Common household chemicals pose new threat to brain health, study finds

A team of researchers from the Case Western Reserve University School of Medicine has provided fresh insight into the dangers some common household chemicals pose to brain health. They suggest that chemicals found in a wide range of items, from furniture to hair products, may be linked to neurological conditions like multiple sclerosis and autism spectrum disorders.

Neurological problems impact millions of people, but only a fraction of cases can be attributed to genetics alone, indicating that unknown environmental factors are important contributors.

The new study published today in the journal Nature Neuroscience, discovered that some common home chemicals specifically affect the brain's oligodendrocytes, a specialized cell type that generates the protective insulation around nerve cells.

"Loss of oligodendrocytes underlies multiple sclerosis and other neurological diseases," said the study's principal investigator, Paul Tesar, the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and director of the Institute for Glial Sciences at the School of Medicine. "We now show that specific chemicals in consumer products can directly harm oligodendrocytes, representing a previously unrecognized risk factor for neurological disease."

On the premise that not enough thorough research has been done on the impact of chemicals on brain health, the researchers analyzed over 1,800 chemicals that may be exposed to humans. They identified chemicals that selectively damaged oligodendrocytes belong to two classes: organophosphate flame retardants and quaternary ammonium compounds. Since quaternary ammonium compounds are present in many personal-care products and disinfectants, which are being used more frequently since the COVID-19 pandemic began, humans are regularly exposed to these chemicals. And many electronics and furniture include organophosphate flame retardants.

The researchers used cellular and organoid systems in the laboratory to show that quaternary ammonium compounds cause oligodendrocytes to die, while organophosphate flame retardants prevented the maturation of oligodendrocytes.

They demonstrated how the same chemicals damage oligodendrocytes in the developing brains of mice. The researchers also linked exposure to one of the chemicals to poor neurological outcomes in children nationally.

"We found that oligodendrocytes -- but not other brain cells -- are surprisingly vulnerable to quaternary ammonium compounds and organophosphate flame retardants," said Erin Cohn, lead author and graduate student in the School of Medicine's Medical Scientist Training Program. "Understanding human exposure to these chemicals may help explain a missing link in how some neurological diseases arise."

The association between human exposure to these chemicals and effects on brain health requires further investigation, the experts warned. Future research must track the chemical levels in the brains of adults and children to determine the amount and length of exposure needed to cause or worsen disease.

"Our findings suggest that more comprehensive scrutiny of the impacts of these common household chemicals on brain health is necessary," Tesar said. "We hope our work will contribute to informed decisions regarding regulatory measures or behavioral interventions to minimize chemical exposure and protect human health."

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A backpack full of multiple sclerosis therapy

Multiple sclerosis (MS) is a devastating autoimmune disease that destroys the protective myelin covering around nerves, disrupting communication between the brain and body, and causing patients' ability to move and function to progressively decline. The MS atlas reported in 2020 that someone is diagnosed with MS every five minutes around the world, adding to about 2.8 million individuals that currently have to live with the disease. Alarmingly, since 2013, the world-wide prevalence of MS has risen by 30%.

A key driver of MS is the sudden inflammation of nerves caused by so-called myeloid cells of the "innate" immune system in vulnerable regions of the brain and spinal cord, which together form the central nervous system (CNS). These "acute inflammatory lesions" then attract other myeloid cells, as well as self-reactive T and B cells that belong to the immune system's second arm, known as the "adaptive immune system" and directly attack the myelin covering. While no cure is available for MS, existing disease-modifying therapies in the form of small molecule and protein drugs either directly target the self-reactive immune cells or broadly dampen inflammation. However, many of those therapies cause severe side effects in different parts of the body, including the immune system itself, and thus carry significant health risks.

Now, a research team at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) has developed a cell therapy as a strong alternative to existing small molecule and protein therapies that leverages myeloid cells, the very type of immune cells that cause the MS-triggering nerve inflammation in patients.

To transform potentially inflammatory myeloid cells into therapeutic cells, they isolated and cultured monocytes (a type of myeloid cell) from the bone marrow of donor mice and stably attached tiny microparticles, termed "backpacks," to the cells' surfaces. These backpacks are loaded with anti-inflammatory molecules that direct the carrier cells' differentiation into anti-inflammatory cells in vivo. When infused back into a mouse model of MS, the backpack-laden monocytes were able to affect MS-specific immune responses, and partially reverse hind limb paralysis and improve motor functions. The results are published in the Proceedings of the National Academy of Sciences (PNAS).

"Current MS therapies do not specifically target myeloid cells. These are very plastic cells that can toggle between different states and are thus hard to control. Our biomaterial-based backpack approach is a highly effective way to keep them locked into their anti-inflammatory state," said senior author Samir Mitragotri, Ph.D., who is a Core Faculty member at the Wyss Institute. "In many ways simpler than other cell therapies, myeloid cells can be easily obtained from patients' peripheral blood, modified with backpacks in a short culture step, and reinfused back into the original donor, where they find their way to inflammatory lesions and affect the MS-specific immune response not only locally, but more broadly." Mitragotri is also the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS.

