Introduction: Alzheimer’s disease is an irreversible brain disorder characterized by distortion of memory and other mental functions. Although, several psychometric tests are available for diagnosis of Alzheimer’s, there is a great concern about the validity of these tests at recognizing the early onset of the disease. Currently, brain magnetic resonance imaging is not commonly utilized in the diagnosis of Alzheimer’s, because researchers are still puzzled by the association of brain regions with the disease status and its progress. Moreover, MRI data tend to be of high dimensional nature requiring advanced statistical methods to accurately analyze them. In the past decade, the application of Least Absolute Shrinkage and Selection Operator (LASSO) has become increasingly popular in the analysis of high dimensional data. With LASSO, only a small number of the regression coefficients are believed to have a non-zero value, and therefore allowed to enter the model; other coefficients are while others are shrunk to zero. Aim: Determine the non-zero regression coefficients in models predicting patients’ classification (Normal, mild cognitive impairment (MCI), or Alzheimer’s) using both non-ordinal and ordinal LASSO. Methods: Pre-processed high dimensional MRI data of the Alzheimer’s Disease Neuroimaging Initiative was analyzed. Predictors of the following model were differentiated: Alzheimer’s vs. normal, Alzheimer’s vs. normal and MCI, Alzheimer’s and MCI vs. Normal. Cross-validation followed by ordinal LASSO was executed on these same sets of models. Results: Results were inconclusive. Two brain regions, frontal lobe and putamen, appeared more frequently in the models than any other region. Non-ordinal multinomial models performed better than ordinal multinomial models with higher accuracy, sensitivity, and specificity rates. It was determined that majority of the models were best suited to predict MCI status than the other two statues. Discussion: In future research, the other stages of the disease, different statistical analysis methods, such as elastic net, and larger samples sizes should be explored when using brain MRI for Alzheimer’s disease classification.

Alzheimer's Disease (AD) is a neurodegenerative disease that causes complications with thinking capability, memory and behavior. AD is a major public health problem among the elderly in developed and developing countries. With the growth of AD around the world, there is a need to further expand our understanding of the roles different clinical measurements can have in the diagnosis of AD. In this work, we propose a machine learning-based technique to distinguish control subjects with no cognitive impairments, AD subjects, and subjects with mild cognitive impairment (MCI), often seen as precursors of AD. We utilized several machine learning (ML) techniques and found that Gradient Boosting Decision Trees achieved the highest performance above 84% classification accuracy. Also, we determined the importance of the features (clinical biomarkers) contributing to the proposed multi-class classification system. Further investigation on the biomarkers will pave the way to introduce better treatment plan for AD patients.

Alzheimer’s disease (AD) is among the top 10 causes of global mortality, and dementia imposes a yearly $1 trillion USD economic burden. Of particular importance, women and minoritized groups are disproportionately affected by AD, with females having higher risk of developing AD compared to male cohorts. Differentiating mild cognitive impairment (MCIstable) from early stage Alzheimer’s disease (MCIAD) is vital worldwide. Despite genetic markers, such as apo-lipoprotein-E (APOE), identification of patients before they develop early stages of MCIAD, a critical period for possible pharmaceutical intervention, is not yet possible. Based on review of the literature three key limitations in existing AD-specific prediction models are apparent: 1) models developed by traditional statistics which overlook nonlinear relationships and complex interactions between features, 2) machine learning models are based on difficult to acquire, occasionally invasive, manually selected, and costly data, and 3) machine learning models often lack interpretability. Rapid, accurate, low-cost, easily accessible, non-invasive, interpretable and early clinical evaluation of AD is critical if an intervention is to have any hope at success. To support healthcare decision making and planning, and potentially reduce the burden of AD, this research leverages the Alzheimer’s Disease Neuroimaging Initiative (ADNI1/GO/2/3) database and a mathematical modelling approach based on supervised machine learning to identify 1) predictive markers of AD, and 2) patients at the highest risk of AD. Specifically we implemented a supervised XGBoost classifier with diagnostic (Exp 1) and prognostic (Exp 2) objectives. In experiment 1 (n=441) classification of AD (n=72) was performed in comparison to healthy controls (n= 369), while experiment 2 (n=738) involved classification of MCIstable (n = 444) compared to MCIAD(n = 294). In Experiment 1, machine learning tools identified three features (i.e., Everyday Cognition Questionnaire (Study partner) - Total, Alzheimer’s Disease Assessment Scale (13 items) and Delayed Total Recall) with ROC AUC scores consistently above 97%. Low performance on delayed recall alone appears to distinguish most AD patients. This finding is consistent with the pathophysiology of AD with individuals having problems storing new information into long-term memory. In experiment 2, the algorithm identified the major indicators of MCI-to-AD progression by integrating genetic, cognitive assessment, demographic and brain imaging to achieve ROC AUC scores consistently above 87%. This speaks to the multi-faceted nature of MCI progression and the utility of comprehensive feature selection. These features are important because they are non-invasive and easily collected. As an important focus of this research, the interpretability of the ML models and their predictions were investigated. The interpretable model for both experiments maintained performance with their complex counterparts while improving their interpretability. The interpretable models provide an intuitive explanation of the decision process which are vital steps towards the clinical adoption of machine learning tools for AD evaluation. The models can reliably predict patient diagnosis (Exp 1) and prognosis (Exp 2). In summary, our work extends beyond the identification of high-risk factors for developing AD. We identified accessible clinical features, together with clinically operable decision routes, to reliably and rapidly predict patients at the highest risk of developing Alzheimer’s disease. We addressed the aforementioned limitations by providing an intuitive explanation of the decision process among the high-risk non-invasive and accessible clinical features that lead to the patient’s risk. / Thesis / Master of Science in Biomedical Engineering / Early identification of patients at the highest risk of Alzheimer’s disease (AD) is crucial for possible pharmaceutical intervention. Existing prediction models have limitations, including inaccessible data and lack of interpretability. This research used a machine learning approach to identify patients at the highest risk of Alzheimer’s disease and found that certain clinical features, such as specific executive function- related cognitive testing (i.e., task switching), combined with genetic predisposition, brain imaging, and demographics, were important contributors to AD risk. The models were able to reliably predict patient diagnosis and prognosis and were designed to be low-cost, non-invasive, clinically operable and easily accessible. The interpretable models provided an intuitive explanation of the decision process, making it a valuable tool for healthcare decision-making and planning.

