Is there something in the air?

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Air pollution is an international problem in the post-industrial world. Poor air quality has been associated with an increasing number of medical conditions.

For a long time there has been indications that neurodegenerative conditions – such as Parkinson’s and Alzheimer’s – could also be associated with air pollution.

Recently, several research reports have been published providing compelling evidence further supporting the association and raising new questions. 

In today’s post, we will review some of that research and discuss what could be done next (SPOILER ALERT: the solution involves needing cleaner air).

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Vast. Source: Unequal

I have been extremely fortunate in my life to have travelled to a few of the major cities of the world, but none have had as much impact on me upon arrival as Mexico city.

The pilot had announced over the loud speaker that we were approaching the outskirts of the city, and I looked out of my window to catch a first glimpse of the central American metapolis. Block after block of dwellings passed beneath us, and I thought “great, we’ll be landing soon“.

Mexico City: Really vast. Source: lsecities

Three minutes later, block after block of dwellings were still passing beneath us.

It was the first really vast city that I had ever visited.

Covering approximately 1,500 square kilometers (580 sq miles) of an old volcanic crater, the city is huge. By comparison, New York city covers only 1/2 the area (approximately 780 square kilometers or 300 sq miles – Source).

Home to over 8 million people, Mexico city was an amazing place to explore.

Palacio de Bellas Artes. Source: Turkishairlines

The art, the culture, the history, and the food – lots to see and experience!

Bosque de Chapultepec. Source: Jetsetter

But like all big cities, Mexico city has its share of problems. In addtion to sinking more than 10 metres over the past century (Click here to read more about this), Mexico City also has a terrible air population problem.

And this latter issue has recently been implicated in some Parkinson’s related research.

What do you mean?

This research report was published recently:

Title: Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles. The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract likely a key brainstem portal.
Authors: Calderón-Garcidueñas L, González-Maciel A, Reynoso-Robles R, Hammond J, Kulesza R, Lachmann I, Torres-Jardón R, Mukherjee PS, Maher BA.
Journal: Environ Res. 2020 Sep 1:110139. Online ahead of print.
PMID: 32888951

In this study, the researchers were interested in the association between air pollution and neurodegenerative conditions.

Wait. What? There’s an association between neurodegenerative conditions and air pollution?

Yep.

The prestigious scientific journal Science did a very good write up about this topic a couple of years ago:

Source: ScienceMag

The review highlighted the growing number of studies pointing towards fine airborne particles that can enter the body (via the nose and mouth), and result in inflammatory reactions – raising the levels of cytokines (or messenger proteins that alert the immune system):

Source: ScienceMag

The review also touched on some of the early research conducted by Mexican researchers involved in the report mentioned at the top of this post.

Such as this report:

Title: Brain inflammation and Alzheimer’s-like pathology in individuals exposed to severe air pollution.
Authors: Calderón-Garcidueñas L, Reed W, Maronpot RR, Henríquez-Roldán C, Delgado-Chavez R, Calderón-Garcidueñas A, Dragustinovis I, Franco-Lira M, Aragón-Flores M, Solt AC, Altenburg M, Torres-Jardón R, Swenberg JA.
Journal: Toxicol Pathol. 2004 Nov-Dec;32(6):650-8.
PMID: 15513908                (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers (collaborating with international scientists) analysed the autopsied brains of cognitively and neurologically normal indviduals. The brains were collected from 9 lifelong residents of cities with low air pollution and 10 lifelong residents of cities with high air pollution.

The investigators examined the brains using two marker:

  • Cyclooxygenase-2 (or COX2), which is an inflammatory mediator
  • Alzheimer’s-associated 42-amino acid form of β-amyloid (Aβ42)

What they found was very interesting:

The brains of residents from cities with severe air pollution had significantly higher (p=0.01) levels of COX2 and greater accumulation of Aβ42 (compared to brains from residents of low air pollution cities).

The average age of the low- and high-air pollution groups was 58.1 and 51.2 years, respectively. The researchers were curious to see if brains from younger individuals might show similar results, so they followed up this study by looking at children and young adults:

Title: Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults.
Authors: Calderón-Garcidueñas L, Kavanaugh M, Block M, D’Angiulli A, Delgado-Chávez R, Torres-Jardón R, González-Maciel A, Reynoso-Robles R, Osnaya N, Villarreal-Calderon R, Guo R, Hua Z, Zhu H, Perry G, Diaz P. J
Journal: Alzheimers Dis. 2012;28(1):93-107.
PMID: 21955814

In this study, the researchers analysed the postmortem brains of 8 children from clean air environments and 35 children who had been exposed to high levels of air pollution. They looked at a broad range of markers in these brain (including oxidative stress, DNA damage signaling, inflammation, and neurodegeneration pathways).

