23 May 2020

Part 2 of 2

For decades, studies of pulmonary and vascular systems dominated the air-pollution-research landscape. Researchers paid scant attention to the brain, which they considered safely ensconced behind the blood-brain barrier. But the science has begun to change. Evidence has been steadily trickling in that exposure to ambient air pollution, even at levels near the upper limits set by the World Health Organization, can affect the central nervous system. Over the last decade, numerous epidemiological studies have tied pollution to increased risk for cognitive decline and dementia (see Part 1 of this story). 

Though the data is often equivocal, scientists are asking, just how do pollutants damage the brain? Chronic deterioration of the cardio- and cerebrovascular systems may be to blame, but researchers are also finding that particulate matter gets into the central nervous system, either through olfactory nerves or across the blood-brain barrier, and then harms neurons and glia directly. Particulate matter and diffuse Aβ plaques, hyperphosphorylated tau, and aggregates of α-synuclein have even been detected in olfactory bulbs in the brains of young people who lived in Mexico City, where air pollution is high. Overall, what little evidence there is thus far points to both direct and indirect effects of air pollutants on the brain.

Poison on the Brain? Air pollution can directly affect the brain through olfactory or vagal nerves, or indirectly by stressing the circulatory system. [Courtesy of Genc et al., 2012.] 

The indirect effects are borne out by recent epidemiological studies. As reported in the March 30 JAMA Neurology, researchers led by Giulia Grande at the Karolinska Institute, Stockholm, studied nearly 3,000 people in the Swedish National Study on Aging and Care in the Stockholm suburb of Kungsholmen (SNAC-K). When participants enrolled, between 2001 and 2004, they were 60 or older and without dementia, but after an average of six years of follow-up, 364 of them had developed it. Intriguingly, the incidence for this diagnosis was 50 percent higher in those who had been exposed to the highest levels of nitrogen oxides or PM_2.5 in the five years prior. Notably, incident cardiovascular disease increased the risk even further. The authors estimated that stroke alone accounted for half of the air pollution-related dementia cases.

Researchers led by Tarik Benmarhnia at the Scripps Institution of Oceanography, La Jolla, California, calculated that among almost 35,000 people who enrolled between 1996 and 2003 in the Canadian Community Health Surveys in Ontario, three-year exposure to NO₂ and PM_2.5 increased the risk for dementia by about 10 and 30 percent, respectively. In the February 1 International Journal of Epidemiology, first author Sindana Ilango and colleagues reported that cardiovascular disease explained 21 percent of the dementia risk from PM_2.5, and 9 percent from NO₂.

This indirect effect was weaker than that observed in the SNAC-K. That said, the Ontario exposure data was taken five to 17 years prior to people’s dementia diagnosis, whereas the Swedish study picked up barely any effect of exposures going back longer than five years before diagnosis. Herein lies some of the complexity of comparing people’s exposure to air pollution. A separate analysis of the Canadian cohort attributed 6 percent of their incident dementia to air pollution, namely NO₂, PM_2.5, and ozone (Chen et al., 2017). 

Then what about direct effects on the brain? Scientists are beginning to examine this question with human imaging and animal models.

One potential route is via the olfactory bulb. Olfactory nerves in the nose carry a variety of cargo into the brain, including narcotics, therapeutics such as insulin, and some viruses. In the case of pollutants, the research has focused on ultrafine particles. At less than 0.1 micrometers in diameter, UFPs are even smaller than PM_2.5. The EPA does not regulate them, hence they are not routinely monitored in the U.S. Researchers are setting up their own monitoring equipment to measure levels in ambient air that is pumped into animal facilities. While this research is still coming in, it already indicates these small particles could be particularly harmful.

