RESUMEN
Severe air pollution exposures produce systemic, respiratory, myocardial, and brain inflammation and Alzheimer's 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 É4 MC children and in left hippocampus in MC APOE É4 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 É4 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.
Asunto(s)
Contaminación del Aire/efectos adversos , Enfermedad de Alzheimer/metabolismo , Apolipoproteína E4/genética , Ácido Aspártico/análogos & derivados , Creatina/metabolismo , Hipocampo/metabolismo , Adolescente , Adulto , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Ácido Aspártico/metabolismo , Índice de Masa Corporal , Niño , Estudios de Cohortes , Familia , Femenino , Humanos , Masculino , México/epidemiología , Estudios Prospectivos , Espectroscopía de Protones por Resonancia Magnética , Población Urbana , Proteínas tau/metabolismoRESUMEN
Children's urban air pollution exposures result in systemic and brain inflammation and the early hallmarks of Alzheimer's 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.
Asunto(s)
Contaminación del Aire , Apolipoproteína E4/genética , Encéfalo/metabolismo , Inteligencia/genética , Trastornos de la Memoria , Memoria a Corto Plazo/fisiología , Adolescente , Factores de Edad , Análisis de Varianza , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Niño , Colina/metabolismo , Creatina/metabolismo , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/genética , Trastornos de la Memoria/patología , México , Pruebas Neuropsicológicas , Olfato/genética , Escalas de WechslerRESUMEN
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-ß 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 Alzheimer's and Parkinson's diseases.
RESUMEN
Air pollution induces systemic inflammation, as well as respiratory, myocardial and brain inflammation in children. Peak bone mass is influenced by environmental factors. We tested the hypothesis that six-year-olds with lifetime exposures to urban air pollution will have alterations in inflammatory markers and bone mineral density (BMD) as opposed to low-polluted city residents when matched for BMI, breast feeding history, skin phototype, age, sex and socioeconomic status. This pilot study included 20 children from Mexico City (MC) (6.17 years ± 0.63 years) and 15 controls (6.27 years ± 0.76 years). We performed full paediatric examinations, a history of outdoor exposures, seven-day dietary recalls, serum inflammatory markers and dual-energy X-ray absorptiometry (DXA). Children in MC had significantly higher concentrations of IL-6 (p=0.001), marked reductions in total blood neutrophils (p= 0.0002) and an increase in monocytes (p=0.005). MC children also had an insufficient Vitamin D intake and spent less time outdoors than controls (p<0.001) in an environment characterized by decreased UV light, with ozone and fine particulates concentrations above standard values. There were no significant differences between the cohorts in DXA Z scores. The impact of systemic inflammation, vitamin D insufficiency, air pollution, urban violence and poverty may have long-term bone detrimental outcomes in exposed paediatric populations as they grow older, increasing the risk of low bone mass and osteoporosis. The selection of reference populations for DXA must take into account air pollution exposures.
Asunto(s)
Contaminación del Aire/análisis , Monitoreo del Ambiente/estadística & datos numéricos , Osteoporosis/epidemiología , Salud Urbana/estadística & datos numéricos , Biomarcadores/sangre , Densidad Ósea , Estudios de Casos y Controles , Niño , Estudios de Cohortes , Exposición a Riesgos Ambientales , Femenino , Humanos , Masculino , México/epidemiología , Osteoporosis/diagnóstico , Proyectos Piloto , Pobreza , Estudios Prospectivos , Población Urbana/estadística & datos numéricos , Violencia , Deficiencia de Vitamina D/epidemiologíaRESUMEN
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 Alzheimer's and Parkinson's 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.
Asunto(s)
Contaminación del Aire/efectos adversos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Parkinson/diagnóstico , Adolescente , Adulto , Edad de Inicio , Enfermedad de Alzheimer/etiología , Péptidos beta-Amiloides/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Niño , Ciudades , Femenino , Humanos , Masculino , México , Estrés Oxidativo , Enfermedad de Parkinson/etiología , Material Particulado , Pliegue de Proteína , Población Urbana , Adulto Joven , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismoRESUMEN
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-ß 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 children's 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.
Asunto(s)
Contaminación del Aire/efectos adversos , Encéfalo/patología , Trastornos del Conocimiento/inducido químicamente , Discapacidades del Desarrollo/inducido químicamente , Inflamación/inducido químicamente , Leucoencefalopatías/inducido químicamente , Mapeo Encefálico , Niño , Trastornos del Conocimiento/patología , Citocinas/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Imagenología Tridimensional , Inflamación/patología , Recuento de Leucocitos , Leucoencefalopatías/patología , Imagen por Resonancia Magnética , Masculino , Pruebas NeuropsicológicasRESUMEN
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.
