Valerie Jewells

Air Pollution, Cognitive Deficits and Brain Abnormalities: A Pilot Study with Children and Dogs.

Exposure to air pollution is associated with neuroinflammation in healthy children and dogs in Mexico City. Comparative studies were carried out in healthy children and young dogs similarly exposed to ambient pollution in Mexico City. Children from Mexico City (n: 55) and a low polluted city (n:18) underwent psychometric testing and brain magnetic resonance imaging MRI. Seven healthy young dogs with similar exposure to Mexico City air pollution had brain MRI, measurement of mRNA abundance of two inflammatory genes cyclooxygenase-2, and interleukin 1 beta in target brain areas, and histopathological evaluation of brain tissue. Children with no known risk factors for neurological or cognitive disorders residing in a polluted urban environment exhibited significant deficits in a combination of fluid and crystallized cognition tasks. Fifty-six percent of Mexico City children tested showed prefrontal white matter hyperintense lesions and similar lesions were observed in dogs (57%). Exposed dogs had frontal lesions with vascular subcortical pathology associated with neuroinflammation, enlarged Virchow-Robin spaces, gliosis, and ultrafine particulate matter deposition. Based on the MRI findings, the prefrontal cortex was a target anatomical region in Mexico City children and its damage could have contributed to their cognitive dysfunction. The present work presents a groundbreaking, interdisciplinary methodology for addressing relationships between environmental pollution, structural brain alterations by MRI, and cognitive deficits/delays in healthy children.

Temporal and Spatial Development of Axonal Maturation and Myelination of White Matter in the Developing Brain

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) has been widely used to investigate the development of white matter (WM). However, information about this development in healthy children younger than 2 years of age is lacking, and most previous studies have only measured fractional anisotropy (FA). This study used FA and radial and axonal diffusivities in children younger than 2 years of age, aiming to determine the temporal and spatial development of axonal maturation and myelination of WM in healthy children. MATERIALS AND METHODS: A total of 60 healthy pediatric subjects were imaged by using a 3T MR imaging scanner. They were divided into 3 groups: 20 at 3 weeks, 20 at 1 year of age, and 20 at 2 years of age. All subjects were imaged asleep without sedation. FA and axial and radial diffusivities were obtained. Eight regions of interest were defined, including both central and peripheral WM for measuring diffusion parameters. RESULTS: A significant elevation in FA (P < .0001) and a reduction in axial and radial diffusivities (P < .0001) were observed from 22 days to 1 year of age, whereas only radial diffusivity showed significant changes (P = .0014) from 1 to 2 years of age. The region-of-interest analysis revealed that FA alone may not depict the underlying biologic underpinnings of WM development, whereas directional diffusivities provide more insights into the development of WM. Finally, the spatial development of WM begins from the central to the peripheral WM and from the occipital to the frontal lobes. CONCLUSIONS: With both FA and directional diffusivities, our results demonstrate the temporal and spatial development of WM in healthy children younger than 2 years of age.

Exposure to severe urban air pollution influences cognitive outcomes, brain volume and systemic inflammation in clinically healthy children

Exposure to severe air pollution produces neuroinflammation and structural brain alterations in children. We tested whether patterns of brain growth, cognitive deficits and white matter hyperintensities (WMH) are associated with exposures to severe air pollution. Baseline and 1 year follow-up measurements of global and regional brain MRI volumes, cognitive abilities (Wechsler Intelligence Scale for Children-Revised, WISC-R), and serum inflammatory mediators were collected in 20 Mexico City (MC) children (10 with white matter hyperintensities, WMH(+), and 10 without, WMH(-)) and 10 matched controls (CTL) from a low polluted city. There were significant differences in white matter volumes between CTL and MC children - both WMH(+) and WMH(-) - in right parietal and bilateral temporal areas. Both WMH(-) and WMH(+) MC children showed progressive deficits, compared to CTL children, on the WISC-R Vocabulary and Digit Span subtests. The cognitive deficits in highly exposed children match the localization of the volumetric differences detected over the 1 year follow-up, since the deficits observed are consistent with impairment of parietal and temporal lobe functions. Regardless of the presence of prefrontal WMH, Mexico City children performed more poorly across a variety of cognitive tests, compared to CTL children, thus WMH(+) is likely only partially identifying underlying white matter pathology. Together these findings reveal that exposure to air pollution may perturb the trajectory of cerebral development and result in cognitive deficits during childhood.

