Fast Predictive Simple Geodesic Regression

Deformable image registration and regression are important tasks in medical image analysis. However, they are computationally expensive, especially when analyzing large-scale datasets that contain thousands of images. Hence, cluster computing is typically used, making the approaches dependent on such computational infrastructure. Even larger computational resources are required as study sizes increase. This limits the use of deformable image registration and regression for clinical applications and as component algorithms for other image analysis approaches. We therefore propose using a fast predictive approach to perform image registrations. In particular, we employ these fast registration predictions to approximate a simplified geodesic regression model to capture longitudinal brain changes. The resulting method is orders of magnitude faster than the standard optimization-based regression model and hence facilitates large-scale analysis on a single graphics processing unit (GPU). We evaluate our results on 3D brain magnetic resonance images (MRI) from the ADNI datasets.Comment: 19 pages, 10 figures, 13 table

Multi-Channel Stochastic Variational Inference for the Joint Analysis of Heterogeneous Biomedical Data in Alzheimer's Disease

The joint analysis of biomedical data in Alzheimer's Disease (AD) is important for better clinical diagnosis and to understand the relationship between biomarkers. However, jointly accounting for heterogeneous measures poses important challenges related to the modeling of the variability and the interpretability of the results. These issues are here addressed by proposing a novel multi-channel stochastic generative model. We assume that a latent variable generates the data observed through different channels (e.g., clinical scores, imaging, ...) and describe an efficient way to estimate jointly the distribution of both latent variable and data generative process. Experiments on synthetic data show that the multi-channel formulation allows superior data reconstruction as opposed to the single channel one. Moreover, the derived lower bound of the model evidence represents a promising model selection criterion. Experiments on AD data show that the model parameters can be used for unsupervised patient stratification and for the joint interpretation of the heterogeneous observations. Because of its general and flexible formulation, we believe that the proposed method can find important applications as a general data fusion technique.Comment: accepted for presentation at MLCN 2018 workshop, in Conjunction with MICCAI 2018, September 20, Granada, Spai

CSF and Brain Structural Imaging Markers of the Alzheimer's Pathological Cascade

10.1371/journal.pone.0047406PLoS ONE712

(Extra)Ordinary Gauge/Anomaly Mediation

We study anomaly mediation models with gauge mediation effects from messengers which have a general renormalizable mass matrix with a supersymmetry-breaking spurion. Our models lead to a rich structure of supersymmetry breaking terms in the visible sector. We derive sum rules among the soft scalar masses for each generation. Our sum rules for the first and second generations are the same as those in general gauge mediation, but the sum rule for the third generation is different because of the top Yukawa coupling. We find the parameter space where the tachyonic slepton problem is solved. We also explore the case in which gauge mediation causes the anomalously small gaugino masses. Since anomaly mediation effects on the gaugino masses exist, we can obtain viable mass spectrum of the visible sector fields.Comment: 24 pages, 10 figure

Combining Anomaly and Z' Mediation of Supersymmetry Breaking

We propose a scenario in which the supersymmetry breaking effect mediated by an additional U(1)' is comparable with that of anomaly mediation. We argue that such a scenario can be naturally realized in a large class of models. Combining anomaly with Z' mediation allows us to solve the tachyonic slepton problem of the former and avoid significant fine tuning in the latter. We focus on an NMSSM-like scenario where U(1)' gauge invariance is used to forbid a tree-level mu term, and present concrete models, which admit successful dynamical electroweak symmetry breaking. Gaugino masses are somewhat lighter than the scalar masses, and the third generation squarks are lighter than the first two. In the specific class of models under consideration, the gluino is light since it only receives a contribution from 2-loop anomaly mediation, and it decays dominantly into third generation quarks. Gluino production leads to distinct LHC signals and prospects of early discovery. In addition, there is a relatively light Z', with mass in the range of several TeV. Discovering and studying its properties can reveal important clues about the underlying model.Comment: Minor changes: references added, typos corrected, journal versio

Generation and quality control of lipidomics data for the alzheimers disease neuroimaging initiative cohort.

Alzheimers disease (AD) is a major public health priority with a large socioeconomic burden and complex etiology. The Alzheimer Disease Metabolomics Consortium (ADMC) and the Alzheimer Disease Neuroimaging Initiative (ADNI) aim to gain new biological insights in the disease etiology. We report here an untargeted lipidomics of serum specimens of 806 subjects within the ADNI1 cohort (188 AD, 392 mild cognitive impairment and 226 cognitively normal subjects) along with 83 quality control samples. Lipids were detected and measured using an ultra-high-performance liquid chromatography quadruple/time-of-flight mass spectrometry (UHPLC-QTOF MS) instrument operated in both negative and positive electrospray ionization modes. The dataset includes a total 513 unique lipid species out of which 341 are known lipids. For over 95% of the detected lipids, a relative standard deviation of better than 20% was achieved in the quality control samples, indicating high technical reproducibility. Association modeling of this dataset and available clinical, metabolomics and drug-use data will provide novel insights into the AD etiology. These datasets are available at the ADNI repository at http://adni.loni.usc.edu/

Contrasting prefrontal cortex contributions to episodic memory dysfunction in behavioural variant frontotemporal dementia and alzheimer's disease

Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer's disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures

Diagnostic and economic evaluation of new biomarkers for Alzheimer's disease: the research protocol of a prospective cohort study

