Convolutional Neural Networks to Assess Steno-Occlusive Disease Using Cerebrovascular Reactivity.

Cerebrovascular Reactivity (CVR) is a provocative test used with Blood oxygenation level-dependent (BOLD) Magnetic Resonance Imaging (MRI) studies, where a vasoactive stimulus is applied and the corresponding changes in the cerebral blood flow (CBF) are measured. The most common clinical application is the assessment of cerebral perfusion insufficiency in patients with steno-occlusive disease (SOD). Globally, millions of people suffer from cerebrovascular diseases, and SOD is the most common cause of ischemic stroke. Therefore, CVR analyses can play a vital role in early diagnosis and guiding clinical treatment. This study develops a convolutional neural network (CNN)-based clinical decision support system to facilitate the screening of SOD patients by discriminating between healthy and unhealthy CVR maps. The networks were trained on a confidential CVR dataset with two classes: 68 healthy control subjects, and 163 SOD patients. This original dataset was distributed in a ratio of 80%-10%-10% for training, validation, and testing, respectively, and image augmentations were applied to the training and validation sets. Additionally, some popular pre-trained networks were imported and customized for the objective classification task to conduct transfer learning experiments. Results indicate that a customized CNN with a double-stacked convolution layer architecture produces the best results, consistent with expert clinical readings.

Invalidation of fMRI experiments secondary to neurovascular uncoupling in patients with cerebrovascular disease.

PURPOSE: Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is a technique used to infer neuronal activity from the observed changes in blood flow. Cerebrovascular reactivity (CVR) is the ability of arterioles to increase blood flow in response to vasodilatory stimulus. We hypothesize that in areas of disease where there is exhausted vascular reserve and impaired CVR there will be diminished blood flow response following neuronal activation, and that these areas would appear as false-negative tests on BOLD fMRI. MATERIALS AND METHODS: Patients with steno-occlusive disease and unilateral hemodynamic impairment received a standardized hypercapnic stimuli while being imaged with BOLD fMRI to generate CVR maps. These were compared to traditional BOLD fMRI maps of neuronal activation in the motor cortex in response to a motor task. RESULTS: Neuronal activation from the motor task was found to be linearly correlated with CVR (n = 11 patients, R = 0.82). Regions with positive (normal) CVR showed positive activation on BOLD fMRI, while regions with negative CVR had attenuated neuronal activation on BOLD fMRI. CONCLUSION: In areas with cerebrovascular disease where CVR is impaired, there is uncoupling of neuronal activation and blood flow that confounds traditional BOLD fMRI. CVR mapping is a noninvasive MRI-based imaging technique that can provide information about the vascular reactivity of the brain that is important to consider when interpreting traditional BOLD fMRI studies. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1448-1455.

Vitamin D metabolic pathway genes and risk of multiple sclerosis in Canadians.

BACKGROUND: Multiple sclerosis (MS) is determined by interactions between genes and environment and the influence of vitamin D adequacy has been proposed. Previous studies have shown that serum 25-hydroxyvitamin D (25(OH)D) levels are genetically influenced. Polymorphisms in vitamin D pathway genes are candidates for association with MS susceptibility. METHODS: MS patients (n=1364) and their unaffected first-degree relatives (n=1661) were ascertained through the Canadian Collaborative study. Seventy-one SNPs, across four genes [vitamin D receptor (VDR), 1-alpha-hydroxylase (CYP27B1) enzyme, vitamin D binding protein (DBP), 24-hydroxylase (CYP24)], were genotyped and tested for association with MS susceptibility using TDT in PLINK. Secondary analyses included stratification for HLA-DRB1*15 and parent of origin transmission effects. RESULTS: We found no significant association of vitamin D pathway genes with MS susceptibility after correction for multiple comparisons. However, the VDR Fok1 variant (rs2228570), selected for previously positive associations with MS susceptibility and 25(OH)D levels in MS patients showed marginally distorted transmission in DRB15-negative patients (p=0.03). There was no evidence for differential maternal versus paternal allele transmission. CONCLUSIONS: The findings fail to directly connect vitamin D metabolism genes to MS susceptibility, despite a large sample size and comprehensive gene coverage.

