Early Alzheimer\u27s and Parkinson\u27s 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 cardiovascularrelated 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\u27s and Parkinson\u27s diseases. We contend misfolding of hyperphosphorylated tau (HPrc), 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

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 (PM(2.5)) 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 Urban Air Pollution and Bone Health in Clinically Healthy Six-year-old Children

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\u3c0.001) 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

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 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

Exposure to Urban Air Pollution and Bone Health in Clinically Healthy Six-year-old Children

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

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

BackgroundControlled 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.ObjectivesThe 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.MethodsWe 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.ResultsMexico 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).ConclusionsChronic exposure of children to PM2.5 is associated with increased levels of circulating endothelin-1 and elevated mean pulmonary arterial pressure

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 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

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

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

Izloženost gradskom onečišćenju zraka i zdravlje kostiju u klinički zdravoj šestogodišnjoj djeci

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.Onečišćenje zraka uzrokuje sistemsku upalu, kao i respiratorne, miokardijalne i moždane upale kod djece. Čimbenici iz okoliša utječu na vršnu koštanu masu. Ispitali smo hipotezu da šestogodišnjaci s cjeloživotnom izloženosti gradskom onečišćenju zraka imaju drugačije upalne pokazatelje i mineralnu gustoću kostiju (BMD) od djece iz gradova s niskom razinom onečišćenja kada usporedimo tjelesni indeks mase, povijest dojenja, fototip kože, dob, spol i društveno-ekonomski položaj. Ova pilot-studija uključuje dvadesetero djece iz glavnoga grada Méxica (6,17 ± 0,63) godina i petnaestero kontrolne djece (6,27 ± 0,76) godina. Obavili smo cjelovite pedijatrijske preglede, prikupili povijesti vanjske izloženosti, sedmodnevne analize prehrane, serumske razine upalnih pokazatelja i dvoenergetsku apsorpciometriju X-zraka (DXA). Djeca iz Méxica imala su značajno više koncentracije IL-6 (p=0,001), izrazito smanjen ukupni broj krvnih neutrofila (p=0,0002) i povećan broj monocita (p=0,005). Djeca iz Méxica također su unosila nedovoljnu količinu vitamina D i provodila manje vremena na otvorenome od kontrolnih ispitanika (p<0,001), i to u okružju obilježenom smanjenom UV svjetlošću te koncentracijama ozona i čestične materije iznad standardnih vrijednosti. Nije bilo značajnih razlika između kohorta u Z-vrijednostima DXA. Učinci sistemske upale, insufi cijencije vitamina D, onečišćenja zraka, gradskog nasilja i siromaštva mogu imati dugoročne štetne posljedice na kosti u izloženim pedijatrijskim populacijama kako one odrastaju, povećavajući tako njihov rizik od smanjenja koštane mase i osteoporoze. Pri odabiru referentne populacije za DXA bi se ubuduće trebala uzimati u obzir i izloženost onečišćenom zraku