Doc number: 72 Abstract Background: New research criteria for the diagnosis of Alzheimer's disease (AD) have recently been developed to enable an early diagnosis of AD pathophysiology by relying on emerging biomarkers. To enable efficient allocation of health care resources, evidence is needed to support decision makers on the adoption of emerging biomarkers in clinical practice. The research goals are to 1) assess the diagnostic test accuracy of current clinical diagnostic work-up and emerging biomarkers in MRI, PET and CSF, 2) perform a cost-consequence analysis and 3) assess long-term cost-effectiveness by an economic model. Methods/design: In a cohort design 241 consecutive patients suspected of having a primary neurodegenerative disease are approached in four academic memory clinics and followed for two years. Clinical data and data on quality of life, costs and emerging biomarkers are gathered. Diagnostic test accuracy is determined by relating the clinical practice and new research criteria diagnoses to a reference diagnosis. The clinical practice diagnosis at baseline is reflected by a consensus procedure among experts using clinical information only (no biomarkers). The diagnosis based on the new research criteria is reflected by decision rules that combine clinical and biomarker information. The reference diagnosis is determined by a consensus procedure among experts based on clinical information on the course of symptoms over a two-year time period. A decision analytic model is built combining available evidence from different resources among which (accuracy) results from the study, literature and expert opinion to assess long-term cost-effectiveness of the emerging biomarkers. Discussion: Several other multi-centre trials study the relative value of new biomarkers for early evaluation of AD and related disorders. The uniqueness of this study is the assessment of resource utilization and quality of life to enable an economic evaluation. The study results are generalizable to a population of patients who are referred to a memory clinic due to their memory problems. Trial registration: NCT0145089

Predicting progression of mild cognitive impairment to dementia using neuropsychological data: a supervised learning approach using time windows

Background: Predicting progression from a stage of Mild Cognitive Impairment to dementia is a major pursuit in current research. It is broadly accepted that cognition declines with a continuum between MCI and dementia. As such, cohorts of MCI patients are usually heterogeneous, containing patients at different stages of the neurodegenerative process. This hampers the prognostic task. Nevertheless, when learning prognostic models, most studies use the entire cohort of MCI patients regardless of their disease stages. In this paper, we propose a Time Windows approach to predict conversion to dementia, learning with patients stratified using time windows, thus fine-tuning the prognosis regarding the time to conversion. Methods: In the proposed Time Windows approach, we grouped patients based on the clinical information of whether they converted (converter MCI) or remained MCI (stable MCI) within a specific time window. We tested time windows of 2, 3, 4 and 5 years. We developed a prognostic model for each time window using clinical and neuropsychological data and compared this approach with the commonly used in the literature, where all patients are used to learn the models, named as First Last approach. This enables to move from the traditional question "Will a MCI patient convert to dementia somewhere in the future" to the question "Will a MCI patient convert to dementia in a specific time window". Results: The proposed Time Windows approach outperformed the First Last approach. The results showed that we can predict conversion to dementia as early as 5 years before the event with an AUC of 0.88 in the cross-validation set and 0.76 in an independent validation set. Conclusions: Prognostic models using time windows have higher performance when predicting progression from MCI to dementia, when compared to the prognostic approach commonly used in the literature. Furthermore, the proposed Time Windows approach is more relevant from a clinical point of view, predicting conversion within a temporal interval rather than sometime in the future and allowing clinicians to timely adjust treatments and clinical appointments.FCT under the Neuroclinomics2 project [PTDC/EEI-SII/1937/2014, SFRH/BD/95846/2013]; INESC-ID plurianual [UID/CEC/50021/2013]; LASIGE Research Unit [UID/CEC/00408/2013

Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice.

BackgroundSpinal Toll-like receptors (TLRs) and signaling intermediaries have been implicated in persistent pain states. We examined the roles of two major TLR signaling pathways and selected TLRs in a mononeuropathic allodynia.MethodsL5 spinal nerve ligation (SNL) was performed in wild type (WT, C57BL/6) male and female mice and in male Tlr2-/-Tlr3-/-, Tlr4-/-, Tlr5-/-, Myd88-/-, Triflps2, Myd88/Triflps2, Tnf-/-, and Ifnar1-/- mice. We also examined L5 ligation in Tlr4-/- female mice. We examined tactile allodynia using von Frey hairs. Iba-1 (microglia) and GFAP (astrocytes) were assessed in spinal cords by immunostaining. Tactile thresholds were analyzed by 1- and 2-way ANOVA and the Bonferroni post hoc test was used.ResultsIn WT male and female mice, SNL lesions resulted in a persistent and robust ipsilateral, tactile allodynia. In males with TLR2, 3, 4, or 5 deficiencies, tactile allodynia was significantly, but incompletely, reversed (approximately 50%) as compared to WT. This effect was not seen in female Tlr4-/- mice. Increases in ipsilateral lumbar Iba-1 and GFAP were seen in mutant and WT mice. Mice deficient in MyD88, or MyD88 and TRIF, showed an approximately 50% reduction in withdrawal thresholds and reduced ipsilateral Iba-1. In contrast, TRIF and interferon receptor null mice developed a profound ipsilateral and contralateral tactile allodynia. In lumbar sections of the spinal cords, we observed a greater increase in Iba-1 immunoreactivity in the TRIF-signaling deficient mice as compared to WT, but no significant increase in GFAP. Removing MyD88 abrogated the contralateral allodynia in the TRIF signaling-deficient mice. Conversely, IFNβ, released downstream to TRIF signaling, administered intrathecally, temporarily reversed the tactile allodynia.ConclusionsThese observations suggest a critical role for the MyD88 pathway in initiating neuropathic pain, but a distinct role for the TRIF pathway and interferon in regulating neuropathic pain phenotypes in male mice