Season of birth and anorexia nervosa.

Our aim was to investigate whether there is a season-of-birth effect in anorexia nervosa. In a meta-analysis, we compared the distribution of anorexia births (n = 1293) from four independent UK cohorts to that of the general UK population (n = 21 914 037), using both the Walter & Elwood seasonality and chi-squared tests. We found an excess of anorexia births from March to June (odds ratio (OR) = 1.15, 95% CI 1.03-1.29, P = 0.012) and a deficit from September to October (OR = 0.8, 95% CI 0.68-0.94, P = 0.007). These results indicate that environmental risk factor(s) are operative during gestation or immediately after birth and their identification will be important for disease prevention strategies.

The emerging role of vitamin D binding protein in multiple sclerosis.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). A growing body of evidence supports a role for vitamin D in MS aetiology. Vitamin D binding protein (DBP) is the major plasma carrier of vitamin D metabolites and genetic differences in DBP gene have been found to influence vitamin D levels. We review here evidence supporting a role of DBP in MS. Several recent studies show that DBP levels in the cerebrospinal fluid correlate with MS course, being lower during relapses and higher in the secondary progressive phase. Further studies are needed to elucidate the potential use of DBP as a biological marker of MS course, but may be of use given the current lack of diagnostic tools for the prediction of MS development and progression.

Heterogeneity in multiple sclerosis: scratching the surface of a complex disease.

Multiple Sclerosis (MS) is the most common demyelinating disease of the central nervous system. Although the etiology and the pathogenesis of MS has been extensively investigated, no single pathway, reliable biomarker, diagnostic test, or specific treatment have yet been identified for all MS patients. One of the reasons behind this failure is likely to be the wide heterogeneity observed within the MS population. The clinical course of MS is highly variable and includes several subcategories and variants. Moreover, apart from the well-established association with the HLA-class II DRB1*15:01 allele, other genetic variants have been shown to vary significantly across different populations and individuals. Finally both pathological and immunological studies suggest that different pathways may be active in different MS patients. We conclude that these "MS subtypes" should still be considered as part of the same disease but hypothesize that spatiotemporal effects of genetic and environmental agents differentially influence MS course. These considerations are extremely relevant, as outcome prediction and personalised medicine represent the central aim of modern research.

Effects of genistein following fractionated lung irradiation in mice.

BACKGROUND AND PURPOSE: This study investigated protection of lung injury by genistein following fractionated doses of radiation and its effect on tumor response. MATERIAL AND METHODS: C3H/HeJ mice were irradiated (100 kVp X-rays) with 9 fractions of 3.1 Gy over 30 days (approximately equivalent to 10 Gy single dose) and were maintained on a genistein diet ( approximately 10mg/kg). Damage was assessed over 28 weeks in lung cells by a cytokinesis block micronucleus (MN) assay and by changes in breathing rate and histology. Tumor protection was assessed using a colony assay to determine cell survival following in situ irradiation of small lung nodules (KHT fibrosarcoma). RESULTS: Genistein caused about a 50% reduction in the MN damage observed during the fractionated radiation treatment and this damage continued to decrease at later times to background levels by 16 weeks. In mice not receiving Genistein MN levels remained well above background out to 28 weeks after irradiation. Genistein reduced macrophage accumulation by 22% and reduced collagen deposition by 28%. There was minimal protection against increases in breathing rate or severe morbidity during pneumonitis. No tumor protection by genistein treatment was observed. CONCLUSIONS: Genistein at the dose levels used in this study partially reduced the extent of fibrosis developing in mouse lung caused by irradiation but gave minimal protection against pneumonitis. There was no evidence that genistein caused protection of small tumors growing in the lung.