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Inflammation & Cognition: What the Latest Research Says About Long Term Effects and New Treatments

Victoria Sambursky

Chronic inflammatory diseases are the most significant cause of death in the world. The World Health Organization (WHO) ranks chronic diseases as the greatest threat to human health. The prevalence of diseases associated with chronic inflammation is anticipated to increase persistently for the next 30 years in the United States (Pahwa, R. et al., 2020). Inflammation occurs naturally in the body, and many people will experience acute inflammation at some point in the lifetime. However, chronic inflammation may trigger the beginning of disease if left untreated.

Alzheimer’s disease and other dementias are often the more well-known neurodegenerative issues related to chronic inflammation. However, other cognitive issues, such as poor attention and processing speed, can occur through different inflammatory processes. In this article, we take a deep dive into the effects of chronic inflammation and reveal the latest research on its impacts on cognition and potential treatment. We also report how one study’s findings may be used as an early marker for cognitive deterioration in patients with inflammatory diseases.

Inflammation: The Good, Bad & the Ugly

According to Dr. Robert H. Shmerling, an associate professor of medicine at Harvard Medical School, “Some inflammation is good. Too much is often bad. The goal is to recognize when inflammation is simply doing its job and when it can potentially cause problems (Harvard Health, 2020).” So when does inflammation become a serious health issue? Inflammation is the body’s way of signaling the immune system to heal and repair damaged tissue and defend itself against foreign invaders, such as viruses. There are two types of inflammation: acute and chronic. Acute inflammation occurs after an incident such as a cut on the arm or a sore throat. It is a short-term response with localized effects. However, if the inflammatory process goes on for too long or if the response occurs in areas where it is not needed, it can become a significant issue.

Changes in the inflammatory response from short to long-lived can cause a breakdown of immune tolerance. This can lead to major changes in tissues and organs, increasing the risk for various non-communicable diseases in young and older individuals (Furman, D. et al., 2019). For example, chronic inflammation has been linked to certain diseases such as heart disease and may also lead to autoimmune disorders, such as lupus. It can also lead to poor responses to vaccines and even mental health disorders such as depression. It has also become evident that the immune system can affect the function of the central nervous system (CNS), including altering cognitive processes (Kohman, R., 2012).

How Does Chronic Inflammation Effect Cognition?

Immunosenescence, or the aging immune system, has been repeatedly linked with cognitive processes and neurodegenerative diseases. The chronic release of pro-inflammatory cytokines in the central nervous system (CNS) leads to reduced brain-derived neurotrophic factor (BDNF) levels, associated with neurogenesis, oxidative stress, and cell death (cellular senescence), which are all involved with cognitive decline (Barbé-Tuana, F. et al., 2020). Oxidative stress, or an imbalance between free radicals and antioxidants in the body, plays a main role in maintaining the chronic inflammation observed in age-dependent disorders. Furthermore, increases in oxidative stress can lead to cellular senescence. Senescence is when a cell permanently stops dividing but does not die. Over time, these cells build up and release harmful substances that may cause inflammation and damage to nearby healthy cells (Tangestani Fard, M. & Stough, C., 2019).

The Role of Microglia

The impact of immune activation on the CNS is important for older individuals, as the brain’s resident immune cells, microglia, acquire a pro-inflammatory profile. The low-grade chronic neuroinflammation that develops with normal aging likely contributes to the susceptibility to cognitive deficits. Understanding why microglia show increased inflammatory activity and identifying effective treatments to reduce microglial activation has been shown to have beneficial effects on cognitive performance (Kohman, R., 2012). For example, one study linked chronic inflammation in diabetes to poor cognitive impairment. The study results showed that CSF1R (a colony-stimulating factor 1 receptor) silencing resulted in a 94 percent knockdown of residential microglia to relieve inflammation and improve the myelination of white matter in the brain (Jackson, L. et al., 2020). This action prevented cognitive decline in diabetic animals. It is important to note that microglia also promote regeneration after injury. Therefore, effective treatments must lessen inflammatory activity while also preserving microglia’s neuroprotective function.

New studies suggest that inflammation can affect cognition even earlier in life. A team in the University’s Center for Human Brain Health investigated the link between mental fog and inflammation. A study published in Neuroimage shows that inflammation appears to harm the brain’s readiness to reach and maintain an alert state. One of the senior authors of the study, Dr. Mazaheri, states, “Scientists have long suspected a link between inflammation and cognition, but it is challenging to be clear about the cause and effect. For example, people living with a medical condition might complain of cognitive impairment. However, it is hard to tell if this is due to the inflammation associated with these conditions or for other reasons (Science Direct, 2019).”