Many cell therapies, such as the famed CAR-T cell therapies, require the mobilization of immune cells from specific tissue compartments in the body with drugs, genetic modification, and then amplification over weeks outside of the body. Myeloid cells can be directly retrieved using established methods and modified with backpacks within hours, making the therapy more easily translatable. In addition, some myeloid cell types possess the ability to traverse the blood-brain barrier, which makes them particularly suitable for treating CNS diseases.

New spin for cellular backpacks

Mitragotri's group had previously found that when they attached small disc-shaped backpacks to cells of the myeloid lineage, they remained stably exposed on the cells' surface, whereas many other cells would readily internalize and inactivate them. Adding certain molecules to the backpacks allowed the team sustained control over the cells' behavior. They made use of this finding in a tumor-fighting cell therapy consisting of backpack-laden macrophages, which is a specific type of myeloid cell. In their new study, they focused on monocytes, which also belong to the myeloid differentiation lineage and are a precursor to macrophages. Monocytes can effectively infiltrate the brain and then differentiate into macrophages, which are one of the predominant inflammatory cell types in active MS lesions.

"Because of their ability to invade the CNS, infiltrate inflammatory lesions, and differentiate into macrophages, a backpack strategy allowing control over monocyte differentiation made extreme sense," said first author Neha Kapate, a graduate student working with Mitragotri. "We decided on backpacks that contained interleukin-4 [IL-4] and dexamethasone, two molecules that we later found to provide a synergistic anti-inflammatory effect."

The team fabricated their micrometer-size backpacks via a process known as serial "spin coating," in which thin films made up of a PLGA polymer and other biocompatible substances, and containing the anti-inflammatory molecules are layered on top of each other like layers of an onion. As a final step, the outer surface of the backpack was furnished with an antibody fragment to allow it to stick to monocytes.

Cellular backpacks get legs

To test the backpack-laden monocytes for their therapeutic efficacy, the researchers isolated monocytes from healthy donor mice and, in a short cell culture step, attached the backpacks to them. They then infused the modified cells into a mouse model of MS, known among researchers as experimental autoimmune encephalomyelitis (EAE) model. "When we infused backpack-carrying monocytes and, in parallel, unaltered control monocytes into EAE mice with ongoing nerve inflammation, backpack-carrying monocytes more effectively infiltrated into inflamed CNS lesions. They also reduced inflammation inside the lesions and shifted the local and systemic MS-associated immune response towards a therapeutic outcome," said Kapate. "The resulting anti-inflammatory monocytes also elicited cross-talk effects with other immune cell populations, such as specific T helper cells that are linked to the self-directed adaptive auto-immune response."

The disease symptoms in EAE mice treated with backpack-laden monocytes were significantly improved and, by the end of the study, the animals merely exhibited a limp tail, compared to complete a paralysis in the control animals' hind limbs. The treatment also extended the animals' survival -- all mice receiving backpack-carrying monocytes survived to the end of the study, whereas a significant number of the control mice had died. Importantly, the magnitude of therapeutic benefit the team observed is on par with reported therapeutic treatments that had been tested in other studies using the same model. Since the EAE model mainly mimics the progressive form of MS and not the more prevalent "relapsing-remitting" form, with which the disease begins in about 85% of MS patients, and which at later stages can also become progressive, the team plans to also investigate their approach in models of relapsing-remitting MS. Being able to suppress inflammation early on could have enormous benefits for patients.

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Brain discovery holds key to boosting body's ability to fight Alzheimer's, MS

UVA Health researchers have discovered a molecule in the brain responsible for orchestrating the immune system's responses to Alzheimer's disease and multiple sclerosis (MS), potentially allowing doctors to supercharge the body's ability to fight those and other devastating neurological diseases.

The molecule the researchers identified, called a kinase, is crucial to both removing plaque buildup associated with Alzheimer's and preventing the debris buildup that causes MS, the researchers found. It does this, the researchers showed, by directing the activity of brain cleaners called microglia. These immune cells were once largely ignored by scientists but have, in recent years, proved vital players in brain health.

UVA's important new findings could one day let doctors augment the activity of microglia to treat or protect patients from Alzheimer's, MS and other neurodegenerative diseases, the researchers report.

"Unfortunately, medical doctors do not currently possess effective treatments to target the root causes of most neurodegenerative diseases, such as Alzheimer's, Parkinson's or ALS [amyotrophic lateral sclerosis, commonly called Lou Gehrig's disease]. In our studies, we have discovered a master controller of the cell type and processes that are required to protect the brain from these disorders," said senior researcher John Lukens, PhD, of the University of Virginia School of Medicine and its Center for Brain Immunology and Glia (BIG), as well as the Carter Immunology Center and the UVA Brain Institute. "Our work further shows that targeting this novel pathway provides a potent strategy to eliminate the toxic culprits that cause memory loss and impaired motor control in neurodegenerative disease."

