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DEVELOPMENT OF BIOMARKERS OF SMALL VESSEL DISEASE IN AGING
Title
DEVELOPMENT OF BIOMARKERS OF SMALL VESSEL DISEASE IN AGING
Creator
Makkinejad, Nazanin
Date
2021
Description
Age-related neuropathologies including cerebrovascular and neurodegenerative diseases play a critical role in cognitive dysfunction, and...
Show moreAge-related neuropathologies including cerebrovascular and neurodegenerative diseases play a critical role in cognitive dysfunction, and development of dementia. Designing methodologies for early prediction of these diseases are much needed. Since multiple pathologies commonly coexist in brains of older adults, clinical diagnosis lacks the specificity to isolate the pathology of interest, and gold standard is determined only at autopsy. Magnetic resonance imaging (MRI) provides a non-invasive tool to study abnormalities in brain characteristics that is unique to each pathology. Utilizing ex-vivo MRI for brain imaging proves to be useful as it eliminates two important biases of in-vivo MRI. First, no additional pathology would develop between imaging and pathologic examination, and second, frail older adults would not be excluded from MRI.Hence, the aims of this dissertation were two-fold: to study brain correlates of age- related neuropathologies, and to develop and validate classifiers of small vessel diseases by combining ex-vivo MRI and pathology in a large community cohort of older adults. The structure of the project is as follows.First, the association of amygdala volume and shape with transactive response DNA-binding protein 43 (TDP-43) pathology was investigated. Using a regularized regression technique, higher TDP-43 was associated with lower amygdala volume. Also, shape analysis of amygdala showed unique patterns of spatial atrophy associated with TDP-43 independent of other pathologies. Lastly, using linear mixed effect models, amygdala volume was shown to explain an additional portion of variance in cognitive decline above and beyond what was explained by the neuropathologies and demographics.Second, the previous study was extended to analyze other subcortical regions including the hippocampus, thalamus, nucleus accumbens, caudate, and putamen, and was also conducted in a larger dataset. The results showed unique contribution of TDP-43, neurofibrillary tangles (hallmark characteristic of Alzheimer’s disease pathology), and atherosclerosis (a cerebrovascular pathology) to atrophy on the surface of subcortical structures. Understanding the independent effects of each pathology on volume and shape of different brain regions can form a basis for the development of classifiers of age-related neuropathologies.Third, an in-vivo classifier of arteriolosclerosis was developed and validated. Arteriolosclerosis is one of the main pathologies of small vessel disease, is associated with cognitive decline and dementia, and currently has no standard biomarker available. In this work, the classifier was developed ex-vivo using machine learning (ML) techniques and was then translated to in-vivo. The in-vivo classifier was packaged as a software called ARTS, which outputs a score that is the likelihood of arteriolosclerosis when the required input is given to the software. It was tested and validated in various cohorts and showed to have high performance in predicting the pathology. It was also shown that higher ARTS score was associated with greater cognitive decline in domains that are specific to small vessel disease.Fourth, motivated by current trends and superiority of deep learning (DL) techniques in classification tasks in computer vision and medical imaging, a preliminary study was designed to use DL for training an ex-vivo classifier of arteriolosclerosis. Specifically, convolutional neural networks (CNNs) were applied on 3 Tesla ex-vivo MR images directly without providing prior information of brain correlates of arteriolosclerosis. One interesting aspect of the results was that the network learnt that white matter hyperintense lesions contributed the most to classification of arteriolosclerosis. These results were encouraging, and more future work will exploit the capability of DL techniques alongside the traditional ML approaches for more automation and possibly better performance.Finally, a preliminary classifier of arteriolosclerosis and small vessel atherosclerosis was developed since the existence of both pathologies in brain have devastating effects on cognition. The methodology was similar to the one used for development of arteriolosclerosis classifier with minor differences. The classifier showed a good performance in-vivo, although the testing needs to be assessed in more cohorts.The comprehensive study of age-related neuropathologies and their contribution to abnormalities of subcortical brain structures offers a great potential to develop a biomarker of each pathology. Also, the finding that the MR-based classifier of arteriolosclerosis showed high performance in-vivo demonstrate the potential of ex-vivo studies for development of biomarkers that are precise (because they are based on autopsy, which is the gold standard) and are expected to work well in-vivo. The implications of this study include development of biomarkers that could potentially be used in refined participant selection and enhanced monitoring of the treatment response in clinical drug and prevention trials.
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MULTIVARIABLE SIMULATION PLATFORM FOR TYPE 1 DIABETES AND AUTOMATIC MEAL HANDLING IN ARTIFICIAL PANCREAS SYSTEMS
Title
MULTIVARIABLE SIMULATION PLATFORM FOR TYPE 1 DIABETES AND AUTOMATIC MEAL HANDLING IN ARTIFICIAL PANCREAS SYSTEMS
Creator
Samadi, Sediqeh
Date
2019
Description
Artificial pancreas (AP) systems are designed to automate the glucose control in type 1 diabetes mellitus (T1DM). Multivariable artificial...
