Alzheimer's Disease Conversion Research Articles

A Multi-Dimensional Comparison of Alzheimer's Disease Neurodegenerative Biomarkers.

In the 2018 AT(N) framework, neurodegenerative (N) biomarkers plays an essential role in the research and staging of Alzheimer's disease (AD); however, the different choice of N may result in discordances. We aimed to compare different potential N biomarkers. We examined these N biomarkers among 1,238 participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) in their 1) diagnostic utility, 2) cross-sectional and longitudinal correlations between different N biomarkers and clinical variables, and 3) the conversion risk of different N profiles. Six neurodegenerative biomarkers changed significantly from preclinical AD, through prodromal AD to AD dementia stage, thus they were chosen as the candidate N biomarkers: hippocampal volume (HV), 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET), cerebrospinal fluid (CSF), total tau (T-tau), plasma neurofilament light chain (NFL), CSF NFL, and CSF neurogranin (Ng). Results indicated that FDG-PET not only had the greatest diagnostic utility in differentiating AD from controls (area under the curve: FDG-PET, 0.922), but also had the strongest association with cognitive scores. Furthermore, FDG-PET positive group showed the fastest memory decline (hazard ratio: FDG-PET, 3.45), which was also true even in the presence of amyloid-β pathology. Moreover, we observed great discordances between three valuable N biomarkers (FDG-PET, HV, and T-tau). These results underline the importance of using FDG-PET as N in terms of cognitive decline and AD conversion, followed by HV, and could be a great complement to the AT(N) framework.

Establishing an individualized model of conversion from normal cognition to Alzheimer's disease after 4years, based on cognitive, brain morphology and neuropsychiatric characteristics.

The impact of neuropsychiatric symptoms (NPS) on cognitive performance has been reported, and this impact was better defined in the aging population. Yet the potential of using the impact of NPS on brain and cognitive performance in a longitudinal setting, as prediction of conversion - have remained questionable. This study proposes to establish a predictive model of conversion to Alzheimer's disease (AD) and mild cognitive impairment (MCI) based on current cognitive performance, NPS and their associations with brain morphology. 156 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative database cognitively stable after a 4-year follow-up were compared to 119 MCI participants who converted to AD. Each participant underwent a neuropsychological assessment evaluating verbal memory, language, executive and visuospatial functions, a neuropsychiatric inventory evaluation and a 3Tesla MRI. The statistical analyses consisted of 1) baseline comparison between the groups; 2) analysis of covariance model (controlling demographic parameters including functional abilities) to specify the variables that distinguish the two subgroups and; 3) used the significant ANCOVA variables to construct a binary logistic regression model that generates a probability equation to convert to a lower cognitive performance state. Results showed that MCI who converted to AD in comparison to stable MCI, exhibited a higher NPS prevalence, a lower cognitive performance and a higher number of involved brain structures. Functional abilities, memory performance and the sizes of inferior temporal, hippocampal and amygdala sizes were significant predictors of MCI to AD conversion. We also report two models of conversion that can be implemented on an individual basis for calculating the percentage risk of conversion after 4years. These analytical methods might be a good way to anticipate cognitive and brain declines.

Predicting conversion from mild cognitive impairment to Alzheimer’s disease with multimodal latent factors

ABSTRACT Introduction We studied the ability of latent factor scores to predict conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) and investigated whether multimodal factor scores improve predictive power, relative to single-modal factor scores. Method We conducted exploratory factor analyses (EFAs) and confirmatory factor analyses (CFAs) of the baseline data of MCI subjects in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to generate factor scores for three data modalities: neuropsychological (NP), magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF). Factor scores from single or multiple modalities were entered in logistic regression models to predict MCI to AD conversion for 160 ADNI subjects over a 2-year interval. Results NP factors attained an area under the curve (AUC) of .80, with a sensitivity of .66 and a specificity of .77. MRI factors reached a comparable level of performance (AUC = .80, sensitivity = .66, specificity = .78), whereas CSF factors produced weaker prediction (AUC = .70, sensitivity = .56, specificity = .79). Combining NP factors with MRI or CSF factors produced better prediction than either MRI or CSF factors alone. Similarly, adding MRI factors to NP or CSF factors produced improvements in prediction relative to NP or CSF factors alone. However, adding CSF factors to either NP or MRI factors produced no improvement in prediction. Conclusions Latent factor scores provided good accuracy for predicting MCI to AD conversion. Adding NP or MRI factors to factors from other modalities enhanced predictive power but adding CSF factors did not.