Remarkably, 40% of the young brains exposed to high air pollution exhibited accumulation of Alzheimer’s-associated tau protein and 51% of them had β-amyloid deposits…

…compared with 0% in clean air environment control brains.

And it didn’t stop there.

An elevation of neuroinflammation and oxidative stress markers, as well as Alzheimer’s-associated pathology, was present in the young brains exposed to high air pollution.

There were also signs of compensatory measures – raising the possiblity that some individuals may be better at dealing with the pollution and getting rid of it, while in others some of these proteins might be building up over time (potentially resulting in trouble later in life).

(Thinking about moving to the country-side yet?)

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RECAP #1:  Numerous studies have associated air pollution with an increased risk of neurodegeneration.

Studies analysing postmortem brain tissue suggests higher levels of markers for oxidative stress, inflammation and Alzheimer’s-associated pathology in individuals exposed to higher levels of air pollution.

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Interesting. What does the new study report?

In the new study (mentioned at the top of this post), the researchers expanded on their initial results with a much larger sample size. They collected postmortem brains from 186 young Mexico City residents (average age 27 years old, the age range of the cases was 11 months to 40 years of age).

They analysed the brains for the presence of both tau and β-amyloid, but they also looked for Parkinson’s-associated alpha-synuclein and the motor neuron disease-associated protein TDP-43, in addition to a range of further analyses.

They found accumulation of tau protein in 55% (n=100) of the brains analysed, alpha-synuclein protein accumulation was present in 23% (n=42) of the brains, and 18% (n=34) had a build up of TDP-43. Even a brain from an 11 month old baby had build up of β-amyloid in the frontal cortex of the brain.

And curiously, overlaps of all four of these “neurodegenerative markers” (tau, β-amyloid, alpha-synuclein and TDP-43) was present in 10.98% (20/182) of the cases analysed.

What?!?

Interesting, huh?

So pollution causes neurodegeneration?

That can’t be assumed from this data.

These neurodegeneration-associated proteins may have multiple roles, including protection against pollutants. When the brain is exposed to a pollutant, these proteins may cluster and aggregate in a “protective” fashion to try and capture the pollutant, preventing it from spreading and causing damage.

The appearance of these markers does not necessarily mean that neurodegeneration is going to occur.

Has this ever been seen before? Multiple neurodegenerative proteins in the same brain?

Yes, it has. Very recently, in fact, this report was published:

Title: Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults.
Authors: Karanth S, Nelson PT, Katsumata Y, Kryscio RJ, Schmitt FA, Fardo DW, Cykowski MD, Jicha GA, Van Eldik LJ, Abner EL.
Journal: JAMA Neurol. 2020 Jun 22:e201741.
PMID: 32568358

In this study, the researchers used brain autopsy data from the University of Kentucky Alzheimer Disease Center (UK-ADC) brain bank. Brain samples from 375 individuals (average age at death was 86 years) were used in the analysis, and the investigators went looking for cases where all four of the “neurodegenerative markers” mentioned above (tau, β-amyloid, alpha-synuclein and TDP-43) were present in the same brain.

Remarkably, they found that 46 (12.3%) of the brains had all four markers present – a similar statistic to the Mexico City study discussed above – and 41 of those cases had a diagnosis of dementia. The scientists also noted that reports of mild cognitive impairment transitioned to a diagnosis of dementia more rapidly in those cases that had all 4 neurodegenerative markers.

The researchers concluded that quadruple misfolded proteins are a common but under-appreciated phenotype that is associated with impaired cognition

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RECAP #2:  A new report indicates that postmortem analysis of the brains of young inhabitants of Mexico city have frequent incidence of markers associated with neurodegenerative conditions. In some cases, multiple markers are observed in the same brain.

Another report from the state of Kentucky in the US, found that multiple markers are also found aged brains.

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So it’s not just something in the air in Mexico City perhaps?

Unlikely. Other studies around the world have indicated that air quality may be associated with neurodegenerative conditions.

Such as?

This week, this report was published:

Title: Long-term effects of PM2·5 on neurological disorders in the American Medicare population: a longitudinal cohort study
Authors: Shi L, Wu X, Yazdi MD, Braun D, Awad YA, Wei Y, Liu P, Di Q, Wang Y, Schwartz J, Dominici F, Kioumourtzoglou M-A, Zanobetti A.
Journal: Lancet Planet Health. 2020 Oct 19:S2542-5196(20)30227-8.
PMID: 33091388                    (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers collected data of Medicare beneficiaries (aged ≥65 years) between 2000–2016. They then assigned postal code-based air pollution concentrations to each case and looked for any associations.

