Multimodal and Multiscale Deep Neural Networks for the Early Diagnosis of Alzheimer's Disease using structural MR and FDG-PET images.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease where biomarkers for disease based on pathophysiology may be able to provide objective measures for disease diagnosis and staging. Neuroimaging scans acquired from MRI and metabolism images obtained by FDG-PET provide in-vivo measurements of structure and function (glucose metabolism) in a living brain. It is hypothesized that combining multiple different image modalities providing complementary information could help improve early diagnosis of AD. In this paper, we propose a novel deep-learning-based framework to discriminate individuals with AD utilizing a multimodal and multiscale deep neural network. Our method delivers 82.4% accuracy in identifying the individuals with mild cognitive impairment (MCI) who will convert to AD at 3 years prior to conversion (86.4% combined accuracy for conversion within 1-3 years), a 94.23% sensitivity in classifying individuals with clinical diagnosis of probable AD, and a 86.3% specificity in classifying non-demented controls improving upon results in published literature

Predicting Alzheimer’s disease progression using multi-modal deep learning approach

Alzheimer’s disease (AD) is a progressive neurodegenerative condition marked by a decline in cognitive functions with no validated disease modifying treatment. It is critical for timely treatment to detect AD in its earlier stage before clinical manifestation. Mild cognitive impairment (MCI) is an intermediate stage between cognitively normal older adults and AD. To predict conversion from MCI to probable AD, we applied a deep learning approach, multimodal recurrent neural network. We developed an integrative framework that combines not only cross-sectional neuroimaging biomarkers at baseline but also longitudinal cerebrospinal fluid (CSF) and cognitive performance biomarkers obtained from the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI). The proposed framework integrated longitudinal multi-domain data. Our results showed that 1) our prediction model for MCI conversion to AD yielded up to 75% accuracy (area under the curve (AUC) = 0.83) when using only single modality of data separately; and 2) our prediction model achieved the best performance with 81% accuracy (AUC = 0.86) when incorporating longitudinal multi-domain data. A multi-modal deep learning approach has potential to identify persons at risk of developing AD who might benefit most from a clinical trial or as a stratification approach within clinical trials

An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease

Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD

Hierarchical Two-Stage Cost-Sensitive Clinical Decision Support System for Screening Prodromal Alzheimer's Disease and Related Dementias

Background: The detection of subtle cognitive impairment in a clinical setting is difficult. Because time is a key factor in small clinics and research sites, the brief cognitive assessments that are relied upon often misclassify patients with very mild impairment as normal. Objective: In this study, we seek to identify a parsimonious screening tool in one stage, followed by additional assessments in an optional second stage if additional specificity is desired, tested using a machine learning algorithm capable of being integrated into a clinical decision support system. Methods: The best primary stage incorporated measures of short-term memory, executive and visuospatial functioning, and self-reported memory and daily living questions, with a total time of 5 minutes. The best secondary stage incorporated a measure of neurobiology as well as additional cognitive assessment and brief informant report questionnaires, totaling 30 minutes including delayed recall. Combined performance was evaluated using 25 sets of models, trained on 1,181 ADNI participants and tested on 127 patients from a memory clinic. Results: The 5-minute primary stage was highly sensitive (96.5%) but lacked specificity (34.1%), with an AUC of 87.5% and diagnostic odds ratio of 14.3. The optional secondary stage increased specificity to 58.6%, resulting in an overall AUC of 89.7% using the best model combination of logistic regression and gradient-boosted machine. Conclusion: The primary stage is brief and effective at screening, with the optional two-stage technique further increasing specificity. The hierarchical two-stage technique exhibited similar accuracy but with reduced costs compared to the more common single-stage paradigm

Brain multiplexes reveal morphological connectional biomarkers fingerprinting late brain dementia states.

Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer's disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, 'shape connections' between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus

Longitudinal measurement and hierarchical classification framework for the prediction of Alzheimer's disease.

Accurate prediction of Alzheimer's disease (AD) is important for the early diagnosis and treatment of this condition. Mild cognitive impairment (MCI) is an early stage of AD. Therefore, patients with MCI who are at high risk of fully developing AD should be identified to accurately predict AD. However, the relationship between brain images and AD is difficult to construct because of the complex characteristics of neuroimaging data. To address this problem, we present a longitudinal measurement of MCI brain images and a hierarchical classification method for AD prediction. Longitudinal images obtained from individuals with MCI were investigated to acquire important information on the longitudinal changes, which can be used to classify MCI subjects as either MCI conversion (MCIc) or MCI non-conversion (MCInc) individuals. Moreover, a hierarchical framework was introduced to the classifier to manage high feature dimensionality issues and incorporate spatial information for improving the prediction accuracy. The proposed method was evaluated using 131 patients with MCI (70 MCIc and 61 MCInc) based on MRI scans taken at different time points. Results showed that the proposed method achieved 79.4% accuracy for the classification of MCIc versus MCInc, thereby demonstrating very promising performance for AD prediction