A Machine Learning-Based Holistic Approach to Predict the Clinical Course of Patients within the Alzheimer's Disease Spectrum.

Alzheimer's disease (AD) is a neurodegenerative condition driven by multifactorial etiology. Mild cognitive impairment (MCI) is a transitional condition between healthy aging and dementia. No reliable biomarkers are available to predict the conversion from MCI to AD. To evaluate the use of machine learning (ML) on a wealth of data offered by the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Alzheimer's Disease Metabolomics Consortium (ADMC) database in the prediction of the MCI to AD conversion. We implemented an ML-based Random Forest (RF) algorithm to predict conversion from MCI to AD. Data related to the study population (587 MCI subjects) were analyzed by RF as separate or combined features and assessed for classification power. Four classes of variables were considered: neuropsychological test scores, AD-related cerebrospinal fluid (CSF) biomarkers, peripheral biomarkers, and structural magnetic resonance imaging (MRI) variables. The ML-based algorithm exhibited 86% accuracy in predicting the AD conversion of MCI subjects. When assessing the features that helped the most, neuropsychological test scores, MRI data, and CSF biomarkers were the most relevant in the MCI to AD prediction. Peripheral parameters were effective when employed in association with neuropsychological test scores. Age and sex differences modulated the prediction accuracy. AD conversion was more effectively predicted in females and younger subjects. Our findings support the notion that AD-related neurodegenerative processes result from the concerted activity of multiple pathological mechanisms and factors that act inside and outside the brain and are dynamically affected by age and sex.

Toward a Multimodal Computer-Aided Diagnostic Tool for Alzheimer's Disease Conversion.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. It is one of the leading sources of morbidity and mortality in the aging population AD cardinal symptoms include memory and executive function impairment that profoundly alters a patient’s ability to perform activities of daily living. People with mild cognitive impairment (MCI) exhibit many of the early clinical symptoms of patients with AD and have a high chance of converting to AD in their lifetime. Diagnostic criteria rely on clinical assessment and brain magnetic resonance imaging (MRI). Many groups are working to help automate this process to improve the clinical workflow. Current computational approaches are focused on predicting whether or not a subject with MCI will convert to AD in the future. To our knowledge, limited attention has been given to the development of automated computer-assisted diagnosis (CAD) systems able to provide an AD conversion diagnosis in MCI patient cohorts followed longitudinally. This is important as these CAD systems could be used by primary care providers to monitor patients with MCI. The method outlined in this paper addresses this gap and presents a computationally efficient pre-processing and prediction pipeline, and is designed for recognizing patterns associated with AD conversion. We propose a new approach that leverages longitudinal data that can be easily acquired in a clinical setting (e.g., T1-weighted magnetic resonance images, cognitive tests, and demographic information) to identify the AD conversion point in MCI subjects with AUC = 84.7. In contrast, cognitive tests and demographics alone achieved AUC = 80.6, a statistically significant difference (n = 669, p < 0.05). We designed a convolutional neural network that is computationally efficient and requires only linear registration between imaging time points. The model architecture combines Attention and Inception architectures while utilizing both cross-sectional and longitudinal imaging and clinical information. Additionally, the top brain regions and clinical features that drove the model’s decision were investigated. These included the thalamus, caudate, planum temporale, and the Rey Auditory Verbal Learning Test. We believe our method could be easily translated into the healthcare setting as an objective AD diagnostic tool for patients with MCI.

Prediction of Cognitive Progression in Individuals with Mild Cognitive Impairment Using Radiomics as an Improvement of the ATN System: A Five-Year Follow-Up Study.

