Do Toxic Synergies of Underlying Etiologies Predispose the Positive Association Between Traumatic Brain Injury and ADHD?

Objective: In their meta-analysis, Adeyemo et al. reported a strong association between mild traumatic brain injury (mTBI) and ADHD. However, less is understood about why such an association exists. Method: This commentary focuses on the underlying etiologies of both conditions to reveal potential toxic synergisms that could explain this association. Results: Alcohol and substance abuse are recognized comorbidities in both conditions. The author of this commentary has recently been the first to propose that chronic exposure to nitrous oxide (N2O), an increasing environmental air pollutant and greenhouse gas, may contribute to the cognitive impairment seen in conditions such as ADHD and autism. The toxic synergisms from combined GABA-mimetics, such as ethanol, and nontoxic N2O exposure have been previously elucidated and are further contextualized here. Conclusion: The conclusion of this commentary is that the toxicological interdependence of the underlying etiologies for mTBI and ADHD may help to explain their association as found in the meta-analysis conducted by Adeyemo et al. This commentary explores this dynamic further and, in so doing, underscores the need for additional research to validate these important conclusions.

A model of lipid dysregulation and altered nutrient status in Alzheimer's disease.

INTRODUCTION: Dysregulated lipid metabolism and nutrient status are thought to play a role in the pathophysiology of Alzheimer's disease (AD). However, the precise involvement is not well understood, and it remains unclear exactly how such dysregulated lipid metabolism and altered nutrient status, especially changes in phosphatidylcholine, B12, and folate, are connected to the hallmark pathology in AD (i.e., amyloidogenesis). METHODS: We have postulated that genetic susceptibility (i.e., APOE ε4/ε4) to environmental exposure to emissions of nitrous oxide (N2O) could underlie the onset of AD and its early neuropsychiatric correlates. RESULTS AND DISCUSSION: The current theoretical editorial describes, using clinical, preclinical, and in vitro evidences, how this model contributes not only to amyloidogenesis but also other nonopioid effects, specifically altered lipid metabolism, depletion of vitamin B12, and disruption of the folate-mediated one carbon metabolic pathway.

Environmental factors influencing the link between APOE ε4 and Alzheimer's disease (AD) risk.

While APOE ε4 allele is considered a genetic risk factor for Alzheimer's disease (AD), no relation existed between APOE ε4 and AD in the Yoruba in Nigeria among cohorts included in early prevalence waves. The authors' explanation that other disease susceptibilities may provoke earlier mortality is inconsistent with the Yoruba having a lower incidence of disease risk factors. Cohort enrichment in 2001 has altered the authors' conclusions; Yorba participants homozygous, and not heterozygous, for the ε4 allele had significantly increased risk for AD (HR = 2.95, p = 0.0002) (Hendrie et al., 2014). This is a critical revelation, yet it is not clear why such a temporal relationship exists between risk genotypes and AD among the Yoruba. This letter proposes an explanation.

Environmental factors influencing the link between childhood ADHD and risk of adult coronary artery disease.

Yorbik et al. reported novel findings regarding a hypothesized relationship between childhood attention-deficit hyperactivity disorder (ADHD) and later risk for coronary heart disease in adulthood. The authors found that mean platelet volume (MPV), a marker of platelet reactivity and a presumable biomarker in patients with cardiovascular disease, was significantly elevated in children with ADHD compared to healthy controls. The mechanistic importance of this novel discovery remains unknown and warrants clarification. We have made the novel proposition that environmental exposure to the agricultural and combustion air pollutant, nitrous oxide (N2O), may be an etiological contributor to neurodevelopmental disorders. Clinical studies suggest that N2O may enhance platelet hyperaggregation, possibly via its biphasic role as an MAO inhibitor especially at trace levels of exposure or via the generation of oxidative stress. Therefore, this correspondence briefly details the hypothesis that altered biochemical profiles in neurodevelopmental disorders, derived from chronic environmental exposure to the agricultural and combustion air pollutant, N2O, may promote coronary artery disease in adulthood.