Oligoclonal myelin-reactive T-cell infiltrates derived from multiple sclerosis lesions are enriched in Th17 cells.

In this study, acute and chronic brain and spinal cord lesions, and normal appearing white matter (NAWM), were resected post-mortem from a patient with aggressive relapsing-remitting multiple sclerosis (MS). T-cell infiltrates from the central nervous system (CNS) lesions and NAWM were separated and characterized in-vitro. All infiltrates showed a proliferative response against multiple myelin peptides. Studies of the T-cell receptor (TCR)Vbeta and Jbeta usage revealed a very skewed repertoire with shared complementarity-determining region (CDR)3 lengths detected in all CNS lesions and NAWM. In the acute lesion, genomic profiling of the infiltrating T-cells revealed up-regulated expression of TCRalpha and beta chain, retinoic acid-related orphan nuclear hormone receptor C (RORC) transcription factor, and multiple cytokine genes that mediate Th17 cell expansion. The differentially expressed genes involved in regulation of Th17 cells represent promising targets for new therapies of relapsing-remitting MS.

Internal auditory canal morphology in children with cochlear nerve deficiency

Objective: To describe the internal auditory canal (IAC) and inner ear morphologic characteristics of children with cochlear nerve (CN) deficiency. Study Design: Retrospective case series. Setting: Tertiary referral center. Patients: Fourteen children with small or absent (deficient) CNs have been identified by means of high-resolution magnetic resonance imaging (MRI). Interventions: MRI of the brain. Clinical evaluation. Main Outcome Measures: Review of medical records, audiological testing results, and imaging studies. Images were evaluated for the structure of the cochlear, vestibular and facial nerves, IACs and inner ears. Audiometric thresholds were evaluated in all subjects. Methods: Fourteen children with small or absent (deficient) CNs have been identified by means of high-resolution MRI. A review of the medical records, audiologic testing results, and imaging studies was undertaken. The images were evaluated for the structure of the cochlear, vestibular and facial nerves, IACs, and inner ears. The audiometric thresholds were evaluated in all subjects. Results: Among the 14 patients, 5 had known syndromes. MRI allowed an exact specification of the nervous structures within all ears with normal-size IACs. Precise characterization of the nerves in ears with small IACs was more difficult, requiring a consideration of both imaging findings and functional parameters. Five children had bilateral deficient CNs, whereas the remaining 9 subjects were affected unilaterally. Thus, 19 ears had CN deficiency (absent CN, 16; small CN, 3). Eleven ears had normal-size IACs and deficient CNs. Of the 9 ears with small IACs, 8 had deficient CNs (absent, 7; small, 1) on the basis of both MRI and functional assessments. Two ears with small IACs had clear morphologic and/or functional evidence for the presence of a CN: one had a small-size CN on MRI, whereas another had a single nerve in a small IAC with present facial and auditory functions. Conclusion: The findings of this study suggest that CN deficiency is not an uncommon cause of congenital hearing loss. The findings that most ears with CN deficiency had normal IAC morphology and that two ears with small IACs had CNs present indicate that IAC morphology is an unreliable surrogate marker of CN integrity. On the basis of these findings, we think that high-resolution MRI, rather than CT imaging, should be performed in all cases of pediatric hearing loss, especially in those cases where profound hearing loss has been documented. For ears with small IACs, the resolution of MRI currently remains limiting. In these cases, the determination of CN status frequently requires a variety of anatomic (CT and MRI) and functional tests (auditory brainstem response, otoacoustic emissions, behavioral audiometry, and physical examination).