ObjectiveTo improve the N biomarker in the amyloid/tau/neurodegeneration system by radiomics and study its value for predicting cognitive progression in individuals with mild cognitive impairment (MCI).Materials and MethodsA group of 147 healthy controls (HCs) (72 male; mean age ± standard deviation, 73.7 ± 6.3 years), 197 patients with MCI (114 male; 72.2 ± 7.1 years), and 128 patients with Alzheimer’s disease (AD) (74 male; 73.7 ± 8.4 years) were included. Optimal A, T, and N biomarkers for discriminating HC and AD were selected using receiver operating characteristic (ROC) curve analysis. A radiomics model containing comprehensive information of the whole cerebral cortex and deep nuclei was established to create a new N biomarker. Cerebrospinal fluid (CSF) biomarkers were evaluated to determine the optimal A or T biomarkers. All MCI patients were followed up until AD conversion or for at least 60 months. The predictive value of A, T, and the radiomics-based N biomarker for cognitive progression of MCI to AD were analyzed using Kaplan-Meier estimates and the log-rank test.ResultsThe radiomics-based N biomarker showed an ROC curve area of 0.998 for discriminating between AD and HC. CSF Aβ42 and p-tau proteins were identified as the optimal A and T biomarkers, respectively. For MCI patients on the Alzheimer’s continuum, isolated A+ was an indicator of cognitive stability, while abnormalities of T and N, separately or simultaneously, indicated a high risk of progression. For MCI patients with suspected non-Alzheimer’s disease pathophysiology, isolated T+ indicated cognitive stability, while the appearance of the radiomics-based N+ indicated a high risk of progression to AD.ConclusionWe proposed a new radiomics-based improved N biomarker that could help identify patients with MCI who are at a higher risk for cognitive progression. In addition, we clarified the value of a single A/T/N biomarker for predicting the cognitive progression of MCI.

An explainable Artificial Intelligence approach to study MCI to AD conversion via HD-EEG processing.

An explainable Artificial Intelligence (xAI) approach is proposed to longitudinally monitor subjects affected by Mild Cognitive Impairment (MCI) by using high-density electroencephalography (HD-EEG). To this end, a group of MCI patients was enrolled at IRCCS Centro Neurolesi Bonino Pulejo of Messina (Italy) within a follow-up protocol that included two evaluations steps: T0 (first evaluation) and T1 (three months later). At T1, four MCI patients converted to Alzheimer's Disease (AD) and were included in the analysis as the goal of this work was to use xAI to detect individual changes in EEGs possibly related to the degeneration from MCI to AD. The proposed methodology consists in mapping segments of HD-EEG into channel-frequency maps by means of the power spectral density. Such maps are used as input to a Convolutional Neural Network (CNN), trained to label the maps as "T0" (MCI state) or "T1" (AD state). Experimental results reported high intra-subject classification performance (accuracy rate up to 98.97% (95% confidence interval: 98.68-99.26)). Subsequently, the explainability of the proposed CNN is explored via a Grad-CAM approach. The procedure detected which EEG-channels (i.e., head region) and range of frequencies (i.e., sub-bands) were more active in the progression to AD. The xAI analysis showed that the main information is included in the delta sub-band and that, limited to the analyzed dataset, the highest relevant areas are: the left-temporal and central-frontal lobe for Sb01, the parietal lobe for Sb02, the left-frontal lobe for Sb03 and the left-frontotemporal region for Sb04.

Specificity of Entorhinal Atrophy MRI Scale in Predicting Alzheimer's Disease Conversion.

We compared entorhinal cortex atrophy (ERICA) score vs. medial temporal atrophy (MTA) score's ability to predict conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) using magnetic resonance imaging (MRI). We hypothesized that ERICA would show higher specificity. Data from 61 aMCI patients were analyzed. Positive ERICA was associated with AD conversion with a sensitivity of 56% (95% CI: 30-80%) and a specificity of 78% (63-89%) vs. 69% (41-89%) SE and 60% (44-74%) SP for the MTA. Results suggest that ERICA is superior to MTA in predicting conversion from aMCI to AD in a small sample of participants.

Artificial Intelligence for Alzheimer's Disease: Promise or Challenge?

