Semi-Supervised Multimodal Relevance Vector Regression Improves Cognitive Performance Estimation from Imaging and Biological Biomarkers

Comparison of florbetapir positron emission tomography scans with cerebrospinal fluid biomarkers in healthy individuals and people with mild cognitive impairment or Alzheimer's disease dementia

Accurate recognition of progressive mild cognitive impairment (MCI) is helpful to reduce the risk of developing Alzheimer's disease (AD). However, it is still challenging to extract effective biomarkers from multivariate brain structural magnetic resonance imaging (MRI) features to accurately differentiate the progressive MCI from stable MCI. We develop novel biomarkers by combining subspace learning methods with the information of AD as well as normal control (NC) subjects for the prediction of MCI conversion using multivariate structural MRI data. Specifically, we first learn two projection matrices to map multivariate structural MRI data into a common label subspace for AD and NC subjects, where the original data structure and the one-to-one correspondence between multiple variables are kept as much as possible. Afterwards, the multivariate structural MRI features of MCI subjects are mapped into a common subspace according to the projection matrices. We then perform the self-weighted operation and weighted fusion on the features in common subspace to extract the novel biomarkers for MCI subjects. The proposed biomarkers are tested on Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Experimental results indicate that our proposed biomarkers outperform the competing biomarkers on the discrimination between progressive MCI and stable MCI. And the improvement from the proposed biomarkers is not limited to a particular classifier. Moreover, the results also confirm that the information of AD and NC subjects is conducive to predicting conversion from MCI to AD. In conclusion, we find a good representation of brain features from high-dimensional MRI data, which exhibits promising performance for predicting conversion from MCI to AD.

In recent studies of Alzheimer's disease (AD), it has increasing attentions in identifying mild cognitive impairment (MCI) converters (MCI-C) from MCI non-converters (MCI-NC). Note that MCI is a prodromal stage of AD, with possibility to convert to AD. Most traditional methods for MCI conversion prediction learn information only from MCI subjects (including MCI-C and MCI-NC), not from other related subjects, e.g., AD and normal controls (NC), which can actually aid the classification between MCI-C and MCI-NC. In this paper, we propose a novel domain-transfer learning method for MCI conversion prediction. Different from most existing methods, we classify MCI-C and MCI-NC with aid from the domain knowledge learned with AD and NC subjects as auxiliary domain to further improve the classification performance. Our method contains two key components: (1) the cross-domain kernel learning for transferring auxiliary domain knowledge, and (2) the adapted support vector machine (SVM) decision function construction for cross-domain and auxiliary domain knowledge fusion. Experimental results on the Alzheimer's Disease neuroimaging initiative (ADNI) database show that the proposed method can significantly improve the classification performance between MCI-C and MCI-NC, with aid of domain knowledge learned from AD and NC subjects.

Tensor-based morphometry as a neuroimaging biomarker for Alzheimer's disease: An MRI study of 676 AD, MCI, and normal subjects

Medial temporal lobe atrophy scores translated to clinical practice: Editorial comment on ‘Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut‐offs'

It has been shown that a new procedure (implicit function as squashing time, IFAST) based on artificial neural networks (ANNs) is able to compress eyes-closed resting electroencephalographic (EEG) data into spatial invariants of the instant voltage distributions for an automatic classification of mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects with classification accuracy of individual subjects higher than 92%. Here we tested the hypothesis that this is the case also for the classification of individual normal elderly (Nold) vs. MCI subjects, an important issue for the screening of large populations at high risk of AD. Eyes-closed resting EEG data (10- 20 electrode montage) were recorded in 171 Nold and in 115 amnesic MCI subjects. The data inputs for the classification by IFAST were the weights of the connections within a non linear auto-associative ANN trained to generate the instant voltage distributions of 60-s artifact free EEG data. The most relevant features were selected and coincidently the dataset was split into two halves for the final binary classification (training and testing) performed by a supervised ANN. The classification of the individual Nold and MCI subjects reached 95.87% of sensitivity and 91.06% of specificity (93.46% of accuracy). These results indicate that IFAST can reliably distinguish eyes-closed resting EEG in individual Nold and MCI subjects, and may be used for large-scale periodic screening of large populations at risk of AD and personalized care.