Gunter Obersdörster and colleagues at the University of Rochester, New York, found that after exposing rats once for six hours to UFPs, they showed up in the olfactory bulb one day later, and levels had increased slightly by day seven (Obersdörster et al., 2004). When Deborah Cory-Slechta, also at URochester, exposed mouse pups to UFP levels typically found floating above Los Angeles highways, brain development went off track. Microglia became activated, inflammation ensued, neurons were thinly myelinated, ventricles did not shrink as they normally do as the brain matures, and the mice behaved aberrantly, as if modeling autism spectrum disorders (Allen et al., 2017). 

Smog Over Beijing. [Courtesy of Kentaro Iemoto.]

There are some indications that older mice, both wild-type and 3xTg models of early Alzheimer’s disease, had trouble in radial-arm and novel-object-recognition tests of learning and memory after a two-week exposure to UFPs for four hours per day, four days a week (Jew et al., 2019). In the February 1 Free Radical Biology and Medicine, Caleb (Tuck) Finch, University of Southern California, and colleagues reported that exposure of J20 mice carrying human APP with a familiar AD mutation to particulate matter for 150 hours over 10 weeks increased Aβ production and amyloid plaque load in the cerebral cortex. Others have also reported that air pollution accelerates Aβ production in mice (Kim et al., 2012). 

Finch and colleagues also found that particulates caused oxidative stress to the olfactory epithelium and olfactory bulb of rats, leading to induction of tumor necrosis factor-alpha and an inflammatory response (Cheng et al., 2016). 

Human studies, sparse as they are, have raised some troubling questions about the olfactory bulb, as well. Lilian Calderón-Garcidueñas at the University of Montana, Missoula, has been studying the effects of Mexico City’s air pollution on people for almost four decades. She has correlated exposure with brain abnormalities seen on autopsy.

Calderón-Garcidueñas’ data links air pollution to pathological hallmarks of Alzheimer’s and Parkinson’s diseases in the olfactory bulb, though this is not a brain region typically associated with those neurodegenerative disorders. Among 57 people younger than 20 who came to autopsy, 48, 39, and 36 had signs of hyperphosphorylated tau, α-synuclein aggregates, or diffuse amyloid plaques, respectively (Calderón-Garcidueñas et al., 2013; Calderón-Garcidueñas et al., 2018). A prior study found that 29 of 35 Mexico City residents had accumulated Aβ plaques in their olfactory bulbs, while two had signs of α-synuclein pathology. Nine controls from unpolluted regions appeared unaffected (Calderón-Garcidueñas et al., 2010). 

Remarkably, the paper claims that children as young as 11 months old were affected. In a series of immunohistochemistry images, the researchers show how one 3-year-old had numerous Aβ- and α-synuclein-positive neurons in the glomerular layer of their olfactory bulb. A 2-year-old boy reportedly had particulate matter in his olfactory tract, which runs between the nostrils and the brain, and another 3-year-old had neurons containing hyperphosphorylated tau. Combustion-derived nanoparticles, aka pollutants, were detected by electron microscopy in the mitochondria and endoplasmic reticula of neurons and glia, and among damaged dendrites and myelin sheaths. As per these papers, Calderón-Garcidueñas believes her findings suggest that air pollution may dramatically hasten neurodegenerative processes.

“This has become a topic of great interest, but we need much more data on the olfactory system,” said Jennifer Weuve, Boston University School of Public Health. To generate that data, Weuve plans to correlate people’s sense of smell with air pollution in the Chicago cohorts, and look for air pollutants in, and damage to olfactory bulbs on autopsy (see also Part 1 of this series). 