Volunteers in the study received a salmonella typhoid vaccine that causes temporary inflammation. Participants were tested for cognitive responses in three categories, including alertness, orientation, and executive control. The results showed that inflammation specifically affected brain activity related to staying alert. These subtle changes in brain function may be used as an early marker for cognitive deterioration in patients with inflammatory diseases (Balter, L.JT., et al., 2019).

Prevention & the “Myobundle”

So how can individuals prevent or reduce inflammation they cannot necessarily see or feel? According to Harvard Health, the only way to detect chronic inflammation is to have an evaluation by a doctor.  However, the best approach to reducing inflammation is preventing chronic inflammation conditions (Harvard Health, 2020). Some suggestions include:

  • Monitoring cholesterol. High amounts of “bad” LDL cholesterol can lead to an inflammatory response in the arteries and restrict blood flow.

  • Quit smoking. The toxins from smoking have a direct link to inflammation.

Diet and exercise are well-known to help manage chronic inflammation since they can help control weight and improve sleep. Regular exercise can also help protect against conditions linked with chronic inflammation, especially heart disease and obesity. One study found that just 20 minutes of moderate-intensity exercise can have an anti-inflammatory effect (Dimitrov, S. et al., 2017). Research also points to fighting senescent cells to strengthen the immune system and decrease inflammation (Xu, M. et al.2018). Exercise, especially muscle toning, can help clear out these cells, making way for healthy new ones. It does this by maintaining immune balance through bone marrow homing and increasing senescent T-cells’ death, stimulating the production of new cells (Larenas-Linnemann, D. et al., 2020).

Another study found that exercise exerts anti-inflammatory effects on muscle via the JAK-STAT pathway. This pathway plays a critical role in orchestrating the immune system. Researchers used an in vitro tissue-engineered human skeletal muscle model or a “myobundle” to study the effects of exercise-mimetic electrical stimulation on interferon-γ (IFN-γ) induced muscle weakness. The IFNγ induced activation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway in “myobundles (Clarke, J., 2021)”. This activation could be partially reduced by electrical stimulation, revealing the unknown anti-inflammatory effects of muscle exercise. It also established the use of the human “myobundle” platform for studies of inflammatory muscle disease and therapy.

Making small changes to reduce inflammation can help bring balance and wellness to both mind and body. Dr. Shmerling, the medical editor of Understanding Inflammation from Harvard Health Publishing and an associate professor of medicine at Harvard Medical School, suggests, “It goes back to the basics: maintaining a healthy weight, choosing a good diet, getting plenty of sleep, and exercising regularly (Harvard Health, 2020).”

References:

Balter, L.JT. et al. (2019). Selective effects of acute low-grade inflammation on human visual attention. NeuroImage. (202).

Barbé-Tuana, F. et al. (2020). The interplay between immunosenescence and age-related diseases. Seminars in immunopathology. 42(5): 545–557.

Clarke, J. (2021). Exercise exerts anti-inflammatory effects on muscle via the JAK-STAT pathway. Nat Rev Rheumatol.

Dimitrov, S. et al. (2017). Inflammation and exercise: Inhibition of monocytic intracellular TNF production by acute exercise via β2-adrenergic activation. Brain, Behavior, and Immunity. 61: 60-68.

Furman, D. et al. (2019). Chronic inflammation in the etiology of disease across the life span. Nat Med. 25:1822–1832.

Harvard Health (2020, April). Understanding Acute and Chronic Inflammation. Retrieved February 7, 2020, from https://www.health.harvard.edu/staying-healthy/understanding-acute-and-chronic-inflammation.

Jackson, L. et al. (2020). Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke. J Neuroinflammation. 17(137).

Kohman, R.A. (2012). Aging microglia: relevance to cognition and neural plasticity. Methods Mol Biol. 934:193-218.

Larenas-Linnemann, D. et al. (2020). Enhancing innate immunity against virus in times of Covid-19: Trying to untangle facts from fictions. World Allergy Organization Journal. 13(11).

Pahwa, R. et al. (2020). Chronic Inflammation. StatPearls.

Science Direct (2019, November). Link between inflammation and mental sluggishness shown in new study. Retrieved February 7, 2020, from https://www.sciencedaily.com/releases/2019/11/191115190337.htm.

Tangestani Fard, M. & Stough, C. (2019). A review and hypothesized model of the mechanisms that underpin the relationship between inflammation and cognition in the elderly. Frontiers in Aging Neuroscience. 11(56).

Xu, M. et al(2018). Senolytics improve physical function and increase lifespan in old age. Nat Med. 24:1246–1256.