Alzheimer’s Disease (AD) and other neurodegenerative diseases affect over 20 million people worldwide, and this number is projected to significantly increase in the coming decades. Proposed imaging-based markers have shown steadily improving levels of sensitivity/specificity in classifying individual subjects as AD or normal. Several of these efforts have utilized statistical machine learning techniques, using brain images as input, as means of deriving such AD-related markers. A common characteristic of this line of research is a focus on either (1) using a single imaging modality for classification, or (2) incorporating several modalities, but reporting separate results for each. One strategy to improve on the success of these methods is to leverage all available imaging modalities together in a single automated learning framework. The rationale is that some subjects may show signs of pathology in one modality but not in another – by combining all available images a clearer view of the progression of disease pathology will emerge. Our method is based on the Multi-Kernel Learning (MKL) framework, which allows the inclusion of an arbitrary number of views of the data in a maximum margin, kernel learning framework. The principal innovation behind MKL is that it learns an optimal combination of kernel (similarity) matrices while simultaneously training a classifier. In classification experiments MKL outperformed an SVM trained on all available features by 3% – 4%. We are especially interested in whether such markers are capable of identifying early signs of the disease. To address this question, we have examined whether our multi-modal disease marker (MMDM) can predict conversion from Mild Cognitive Impairment (MCI) to AD. Our experiments reveal that this measure shows significant group differences between MCI subjects who progressed to AD, and those who remained stable for 3 years. These differences were most significant in MMDMs based on imaging data. We also discuss the relationship between our MMDM and an individual’s conversion from MCI to AD.

Structural and functional brain images are playing an important role in helping us understand the changes associated with neurological disorders such as Alzheimer's disease (AD). Recent efforts have now started investigating their utility for diagnosis purposes. This line of research has shown promising results where methods from machine learning (such as Support Vector Machines) have been used to identify AD-related patterns from images, for use in diagnosing new individual subjects. In this paper, we propose a new framework for AD classification which makes use of the Linear Program (LP) boosting with novel additional regularization based on spatial "smoothness" in 3D image coordinate spaces. The algorithm formalizes the expectation that since the examples for training the classifier are images, the voxels eventually selected for specifying the decision boundary must constitute spatially contiguous chunks, i.e., "regions" must be preferred over isolated voxels. This prior belief turns out to be useful for significantly reducing the space of possible classifiers and leads to substantial benefits in generalization. In our method, the requirement of spatial contiguity (of selected discriminating voxels) is incorporated within the optimization framework directly. Other methods have made use of similar biases as a pre-or post-processing step, however, our model incorporates this emphasis on spatial smoothness directly into the learning step. We report on extensive evaluations of our algorithm on MR and FDG-PET images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and discuss the relationship of the classification output with the clinical and cognitive biomarker data available within ADNI.

Precise detection and quantification of white matter hyperintensities (WMH) observed in T2–weighted Fluid Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Images (MRI) is of substantial interest in aging, and age related neurological disorders such as Alzheimer’s disease (AD). This is mainly because WMH may reflect comorbid neural injury or cerebral vascular disease burden. WMH in the older population may be small, diffuse and irregular in shape, and sufficiently heterogeneous within and across subjects. Here, we pose hyperintensity detection as a supervised inference problem and adapt two learning models, specifically, Support Vector Machines and Random Forests, for this task. Using texture features engineered by texton filter banks, we provide a suite of effective segmentation methods for this problem. Through extensive evaluations on healthy middle–aged and older adults who vary in AD risk, we show that our methods are reliable and robust in segmenting hyperintense regions. A measure of hyperintensity accumulation, referred to as normalized Effective WMH Volume, is shown to be associated with dementia in older adults and parental family history in cognitively normal subjects. We provide an open source library for hyperintensity detection and accumulation (interfaced with existing neuroimaging tools), that can be adapted for segmentation problems in other neuroimaging studies.

Alzheimer’s disease (AD) research has recently witnessed a great deal of activity focused on developing new statistical learning tools for automated inference using imaging data. The workhorse for many of these techniques is the Support Vector Machine (SVM) framework (or more generally kernel based methods). Most of these require, as a first step, specification of a kernel matrix between input examples (i.e., images). The inner product between images Ii and Ij in a feature space can generally be written in closed form, and so it is convenient to treat as “given”. However, in certain neuroimaging applications such an assumption becomes problematic. As an example, it is rather challenging to provide a scalar measure of similarity between two instances of highly attributed data such as cortical thickness measures on cortical surfaces. Note that cortical thickness is known to be discriminative for neurological disorders, so leveraging such information in an inference framework, especially within a multi-modal method, is potentially advantageous. But despite being clinically meaningful, relatively few works have successfully exploited this measure for classification or regression. Motivated by these applications, our paper presents novel techniques to compute similarity matrices for such topologically-based attributed data. Our ideas leverage recent developments to characterize signals (e.g., cortical thickness) motivated by the persistence of their topological features, leading to a scheme for simple constructions of kernel matrices. As a proof of principle, on a dataset of 356 subjects from the ADNI study, we report good performance on several statistical inference tasks without any feature selection, dimensionality reduction, or parameter tuning.