Language is a valuable source of clinical information in Alzheimer's Disease, as it declines concurrently with neurodegeneration. Consequently, speech and language data have been extensively studied in connection with its diagnosis. This paper summarises current findings on the use of artificial intelligence, speech and language processing to predict cognitive decline in the context of Alzheimer's Disease, detailing current research procedures, highlighting their limitations and suggesting strategies to address them. We conducted a systematic review of original research between 2000 and 2019, registered in PROSPERO (reference CRD42018116606). An interdisciplinary search covered six databases on engineering (ACM and IEEE), psychology (PsycINFO), medicine (PubMed and Embase) and Web of Science. Bibliographies of relevant papers were screened until December 2019. From 3,654 search results 51 articles were selected against the eligibility criteria. Four tables summarise their findings: study details (aim, population, interventions, comparisons, methods and outcomes), data details (size, type, modalities, annotation, balance, availability and language of study), methodology (pre-processing, feature generation, machine learning, evaluation and results) and clinical applicability (research implications, clinical potential, risk of bias and strengths/limitations). While promising results are reported across nearly all 51 studies, very few have been implemented in clinical research or practice. We concluded that the main limitations of the field are poor standardisation, limited comparability of results, and a degree of disconnect between study aims and clinical applications. Attempts to close these gaps should support translation of future research into clinical practice.
Alzheimer's disease (AD) is the most common form of dementia and is phenotypically heterogeneous. APOE is a triallelic gene which correlates with phenotypic heterogeneity in AD. In this work, we determined the effect of APOE alleles on the disease progression timeline of AD using a discriminative event-based model (DEBM). Since DEBM is a data-driven model, stratification into smaller disease subgroups would lead to more inaccurate models as compared to fitting the model on the entire dataset. Hence our secondary aim is to propose and evaluate novel approaches in which we split the different steps of DEBM into group-aspecific and group-specific parts, where the entire dataset is used to train the group-aspecific parts and only the data from a specific group is used to train the group-specific parts of the DEBM. We performed simulation experiments to benchmark the accuracy of the proposed approaches and to select the optimal approach. Subsequently, the chosen approach was applied to the baseline data of 417 cognitively normal, 235 mild cognitively impaired who convert to AD within 3 years, and 342 AD patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset to gain new insights into the effect of APOE carriership on the disease progression timeline of AD. The presented models could aid understanding of the disease, and in selecting homogeneous group of presymptomatic subjects at-risk of developing symptoms for clinical trials.
Machine learning methods applied to complex biomedical data has enabled the construction of disease signatures of diagnostic/prognostic value. However, less attention has been given to understanding disease heterogeneity. Semi-supervised clustering methods can address this problem by estimating multiple transformations from a (e.g. healthy) control (CN) group to a patient (PT) group, seeking to capture the heterogeneity of underlying pathlogic processes. Herein, we propose a novel method, Smile-GANs (SeMi-supervIsed cLustEring via GANs), for semi-supervised clustering, and apply it to brain MRI scans. Smile-GANs first learns multiple distinct mappings by generating PT from CN, with each mapping characterizing one relatively distinct pathological pattern. Moreover, a clustering model is trained interactively with mapping functions to assign PT into corresponding subtype memberships. Using relaxed assumptions on PT/CN data distribution and imposing mapping non-linearity, Smile-GANs captures heterogeneous differences in distribution between the CN and PT domains. We first validate Smile-GANs using simulated data, subsequently on real data, by demonstrating its potential in characterizing heterogeneity in Alzheimer's Disease (AD) and its prodromal phases. The model was first trained using baseline MRIs from the ADNI2 database and then applied to longitudinal data from ADNI1 and BLSA. Four robust subtypes with distinct neuroanatomical patterns were discovered: 1) normal brain, 2) diffuse atrophy atypical of AD, 3) focal medial temporal lobe atrophy, 4) typical-AD. Further longitudinal analyses discover two distinct progressive pathways from prodromal to full AD: i) subtypes 1 - 2 - 4, and ii) subtypes 1 - 3 - 4. Although demonstrated on an important biomedical problem, Smile-GANs is general and can find application in many biomedical and other domains.
Alzheimer's Disease (AD) ravages the cognitive ability of more than 5 million Americans and creates an enormous strain on the health care system. This paper proposes a machine learning predictive model for AD development without medical imaging and with fewer clinical visits and tests, in hopes of earlier and cheaper diagnoses. That earlier diagnoses could be critical in the effectiveness of any drug or medical treatment to cure this disease. Our model is trained and validated using demographic, biomarker and cognitive test data from two prominent research studies: Alzheimer's Disease Neuroimaging Initiative (ADNI) and Australian Imaging, Biomarker Lifestyle Flagship Study of Aging (AIBL). We systematically explore different machine learning models, pre-processing methods and feature selection techniques. The most performant model demonstrates greater than 90% accuracy and recall in predicting AD, and the results generalize across sub-studies of ADNI and to the independent AIBL study. We also demonstrate that these results are robust to reducing the number of clinical visits or tests per visit. Using a metaclassification algorithm and longitudinal data analysis we are able to produce a "lean" diagnostic protocol with only 3 tests and 4 clinical visits that can predict Alzheimer's development with 87% accuracy and 79% recall. This novel work can be adapted into a practical early diagnostic tool for predicting the development of Alzheimer's that maximizes accuracy while minimizing the number of necessary diagnostic tests and clinical visits.