In total, the data of 63 038 019 individuals was used in the study. The investigators identified 1 million cases of Parkinson’s and 3.4 million cases of Alzheimer’s. When they looked at the air quality data, they found that for each 5 μg/m3 increase in annual PM2·5 concentrations, there was an increased risk of first hospital admission with Parkinson’s and Alzheimer’s.

Wait. What does any of that mean? What is PM2·5 concentrations?

PM2·5 refers to atmospheric particulate matter (or PM) that have a diameter of less than 2.5 micrometers – this is approximately 3% the diameter of a human hair. There are also larger particles (PM10) – a group into which pollen and dust falls.

Source: EPA

PM2·5 particles can originate from different sources, such as motor vehicles, airplanes, power plants, residential wood burning, forest fires, volcanic eruptions, dust storms, etc). They are believed to be more troublesome because – being small and light – they tend to hang around longer in the air than their heavier siblings (like PM10).

Ok, so increases in annual PM2·5 concentrations was associated with a higher risk of Parkinson’s or Alzheimer’s?

Basically yes. The researchers found that for each defined amount of increase in PM2·5 levels (that amount being 5 μg/m3) in the course of a year, there was an increased risk of first hospital admission with Parkinson’s and Alzheimer’s.

And they noted overlaps in PM2·5 levels and the incidence of Parkinson’s in the two maps below:

Source: Lancet

The top map shows the 17-year average of annual PM2·5 concentrations (red areas indicating high levels, green representing low), while occurrence of first Parkinson’s hospital admissions per 100,000 people is illustrated in the bottom map.

Similar results have recently been published by other research groups (Click here to read more about this).

Has anyone ever looked at how air pollution affects Parkinson’s? And can anything be done about it?

Actually yes, researchers have looked.

Scientists in South Korea published this study several years ago:

Title: Short-term air pollution exposure aggravates Parkinson’s disease in a population-based cohort.
Authors: Lee H, Myung W, Kim DK, Kim SE, Kim CT, Kim H.
Journal: Sci Rep. 2017 Mar 16;7:44741.
PMID:28300224                 (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers examined if there were any associations between short-term exposure to PM2.5, nitrogen dioxide, sulfur dioxide, ozone, and carbon monoxide with aggravation of Parkinson’s in Seoul. They used data from the National Health Insurance Service collected between 2002–2013, and defined aggravation of Parkinson’s as emergency hospital admissions. Measures of pollutants concentrations were compared to dates of admissions.

The investigators reported that short-term air pollution exposure (measured in PM2.5) increased risk of Parkinson’s aggravation, and may even influence disease progression. Interestingly, stronger effect were observed in women and during the  cold season. The researchers concluded that their data supports “policy-making to mitigate air pollution and reduce neurodegenerative health effects in our aging society“.

So we need more fresh air?

That seems like a wise take-away from this post. I looked for any research on this, but didn’t have much luck – there doesn’t appear to be much data (happy to be corrected on this).

Perhaps fresh country air may have beneficial effects on the course of PD.

Maybe someone should do some investigations into this.

So what does it all mean?

About three quarters of the Earth’s atmosphere sits within just 12 km (7.5 miles) of the surface. Curiously, this height varies between 9 km (5.6 miles) at the geographic poles to around 17 km (11 miles) at the Equator (Source), but the point is: in the greater cosmic scheme of things – within the vast expanse of the known universe – it is a preciously thin region of space that can sustain life, providing both an agreeable combination of gases and protecting organisms from the full force of solar radiation.

The thin blue line. Source: ScienceMag

Despite full knowledge of this, we humans seem hell-bent on polluting this finite resource in our desperate thirst for a more comfortable life.

Scientific investigations have pointed towards a myriad of health complications associated with this pollution (Click here to read more about this), and now researchers are reporting that above average levels of air pollution may be associated with increased risk of neurodegenerative conditions like Parkinson’s and Alzheimer’s.

The association between classical hallmarks of different neurodegenerative conditions (in the brain) with air pollution is intriguing. Particularly in the brains of very young individuals. And particularly in the absence of any obvious clinical or physiological degeneration. It begs the question: Is alpha synuclein really the smoking gun of Parkinson’s?

Perhaps – as we discussed above – synuclein and some of the other clustering proteins try to mop up pollutants, and with age our ability to remove and clear the “used” synuclein becomes harder. Maybe air pollution is an environmental influencer in the course of the condition. This all needs to be further investigated. Given the levels of air pollution in many densely packed parts of the world, it does not seem likely that air pollution is a trigger for the condition (otherwise there would be a lot more cases).

But the research discussed in today’s post is certainly reason enough for us all to make greater efforts in improving the quality of the air we breathe.

 

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The banner for today’s post was sourced from RTMagazine.

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