Asunto(s)
Contaminación del Aire/efectos adversos , Encéfalo/patología , Trastornos del Conocimiento/inducido químicamente , Cognición , Inflamación/inducido químicamente , Niño , Trastornos del Conocimiento/patología , Femenino , Humanos , Inflamación/patología , Pruebas de Inteligencia , Imagen por Resonancia Magnética , Masculino , México , Fibras Nerviosas Mielínicas/patología , Pruebas Neuropsicológicas , Tamaño de los Órganos , Estudios ProspectivosRESUMEN
Residency in cities with high air pollution is associated with neuroinflammation and neurodegeneration in healthy children, young adults, and dogs. Nonsteroidal anti-inflammatory drugs may offer neuroprotection. The authors measured the plasma concentrations of 3-nitrotyrosine and the cerebro-spinal-fluid concentrations of prostaglandin E2 metabolite and the oligomeric form of amyloid derived diffusible ligand; measured the mRNA expression of cyclooxygenase-2, interleukin 1beta, CD14, and Aquaporin-4 in target brain areas; and evaluated brain MRI, cognition, and neuropathology in 8 dogs treated with a preferential cyclooxygenase-2 inhibitor (Nimesulide) versus 7 untreated litter-matched Mexico City dogs. Nimesulide significantly decreased nitrotyrosine in plasma (p < .0001), frontal gray IL1beta (p = .03), and heart IL1beta (p = .02). No effect was seen in mRNA COX2, amyloid, and PGE2 in CSF or the MRI white matter lesions. All exposed dogs exhibited olfactory bulb and frontal accumulation of Abeta(42) in neurons and blood vessels and frontal vascular subcortical pathology. White matter hyperintense MRI frontal lesions were seen in 4/6 non-treated and 6/8 treated dogs. Nonsteroidal anti-inflammatory drugs may offer limited neuroprotection in the setting of severe air pollution exposures. The search for potentially beneficial drugs useful to ameliorate the brain effects of pollution represents an enormous clinical challenge.
Asunto(s)
Contaminación del Aire/efectos adversos , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Perros/metabolismo , Sulfonamidas/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Acuaporina 4/metabolismo , Encéfalo/anatomía & histología , Encéfalo/patología , Distribución de Chi-Cuadrado , Ciclooxigenasa 2/genética , Inhibidores de la Ciclooxigenasa 2/farmacocinética , Lóbulo Frontal/metabolismo , Inmunohistoquímica , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Imagen por Resonancia Magnética , México , Mucosa Nasal/metabolismo , Ozono/efectos adversos , Proyectos Piloto , Prostaglandinas E/metabolismo , Estadísticas no Paramétricas , Sulfonamidas/farmacocinética , Tirosina/metabolismoRESUMEN
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.
Asunto(s)
Contaminación del Aire/análisis , Encéfalo/fisiopatología , Cognición/fisiología , Adolescente , Contaminación del Aire/efectos adversos , Contaminación del Aire/economía , Animales , Encéfalo/metabolismo , Encéfalo/patología , Niño , Ciclooxigenasa 2/genética , Perros , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Femenino , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Lóbulo Frontal/fisiopatología , Gliosis/etiología , Gliosis/genética , Gliosis/patología , Humanos , Interleucina-1beta/genética , Imagen por Resonancia Magnética , Masculino , Trastornos Mentales/epidemiología , Trastornos Mentales/etiología , Trastornos Mentales/patología , México/epidemiología , Pruebas Neuropsicológicas/estadística & datos numéricos , Material Particulado/análisis , Proyectos Piloto , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Corteza Prefrontal/fisiopatología , Psicometría/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de RiesgoRESUMEN
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 O(3) 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 O(3) 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 mum in aerodynamic diameter (PM(2.5)) before endothelin-1 measurement (p = 0.03). CONCLUSIONS: Chronic exposure of children to PM(2.5) is associated with increased levels of circulating endothelin-1 and elevated mean pulmonary arterial pressure.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Endotelina-1/sangre , Arteria Pulmonar/efectos de los fármacos , Adolescente , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Presión Sanguínea/efectos de los fármacos , Niño , Ciudades , Ecocardiografía Doppler , Femenino , Humanos , Recuento de Leucocitos , Masculino , México , Neutrófilos/efectos de los fármacos , Ozono/análisis , Ozono/toxicidad , Material Particulado/análisis , Material Particulado/toxicidad , Arteria Pulmonar/fisiopatologíaRESUMEN
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 microm (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.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Pulmón/efectos de los fármacos , Ozono/toxicidad , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Salud Urbana , Contaminantes Atmosféricos/análisis , Niño , Humanos , Exposición por Inhalación , Pulmón/diagnóstico por imagen , Masculino , México , Ozono/análisis , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Radiografía , Factores de TiempoRESUMEN
Southwest Metropolitan Mexico City (SWMMC) children are chronically exposed to complex mixtures of air pollutants. In a cross-sectional arm of our study, we investigated the association between exposure to SWMMC atmosphere and nasal abnormalities, hyperinflation, and interstitial markings assessed by chest X-rays, lung function changes, several serum cytokines, and endothelin-1 in 174 children aged 5-17 years vs. 27 control children residents in low-polluted areas. Control children had no nasal lesions, and only one child showed an abnormal chest X-ray. SWMMC children exhibited nasal abnormalities (22%), hyperinflation (67%), interstitial markings (49%), and a mild restrictive pattern by spirometry (10%). Interstitial markings were associated with a decrease in predicted values of FEF(25-75), FEF(75), and the FEV(1)/FVC ratio. Boys had a higher probability of developing interstitial markings with age (P = 0.004). Blood smear findings included toxic granulations in neutrophils and schistocytes. SWMMC children had more serum IL10 and IL6 and less IL8 than controls. In a longitudinal arm of our study, we found a significant seasonal drop in FVC and FEV(1) associated with a 6-month period of high ozone and PM(10) levels. Our data strongly suggest that a lifelong exposure to urban air pollution causes respiratory damage in children. Moreover, a cytokine network becomes imbalanced, with a shift towards upregulation of anti-inflammatory cytokines. Consequently, these children are potentially at risk for developing chronic lung disease and other systemic effects later in life.