Value of Computed Tomography in the Evaluation of Children With Cochlear Nerve Deficiency

Objective: To assess the predictive value of high-resolution computed tomography (HRCT) in the evaluation of children with cochlear nerve deficiency (CND). Study Design: Retrospective review of medical records. Setting: Tertiary referral center, hospital setting. Patients: Nineteen children (31 ears) with CND. Interventions: Magnetic resonance imaging (MRI), HRCT, and audiologic evaluation. Main Outcome Measures: Comparisons of the morphology of the internal auditory canal (IAC), the bony cochlear nerve canal (BCNC) as seen on HRCT, and audiologic data. Results: Of 12 ears with MRI evidence of an absent cochlear nerve (CN) and a normal-size IAC, all had a patent BCNC as revealed by HRCT. Four of these ears failed auditory stimulation after cochlear implantation, confirming clinically significant CND. Of 15 ears with a narrow IAC and a single nerve visible on MRI, 2 (13.3%) had a normal-size BCNC, 4 (26.7%) were narrow, and 9 (60.0%) were absent. One ear with a narrow IAC, normal BCNC, and a single nerve as revealed by MRI has benefited from cochlear implantation. Conclusion: Using BCNC patency, as revealed by HRCT, as a means of identifying CND would miss all cases of absent CNs in the setting of a normal-size IAC. Thus, MRI should be the primary modality for imaging children with severe to profound sensorineural hearing loss. When MRI demonstrates a single nerve within a narrow IAC, the addition of HRCT can further identify more than half of these cases as involving absent CNs because of an absent BCNC. In a subset of patients, CN status remains indeterminate.

Diffusion tensor imaging based network analysis detects alterations of neuroconnectivity in patients with clinically early relapsing‐remitting multiple sclerosis

Although it is inarguable that conventional MRI (cMRI) has greatly contributed to the diagnosis and assessment of multiple sclerosis (MS), cMRI does not show close correlation with clinical findings or pathologic features, and is unable to predict prognosis or stratify disease severity. To this end, diffusion tensor imaging (DTI) with tractography and neuroconnectivity analysis may assist disease assessment in MS. We, therefore, attempted this pilot study for initial assessment of early relapsing‐remitting MS (RRMS). Neuroconnectivity analysis was used for evaluation of 24 early RRMS patients within 2 years of presentation, and compared to the network measures of a group of 30 age‐and‐gender‐matched normal control subjects. To account for the situation that the connections between two adjacent regions may be disrupted by an MS lesion, a new metric, network communicability, was adopted to measure both direct and indirect connections. For each anatomical area, the brain network communicability and average path length were computed and compared to characterize the network changes in efficiencies. Statistically significant (P < 0.05) loss of communicability was revealed in our RRMS cohort, particularly in the frontal and hippocampal/parahippocampal regions as well as the motor strip and occipital lobes. Correlation with the 25‐foot Walk test with communicability measures in the left superior frontal (r = −0.71) as well as the left superior temporal gyrus (r = −0.43) and left postcentral gyrus (r = −0.41) were identified. Additionally identified were increased communicability between the deep gray matter structures (left thalamus and putamen) with the major interhemispheric and intrahemispheric white matter tracts, the corpus callosum, and cingulum, respectively. These foci of increased communicability are thought to represent compensatory changes. The proposed DTI‐based neuroconnectivity analysis demonstrated quantifiable, structurally relevant alterations of fiber tract connections in early RRMS and paves the way for longitudinal studies in larger patient groups. Hum Brain Mapp 34:3376–3391, 2013.