Show moreArtificial pancreas (AP) systems are designed to automate the glucose control in type 1 diabetes mellitus (T1DM). Multivariable artificial pancreas systems have evolved to incorporate various additional physiological measurements beyond the conventional continuous glucose monitoring measurements to better integrate information on the metabolic state of the patients affecting the glycemic dynamics. The changes in the physiological measurements such as heart rate, energy expenditure, skin temperature, and skin conductance measured by wearable devices are indicative of the changes in the metabolic state. The controller receives the physiological measurements in the feed forward manner which accelerates the remedy control decision in response to the disturbances. Although various AP systems are proposed in the literature to accommodate these additional sources of information, the testing and evaluation of these advanced multivariable AP systems are hindered by the requirements of conducting time-consuming and expensive clinical trials. Development of a simulation platform for rapid prototyping and iterative development of AP systems is one of the main contributions of this study. Simulation platform for T1DM includes a compartmental model generating glucose concentration in response to physical activity in addition to meals and infused insulin. The proposed exercise-glucose-insulin model is an extension of the previously developed glucose-insulin model to derive transient variations in glycemic dynamics caused by physical activity and to improve the glucose prediction accuracy. Physiological variables affected by physical activity, such as heart rate, skin temperature, and blood volume pulse are generated in addition to the glucose concentration in the simulator. The simulation platform includes several virtual patients providing a reliable platform for in silico evaluation of different algorithms proposed for automation of glucose control in T1DM. The multivariable simulator will accelerate the development of next-generation artificial pancreas systems.The development of a disturbance detection algorithm is the other contribution of this study. Meals are major disturbances to the glucose homeostasis, and automated detection of meal consumption and carbohydrate estimation of the consumed meal are critical for fully automated artificial pancreas control systems. In this study, a detection algorithm integrating fuzzy logic classification and qualitative analysis is proposed. A fuzzy logic system estimates the carbohydrate content of the meal.
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ENLARGED PERIVASCULAR SPACES IN COMMUNITY-BASED OLDER ADULTS
Title
ENLARGED PERIVASCULAR SPACES IN COMMUNITY-BASED OLDER ADULTS
Creator
Javierre Petit, Carles
Date
2020
Description
Enlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function and vascular dementia...
Show moreEnlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function and vascular dementia. Furthermore, recent studies have investigated the links of EPVS with the glymphatic system (GS), since perivascular spaces are thought to play a major role as the main channels for clearance of interstitial solutes from the brain. However, the relationship of EPVS with age-related neuropathologies is not well understood. Therefore, more conclusive studies are needed to elucidate specific relationships between EPVS and neuropathologies. After demonstration of their neuropathologic correlates, detailed assessment of EPVS severity could provide as a potential biomarker for specific neuropathologies.In this dissertation, our focus was twofold: to develop a fully automatic EPVS segmentation model via deep learning with a set of guidelines for model optimization, and to evaluate both manual and automatic assessment of EPVS severity to investigate the neuropathologic correlates of EPVS, and their contribution to cognitive decline, by combining ex-vivo brain magnetic resonance imaging (MRI) and pathology (from autopsy) in a large community-based cohort of older adults. This project was structured as follows. First, a manual approach was used to assess neuropathologic and cognitive correlates of EPVS burden in a large dataset of community-dwelling older adults. MR images from each participant were rated using a semiquantitative 4-level rating scale, and a group of identified EPVS was histologically evaluated. Two groups of participants in descending order of average cognitive impairment were defined based and studied. Elasticnet regularized ordinal logistic regression was used to assess the neuropathologic correlates of EPVS burden in each group, and linear mixed effects models were used to investigate the associations of EPVS burden with cognitive decline. Second, a fully automatic EPVS segmentation model was implemented via deep learning (DL) using a small dataset of 10 manually segmented brain MR images. Multiple techniques were evaluated to optimize performance, mainly by implementing strategies to reduce model overfitting. The final segmentation model was evaluated in an independent test set and the performance was validated with an expert radiologist. Third, the DL segmentation model was used to segment and quantify EPVS. Quantified EPVS (qEPVS) were evaluated by combining ex-vivo MRI, pathology, and longitudinal cognitive evaluation. EPVS quantification allowed to study qEPVS both in the whole brain and regionally. Two different qEPVS metrics were studied. Elastic-net regularized linear regression was used to assess the neuropathologic correlates of qEPVS within each region of interest (ROI) under study, and linear mixed effects models were used to investigate the associations of qEPVS with cognitive decline. Finally, a preliminary study investigated the longitudinal associations of qEPVS with time. The DL segmentation model was re-trained using 4 in-vivo MR images. EPVS were segmented and quantified in a large longitudinal cohort where each participant was imaged at multiple timepoints. Factors that influenced segmentation performance across timepoints were evaluated, and linear mixed effects models controlling for these factors were used to investigate the associations of qEPVS with time.
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