Decades of experimental and clinical research have contributed to unraveling many mechanisms in the pathogenesis of Alzheimer’s disease (AD), but the puzzle is still incomplete. Although we can suppose that there is no complete set of puzzle pieces, the recent growth of open data-sharing initiatives collecting lifestyle, clinical, and biological data from AD patients has provided a potentially unlimited amount of information about the disease, far exceeding the human ability to make sense of it. Moreover, integrating Big Data from multi-omics studies provides the potential to explore the pathophysiological mechanisms of the entire biological continuum of AD. In this context, Artificial Intelligence (AI) offers a wide variety of methods to analyze large and complex data in order to improve knowledge in the AD field. In this review, we focus on recent findings and future challenges for AI in AD research. In particular, we discuss the use of Computer-Aided Diagnosis tools for AD diagnosis and the use of AI to potentially support clinical practices for the prediction of individual risk of AD conversion as well as patient stratification in order to finally develop effective and personalized therapies.

Harnessing forgetfulness: can episodic-memory tests predict early Alzheimer's disease?

A rapid increase in the number of patients with Alzheimer's disease (AD) is expected over the next decades. Accordingly, there is a critical need for early-stage AD detection methods that can enable effective treatment strategies. In this study, we consider the ability of episodic-memory measures to predict mild cognitive impairment (MCI) to AD conversion and thus, detect early-stage AD. For our analysis, we studied 307 participants with MCI across four years using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using a binary logistic regression, we compared episodic-memory tests to each other and to prominent neuroimaging methods in MCI converter (MCI participants who developed AD) and MCI non-converter groups (MCI participants who did not develop AD). We also combined variables to test the accuracy of mixed-predictor models. Our results indicated that the best predictors of MCI to AD conversion were the following: a combined episodic-memory and neuroimaging model in year one (59.8%), the Rey Auditory Verbal Learning Test in year two (71.7%), a mixed episodic-memory predictor model in year three (77.7%) and the Logical Memory Test in year four (77.2%) of ADNI. Overall, we found that individual episodic-memory measure and mixed models performed similarly when predicting MCI to AD conversion. Comparatively, individual neuroimaging measures predicted MCI conversion worse than chance. Accordingly, our results indicate that episodic-memory tests could be instrumental in detecting early-stage AD and enabling effective treatment.

Specific White Matter Tracts and Diffusion Properties Predict Conversion From Mild Cognitive Impairment to Alzheimer's Disease.

Identifying biomarkers that can assess the risk of developing Alzheimer’s Disease (AD) remains a significant challenge. In this study, we investigated the integrity levels of brain white matter in 34 patients with mild cognitive impairment (MCI) who later converted to AD and 53 stable MCI patients. We used diffusion tensor imaging (DTI) and automated fiber quantification to obtain the diffusion properties of 20 major white matter tracts. To identify which tracts and diffusion measures are most relevant to AD conversion, we used support vector machines (SVMs) to classify the AD conversion and non-conversion MCI patients based on the diffusion properties of each tract individually. We found that diffusivity measures from seven white matter tracts were predictive of AD conversion with axial diffusivity being the most predictive diffusion measure. Additional analyses revealed that white matter changes in the central and parahippocampal terminal regions of the right cingulate hippocampal bundle, central regions of the right inferior frontal occipital fasciculus, and posterior and anterior regions of the left inferior longitudinal fasciculus were the best predictors of conversion from MCI to AD. An SVM based on these white matter tract regions achieved an accuracy of 0.75. These findings provide additional potential biomarkers of AD risk in MCI patients.

Robust Discovery of Mild Cognitive Impairment Subtypes and Their Risk of Alzheimer's Disease Conversion Using Unsupervised Machine Learning and Gaussian Mixture Modeling.

Alzheimer's Disease (AD) is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills. The ability to correctly predict the diagnosis of Alzheimer's disease in its earliest stages can help physicians make more informed clinical decisions on therapy plans. This study aimed to determine whether the unsupervised discovering of latent classes of subjects with Mild Cognitive Impairment (MCI) may be useful in finding different prodromal AD stages and/or subjects with a low MCI to AD conversion risk. Total 18 features relevant to the MCI to AD conversion process led to the identification of 681 subjects with early MCI. Subjects were divided into training (70%) and validation (30%) sets. Subjects from the training set were analyzed using consensus clustering, and Gaussian Mixture Models (GMM) were used to describe the latent classes. The discovered GMM predicted the latent class of the validation set. Finally, descriptive statistics, rates of conversion, and Odds Ratios (OR) were computed for each discovered class. Through consensus clustering, we discovered three different clusters among MCI subjects. The three clusters were associated with low-risk (OR = 0.12, 95%CI = 0.04 to 0.3|), medium-risk (OR = 1.33, 95%CI = 0.75 to 2.37), and high-risk (OR = 3.02, 95%CI = 1.64 to 5.57) of converting from MCI to AD, with the high-risk and low-risk groups highly contrasting. Hence, prodromal AD subjects were present in only two clusters. We successfully discovered three different latent classes among MCI subjects with varied risks of MCI-to-AD conversion through consensus clustering. Two of the discovered classes may represent two different prodromal presentations of Alzheimer´s disease.