Antecedent ADHD, dementia, and metabolic dysregulation: A U.S. based cohort analysis.

INTRODUCTION: Epidemiological and genetic studies have reported a link between antecedent ADHD and dementia. The underpinning mechanisms of these associations are not known and have generated considerable speculation. METHODS: We have extracted hospitalization discharge data on dementia and ADHD (representing a severe phenotype) from the Healthcare Cost and Utilization Project (HCUPnet) and utilized a Poisson regression with two-ways fixed effects to investigate this association. RESULTS: An unadjusted ten-year lagged measure of a severe ADHD phenotype increases hospitalization risk for an all-listed Lewy Body Dementia (LBD) diagnosis (IRR: 1.21, 95% C.I. 1.08-1.35) and Alzheimer's disease (AD) discharge diagnosis (IRR: 1.15, 95% C.I.: 1.05-1.27). However, these relationships may be dependent upon the extent of metabolic dysregulation in a subtype-specific manner, as controlling for diabetes removes the significant association between antecedent ADHD and risk of AD but not LBD. DISCUSSION: These results indicate that the association between antecedent ADHD and dementia risk may be uniquely influenced by metabolic dysregulation, building upon prior discussion in this journal of a purported link between AD and diabetes. We tie the current findings to environmental risk factors that we have previously implicated in the etiology of ADHD to generate testable hypotheses on the underlying brain neurochemistry that may facilitate the link between metabolic dysregulation and dementia subtype risk.

Air pollution and risk of hospitalization for epilepsy: the role of farm use of nitrogen fertilizers and emissions of the agricultural air pollutant, nitrous oxide.

The link between various air pollutants and hospitalization for epilepsy has come under scrutiny. We have proposed that exposure to air pollution and specifically the pervasive agricultural air pollutant and greenhouse gas, nitrous oxide (N2O), may provoke susceptibility to neurodevelopmental disorders. Evidence supports a role of N2O exposure in reducing epileptiform seizure activity, while withdrawal from the drug has been shown to induce seizure-like activity. Therefore, we show here that the statewide use of anthropogenic nitrogen fertilizers (the most recognized causal contributor to environmental N2O burden) is significantly negatively associated with hospitalization for epilepsy in all three pre-specified hospitalization categories, even after multiple pollutant comparison correction (p<.007), while the other identified pollutants were not consistently statistically significantly associated with hospitalization for epilepsy. We discuss potential neurological mechanisms underpinning this association between air pollutants associated with farm use of anthropogenic nitrogen fertilizers and hospitalization for epilepsy.

Use of anthropogenic nitrogen fertilizers in agriculture is associated with per capita ethanol consumption.

It has previously been demonstrated that emissions of the agricultural pollutant, nitrous oxide (N2O), may be a confounder to the relationship between herbicide use and psychiatric impairments, including ADHD. This report attempts to extend this hypothesis by testing whether annual use of anthropogenic nitrogen-based fertilizers in U.S. agriculture (thought to be the most reliable indicator of environmental N2O emissions) is associated with per capita ethanol consumption patterns, a behavior often comorbid with ADHD. State estimates of anthropogenic nitrogen fertilizers from the United States Geological Survey (USGS) were obtained for the years between 1987 and 2006. Our dependent variable was annual per capita ethanol consumption. Ethanol consumption was categorized as beer, wine, spirits, and all alcoholic beverages. Least squares dummy variable method using two-ways fixed effects was utilized. Among states above the 50th percentile in farm use of anthropogenic nitrogen for all years (i.e., agricultural states), a one log-unit increase in farm use of anthropogenic nitrogen fertilizers is associated with a 0.13 gallon increase in total per capita ethanol consumption (p<0.0125). No statistically significant association between farm use of anthropogenic nitrogen and per capita ethanol consumption was found in states below the 50th percentile in farm use of anthropogenic nitrogen. The new findings are in agreement with both behavioral human studies demonstrating a link between N2O preference and alcohol and drug use history as well as molecular studies elucidating shared mechanisms between trace N2O antinociception and alcohol-seeking related behaviors.