Alzheimer's disease (AD) is a complex disorder influenced by many factors, but it is unclear how each factor contributes to disease progression. An in-depth examination of these factors may yield an accurate estimate of time-to-conversion to AD for patients at various disease stages. Recent advances in deep learning have enabled researchers to predict patient's disease onset time by exploring the influencing factors in AD progression. We used 543 subjects with 63 features from 3 data modalities from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The following modalities were used: 1) MRI, 2) genetic and 3) DTC (Demographic, cognitive Tests and Cerebrospinal fluid). The 21 most important features were automatically selected for the three modalities. We used a Deep Learning-based survival analysis model that extends the classic Cox regression model to predict the subjects' disease onset time. Here we re-define the non-AD-progression as "survivor", and AD-progression as "non-survivor". The subjects were divided into two groups: progressive subjects (non-survivor), who were either healthy or diagnosed with Mild Cognitive Impairment (MCI) at initial clinical visit and later developed AD, and non-progressive subjects ("survivor"), who were either healthy or MCI at initial visit but did not develop AD later. We used 10 random sub-samples, selecting 80% of the subjects for training and 20% for testing each time; 20% of training data was used for internal validation. Figure 1 shows the estimated survival rates over 10 years. Both groups had a high survival chance at the start. The progressive group's survival chance dropped much faster and fell below 20% by the end of the period. The non-progressive group's survival chance remained around 50%. Feature importance analysis is displayed in Figure 2. Eight of the top ten most important features are from the cognitive tests, demonstrating their importance in survival analysis. Amygdala and Hippocampus regions, as well as age, are also notable features. Our study demonstrated that using powerful predictive models on multi-modal data can improve prediction of time-to-conversion. This not only leads to a better understanding of AD, but also provides essential tools for practitioners who wish to follow their patients' disease progression.

In recent years, pathological researches of mild cognitive impairment (MCI) subjects and the Alzheimer's disease (AD) patients have gained a great deal of attention. In this study, we used the voxel-based morphometry (VBM) method to analyze the Magnatic Resonance Imaging (MRI) data of gray matter volumes in 98 normal controls (NCs), 91 AD patients and 113 MCI subjects. The measurements of gray matter volumes were calculated for each of the three groups respectively. We found that compared with MCI subjects, AD patients had further atrophy in the following brain regions: right insula, left hippocampus, right fusiform and bilateral middle temporal gyrus. Compared with NCs, AD patients and MCI subjects shared some abnormal brain regions such as bilateral parahippocampal gyrus, bilateral hippocampus, left amygdala and left fusiform. The results provided additional evidences to support the viewpoint that MCI is the transitional stage between normal aging and AD.

Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. Amyloid-beta 1 to 42 peptide (A beta(1-42)), total tau (t-tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy-confirmed AD cases and 52 age-matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t-tau and A beta(1-42) in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy-confirmed CSF data. CSF A beta(1-42) was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for A beta(1-42), t-tau, and APO epsilon 4 allele count provided the best assessment delineation of mild AD. An AD-like baseline CSF profile for t-tau/A beta(1-42) was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study. The CSF biomarker signature of AD defined by A beta(1-42) and t-tau in the autopsy-confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD.

Depressive Symptoms and Mild Cognitive Impairment in the Elderly: An Ominous Combination

Background and Purpose: A majority studies on diagnosis of Alzheimer’s Disease (AD) are based on an assumption: the training and testing data are drawn from the same distribution. However, in the diagnosis of AD and mild cognitive impairment (MCI), this identical-distribution assumption may not hold. To solve this problem, we utilize the transfer learning method into the diagnosis of AD. Methods: The MR (Magnetic Resonance) images were segmented using spm-Dartel toolbox and registrated with Automatic Anatomical Labeling (AAL) atlas, then the gray matter (GM) tissue volume of the anatomical region were computed as characteristic parameter. The information gain was introduced for feature selection. The TrAdaboost algorithm was used to classify AD, MCI, and normal controls (NC) data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, meanwhile, the “knowledge” learned from ADNI was transferred to AD samples from local hospital. The classification accuracy, sensitivity and specificity were calculated and compared with four classical algorithms. Results: In the experiment of transfer task: AD to MCI, 177 AD and 40NC subjects were grouped as training data; 245 MCI and 45 remaining NC subjects were combined as testing data, the highest accuracy achieved 85.4%, higher than the other four classical algorithms. Meanwhile, feature selection that is based on information gain reduced the features from 90 to 7, controlled the redundancy efficiently. In the experiment of transfer task: ADNI to local hospital data, the highest accuracy achieved 93.7%, and the specificity achieved 100%. Conclusions: The experimental results showed that our algorithm has a clear advantage over classic classification methods with higher accuracy and less fluctuation.

IC-P-068: Diffusion tensor imaging of normal appearing white matter in MCI and AD

Distinction between mild cognitive impairment and Alzheimer's disease by CSF amyloid β40 and β42, and protein-conjugated acrolein

Profile of pathogenic proteins in total circulating extracellular vesicles in mild cognitive impairment and during the progression of Alzheimer's disease

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.