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

Alzheimer’s Disease and Alpha-Synuclein Neuropathology in the Olfactory Bulbs Of Children and Young Adults ≤40years Exposed to High Levels of Fine Particulate Matter Air Pollution in Metropolitan Mexico City: APOE4 Carriers at Higher Risk of Suicide Accelerate Their Olfactory Bulb Damage

There is growing evidence that air pollution is a risk factor for a number of neurodegenerative diseases, most notably Alzheimer’s (AD) and Parkinson’s (PD). It is generally assumed that the pathology of these diseases arises only later in life and commonly begins within olfactory eloquent pathways prior to the onset of the classical clinical symptoms. The present study demonstrates that chronic exposure to high levels of air pollution results in AD- and PD-related pathology within the olfactory bulbs of children and relatively young adults ranging in age from 11 months to 40 years. The olfactory bulbs (OBs) of 179 residents of highly polluted Metropolitan Mexico City were evaluated for AD- and alpha-synuclein-related pathology. Even in toddlers, hyperphosphorilated tau (hTau) and Lewy neurites (LN) were identified in the olfactory bulbs. By the second decade, 86% of the bulbs exhibited hTau (50/57), 76% LNs (45/57), 77% vascular amyloid (44/57), and 60% (34/57) mild diffuse amyloid plaques. During the first two decades, OBs neurovasculature unit damage is associated with combustion-derived nanoparticles and myelinated and unmyelinated axonal damage was evident. OB hTau neurites were associated with pretangle stages 1a and 1b in subjects ≤20 years of age, strongly suggesting olfactory deficits could potentially be an early guide of AD hTau stages. Compared to noncarriers, APOE4 carriers were 6 to 13 times more likely to exhibit OB vascular amyloid, neuronal amyloid accumulation, alpha-synuclein aggregates, hTau neurofibrillary tangles, and neurites. Remarkably, within this data set the APOE4 carriers were 4.7 times more likely than non-carriers to have committed suicide. The present findings, along with previous evidence that over a third of clinically healthy teens and young residents from the targeted pollution areas exhibit low scores on an odor identification test, support the concept that olfactory testing may aid in identifying young persons at high risk for neurodegenerative disease. Neuroprotective interventions in air pollution exposed individuals in the first two decades are critical. Air pollution control should be prioritized

Mexico City Normal Weight Children Exposed to High Concentrations of Ambient PM\u3csub\u3e2.5\u3c/sub\u3e Show High Blood Leptin and Endothelin-1, Vitamin D Deficiency, and Food Reward Hormone Dysregulation versus Low Pollution Controls. Relevance for Obesity and Alzheimer Disease

Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM 2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer’s disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1±3.2 years olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM 2.5 exposures. Mexico City children had higher leptin and endothelin-1 (p 2.5 exposed children. Mexico City APOE 4 v 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin D \u3c 30 ng/mL was documented in 87% of Mexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12 h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes signal the future trajectory in urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer’s disease. Increased efforts should be made to decrease pediatric PM 2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer disease

Prefrontal White Matter Pathology in Air Pollution Exposed Mexico City Young Urbanites and Their Potential Impact on Neurovascular Unit Dysfunction and the Development of Alzheimer’s Disease

