Antonieta Mora-Tiscareño

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.

Elevated Plasma Endothelin-1 and Pulmonary Arterial Pressure in Children Exposed to Air Pollution

Background Controlled exposures of animals and humans to particulate matter (PM) or ozone air pollution cause an increase in plasma levels of endothelin-1, a potent vasoconstrictor that regulates pulmonary arterial pressure. Objectives The primary objective of this field study was to determine whether Mexico City children, who are chronically exposed to levels of PM and O3 that exceed the United States air quality standards, have elevated plasma endothelin-1 levels and pulmonary arterial pressures. Methods We conducted a study of 81 children, 7.9 ± 1.3 years of age, lifelong residents of either northeast (n = 19) or southwest (n = 40) Mexico City or Polotitlán (n = 22), a control city with PM and O3 levels below the U.S. air quality standards. Clinical histories, physical examinations, and complete blood counts were done. Plasma endothelin-1 concentrations were determined by immunoassay, and pulmonary arterial pressures were measured by Doppler echocardiography. Results Mexico City children had higher plasma endothelin-1 concentrations compared with controls (p < 0.001). Mean pulmonary arterial pressure was elevated in children from both northeast (p < 0.001) and southwest (p < 0.05) Mexico City compared with controls. Endothelin-1 levels in Mexico City children were positively correlated with daily outdoor hours (p = 0.012), and 7-day cumulative levels of PM air pollution < 2.5 μm in aerodynamic diameter (PM2.5) before endothelin-1 measurement (p = 0.03). Conclusions Chronic exposure of children to PM2.5 is associated with increased levels of circulating endothelin-1 and elevated mean pulmonary arterial pressure.

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.

Early Alzheimer's and Parkinson's Disease Pathology in Urban Children: Friend versus Foe Responses—It Is Time to Face the Evidence

Chronic exposure to particulate matter air pollution is known to cause inflammation leading to respiratory- and cardiovascular-related sickness and death. Mexico City Metropolitan Area children exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, and innate and adaptive immune responses. Early dysregulated neuroinflammation, brain microvascular damage, production of potent vasoconstrictors, and perturbations in the integrity of the neurovascular unit likely contribute to progressive neurodegenerative processes. The accumulation of misfolded proteins coincides with the anatomical distribution observed in the early stages of both Alzheimers and Parkinsons diseases. We contend misfolding of hyperphosphorylated tau (HPπ), alpha-synuclein, and beta-amyloid could represent a compensatory early protective response to the sustained systemic and brain inflammation. However, we favor the view that the chronic systemic and brain dysregulated inflammation and the diffuse vascular damage contribute to the establishment of neurodegenerative processes with childhood clinical manifestations. Friend turns Foe early; therefore, implementation of neuroprotective measures to ameliorate or stop the inflammatory and neurodegenerative processes is warranted in exposed children. Epidemiological, cognitive, structural, and functional neuroimaging and mechanistic studies into the association between air pollution exposures and the development of neuroinflammation and neurodegeneration in children are of pressing importance for public health.

White Matter Hyperintensities, Systemic Inflammation, Brain Growth, and Cognitive Functions in Children Exposed to Air Pollution