Toxic Brain Buildup

Many neurodegenerative diseases, including Alzheimer's and MS, are thought to be caused by the brain's inability to cleanse itself of toxic buildup. Recent advances in neuroscience research have shed light on the importance of microglia in removing harmful debris from the brain, but UVA's new discovery offers practical insights into how this cleaning process occurs -- and the dire consequences when it doesn't.

Using a mouse model of Alzheimer's disease, the UVA researchers found that a lack of the molecule they identified, spleen tyrosine kinase, triggered plaque buildup in the brain and caused the mice to suffer memory loss -- like the symptoms seen in humans with Alzheimer's. Further, the neuroscientists were able to reduce the plaque buildup by activating this molecule and microglia in the brain, suggesting a potential treatment approach for human patients, though that would require significantly more research and testing.

"Our work has described a critical element of microglial function during Alzheimer's disease and MS," said researcher Hannah Ennerfelt, the first author of a new scientific paper outlining the findings. "Understanding the underlying biology of these cells during neurodegeneration may allow for scientists and doctors to develop increasingly informed and effective therapeutic interventions."

A lack of the molecule in a mouse model of MS, meanwhile, led to the buildup of damaged myelin, a protective coating on nerve cells. When myelin is damaged, the cells cannot transmit messages properly, causing MS symptoms such as mobility problems and muscle spasms. The UVA researchers conclude in a new scientific paper that the molecule they identified, abbreviated as SYK, is "critically involved" in the crucial removal of myelin debris. "If boosting SYK activity in microglia can decrease the amount of myelin debris in MS lesions, developing new drugs to target SYK could stop the progression of MS and help to reverse the damage," said Elizabeth L. Frost, PhD, a critical researcher on the project. "This is an especially promising option given that most of the currently available drugs for MS treatment dampen adaptive immunity. These immunosuppressive drugs lead to susceptibility to infection and higher risk of potentially fatal side effects like progressive multifocal leukoencephalopathy. Additionally, some forms of MS do not have a strong involvement of the immune system, and therefore there are currently very limited treatment options for those patients."

"Targeting SYK in microglia," she noted, "would circumvent multiple limitations of present-day therapeutics for MS."

Based on their promising results, the researchers report that targeting the molecule to stimulate the brain's immune activity could offer a way to treat not just Alzheimer's and MS but a "spectrum" of neurodegenerative diseases.

"These findings are especially exciting because they point to a treatment avenue in which we could alter the behavior of these native brain cells, microglia, to behave in a more neuroprotective way," said researcher Coco Holliday, a UVA undergraduate working in the Lukens lab. "It could potentially be applied to a variety of different neurological diseases that all share the problem of a buildup of toxic waste in the brain. It's been a very exciting project to be a part of."

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New MRI technique could improve diagnosis and treatment of multiple sclerosis

It is important that multiple sclerosis (MS) is diagnosed and treated as early as possible in order to delay progression of the disease. The technique of magnetic resonance imaging (MRI) plays a key role in this process. In the search for ever better methods, a new MRI technique has been used at MedUni Vienna as part of a research project that could pave the way to quicker assessment of disease activity in MS. The study was conducted by a research team led by Wolfgang Bogner at MedUni Vienna's Department of Biomedical Imaging and Image-guided Therapy and was recently published in the journal Radiology.

Multiple sclerosis is a disease of the central nervous system that manifests itself in changes (lesions) primarily in the brain. As yet, there is no cure for MS, but it can be effectively treated. Early diagnosis is critical to the prognosis, with highly detailed imaging techniques playing a major role. Although conventional MRI can detect brain lesions, scientists are researching methods to detect the changes at an earlier microscopic or biochemical stage. The method known as proton MR spectroscopy has been identified as a promising tool for this purpose.

Using this technique, the research group led by Eva Niess (formerly Heckova) and Wolfgang Bogner from MedUni Vienna's Department of Biomedical Imaging and Image-guided Therapy, working with scientists from MedUni Vienna's Department of Neurology, went one step further in their recently published study. The team used MR spectroscopy with a 7-tesla magnet to compare the neurochemical changes in the brains of 65 MS patients with those of 20 healthy controls. This particularly powerful imaging tool was co-developed by MedUni Vienna researchers and has been used for scientific studies, e.g., of the brain, at MedUni Vienna's Center of Excellence for High-Field MR since it was commissioned in 2008.

Identifying and predicting changes

Using 7-tesla MRI, MedUni Vienna researchers have now been able to identify MS-relevant neurochemicals, i.e. chemicals involved in the function of the nervous system. "This allowed us to visualize brain changes in regions that appear normal on conventional MRI scans," says study leader Wolfgang Bogner, pointing to one of the study's main findings. According to the study's lead author, Eva Niess, these findings could play a significant role in the care of MS patients in the future: "Some neurochemical changes that we've been able to visualize with the new technique occur early in the course of the disease and might not only correlate with disability but also predict further disease progression."

Clinical studies and further developments follow

More research is needed before these findings can be incorporated into clinical applications, explain Niess and Bogner. They say that the results already show 7-tesla spectroscopic MR imaging to be a valuable new tool in the diagnosis of multiple sclerosis and in the treatment of MS patients.

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