If more research solidifies a scientific consensus that air pollution brings on dementia, and perhaps specifically Alzheimer’s disease, then it could inform policy reform. A clear dementia finding might add urgency to already existing arguments for air pollution control, such as its effect on respiratory health and climate. “There are things that we as a society need to decide are important,” said Melinda Power, George Washington University, Washington, D.C. “For many people, dementia is very scary and a reason why people might want to act. Even if we know that lowering air pollution is better for other reasons, if we can show it reduces dementia that might be a powerful motivator.”—Tom Fagan

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References

News Citations

1. Air Pollution and Dementia—Through Hazy Data, Links Emerge 22 May 2020

Research Models Citations

1. J20 (PDGF-APPSw,Ind)

Paper Citations

1. Genc S, Zadeoglulari Z, Fuss SH, Genc K. The adverse effects of air pollution on the nervous system. J Toxicol. 2012;2012:782462. PubMed.
2. Chen H, Kwong JC, Copes R, Hystad P, van Donkelaar A, Tu K, Brook JR, Goldberg MS, Martin RV, Murray BJ, Wilton AS, Kopp A, Burnett RT. Exposure to ambient air pollution and the incidence of dementia: A population-based cohort study. Environ Int. 2017 Nov;108:271-277. Epub 2017 Sep 13 PubMed.
3. Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C. Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol. 2004 Jun;16(6-7):437-45. PubMed.
4. Allen JL, Oberdorster G, Morris-Schaffer K, Wong C, Klocke C, Sobolewski M, Conrad K, Mayer-Proschel M, Cory-Slechta DA. Developmental neurotoxicity of inhaled ambient ultrafine particle air pollution: Parallels with neuropathological and behavioral features of autism and other neurodevelopmental disorders. Neurotoxicology. 2017 Mar;59:140-154. Epub 2015 Dec 22 PubMed.
5. Jew K, Herr D, Wong C, Kennell A, Morris-Schaffer K, Oberdörster G, O'Banion MK, Cory-Slechta DA, Elder A. Selective memory and behavioral alterations after ambient ultrafine particulate matter exposure in aged 3xTgAD Alzheimer's disease mice. Part Fibre Toxicol. 2019 Nov 26;16(1):45. PubMed.
6. Kim SH, Knight EM, Saunders EL, Cuevas AK, Popovech M, Chen LC, Gandy S. Rapid doubling of Alzheimer's amyloid-β40 and 42 levels in brains of mice exposed to a nickel nanoparticle model of air pollution. F1000Res. 2012 Dec 21;1 PubMed.
7. Cheng H, Saffari A, Sioutas C, Forman HJ, Morgan TE, Finch CE. Nanoscale Particulate Matter from Urban Traffic Rapidly Induces Oxidative Stress and Inflammation in Olfactory Epithelium with Concomitant Effects on Brain. Environ Health Perspect. 2016 Oct;124(10):1537-1546. Epub 2016 May 17 PubMed.
8. Calderón-Garcidueñas L, Franco-Lira M, Mora-Tiscareño A, Medina-Cortina H, Torres-Jardón R, Kavanaugh M. Early Alzheimer's and Parkinson's disease pathology in urban children: Friend versus Foe responses--it is time to face the evidence. Biomed Res Int. 2013;2013:161687. Epub 2013 Feb 7 PubMed.
9. Calderón-Garcidueñas L, González-Maciel A, Reynoso-Robles R, Kulesza RJ, Mukherjee PS, Torres-Jardón R, Rönkkö T, Doty RL. Alzheimer's disease and alpha-synuclein pathology in the olfactory bulbs of infants, children, teens and adults ≤ 40 years in Metropolitan Mexico City. APOE4 carriers at higher risk of suicide accelerate their olfactory bulb pathology. Environ Res. 2018 Oct;166:348-362. Epub 2018 Jun 20 PubMed.
10. Calderón-Garcidueñas L, Franco-Lira M, Henríquez-Roldán C, Osnaya N, González-Maciel A, Reynoso-Robles R, Villarreal-Calderon R, Herritt L, Brooks D, Keefe S, Palacios-Moreno J, Torres-Jardón R, Medina-Cortina H, Delgado-Chávez R, Aiello-Mora M, Maronpot RR, Doty RL. Urban air pollution: influences on olfactory function and pathology in exposed children and young adults. Exp Toxicol Pathol. 2010 Jan;62(1):91-102. PubMed.

Further Reading

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