A Critical Proton MR Spectroscopy Marker of Alzheimer Early Neurodegenerative Change: Low Hippocampal NAA/Cr Ratio Impacts APOE 4 Mexico City Children and Their Parents.

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 BMI in paired healthy children and one parent sharing the same APOE alleles. We used (1) H-MRS to interrogate bilateral hippocampal single-voxel in 57 children (12.45± 3.4 years) and their 48 parents (37.5± 6.78 years) low pollution city v Mexico City (MC). NAA/Cr, Cho/Cr, and mI/Cr metabolite ratios were analysed. The right hippocampus N-acetylaspartate/creatine (NAA/Cr) was significantly different between cohorts (p=0.007). The NAA/Cr ratio in right hippocampus: controls v APOE 4 MC children and left hippocampus: MC APOE 4 parents v 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, behavioural 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 4 carriers are at higher risk. Gene /environmental factors are critical in the development of Alzheimer\u27s disease 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 Alzheimer\u27s and Parkinson\u27s diseases

Air Pollution and Children: Neural and Tight Junction Antibodies and Combustion Metals, the Role of Barrier Breakdown and Brain Immunity in Neurodegeneration

Millions of children are exposed to concentrations of air pollutants, including fine particulate matter (PM2.5), above safety standards. In the Mexico City Metropolitan Area (MCMA) megacity, children show an early brain imbalance in oxidative stress, inflammation, innate and adaptive immune response-associated genes, and blood-brain barrier breakdown. We investigated serum and cerebrospinal fluid (CSF) antibodies to neural and tight junction proteins and environmental pollutants in 139 children ages 11.91 ± 4.2 y with high versus low air pollution exposures. We also measured metals in serum and CSF. MCMA children showed significantly higher serum actin IgG, occludin/zonulin 1 IgA, IgG, myelin oligodendrocyte glycoprotein IgG and IgM (p \u3c 0.01), myelin basic protein IgA and IgG, S-100 IgG and IgM, and cerebellar IgG (p \u3c 0.001). Serum IgG antibodies to formaldehyde, benzene, and bisphenol A, and concentrations of Ni and Cd were significantly higher in exposed children (p \u3c 0.001). CSF MBP antibodies and nickel concentrations were higher in MCMA children (p = 0.03). Air pollution exposure damages epithelial and endothelial barriers and is a robust trigger of tight junction and neural antibodies. Cryptic ‘self’ tight junction antigens can trigger an autoimmune response potentially contributing to the neuroinflammatory and Alzheimer and Parkinson’s pathology hallmarks present in megacity children. The major factor determining the impact of neural antibodies is the integrity of the blood-brain barrier. Defining the air pollution linkage of the brain/immune system interactions and damage to physical and immunological barriers with short and long term neural detrimental effects to children’s brains ought to be of pressing importance for public health

On Phase II Monitoring of the Probability Distributions of Univariate Continuous Processes

Statistical process control (SPC) charts are widely used in industry for monitoring the stability of certain sequential processes like manufacturing, health care systems etc. Most SPC charts assume that the parametric form of the “in-control” process distribution F1 is available. However, it has been demonstrated in the literature that their performances are unreliable when the pre-specified process distribution is incorrect. Moreover, most SPC charts are designed to detect any shift in mean and/or variance. In real world problems, shifts in higher moments can happen without much change in mean or variance. If we fail to detect those and let the process run, it can eventually become worse and a shift in mean or variance can creep in. Moreover, the special cause that initiated the shift can inflict further damage to the system, and it may become a financial challenge to fix it. This paper provides an efficient and easy-to-use control chart for Phase II monitoring of univariate continuous processes when the parametric form of the “in-control” process distribution is unknown, but Phase I observations that are believed to be i.i.d. realizations from unknown F1 are available. Data-driven practical guidelines are also provided to choose the tuning parameter and the corresponding control limit of the proposed SPC chart. Numerical simulations and a real-life data analysis show that it can be used in many practical applications