Deep learning prediction of mild cognitive impairment conversion to Alzheimer's disease at 3 years after diagnosis using longitudinal and whole-brain 3D MRI.

BackgroundWhile there is no cure for Alzheimer’s disease (AD), early diagnosis and accurate prognosis of AD may enable or encourage lifestyle changes, neurocognitive enrichment, and interventions to slow the rate of cognitive decline. The goal of our study was to develop and evaluate a novel deep learning algorithm to predict mild cognitive impairment (MCI) to AD conversion at three years after diagnosis using longitudinal and whole-brain 3D MRI.MethodsThis retrospective study consisted of 320 normal cognition (NC), 554 MCI, and 237 AD patients. Longitudinal data include T1-weighted 3D MRI obtained at initial presentation with diagnosis of MCI and at 12-month follow up. Whole-brain 3D MRI volumes were used without a priori segmentation of regional structural volumes or cortical thicknesses. MRIs of the AD and NC cohort were used to train a deep learning classification model to obtain weights to be applied via transfer learning for prediction of MCI patient conversion to AD at three years post-diagnosis. Two (zero-shot and fine tuning) transfer learning methods were evaluated. Three different convolutional neural network (CNN) architectures (sequential, residual bottleneck, and wide residual) were compared. Data were split into 75% and 25% for training and testing, respectively, with 4-fold cross validation. Prediction accuracy was evaluated using balanced accuracy. Heatmaps were generated.ResultsThe sequential convolutional approach yielded slightly better performance than the residual-based architecture, the zero-shot transfer learning approach yielded better performance than fine tuning, and CNN using longitudinal data performed better than CNN using a single timepoint MRI in predicting MCI conversion to AD. The best CNN model for predicting MCI conversion to AD at three years after diagnosis yielded a balanced accuracy of 0.793. Heatmaps of the prediction model showed regions most relevant to the network including the lateral ventricles, periventricular white matter and cortical gray matter.ConclusionsThis is the first convolutional neural network model using longitudinal and whole-brain 3D MRIs without extracting regional brain volumes or cortical thicknesses to predict future MCI to AD conversion at 3 years after diagnosis. This approach could lead to early prediction of patients who are likely to progress to AD and thus may lead to better management of the disease.

Deep-MEG: spatiotemporal CNN features and multiband ensemble classification for predicting the early signs of Alzheimer\u2019s disease with magnetoencephalography

In this paper, we present the novel Deep-MEG approach in which image-based representations of magnetoencephalography (MEG) data are combined with ensemble classifiers based on deep convolutional neural networks. For the scope of predicting the early signs of Alzheimer’s disease (AD), functional connectivity (FC) measures between the brain bio-magnetic signals originated from spatially separated brain regions are used as MEG data representations for the analysis. After stacking the FC indicators relative to different frequency bands into multiple images, a deep transfer learning model is used to extract different sets of deep features and to derive improved classification ensembles. The proposed Deep-MEG architectures were tested on a set of resting-state MEG recordings and their corresponding magnetic resonance imaging scans, from a longitudinal study involving 87 subjects. Accuracy values of 89% and 87% were obtained, respectively, for the early prediction of AD conversion in a sample of 54 mild cognitive impairment subjects and in a sample of 87 subjects, including 33 healthy controls. These results indicate that the proposed Deep-MEG approach is a powerful tool for detecting early alterations in the spectral–temporal connectivity profiles and in their spatial relationships.

