Brain Fog - Can Chemotherapy Lead to Alzheimer’s Disease?

by Women's Brain Health Initiative:Cancer and its treatments can cause a variety of side effects, some of which individuals can recover from quickly, while others persist long after treatment has ended. Approximately 70% of cancer patients report experiencing cognitive impairment after chemotherapy, including diminished short-term memory, reasoning, reading comprehension, and multitasking ability – a condition commonly referred to as “chemo brain” or “chemo fog.”For several years, these cognitive changes were attributed to depression or anxiety over the diagnosis and treatment of cancer. More recently, however, researchers have begun investigating the relationship between cancer treatments and cognitive function. While research findings have varied, it appears that many mechanisms contribute to cognitive decline in cancer patients – and not just chemotherapy.For instance, in one review of the literature, the authors concluded that it is likely that many factors contribute to cognitive dysfunction among cancer patients, such as the impact of surgery and anaesthesia, as well as the presence of fatigue or menopause, psychological states (e.g. anxiety and depression), and other comorbid conditions.A recent study published in Neuroscience suggests that the memory and thinking problems experienced by cancer survivors are not just the result of chemotherapy treatment but may start as tumors begin to form and develop. The researchers found that female mice with a form of breast cancer demonstrated impaired performance on learning and memory tests before chemotherapy drugs were administered.The scientists first conducted a series of cognitive tests on the female mice (half of them with cancer, the other half without) to investigate the impact of the tumor on brain function. After the initial data was collected, the mice either received the chemotherapy drugs, methotrexate and 5-fluouracil, or a saline solution. The mice were then retested on the same trials and some additional ones. Once testing was complete, the brain images, tissue and blood samples were used to analyze changes to brain structure and cytokine activity (proteins released by the immune system to help fight off infections or diseases).The researchers found that prior to treatment, the mice with tumors performed worse on learning and memory tests compared to their healthy counterparts. After chemotherapy, the performance of cancerous mice worsened and the non-cancerous mice also showed signs of cognitive impairment. “Our work isolated that the cancer is responsible for some of the memory and thinking complaints experienced by cancer survivors, and that drug therapy adds to the problem,” says Dr. Gordon Winocur, lead author on the study and senior scientist at Baycrest’s Rotman Research Institute. “Both factors independently affect brain function in different ways, which can lead to the development of other psychological disturbances, such as anxiety and depression.”Through the study, the researchers were also able to identify three different, but related, brain changes caused by the progression of cancer and the drugs used in treatment:

1. As the tumor develops, the body's immune system responds by releasing cytokines to inhibit the cancer's development. The researchers discovered that the body's reaction causes inflammation in the brain's nervous system, which impacts its function;
2. Chemotherapy was found to limit the production of new brain cells in regions responsible for memory function, which leads to a loss of memory; and
3. The combination of tumor growth and chemotherapy led to shrinkage in brain regions that are important for learning and memory.

"Understanding the nature of the cognitive impairment and the underlying biological mechanisms are essential to the development of an effective treatment for chemo brain. Our work shows that a targeted approach addressing all three issues is necessary to successfully treat the condition,” explains Dr. Winocur.“People are living longer thanks to more effective chemotherapy and cancer treatments. Addressing chemo brain will help improve a patient's quality of life since these side effects can lead to emotional and mental health issues that affect a person's ability to function in society."In another recent study, researchers from the Department of Neuro-oncology at the University of Texas MD Anderson Cancer Center (Kesler et al., 2017) sought to investigate the risk of Alzheimer’s disease (AD) in breast cancer survivors.The researchers first identified a machine-learning algorithm that could accurately discriminate between healthy women and women with mild cognitive impairment (MCI) who later developed AD. The algorithm performed with 86% accuracy, consistent with previous studies of AD conversions (from MCI). The researchers then applied the algorithm to a separate sample of breast cancer survivors to predict individual probability of developing AD. Survivors with a history of chemotherapy treatment showed significantly higher AD probability compared to chemotherapy-naïve survivors, as well as healthy female controls. Survivors without a history of chemotherapy also demonstrated higher AD probability compared to healthy controls. The researchers therefore concluded that patients with breast cancer, especially those who received chemotherapy, may have an increased risk for Alzheimer’s disease. Additionally, the findings suggested that breast cancer and/or chemotherapy may exacerbate an existing genetic risk for AD.The researchers further found that chemotherapy-treated survivors who are older and have lower cognitive reserve (i.e. have a lower capacity to maintain normal cognitive function in the presence of brain pathology) are at an increased risk of developing AD, consistent with previous studies.It is important to note that the results of this study do not suggest that cancer or its treatments cause AD, but point to shared risk factors including a common neural phenotype of brain structure alterations.In another study involving breast cancer patients, the researchers (Mehlsen et al., 2009) examined whether individuals receiving chemotherapy differed in cognitive changes during treatment compared with cardiac patients and healthy controls. The researchers recruited 34 cancer patients, 12 cardiac patients, and 12 healthy controls all between the ages of 18 and 65 years old. No significant change in neuropsychological testing between the three groups was observed at the various time points of testing. The researchers therefore concluded that chemotherapy does not confer an increased risk for cognitive dysfunction, nor does it protect against it.However, there are several limitations of this study that may skew the results of cognitive performance, including the small sample size, the discrepancy in follow-up between the cancer patients (6 months) and the controls (3 months), and the wide age range. Moreover, immediate cognitive deficits may have been missed as the cancer patients were evaluated too long after receiving chemotherapy.While many studies have demonstrated the adverse effects of chemotherapy on cognition shortly after administration, the long-term effects remain largely unknown. This is because only a limited number of studies have examined the long-term cognitive implications of cancer treatment.In one such study, the researchers found that breast cancer survivors over the age of 65 who received chemotherapy exhibited neurocognitive deficits ten years after chemotherapy compared to their healthy counterparts (Yamada et al., 2010). The cancer survivors not only performed considerably worse on dementia screening, but also scored significantly lower on domains of attention, working memory, psychomotor speed, and elements of executive functioning on neuropsychological testing.In another study, the researchers investigated whether chemotherapy for breast cancer was associated with worse cognitive performance more than 20 years after treatment (Koppelmans et al., 2012). In total, 196 patients who underwent cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy between 50 and 80 years of age were recruited. The researchers found that, even 20 years after the completion of CMF chemotherapy, treated patients performed worse on learning, verbal memory, information processing, inhibition, and psychomotor speed than random population controls. Interestingly, though, the chemotherapy group performed no differently on dementia screening than did the random controls.Importantly, other studies involving breast cancer patients have shown some reversibility after the cessation of chemotherapy (Jansen et al., 2011). One study actually observed that patients generally performed better on neuropsychological testing as time elapsed since their chemotherapy treatment. However, 21% of the participants still displayed deficits on neuropsychological testing nine months post-treatment (on average), chiefly in verbal-semantic memory (Weis et al., 2009).It is clear that cognitive dysfunction associated with cancer treatment, particularly chemotherapy, is a complex phenomenon. The research findings to date have been inconclusive or, at times, contradictory as it is difficult to dissect the effect of cancer itself, its effect on mood and energy, and its treatment on cognitive function. Accordingly, the term “chemo brain,” though widely use, may be misleading, as it is unlikely that chemotherapy is the sole cause of cognitive impairment in cancer survivors. More research is needed to understand this condition.Source: MIND OVER MATTER V6