 3D MB-SWIFT readout. The analytical solution describing the spin evolution during aLL and the correction required for segmented acquisition were derived. The simultaneous B1 and T1 mapping were demonstrated on a phantom. T1? values in the rat brain in vivo and the Gd-DTPA phantom were compared to those obtained with a previously introduced steady–state (SS) method. Results: 1) For ESCS, orientation dependent activations were detected in brain areas that transmit the motor and sensory information. 2) OS-DBS of the STN reached maximal activation of related brain areas in correspondence with an in-plane 180° stimulation angle, which was consistent with the main mediolateral direction of the STN fibers confirmed with high resolution diffusion imaging and histology. Varying the in-plane OS-DBS stimulation angle in the EC resulted in the modulation of multiple downstream brain areas involved in memory and cognition. In contrast, no angle dependence of brain activation was observed when stimulating the MSN, consistent with predictions based on the electrode configuration and on the main axonal directions of the targets derived from diffusion MRI tractography and histology. 3) The aLL method allows for simultaneous T1 and B1 mapping, while the aLL method with the application of MP modules can provide simultaneous T1 and T1? maps. T1? values were similar with both aLL and SS techniques. However, aLL resulted in more robust quantitative mapping as compared with the SS method and provided the advantage of generating T1 maps in a single acquisition. Conclusions: 1) OS-ESCS allows the targeting of spinal fibers of different orientations, ultimately making stimulation less dependent on the precision of the electrode implantation. 2) OS-DBS stimulation angle modulates the activation of brain areas relevant to AD and Parkinson’s disease (PD), thus holding great promise for DBS treatment of the diseases. 3) The proposed aLL method offers a new flexible tool for quantitative T1, T1?, and B1 mappings.
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    Effect of anti-amyloid β antibody on Aβ trafficking at the blood-brain barrier
    (2021-12) Li, Chenxu
    Alzheimer’s disease (AD) is broadly recognized as a global public health priority, which has been characterized by the atrophy of the brain and the impairment of memory. The abnormal accumulation of amyloid-beta (Aβ) peptides in the brain have been identified as a major contributor to AD. Thus, the use of monoclonal antibodies (mAbs) to alter Aβ trafficking kinetics at the blood-brain barrier (BBB) represents a promising therapeutic strategy. While anti-Aβ antibodies have been shown to bind and clear Aβ deposits from the brain, the effects of anti-Aβ antibodies on Aβ trafficking in the blood-to-brain direction remain unclear. Plasma Aβ levels are shown to correlate with AD risk, and the overall amount of Aβ in the periphery is estimated to be ~10 fold greater than the amount in the brain. Therefore, Aβ trafficking in the blood-to-brain direction cannot be ignored. We proposed that anti-Aβ mAbs are not required to enter the brain to elicit their therapeutic actions, and mAbs in the circulatory system would be sufficiently effective to change the Aβ trafficking at the BBB. To clarify the effects of anti-Aβ antibodies on Aβ trafficking in both the blood-to-brain and brain-to-blood directions, we conducted a series of Aβ uptake/ transport assays with BBB cell monolayers following exposure to IgG4.1, a well-characterized anti-Aβ mAb. In a wild-type mice model, brain uptake of 125I labeled Aβ40 tended to increase in the presence of systemically injected IgG4.1. In studies examining the endothelial cell uptake of Aβ in vitro, IgG4.1 significantly prevented both Aβ40 and Aβ42 cellular uptake through the formation of immune complexes. Moreover, Aβ42 has a higher magnitude of cellular uptake and is more susceptible to IgG4.1 than that of Aβ40. Overall, our in vitro studies support the premise that IgG4.1 affects Aβ trafficking kinetics (especially Aβ42) without entering into the brain.