Air pollution exposures are linked to neuroinflammation and neuropathology in young urbanites. Forty percent of exposed children and young adults exhibit frontal tau hyperphosphorylation and 51% have amyloid-β diffuse plaques compared to 0% in low pollution controls. In older adults, white matter hyperintensities (WMH) are associated with cognitive deficits while inflammatory markers correlate with greater atrophy than expected for age. We investigated patterns of WMH, magnetic resonance imaging (MRI) volume growth, blood inflammatory mediators, and cognition in matched children from two urban cohorts: one severely and one minimally exposed to air pollution. Baseline and one year follow-up measurements of cognitive abilities, brain MRI volumes, and blood were collected in 20 Mexico City (MC) children (10 with WMH+, and 10 without WMH-) and 10 matched controls (WMH-). MC WMH- children display the profile of classical pro-inflammatory defensive responses: high interleukin 12, production of powerful pro-inflammatory cytokines, and low concentrations of key cytokines and chemokines associated with neuroprotection. MC WMH+ children exhibit a response involved in resolution of inflammation, immunoregulation, and tissue remodeling. The MC WMH+ group responded to the air pollution-associated brain volumetric alterations with white and grey matter volume increases in temporal, parietal, and frontal regions and better cognitive performance compared to MC WMH-. We conclude that complex modulation of cytokines and chemokines influences childrens central nervous system structural and volumetric responses and cognitive correlates resulting from environmental pollution exposures. Identification of biomarkers associating systemic inflammation to brain growth is critical for detecting children at higher risk for cognitive deficits and neurodegeneration, thereby warranting early implementation of neuroprotective measures.

Lung radiology and pulmonary function of children chronically exposed to air pollution

We analyzed the chest radiographs (CXRs) of 249 clinically healthy children, 230 from southwest Mexico City and 19 from Tlaxcala. In contrast to children from Tlaxcala, children from southwest Mexico City were chronically exposed to ozone levels exceeding the U.S. National Ambient Air Quality Standards for an average of 4.7 hr/day and to concentrations of particulate matter (PM) with aerodynamic diameters ≤2.5 μm (PM2.5) above the annual standard. CXRs of Mexico City children demonstrated bilateral hyperinflation (151 of 230) and increased linear markings (121 of 230). Hyperinflation and interstitial markings were significantly more common in Mexico City children (p < 0.0002 and 0.00006 respectively). Mexico City boys had a higher probability of developing interstitial markings with age (p = 0.004). Computed tomography (CT) scans were obtained in 25 selected Mexico City children with abnormal CXRs. Mild bronchial wall thickening was seen in 10 of 25, prominent central airways in 4 of 25, air trapping in 8 of 21, and pulmonary nodules in 2 of 21. Only 7.8% of Mexico City children had abnormal lung function tests based on predicted values. These findings are consistent with bronchiolar, peribronchiolar, and/or alveolar duct inflammation, possibly caused by ozone, PM, and lipopolysaccharide exposure. The epidemiologic implications of these findings are important for children residing in polluted environments, because bronchiolar disease could lead to chronic pulmonary disease later in life.

Exposure to air pollution is associated with lung hyperinflation in healthy children and adolescents in Southwest Mexico City: a pilot study.