The Role of Endogenous IFN-β in the Regulation of Th17 Responses in Patients with Relapsing-Remitting Multiple Sclerosis

IFN-β has been used as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). Because only a few studies have addressed the role of endogenous IFN-β in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In vitro studies have demonstrated that IFN-β inhibits IL-17A, IL-17F, IL-21, IL-22, and IFN-γ secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion 1 and suppressor of cytokine secretion 3. We found that patients with RRMS have increased serum and cerebrospinal fluid Th17 (IL-17A and IL-17F) cytokine levels in comparison with the control subjects, suggesting that deficient endogenous IFN-β secretion or signaling can contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFN-β from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison with healthy controls. In addition, in vitro studies have revealed deficient endogenous and exogenous IFN-β signaling in the CD4+ cells derived from patients with MS. Interestingly, upon inhibition of the endogenous IFN-β signaling by silencing IFN regulatory factor (IRF) 7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22, and IL-9, suggesting that endogenous IFN-β suppresses the secretion of these pathogenic cytokines. In vivo recombinant IFN-β–1a treatment induced IFNAR1 and its downstream signaling molecules’ gene expression, suggesting that treatment reconstitutes a deficient endogenous IFN-β regulation of the CD4+ T cells’ pathogenic cytokine production in patients with MS.

Interactive and additive influences of Gender, BMI and Apolipoprotein 4 on cognition in children chronically exposed to high concentrations of PM2.5 and ozone. APOE 4 females are at highest risk in Mexico City.

Childrens air pollution exposures are associated with systemic and brain inflammation and the early hallmarks of Alzheimers disease (AD). The Apolipoprotein E (APOE) 4 allele is the most prevalent genetic risk for AD, with higher risk for women. We assessed whether gender, BMI, APOE and metabolic variables in healthy children with high exposures to ozone and fine particulate matter (PM2.5) influence cognition. The Wechsler Intelligence Scale for Children (WISC-R) was administered to 105 Mexico City children (12.32±5.4 years, 69 APOE 3/3 and 36 APOE 3/4). APOE 4v 3 children showed decrements on attention and short-term memory subscales, and below-average scores in Verbal, Performance and Full Scale IQ. APOE 4 females had higher BMI and females with normal BMI between 75-94% percentiles had the highest deficits in Total IQ, Performance IQ, Digit Span, Picture Arrangement, Block Design and Object Assembly. Fasting glucose was significantly higher in APOE 4 children p=0.006, while Gender was the main variable accounting for the difference in insulin, HOMA-IR and leptin (p<.05). Gender, BMI and APOE influence childrens cognitive responses to air pollution and glucose is likely a key player. APOE 4 heterozygous females with >75% to <94% BMI percentiles are at the highest risk of severe cognitive deficits (1.5-2SD from average IQ). Young female results highlight the urgent need for gender-targeted health programmes to improve cognitive responses. Multidisciplinary intervention strategies could provide paths for prevention or amelioration of female air pollution targeted cognitive deficits and possible long-term AD progression.

Segmenting Hippocampus from Infant Brains by Sparse Patch Matching with Deep-Learned Features

Accurate segmentation of the hippocampus from infant MR brain images is a critical step for investigating early brain development. Unfortunately, the previous tools developed for adult hippocampus segmentation are not suitable for infant brain images acquired from the first year of life, which often have poor tissue contrast and variable structural patterns of early hippocampal development. From our point of view, the main problem is lack of discriminative and robust feature representations for distinguishing the hippocampus from the surrounding brain structures. Thus, instead of directly using the predefined features as popularly used in the conventional methods, we propose to learn the latent feature representations of infant MR brain images by unsupervised deep learning. Since deep learning paradigms can learn low-level features and then successfully build up more comprehensive high-level features in a layer-by-layer manner, such hierarchical feature representations can be more competitive for distinguishing the hippocampus from entire brain images. To this end, we apply Stacked Auto Encoder (SAE) to learn the deep feature representations from both T1- and T2-weighed MR images combining their complementary information, which is important for characterizing different development stages of infant brains after birth. Then, we present a sparse patch matching method for transferring hippocampus labels from multiple atlases to the new infant brain image, by using deep-learned feature representations to measure the interpatch similarity. Experimental results on 2-week-old to 9-month-old infant brain images show the effectiveness of the proposed method, especially compared to the state-of-the-art counterpart methods.