Cerebral Blood Flow Predicts Conversion of Mild Cognitive Impairment into Alzheimer's Disease and Cognitive Decline: An Arterial Spin Labeling Follow-up Study.

This is the first longitudinal study to assess regional cerebral blood flow (rCBF) changes during the progression from normal control (NC) through mild cognitive impairment (MCI) and Alzheimer's disease (AD). We aim to determine if perfusion MRI biomarkers, derived from our prior cross-sectional study, can predict the onset and cognitive decline of AD. Perfusion MRIs using arterial spin labeling (ASL) were acquired in 15 stable-NC, 14 NC-to-MCI, 16 stable-MCI, and 18 MCI/AD-to-AD participants from the Cardiovascular Health Study (CHS) cognition study. Group comparisons, predictions of AD conversion and time to conversion, and Modified Mini-Mental State Examination (3MSE) from rCBF were performed. Compared to the stable-NC group: 1) the stable-MCI group exhibited rCBF decreases in the right temporoparietal (p = 0.00010) and right inferior frontal and insula (p = 0.0094) regions; and 2) the MCI/AD-to-AD group exhibited rCBF decreases in the bilateral temporoparietal regions (p = 0.00062 and 0.0035). Compared to the NC-to-MCI group, the stable-MCI group exhibited a rCBF decrease in the right hippocampus region (p = 0.0053). The baseline rCBF values in the posterior cingulate cortex (PCC) (p = 0.0043), bilateral superior medial frontal regions (BSMF) (p = 0.012), and left inferior frontal (p = 0.010) regions predicted the 3MSE scores for all the participants at follow-up. The baseline rCBF in the PCC and BSMF regions predicted the conversion and time to conversion from MCI to AD (p < 0.05; not significant after multiple corrections). We demonstrated the feasibility of ASL in detecting rCBF changes in the typical AD-affected regions and the predictive value of baseline rCBF on AD conversion and cognitive decline.

Random forest model for feature-based Alzheimer's disease conversion prediction from early mild cognitive impairment subjects.

Alzheimer's Disease (AD) conversion prediction from the mild cognitive impairment (MCI) stage has been a difficult challenge. This study focuses on providing an individualized MCI to AD conversion prediction using a balanced random forest model that leverages clinical data. In order to do this, 383 Early Mild Cognitive Impairment (EMCI) patients were gathered from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Of these patients, 49 would eventually convert to AD (EMCI_C), whereas the remaining 334 did not convert (EMCI_NC). All of these patients were split randomly into training and testing data sets with 95 patients reserved for testing. Nine clinical features were selected, comprised of a mix of demographic, brain volume, and cognitive testing variables. Oversampling was then performed in order to balance the initially imbalanced classes prior to training the model with 1000 estimators. Our results showed that a random forest model was effective (93.6% accuracy) at predicting the conversion of EMCI patients to AD based on these clinical features. Additionally, we focus on explainability by assessing the importance of each clinical feature. Our model could impact the clinical environment as a tool to predict the conversion to AD from a prodromal stage or to identify ideal candidates for clinical trials.

Early diagnosis of Alzheimer's disease on ADNI data using novel longitudinal score based on functional principal component analysis.

Methods: Alzheimer's disease (AD) is a worldwide prevalent age-related neurodegenerative disease with no available cure yet. Early prognosis is therefore crucial for planning proper clinical intervention. It is especially true for people diagnosed with mild cognitive impairment, to whom the prediction of whether and when the future disease onset would happen is particularly valuable. However, such prognostic prediction has been proven to be challenging, and previous studies have only achieved limited success. Approach: In this study, we seek to extract the principal component of the longitudinal disease progression trajectory in the early stage of AD, measured as the magnetic resonance imaging (MRI)-derived structural volume, to predict the onset of AD for mild cognitive impaired patients two years ahead. Results: Cross-validation results of LASSO regression using the longitudinal functional principal component (FPC) features show significant improved predictive power compared to training using the baseline volume 12 months before AD conversion [area under the receiver operating characteristic curve (AUC) of 0.802 versus 0.732] and 24 months before AD conversion (AUC of 0.816 versus 0.717). Conclusions: We present a framework using the FPCA to extract features from MRI-derived information collected from multiple timepoints. The results of our study demonstrate the advantageous predictive power of the population-based longitudinal features to predict the disease onset compared with using only cross-sectional data-based on volumetric features extracted from a single timepoint, demonstrating the improved prediction power using FPC-derived longitudinal features.