abstract: The apolipoprotein E (APOE) e4 genotype is the most prevalent known genetic risk factor for Alzheimer's disease (AD). In this paper, we examined the longitudinal effect of APOE e4 on hippocampal morphometry in Alzheimer's Disease Neuroimaging Initiative (ADNI). Generally, atrophy of hippocampus has more chance occurs in AD patients who carrying the APOE e4 allele than those who are APOE e4 noncarriers. Also, brain structure and function depend on APOE genotype not just for Alzheimer's disease patients but also in health elderly individuals, so APOE genotyping is considered critical in clinical trials of Alzheimer's disease. We used a large sample of elderly participants, with the help of a new automated surface registration system based on surface conformal parameterization with holomorphic 1-forms and surface fluid registration. In this system, we automatically segmented and constructed hippocampal surfaces from MR images at many different time points, such as 6 months, 1- and 2-year follow up. Between the two different hippocampal surfaces, we did the high-order correspondences, using a novel inverse consistent surface fluid registration method. At each time point, using Hotelling's T^2 test, we found significant morphological deformation in APOE e4 carriers relative to noncarriers in the entire cohort as well as in the non-demented (pooled MCI and control) subjects, affecting the left hippocampus more than the right, and this effect was more pronounced in e4 homozygotes than heterozygotes. / Dissertation/Thesis / Masters Thesis Computer Science 2015

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Alzheimer's disease (AD) is an increasing problem in modern society, both with regards to public health and cost of care. The causes of AD are not yet fully understood, and there is no cure or inhibiting drug. The aim of this thesis is to investigate the association between the bile acid profile as an indicator of dysbiosis and AD and mild cognitive impairment (MCI) using machine learning algorithms. The hypothesis that bile acid data can be used to predict AD or MCI at the time of diagnosis has been tested, and could not be confirmed. Somewhat better test results were obtained for the transition from normal cognitive function to MCI and from MCI to AD over time. Limitations relevant for this study included the possible uncertainties in the diagnostic patient data as well as in the relationship between bile acids and dysbiosis. The results from transitions in patient's diagnosis could warrant further research on the relationship between the bile acid profile or dysbiosis and changes in cognitive function. We suggest such research is conducted with more sophisticated models. / Alzheimers sjukdom (AD) är ett viktigt och ökande problem i dagens samhälle, både vad gäller folkhälsan och kostnaderna för samhället. Orsakerna bakom AD är än idag inte helt utredda och det finns inget botemedel eller bromsmedicin. Målet med den här studien är att undersöka sambandet mellan gallsyraprofilen som en indikator på dysbios och AD och mild kognitiv störning (MCI) med hjälp av maskininlärningsalgoritmer. Hypotesen att gallsyraprofilen kan användas för att förutsäga AD eller MCI vid diagnostillfället har studerats och kunde inte fastställas. Något bättre resultat erhölls vad gäller övergången från normal kognitiv funktion till MCI och från MCI till AD över tid. Begränsningar som är relavanta för studien inkluderar möjlig osäkerhet vad gäller diagnosen och även vad gäller sambandet mellan gallsyraprofilen och dysbios. Resultaten från förändringen i patienters diagnos kan vara en grund för fortsatt forskning om samband mellan gallsyraprofilen eller dysbios och förändringar i kognitiv funktion. Vi föreslår att mer sofistikerade modeller används för sådan forskning.