Millions of urban children are chronically exposed to high concentrations of air pollutants, i.e., fine particulate matter (PM2.5) and ozone, associated with increased risk for Alzheimer’s disease. Compared with children living with clear air those in Mexico City (MC) exhibit systemic, brain and intrathecal inflammation, low CSF Aβ 42, breakdown of the BBB, attention and short-term memory deficits, prefrontal white matter hyperintensities, damage to epithelial and endothelial barriers, tight junction and neural autoantibodies, and Alzheimer and Parkinson\u27s hallmarks. The prefrontal white matter is a target of air pollution. We examined by light and electron microscopy the prefrontal white matter of MC dogs (n: 15, age 3.17±0.74 years), children and teens (n: 34, age: 12.64±4.2 years) versus controls. Major findings in MC residents included leaking capillaries and small arterioles with extravascular lipids and erythrocytes, lipofuscin in pericytes, smooth muscle and endothelial cells (EC), thickening of cerebrovascular basement membranes with small deposits of amyloid, patchy absence of the perivascular glial sheet, enlarged Virchow-Robin spaces and nanosize particles (20-48 nm) in EC, basement membranes, axons and dendrites. Tight junctions, a key component of the neurovascular unit (NVU) were abnormal in MC versus control dogs (χ2 \u3c0.0001), and white matter perivascular damage was significantly worse in MC dogs (p= 0.002). The integrity of the NVU, an interactive network of vascular, glial and neuronal cells is compromised in MC young residents. Characterizing the early NVU damage and identifying biomarkers of neurovascular dysfunction may provide a fresh insight into Alzheimer pathogenesis and open opportunities for pediatric neuroprotection

Hallmarks of Alzheimer Disease are Evolving Relentlessly in Metropolitan Mexico City Infants, Children and Young Adults. APOE4 Carriers Have Higher Suicide Risk and Higher Odds of Reaching NFT Stage V at ≤ 40 Years of Age

Exposures to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards are associated with Alzheimer’s disease (AD) risk. Metropolitan Mexico City (MMC) residents have life time exposures to PM2.5 and O3 above USEPA standards. We investigated AD intra and extracellular protein aggregates and ultrastructural neurovascular pathology in 203 MMC residents age 25.36±9.23y. Immunohistochemical methods were used to identify AT8 hyperphosphorilated tau (Htau) and 4G8 (amyloid β 17-24). Primary outcomes: staging of Htau and amyloid, per decade and cumulative PM2.5 (CPM 2.5) above standard. Apolipoprotein E allele 4 (APOE4), age and cause of death were secondary outcomes. Subcortical pretangle stage b was identified in an 11month old baby. Cortical tau pretangles, neurofibrillary tangles (NFT) Stages I-II, amyloid phases 1-2, Htau in substantia nigrae, auditory, oculomotor, trigeminal and autonomic systems were identified by the 2nd decade. Progression to NFT stages III-V was present in 24.8 % of 30-40y old subjects. APOE4 carriers have 4.92 times higher suicide odds (p=0.0006), and 23.6 times higher odds of NFT V (p \u3c 0·0001) v APOE4 non-carriers having similar CPM2.5 exposure and age. Age (p = 0.0062) and CPM2.5 (p = 0.0178) were significant for developing NFT V. Combustion-derived nanoparticles were associated with early and progressive damage to the neurovascular unit. Alzheimer’s disease starting in the brainstem of young children and affecting 99.5% of young urbanites is a serious health crisis. Air pollution control should be prioritised. Childhood relentless Htau makes a fundamental target for neuroprotective interventions and the first two decades are critical. We recommend the concept of preclinical AD be revised and emphasize the need to define paediatric environmental, nutritional, metabolic and genetic risk factor interactions of paramount importance to prevent AD. AD evolving from childhood is threating the wellbeing of our children and future generations

Exposures to Fine Particulate Matter and Ozone Above USA Standards are Associated with Auditory Brainstem Dysmorphology and Delayed Auditory Brainstem Evoked Potentials in Healthy Dogs