Early diagnosis model of Alzheimer’s disease based on sparse logistic regression with the generalized elastic net

Accurate prediction of high-risk group who may convert to Alzheimer’s disease (AD) patients is critical for the future treatment of patients. Recently, logistic regression is used for the early diagnosis of AD. However, due to the high-dimensional small sample characteristics of AD data, this brings difficulties to logistic regression-aided diagnosis. To solve the problem, in this paper, we propose sparse logistic regression with the generalized elastic net for the early diagnosis of AD. The generalized elastic net is composed of Lp regularization and L2 regularization. The Lp regularization can produce sparse solutions. L2 regularization ensures that the correlated brain regions are in solution. We evaluate our proposed method on 197 subjects from the baseline MRI data of ADNI database. Our proposed method achieves classification accuracy of 96.10, 84.67, and 75.87 %, for AD vs. HC, MCI vs. HC, and cMCI vs. sMCI, respectively. Experimental results show that, compared with previous methods, our proposed method captures distinct brain regions that are significantly related to AD conversion and provides a significant enhancement in AD classification.

Serum Phosphatidylethanolamine and Lysophosphatidylethanolamine Levels Differentiate Alzheimer's Disease from Controls and Predict Progression from Mild Cognitive Impairment.

There is intense interest in the development of blood-based biomarkers, not only that can differentiate Alzheimer's disease (AD) from controls, but that can also predict conversion from mild cognitive impairment (MCI) to AD. Serum biomarkers carry the potential advantage over imaging or spinal fluid markers both in terms of cost and invasiveness. Our objective was to measure the potential for serum lipid markers to differentiate AD from age-matched healthy controls as well as to predict conversion from MCI to AD. Using a publicly-available dataset, we examined the relationship between baseline serum levels of 349 known lipids from 16 classes of lipids to differentiate disease state as well as to predict the conversion from MCI to AD. We observed that several classes of lipids (cholesteroyl ester, phosphatidylethanolamine, lysophosphatidylethanolamine, and acylcarnitine) differentiated AD from normal controls. Among these, only two classes, phosphatidylethanolamine (PE) and lysophosphatidylethanolamine (lyso-PE), predicted time to conversion from MCI to AD. Low levels of PE and high levels of lyso-PE result in two-fold faster median time to progression from MCI to AD, with hazard ratios 0.62 and 1.34, respectively. These data suggest that serum PE and lyso-PE may be useful biomarkers for predicting MCI to AD conversion. In addition, since PE is converted to lyso-PE by phospholipase A2, an important inflammatory mediator that is dysregulated in AD, these data suggest that the disrupted serum lipid profile here may be related to an abnormal inflammatory response early in the AD pathologic cascade.

Functional Ensemble Survival Tree: Dynamic Prediction of Alzheimer’s Disease Progression Accommodating Multiple Time-Varying Covariates

Abstract With the exponential growth in data collection, multiple time-varying biomarkers are commonly encountered in clinical studies, along with a rich set of baseline covariates. This paper is motivated by addressing a critical issue in the field of Alzheimer’s disease (AD) in which we aim to predict the time for AD conversion in people with mild cognitive impairment to inform prevention and early treatment decisions. Conventional joint models of biomarker trajectory with time-to-event data rely heavily on model assumptions and may not be applicable when the number of covariates is large. This motivated us to consider a functional ensemble survival tree framework to characterize the joint effects of both functional and baseline covariates in predicting disease progression. The proposed framework incorporates multivariate functional principal component analysis to characterize the changing patterns of multiple time-varying neurocognitive biomarker trajectories and then nest these features within an ensemble survival tree in predicting the progression of AD. We provide a fast implementation of the algorithm that accommodates personalized dynamic prediction that can be updated as new observations are gathered to reflect the patient’s latest prognosis. The algorithm is empirically shown to perform well in simulation studies and is illustrated through the analysis of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (http://adni.loni.usc.edu/). We provide implementation of our proposed method in an R package funest.