Characterizing the subtle changes of functional brain networks associated with the pathological cascade of Alzheimer's disease (AD) is important for early diagnosis and prediction of disease progression prior to clinical symptoms. We developed a new deep learning method, termed multiple graph Gaussian embedding model (MG2G), which can learn highly informative network features by mapping high-dimensional resting-state brain networks into a low-dimensional latent space. These latent distribution-based embeddings enable a quantitative characterization of subtle and heterogeneous brain connectivity patterns at different regions and can be used as input to traditional classifiers for various downstream graph analytic tasks, such as AD early stage prediction, and statistical evaluation of between-group significant alterations across brain regions. We used MG2G to detect the intrinsic latent dimensionality of MEG brain networks, predict the progression of patients with mild cognitive impairment (MCI) to AD, and identify brain regions with network alterations related to MCI.
Objective: Deriving disease subtypes from electronic health records (EHRs) can guide next-generation personalized medicine. However, challenges in summarizing and representing patient data prevent widespread practice of scalable EHR-based stratification analysis. Here, we present a novel unsupervised framework based on deep learning to process heterogeneous EHRs and derive patient representations that can efficiently and effectively enable patient stratification at scale. Materials and methods: We considered EHRs of $1,608,741$ patients from a diverse hospital cohort comprising of a total of $57,464$ clinical concepts. We introduce a representation learning model based on word embeddings, convolutional neural networks and autoencoders (i.e., "ConvAE") to transform patient trajectories into low-dimensional latent vectors. We evaluated these representations as broadly enabling patient stratification by applying hierarchical clustering to different multi-disease and disease-specific patient cohorts. Results: ConvAE significantly outperformed several common baselines in a clustering task to identify patients with different complex conditions, with $2.61$ entropy and $0.31$ purity average scores. When applied to stratify patients within a certain condition, ConvAE led to various clinically relevant subtypes for different disorders, including type 2 diabetes, Parkinson's disease and Alzheimer's disease, largely related to comorbidities, disease progression, and symptom severity. Conclusions: Patient representations derived from modeling EHRs with ConvAE can help develop personalized medicine therapeutic strategies and better understand varying etiologies in heterogeneous sub-populations.
In the early 2000s a group of scientists at Stanford University, California, revived a grisly procedure used in the 1950s known as parabiosis. They paired living mice, young with old, peeled back their skin and stitched together their sides so the two animals shared the same blood circulatory system. A month later, they found signs of rejuvenation in the muscles and livers of the old mice. The findings, published in 2005, turned the minds of scientists, entrepreneurs and the public to the potential of young blood to rejuvenate ageing people. By 2016, enough interest had grown to prompt a US-based startup called Ambrosia to start offering pricey infusions of young plasma – the cell-free component of blood.
Brain-Computer Interface (BCI) is a powerful communication tool between users and systems, which enhances the capability of the human brain in communicating and interacting with the environment directly. Advances in neuroscience and computer science in the past decades have led to exciting developments in BCI, thereby making BCI a top interdisciplinary research area in computational neuroscience and intelligence. Recent technological advances such as wearable sensing devices, real-time data streaming, machine learning, and deep learning approaches have increased interest in electroencephalographic (EEG) based BCI for translational and healthcare applications. Many people benefit from EEG-based BCIs, which facilitate continuous monitoring of fluctuations in cognitive states under monotonous tasks in the workplace or at home. In this study, we survey the recent literature of EEG signal sensing technologies and computational intelligence approaches in BCI applications, compensated for the gaps in the systematic summary of the past five years (2015-2019). In specific, we first review the current status of BCI and its significant obstacles. Then, we present advanced signal sensing and enhancement technologies to collect and clean EEG signals, respectively. Furthermore, we demonstrate state-of-art computational intelligence techniques, including interpretable fuzzy models, transfer learning, deep learning, and combinations, to monitor, maintain, or track human cognitive states and operating performance in prevalent applications. Finally, we deliver a couple of innovative BCI-inspired healthcare applications and discuss some future research directions in EEG-based BCIs.
What lies ahead for Alzheimer's therapy development? While anti-amyloid antibodies are at last signaling some success, researchers agree that these expensive--and, thus far, at best modestly effective--biologic drugs can form only part of the arsenal needed to fight the disease. Researchers at the 12th Clinical Trials on Alzheimer's Disease conference, held December 4–7 in San Diego, California, broadly agreed that an array of therapeutic approaches will be needed to target symptomatic stages, or to combine with antibodies to boost efficacy. Speakers also discussed how to improve the dismal success rate of Alzheimer's clinical trials. In particular, there is a push to spend more time in Phase 2 to find the right dose and confirm physiological effects of the drug at hand.
In the year just past, Alzheimer's researchers, families, and stakeholders felt renewed hope that new treatments might be within grasp. While the Lazarus story of aducanumab may or may not be enough for FDA approval this year, data from its Phase 3 program solidified a broader signal across four different anti-amyloid antibodies that amyloid can be removed from the brain and that maybe--just maybe--this will also benefit cognition and function if given early at a sufficient dose. The prospect that the amyloid hypothesis is druggable, alone, was enough to re-energize the field. The hope that further trials to define the best doses, patient groups, and treatment regimens will eventually pay off was cause for even more enthusiasm. A boost in funding announced as the U.S. Congress headed for its holiday break also gave cause for celebration going into 2020, though the funding picture is less rosy in other countries. The NIH budget for AD research now stands at $2.8 billion, a $350 million ...