Fast parallel image registration on CPU and GPU for diagnostic classification of Alzheimer's disease

Nonrigid image registration is an important, but time-consuming task in medical image analysis. In typical neuroimaging studies, multiple image registrations are performed, i.e., for atlas-based segmentation or template construction. Faster image registration routines would therefore be beneficial. In this paper we explore acceleration of the image registration package elastix by a combination of several techniques: (i) parallelization on the CPU, to speed up the cost function derivative calculation; (ii) parallelization on the GPU building on and extending the OpenCL framework from ITKv4, to speed up the Gaussian pyramid computation and the image resampling step; (iii) exploitation of certain properties of the B-spline transformation model; (iv) further software optimizations. The accelerated registration tool is employed in a study on diagnostic classification of Alzheimer's disease and cognitively normal controls based on T1-weighted MRI. We selected 299 participants from the publicly available Alzheimer's Disease Neuroimaging Initiative database. Classification is performed with a support vector machine based on gray matter volumes as a marker for atrophy. We evaluated two types of strategies (voxel-wise and region-wise) that heavily rely on nonrigid image registration. Parallelization and optimization resulted in an acceleration factor of 4-5x on an 8-core machine. Using OpenCL a speedup factor of 2 was realized for computation of the Gaussian pyramids, and 15-60 for the resampling step, for larger images. The voxel-wise and the region-wise classification methods had an area under the receiver operator characteristic curve of 88 and 90%, respectively, both for standard and accelerated registration. We conclude that the image registration package elastix was substantially accelerated, with nearly identical results to the non-optimized version. The new functionality will become available in the next release of elastix as open source under the BSD license.Intelligent SystemsElectrical Engineering, Mathematics and Computer Scienc

Neuroimaging feature terminology: A controlled terminology for the annotation of brain imaging features

textabstractOntologies and terminologies are used for interoperability of knowledge and data in a standard manner among interdisciplinary research groups. Existing imaging ontologies capture general aspects of the imaging domain as a whole such as methodological concepts or calibrations of imaging instruments. However, none of the existing ontologies covers the diagnostic features measured by imaging technologies in the context of neurodegenerative diseases. Therefore, the Neuro-Imaging Feature Terminology (NIFT) was developed to organize the knowledge domain of measured brain features in association with neurodegenerative diseases by imaging technologies. The purpose is to identify quantitative imaging biomarkers that can be extracted from multi-modal brain imaging data. This terminology attempts to cover measured features and parameters in brain scans relevant to disease progression. In this paper, we demonstrate the systematic retrieval of measured indices from literature and how the extracted knowledge can be further used for disease modeling that integrates neuroimaging features with molecular processes

Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-beta deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions

Sleep-Disordered Breathing Risk with Comorbid Insomnia Is Associated with Mild Cognitive Impairment

Featured Application This study aims to identify candidate modifiable risk factors of cognitive disease. Future applications of this study include the optimization of sleep to ameliorate cognitive decline. Introduction: Few studies have evaluated the combined association between SDB with comorbid insomnia and mild cognitive impairment (MCI). To test the hypothesis that SDB with comorbid insomnia is associated with greater odds of MCI than either sleep disorder independently, we used ADNI data to evaluate cross-sectional associations between SDB risk with comorbid insomnia status and MCI. Methods: Participants with normal cognition or MCI were included. Insomnia was defined by self-report. SDB risk was assessed by modified STOP-BANG. Logistic regression models evaluated associations between four sleep disorder subgroups (low risk for SDB alone, low risk for SDB with insomnia, high risk for SDB alone, and high risk for SDB with insomnia) and MCI. Models adjusted for age, sex, BMI, APOE4 genotype, race, ethnicity, education, marital status, hypertension, cardiovascular disease, stroke, alcohol abuse, and smoking. Results: The sample (n = 1391) had a mean age of 73.5 +/- 7.0 years, 44.9% were female, 72.0% were at low risk for SDB alone, 13.8% at low risk for SDB with insomnia, 10.1% at high risk for SDB alone, and 4.1% at high risk for SDB with insomnia. Only high risk for SDB with comorbid insomnia was associated with higher odds of MCI (OR 3.22, 95% CI 1.57-6.60). Conclusion: Studies are needed to evaluate SDB with comorbid insomnia as a modifiable risk factor for MCI