A neuroimaging feature extraction model is designed to extract region-based image features whose values are predicted by base learners trained on raw neuroimaging morphological variables. The main objectives are to identify Alzheimer’s disease (AD) in its earliest manifestations, and be able to predict and gauge progression of the disease through the stages of mild cognitive impairment (EMCI), late MCI (LMCI) and AD. The model was evaluated on the ADNI database and showed 75.26% accuracy for the challenging EMCI diagnosis based on the 10-fold cross-validation. Our approach also performed well for the other binary classifications: EMCI vs. LMCI (72.3%), EMCI vs. AD (95%), LMCI vs. AD (84.3%), CN vs. LMCI (77.5%), and CN vs. AD (96.5%). By applying the model to the Genome-wide Association Study, along with the sparse Partial Least Squares regression method, we successfully detected risk genes such as the APOE, TOMM40, RVRL2 and APOC1 along with the new finding of rs917100. Moreover, the research aimed to investigate the relationship of different biomarkers; especially the imaging biomarkers to better understand the precise biologic changes that characterize Alzheimer’s disease. The unique and independent contribution of APOE4 allele status (E4+\E4-), amyloid (Aβ) load status (Amy+\Amy-) and combined APOE4 and Aβ status on regional cortical thickness (CTh) and cognition were evaluated via a series of two-way ANCOVAs with post-hoc Tukey HSD tests. Results showed that decreased CTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4+ status is associated with increased CTh, in medial and inferior temporal regions. Diverging association patterns of global and regional Aβ load with cortical volume were found in the entorhinal, temporal pole and parahippocampal regions, which were positively associated with regional Aβ load, but with a negative correlation for global Aβ load in MCI stages. In addition, strong positive correlations were shown between baseline regional CTh and the difference of CTh in each region between the CN and AD, even after adjusting for the regional Aβ and APOE genotype (E4+: r = 0.521 and E4-: r = 0.694).

Indiana University-Purdue University Indianapolis (IUPUI) / Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. Many researchers believe that an effective AD treatment will prevent the development of disease rather than treat the disease after a diagnosis. Therefore, the development of tools to detect AD-related pathology in early stages is an important goal. In this report, MRI-based markers of neurodegeneration are explored as biomarkers of AD. In the first chapter, the sensitivity of cross-sectional MRI biomarkers to neurodegenerative changes is evaluated in AD patients and in patients with a diagnosis of mild cognitive impairment (MCI), a prodromal stage of AD. The results in Chapter 1 suggest that cross-sectional MRI biomarkers effectively measure neurodegeneration in AD and MCI patients and are sensitive to atrophic changes in patients who convert from MCI to AD up to 1 year before clinical conversion. Chapter 2 investigates longitudinal MRI-based measures of neurodegeneration as biomarkers of AD. In Chapter 2a, measures of brain atrophy rate in a cohort of AD and MCI patients are evaluated; whereas in Chapter 2b, these measures are assessed in a pre-MCI stage, namely older adults with cognitive complaints (CC) but no significant deficits. The results from Chapter 2 suggest that dynamic MRI-based measures of neurodegeneration are sensitive biomarkers for measuring progressive atrophy associated with the development of AD. In the final chapter, a novel biomarker for AD, visual contrast sensitivity, was evaluated. The results demonstrated contrast sensitivity impairments in AD and MCI patients, as well as slightly in CC participants. Impaired contrast sensitivity was also shown to be significantly associated with known markers of AD, including cognitive impairments and temporal lobe atrophy on MRI-based measures. The results of Chapter 3 support contrast sensitivity as a potential novel biomarker for AD and suggest that future studies are warranted. Overall, the results of this report support MRI-based measures of neurodegeneration as effective biomarkers for AD, even in early clinical and preclinical disease stages. Future therapeutic trials may consider utilizing these measures to evaluate potential treatment efficacy and mechanism of action, as well as for sample enrichment with patients most likely to rapidly progress towards AD.

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