Background: Delayed central conduction times in the auditory brainstem have been observed in Mexico City (MC) healthy children breathing fine particulate matter (PM2.5) and ozone (O3) above the current United States Environmental Protection Agency (US-EPA) standards. MC children have α synuclein brainstem accumulation and medial superior olivary complex (MSO) dysmorphology. The present study used a dog model to further investigate the potential effects of air pollution on the function and morphology of the auditory brainstem. Methodology: Twenty-four dogs living in clean air v MC, average age 37.1± 26.3 months, underwent brainstem auditory evoked potential (BAEP) measurements. Eight dogs (4 MC, 4 Controls) were analysed for auditory brainstem morphology and histopathology. Results: MC dogs showed ventral cochlear nuclei hypotrophy and MSO dysmorphology with a significant decrease in cell body size, with many cell bodies \u3c 100 μm2, a significant decrease in neuronal packing density with many regions in the nucleus devoid of neurons and marked gliosis. MC dogs showed significant delayed BAEP absolute wave I, III and V latencies compared to controls. Conclusions: Auditory nuclei dysmorphology and BAEPs consistent with an alteration of the generator sites of the auditory brainstem response waveform are a common denominator for dogs and children in highly polluted MC. This study puts forward the usefulness of BAEPs to study auditory brainstem neurodegenerative changes associated with air pollution in dogs and its potential use in young urbanites as a proxy for an evolving neurodegenerative process towards Alzheimer Disease. Recognition of the role of non-invasive BAEPs in urban dogs is warranted to elucidate novel neurodegenerative pathways link to air pollution and may be a promising early diagnostic strategy for AD

A rare case of mixed germ cell tumor in a teenage girl: a case report

Germ cell tumors represent only 20% to 25% of all benign and malignant ovarian neoplasms. Mixed germ cell tumors are a rare variety of non–dysgerminomatous germ cell tumors. They contain two or more elements; the most frequent combination being a dysgerminoma and an EST (Endodermal Sinus Tumor). We present a case of malignant mixed germ cell tumor comprising of yolk sac tumor, embryonal carcinoma and choriocarcinoma. A 13-year-old girl presented with a huge 25 x 18 cm mass in abdomen with raised values of CA-125, hCG, AFP (alpha-feto protein) and LDH (lactate dehydrogenase). She underwent laparotomy followed by unilateral salpingoopherectomy and infracolic omentectomy. Histopathology report revealed malignant mixed germ cell tumor comprising predominantly of EST with elements of embryonal carcinoma and non-gestational choriocarcinoma. Following surgery, she was started on adjuvant chemotherapy (Bleomycin, Etoposide and Cisplatin regimen). Mixed germ cell tumor (YST/EST, non-gestational choriocarcinoma and embryonal carcinoma) is a very rare tumor. Careful initial surgery with adequate staging biopsies followed by combination chemotherapy can greatly improve the prognosis of these patient

Combustion-Derived Nanoparticles, the Neuroenteric System, Cervical Vagus, Hyperphosphorylated Alpha Synuclein and Tau in Young Mexico City Residents

Mexico City (MC) young residents are exposed to high levels of fine particulate matter (PM2.5), have high frontal concentrations of combustion-derived nanoparticles (CDNPs), accumulation of hyperphosphorylated aggregated α-synuclein (α-Syn) and early Parkinson\u27s disease (PD). Swallowed CDNPs have easy access to epithelium and submucosa, damaging gastrointestinal (GI) barrier integrity and accessing the enteric nervous system (ENS). This study is focused on the ENS, vagus nerves and GI barrier in young MC v clean air controls. Electron microscopy of epithelial, endothelial and neural cells and immunoreactivity of stomach and vagus to phosphorylated ɑ-synuclein Ser129 and Hyperphosphorylated-Tau (Htau) were evaluated and CDNPs measured in ENS. CDNPs were abundant in erythrocytes, unmyelinated submucosal, perivascular and intramuscular nerve fibers, ganglionic neurons and vagus nerves and associated with organelle pathology. ɑSyn and Htau were present in 25/27 MC gastric,15/26 vagus and 18/27 gastric and 2/26 vagus samples respectively. We strongly suggest CDNPs are penetrating and damaging the GI barrier and reaching preganglionic parasympathetic fibers and the vagus nerve. This work highlights the potential role of CDNPs in the neuroenteric hyperphosphorylated ɑ-Syn and tau pathology as seen in Parkinson and Alzheimer\u27s diseases. Highly oxidative, ubiquitous CDNPs constitute a biologically plausible path into Parkinson\u27s and Alzheimer\u27s pathogenesis