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What Causes Chemo Brain?

Know more about the mental changes cancer treatment can cause.

“Chemo brain affects up to 75 % of patients during treatment with 35 % reporting symptoms post-treatment.” - Janelsins et al., 2014

Cancer survival rates have significantly improved due to advances in awareness, screening, prevention, diagnosis, and treatment. For example, the average 5-year survival rates for breast cancer increased from 75% in the 1970s to 91% in the 2000s. Cancer treatment is not without certain side effects. While the unavoidable side effects of life saving chemotherapy on cognitive brain function were recognized previously it was not until the early 2000s that epidemiological and imaging research showed that cognitive decline in breast cancer patients was rooted in physiological changes within the brain.

“The majority of patients receiving chemotherapy experience post-chemotherapy cognitive impairment, sometimes referred to as "chemo brain" or "chemo fog." The cognitive impairment associated with this syndrome can be severe, and can sometimes last for many years after therapy discontinuation.” Sordillo, P.P. et al., 2020.

Acknowledging the reality of chemo brain has been a critical and a much needed start for both: to try and understand the mechanisms that cause chemo brain at the cellular level as well as to study how it can be prevented/treated early so that patients can continue to be functional and productive survivors. Multiple neuroimaging studies have measured alterations in brain structure and function following chemotherapy in cancer patients. These structural and functional brain changes have been found to be related to chemotherapy-related cognitive impairment, particularly in breast cancer patients. Other cancer treatments, such as hormone therapies and targeted therapies, can also induce cognitive deficits.

A basic understanding of what the central nervous system is made of helps appreciate how chemo brain may occur. The central nervous system is made up of the brain and spinal cord. Neurons, also called nerve cells, make up around 10% of the brain; the rest consists of glial cells and astrocytes that support and nourish neurons. The central nervous system is inherently susceptible to the effects of chemotherapeutic drugs and has low recovery capacity.

There are at least 7 mechanisms by which chemotherapy can cause neurological deficits:

  1. As most neurons are non-dividing cells, they lack several DNA repair mechanisms that make them susceptible to DNA-targeting chemotherapy agents. The accumulation of DNA damage caused by chemotherapy can accelerate neuronal dysfunction and death.

  2. Neurons rely on an extensive microtubule-based network for proper functions and communication, making them vulnerable to microtubule-targeting chemotherapy drugs.

  3. Non-neuronal cells, called the glial cells, include astrocytes, oligodendrocytes, and microglia that play essential roles in maintaining the health and normal functions of the CNS. Glial cells have the ability to divide, making them vulnerable to chemotherapy and ultimately reducing the health and plasticity of the CNS.

  4. The adult brain accounts for about 2% of our body weight, but consumes about 20% of glucose-derived energy resulting in a high production of reactive oxygen species (ROS)—a major source of DNA damage that makes the central nervous system particularly vulnerable to chemotherapy related side effects. These side effects are linked to altered neurogenesis and deficits in learning and memory.

  5. There is new compelling evidence regarding glial cells of which are of 3 types: oligodendrocytes, which produce a protective covering around nerve fibers called myelin; astrocytes, star-shaped cells that link neurons to their blood supply; and microglia, which are immune cells that can destroy damaged nerve cells or harmful pathogens. Chemotherapy can damage microglial cells by causing their long-term activation which in turn, leads to inflammation and dysfunction of oligodendrocytes and astrocytes. For example, cells that form oligodendrocytes then have trouble reaching a mature stage, which leads to thinner myelin. Damage to the myelin sheath slows down nerve impulses resulting in neurological problems such as changes in processing speed and IQ.

  6. As we know, a majority of cancer survivors are older, with 50% of new cases diagnosed in patients aged 55–74 years. The stress of having cancer in addition to other conditions such as depression, constant pain, and sleep disturbances can significantly increase the vulnerability of the brain such that a small insult can trigger or set off a series of events that can end in chemo brain.

  7. There are other factors including genetic polymorphisms of apolipoprotein E, catechol-O-methyltransferase and BDNF ( brain derived neurotrophic factor) which may predispose individuals to a higher risk of cognitive impairment.

Understanding the mechanisms of how damage occurs because of therapy provides the underpinnings for new strategies of treatment for chemo brain. There is exciting new research that targets these mechanisms which can hopefully lead to new therapies to stop the damage early so patients can enter survivorship without the burden of chemo brain.

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Reason to Hope

There is new research from Brigham and Women’s Hospital that indicates a Western-style diet that is rich in red and processed meat, sugar and refined grains/carbohydrates is tied to higher risk of colorectal cancer through the intestinal microbiota.  Gastroenterology, 2022;DOI:10.1053/j.gastro.2022.06.054 

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