Air pollution produces adverse health effects. The consequences of lifelong daily exposures to atmospheric pollutants upon the respiratory apparatus of healthy children are of considerable clinical importance. We investigated the association between exposure to a highly polluted urban environment with a complex mixture of air pollutants ? ozone and particulate matter the predominant ones ? and chest x-ray abnormalities in 59 healthy Mexican children who are lifelong residents of Southwest Metropolitan Mexico City (SWMMC), with a negative history of tobacco exposure and respiratory illnesses. Their clinical results and x-ray findings were compared to those of 19 Mexican control children, residents of a low-pollution area, with a similar negative history of tobacco exposure and respiratory illnesses. Ozone concentrations in SWMMC exceeded the U.S. Environmental Protection Agency (U.S. EPA) National Ambient Air Quality Standard (NAAQS) for O3:0.08 ppm as 1-h maximal concentration, not to be exceeded more than 4 times a year, on 71% of days in 1986 and 95% in 1997, with values as high as 0.48 ppm. Ozone maximal peaks are usually recorded between 2 and 5 pm coinciding with children?s outdoor physical activities. Children in the control group reported no upper or lower respiratory symptomatology. Every SWMMC child complained of upper and/or lower respiratory symptoms, including epistaxis, nasal dryness and crusting, cough, shortness of breath, and chest discomfort. Children aged 7–13 yr had the most symptomatology, while 5? to 6-year olds and adolescents with the lowest number of statistically significant outdoor exposure hours had less respiratory symptoms. Bilateral symmetric mild lung hyperinflation was significantly associated with exposure to the SWMMC atmosphere (p=.0004). Chronic and sustained inhalation of a complex mixture of air pollutants, including ozone and particulate matter (PM), is associated with lung hyperinflation, suggestive of small airway disease, in a population of clinically healthy children and adolescents. Small airways are a target of air pollutants in SWMMC children, with ozone and PM being most likely responsible, based on experimental animal, controlled-chamber, and epidemiological data available. Our main concern is the potential likelihood for the development of chronic lung disease in this highly exposed population.Air pollution produces adverse health effects. The consequences of lifelong daily exposures to atmospheric pollutants upon the respiratory apparatus of healthy children are of considerable clinical importance. We investigated the association between exposure to a highly polluted urban environment with a complex mixture of air pollutants-ozone and particulate matter the predominant ones-and chest x-ray abnormalities in 59 healthy Mexican children who are lifelong residents of Southwest Metropolitan Mexico City (SWMMC), with a negative history of tobacco exposure and respiratory illnesses. Their clinical results and x-ray findings were compared to those of 19 Mexican control children, residents of a low-pollution area, with a similar negative history of tobacco exposure and respiratory illnesses. Ozone concentrations in SWMMC exceeded the U.S. Environmental Protection Agency (U.S. EPA) National Ambient Air Quality Standard (NAAQS) for O(3): 0.08 ppm as 1-h maximal concentration, not to be exceeded more than 4 times a year, on 71% of days in 1986 and 95% in 1997, with values as high as 0.48 ppm. Ozone maximal peaks are usually recorded between 2 and 5 pm coinciding with childrens outdoor physical activities. Children in the control group reported no upper or lower respiratory symptomatology. Every SWMMC child complained of upper and/or lower respiratory symptoms, including epistaxis, nasal dryness and crusting, cough, shortness of breath, and chest discomfort. Children aged 7-13 yr had the most symptomatology, while 5- to 6-year olds and adolescents with the lowest number of statistically significant outdoor exposure hours had less respiratory symptoms. Bilateral symmetric mild lung hyperinflation was significantly associated with exposure to the SWMMC atmosphere (p = .0004). Chronic and sustained inhalation of a complex mixture of air pollutants, including ozone and particulate matter (PM), is associated with lung hyperinflation, suggestive of small airway disease, in a population of clinically healthy children and adolescents. Small airways are a target of air pollutants in SWMMC children, with ozone and PM being most likely responsible, based on experimental animal, controlled-chamber, and epidemiological data available. Our main concern is the potential likelihood for the development of chronic lung disease in this highly exposed population.

Decreases in Short Term Memory, IQ, and Altered Brain Metabolic Ratios in Urban Apolipoprotein ε4 Children Exposed to Air Pollution.

Childrens urban air pollution exposures result in systemic and brain inflammation and the early hallmarks of Alzheimers disease (AD). The apolipoprotein E (APOE) ε4 allele is the most prevalent genetic risk for AD. We assessed whether APOE in healthy children modulates cognition, olfaction, and metabolic brain indices. The Wechsler Intelligence Scale for Children (WISC-R) and the University of Pennsylvania Smell Identification Test were administered to 50 Mexico City Metropolitan Area children (13.4 ± 4.8 years, 28 APOE ε3 and 22 APOE ε4). N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, myo-inositol (mI)/Cr, and NAA/mI were calculated using proton magnetic resonance spectroscopy in the white matter of the frontal and parietal lobes, hippocampus, and pons. APOE ε4 versus ε3 children had a reduced NAA/Cr ratio in the right frontal white matter and decrements on attention, short-term memory, and below-average scores in Verbal and Full Scale IQ (>10 points). APOE modulated the group effects between WISC-R and left frontal and parietal white matter, and hippocampus metabolites. Soap was the predominantly failed odor in urban children and, in APOE ε4 versus ε3 carriers, strongly correlated with left hippocampus mI/Cr ratio. APOE modulates responses to air pollution in the developing brain. APOE ε4 carriers could have a higher risk of developing early AD if they reside in a polluted environment. APOE, cognition, and olfaction testing and targeted magnetic resonance spectroscopy may contribute to the assessment of urban children and their results could provide new paths toward the unprecedented opportunity for early neuroprotection and AD prevention.

