Dataset Information

Quantifying Neurodegenerative Progression With DeepSymNet, an End-to-End Data-Driven Approach.

ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and is one of the leading sources of morbidity and mortality in the aging population. There is a long preclinical period followed by mild cognitive impairment (MCI). Clinical diagnosis and the rate of decline is variable. Progression monitoring remains a challenge in AD, and it is imperative to create better tools to quantify this progression. Brain magnetic resonance imaging (MRI) is commonly used for patient assessment. However, current approaches for analysis require strong a priori assumptions about regions of interest used and complex preprocessing pipelines including computationally expensive non-linear registrations and iterative surface deformations. These preprocessing steps are composed of many stacked processing layers. Any error or bias in an upstream layer will be propagated throughout the pipeline. Failures or biases in the non-linear subject registration and the subjective choice of atlases of specific regions are common in medical neuroimaging analysis and may hinder the translation of many approaches to the clinical practice. Here we propose a data-driven method based on an extension of a deep learning architecture, DeepSymNet, that identifies longitudinal changes without relying on prior brain regions of interest, an atlas, or non-linear registration steps. Our approach is trained end-to-end and learns how a patient's brain structure dynamically changes between two-time points directly from the raw voxels. We compare our approach with Freesurfer longitudinal pipelines and voxel-based methods using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our model can identify AD progression with comparable results to existing Freesurfer longitudinal pipelines without the need of predefined regions of interest, non-rigid registration algorithms, or iterative surface deformation at a fraction of the processing time. When compared to other voxel-based methods which share some of the same benefits, our model showed a statistically significant performance improvement. Additionally, we show that our model can differentiate between healthy subjects and patients with MCI. The model's decision was investigated using the epsilon layer-wise propagation algorithm. We found that the predictions were driven by the pallidum, putamen, and the superior temporal gyrus. Our novel longitudinal based, deep learning approach has the potential to diagnose patients earlier and enable new computational tools to monitor neurodegeneration in clinical practice.

SUBMITTER: Pena D

PROVIDER: S-EPMC6788344 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Quantifying Neurodegenerative Progression With DeepSymNet, an End-to-End Data-Driven Approach.

Pena Danilo D Barman Arko A Suescun Jessika J Jiang Xiaoqian X Schiess Mya C MC Giancardo Luca L

Frontiers in neuroscience 20191004

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and is one of the leading sources of morbidity and mortality in the aging population. There is a long preclinical period followed by mild cognitive impairment (MCI). Clinical diagnosis and the rate of decline is variable. Progression monitoring remains a challenge in AD, and it is imperative to create better tools to quantify this progression. Brain magnetic resonance imaging (MRI) is commonly used for patient asses ...[more]

PMID: 31636533

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Project description:See Li and Donohue (doi:10.1093/brain/awy089) for a scientific commentary on this article.Dominantly-inherited Alzheimer's disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer's disease. We use emerging techniques in generative data-driven disease progression modelling to characterize dominantly-inherited Alzheimer's disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset. We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers in three subtypes: 163 PSEN1, 17 PSEN2, and 31 APP) and a baseline visit (age 19-66; up to four visits each, 1.1 ± 1.9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then subcortical regions (∼24 ± 11 years before onset); phosphorylated tau (17 ± 8 years), tau and amyloid-β changes in cerebrospinal fluid; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than predictions that used familial estimates: root mean squared error of 1.35 years versus 5.54 years. The models reveal hidden detail on dominantly-inherited Alzheimer's disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials.

Project description:BackgroundAs the most stable and experimentally accessible epigenetic mark, DNA methylation is of great interest to the research community. The landscape of DNA methylation across tissues, through development and in disease pathogenesis is not yet well characterized. Thus there is a need for rapid and cost effective methods for assessing genome-wide levels of DNA methylation. The Illumina Infinium HumanMethylation450 (450K) BeadChip is a very useful addition to the available methods for DNA methylation analysis but its complex design, incorporating two different assay methods, requires careful consideration. Accordingly, several normalization schemes have been published. We have taken advantage of known DNA methylation patterns associated with genomic imprinting and X-chromosome inactivation (XCI), in addition to the performance of SNP genotyping assays present on the array, to derive three independent metrics which we use to test alternative schemes of correction and normalization. These metrics also have potential utility as quality scores for datasets.ResultsThe standard index of DNA methylation at any specific CpG site is ? = M/(M + U + 100) where M and U are methylated and unmethylated signal intensities, respectively. Betas (?s) calculated from raw signal intensities (the default GenomeStudio behavior) perform well, but using 11 methylomic datasets we demonstrate that quantile normalization methods produce marked improvement, even in highly consistent data, by all three metrics. The commonly used procedure of normalizing betas is inferior to the separate normalization of M and U, and it is also advantageous to normalize Type I and Type II assays separately. More elaborate manipulation of quantiles proves to be counterproductive.ConclusionsCareful selection of preprocessing steps can minimize variance and thus improve statistical power, especially for the detection of the small absolute DNA methylation changes likely associated with complex disease phenotypes. For the convenience of the research community we have created a user-friendly R software package called wateRmelon, downloadable from bioConductor, compatible with the existing methylumi, minfi and IMA packages, that allows others to utilize the same normalization methods and data quality tests on 450K data.

Dataset Information

Quantifying Neurodegenerative Progression With DeepSymNet, an End-to-End Data-Driven Approach.

Publications

Quantifying Neurodegenerative Progression With DeepSymNet, an End-to-End Data-Driven Approach.

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