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    Integrative approaches to understanding the blood-brain barrier in the context of Alzheimer’s disease
    (2024-09) Eberts, Paulina
    The blood-brain barrier (BBB) is a highly selective barrier that is crucial for maintaining brain homeostasis. Disruption of the BBB can have deleterious effects, and it is believed that certain types of BBB damage are central to the etiology of Alzheimer's disease (AD). Given its role in disease onset, disrupted BBB function could be an attractive target for potential early intervention in AD. However, more needs to be understood about its functions in relation to AD to best inform these approaches. This includes understanding the relationship between the BBB and the multitude of factors thought to contribute to AD development, including genetic and nongenetic risk factors. To facilitate this, improved models and strategies are required to identify mechanistic links between risk factors and early features of AD. Animal models have been indispensable in AD research, providing critical insights into disease mechanisms. However, they are limited in their ability to elucidate the specific interactions between hallmark features of AD and the BBB endothelium, partly due to critical species differences. Human in vitro models of the BBB offer a complementary approach, allowing for a highly controlled, tunable environment for the examination of complex, multifactorial interactions with greater throughput. This makes them well-suited for a systems approach, which is particularly beneficial for understanding complex diseases like AD. However, these models also have limitations, such as their lack of maturity, which decreases their relevance to a disease that primarily affects the aged adult population. Despite this, there are considerable opportunities to expand the types of insights that can be gained from them. The purpose of this dissertation is to enhance understanding of BBB functions as they relate to the earliest stages of AD through efforts to improve in vitro models, apply these models, and expand the model toolkit. In Chapter 1, the fundamentals of AD are reviewed and the role of the BBB in this context is presented. This includes a summary of models and approaches typically used to examine the BBB in relation to AD. Chapter 2 describes methods for improving models of the BBB comprised of brain microvascular endothelial-like cells (iBMECs) derived from human induced pluripotent stem cells (hiPSCs) to better represent the adult BBB. This work finds that extending the culture of iBMEC models of the BBB induces quiescence and improves structural organization in the barriers, indicative of a more mature, rested phenotype. Chapter 3 presents the application of in vitro models of the BBB to map out and characterize amyloid-beta binders expressed by the brain endothelium. This work identifies HspB1 as a key amyloid-beta binder expressed by the brain endothelium. Further examination of HspB1 links its behavior to features of genetic and non-genetic risk for AD, namely ApoE isoform and oxidative stress. Chapter 4 discusses the extension of a proximity labeling technology, TurboID, for use in identifying protein-protein interactions at the BBB surface. This includes recombinant expression of TurboID constructs for extracellular use. Design principles determined in AlphaFold for the robust design of constructs implicate linker selection in ensuring proper construct binding activity. Chapter 5 discusses key conclusions from each of these efforts, as well as future directions.
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    Modeling the Early Identification and Intervention of Alzheimer’s Disease
    (2015-09) Michaud, Tzeyu
    Advances in neuroimaging and biomarkers now provide the ability to detect evidence for the pathophysiological process of Alzheimer’s disease (AD) before clinically detectable dementia. Because of these findings, AD research has begun to focus on the preclinical or prodromal stages of the disease. For example, many clinical trials and laboratory-based studied have examined the clinical benefit of earlier AD intervention, such as pre-symptomatic stages of AD, based on the belief that it is more likely to achieve disease modification. The economic evaluation of potential interventions on AD, which mainly extends to include the earlier disease stages by using biomarker testing to predict the risk of disease progression, needs to be updated. Accordingly, the overall objective of this thesis is to quantify the value of using cerebrospinal fluid (CSF) biomarker testing for early-targeted treatment on patients with mild cognitive impairment who are at risk of developing AD. Firstly, I examined whether CSF biomarker testing can categorize MCI patients into different risk groups of developing AD, and thus allowing for targeted early treatment on MCI patients. Secondly, I conducted a cost-effectiveness analysis to evaluate the different treatment strategies with or without testing information involved by developing a decision model to synthesize all relevant evidence and project the expected value of outcomes of interest for each proposed alternative. Finally, I further address key challenges based on the current evidence by estimating the societal value of reducing uncertainty surrounding the decision model through further research. Economic evidence about the relative costs and outcomes of health and social care can assist decision makers in determining the best use of scarce healthcare resources.