A Critical Proton MR Spectroscopy Marker of Alzheimer’s Disease Early Neurodegenerative Change: Low Hippocampal NAA/Cr Ratio Impacts APOE ɛ4 Mexico City Children and Their Parents

Severe air pollution exposures produce systemic, respiratory, myocardial, and brain inflammation and Alzheimers disease (AD) hallmarks in clinically healthy children. We tested whether hippocampal metabolite ratios are associated with contrasting levels of air pollution, APOE, and body mass index (BMI) in paired healthy children and one parent sharing the same APOE alleles. We used 1H-MRS to interrogate bilateral hippocampal single-voxel in 57 children (12.45 ± 3.4 years) and their 48 parents (37.5 ± 6.78 years) from a low pollution city versus Mexico City (MC). NAA/Cr, Cho/Cr, and mI/Cr metabolite ratios were analyzed. The right hippocampus NAA/Cr ratio was significantly different between cohorts (p = 0.007). The NAA/Cr ratio in right hippocampus in controls versus APOE ɛ4 MC children and in left hippocampus in MC APOE ɛ4 parents versus their children was significantly different after adjusting for age, gender, and BMI (p = 0.027 and 0.01, respectively). The NAA/Cr ratio is considered reflective of neuronal density/functional integrity/loss of synapses/higher pTau burden, thus a significant decrease in hippocampal NAA/Cr ratios may constitute a spectral marker of early neurodegeneration in young urbanites. Decreases in NAA/Cr correlate well with cognitive function, behavioral symptoms, and dementia severity; thus, since the progression of AD starts decades before clinical diagnosis, our findings support the hypothesis that under chronic exposures to fine particulate matter and ozone above the standards, neurodegenerative processes start in childhood and APOE ɛ4 carriers are at higher risk. Gene and environmental factors are critical in the development of AD and the identification and neuroprotection of young urbanites at high risk must become a public health priority.

Flavonol-rich dark cocoa significantly decreases plasma endothelin-1 and improves cognition in urban children

Air pollution exposures are linked to systemic inflammation, cardiovascular and respiratory morbidity and mortality, neuroinflammation and neuropathology in young urbanites. In particular, most Mexico City Metropolitan Area (MCMA) children exhibit subtle cognitive deficits, and neuropathology studies show 40% of them exhibiting frontal tau hyperphosphorylation and 51% amyloid-β diffuse plaques (compared to 0% in low pollution control children). We assessed whether a short cocoa intervention can be effective in decreasing plasma endothelin 1 (ET-1) and/or inflammatory mediators in MCMA children. Thirty gram of dark cocoa with 680 mg of total flavonols were given daily for 10.11 ± 3.4 days (range 9–24 days) to 18 children (10.55 years, SD = 1.45; 11F/7M). Key metabolite ratios in frontal white matter and in hippocampus pre and during cocoa intervention were quantified by magnetic resonance spectroscopy. ET-1 significantly decreased after cocoa treatment (p = 0.0002). Fifteen children (83%) showed a marginally significant individual improvement in one or both of the applied simple short memory tasks. Endothelial dysfunction is a key feature of exposure to particulate matter (PM) and decreased endothelin-1 bioavailability is likely useful for brain function in the context of air pollution. Our findings suggest that cocoa interventions may be critical for early implementation of neuroprotection of highly exposed urban children. Multi-domain nutraceutical interventions could limit the risk for endothelial dysfunction, cerebral hypoperfusion, neuroinflammation, cognitive deficits, structural volumetric detrimental brain effects, and the early development of the neuropathological hallmarks of Alzheimers and Parkinsons diseases.