New Clues for Chemotherapy-Induced Cognitive Impairment
How Cancer Treatment Damages Healthy Cells
Cancer starts when a cell escapes apoptosis, carrying DNA replication mutations that go unrepaired. This unregulated cell keeps proliferating, passing its mutations to its progeny while generating new ones. The result is a population of unregulated cells (malignant tumors) that eventually metastasize and take over the host’s body. Conventional cancer treatment starts with surgical resection of the tumor mass, followed by agents that kill any dividing (mitotic) cells in the body (chemotherapy and radiation therapy). These agents don’t just target cancer cells — they also destroy healthy proliferating cells, causing side effects like hair loss, nausea, and cognitive deficits. This article focuses on how chemotherapy disrupts processing speed, working memory, and attention in humans.
Adult Neurogenesis and Memory
Adult neurogenesis is the process of generating functional neurons and glial cells from adult neural precursor/progenitor cells (NPCs) throughout life. It occurs in two regions of the adult brain: the subventricular zone (SVZ) of the lateral ventricle, and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus. Newly generated cells in the SGZ can differentiate into functional neurons and integrate into the hippocampus’s DG as granule cells. Granule cells play a role in memory formation and many aspects of learning — though not long-term memory storage.
Chemo-Brain: A Compelling Link to Neurogenesis
Over 50% of cancer patients undergoing chemotherapy report significant cognitive impairment and declines in overall cognitive processing, collectively known as “chemo-brain“. This makes chemotherapy-induced loss of newly generated hippocampal neurons — and the resulting disruption to adult neurogenesis — a compelling explanation for this cognitive decline.
One of the most “cognitive” oscillations in the human brain is the theta rhythm, generated mainly in the hippocampus and linked to learning and memory. This rhythmic slow activity is also the most efficient synchronized electroencephalographic (EEG) activity recordable from the brain. Since synchronized oscillatory activity supports communication between functionally related brain structures during learning, a chemotherapy-induced disruption in theta activity could block that inter-regional communication and cause learning deficits.
Evidence from a Rat Model of Chemo-Brain
In a study published in the European Journal of Neuroscience, Shors’s group reported that prolonged systemic chemotherapy disrupts both the structural and functional integrity of the hippocampus, leading to highly specific learning impairments. Their results show that chemotherapeutic agents cause the learning deficits seen in “chemo-brain” by decreasing hippocampal adult neurogenesis and theta activity. Interestingly, these agents did not disrupt hippocampus-independent memory for associations learned before treatment.
The researchers evaluated associative learning in adult male Sprague-Dawley rats by recording hippocampal local-field potentials after several weeks of cyclic administration of the chemotherapeutic agent temozolomide (TMZ). TMZ’s effects on learning and theta activity were specific to tasks requiring an association between temporally related but separate events — the rats showed no effect on the expression of an already-acquired trace memory.
TMZ is a small lipophilic monofunctional DNA alkylating agent, commonly used to treat metastatic malignant melanomas and tumors of the central nervous system (CNS), such as Glioblastoma Multiforme (GBM). Shors’s group also found that TMZ selectively affects neurogenesis, not glia generation — possibly because of differences in DNA repair mechanisms between neural precursors and glia. This idea is supported by earlier reports that chemotherapeutic agents unable to cross the blood brain barrier (BBB) — unlike TMZ — still lower hippocampal neurogenesis and cause abnormal dendritic morphology. It’s also been shown that cells surviving radiation therapy tend to differentiate into glial cells rather than neurons.
What This Means for Cancer Patients
Most cancer patients undergoing chemotherapy experience short-term memory loss and difficulty with complex tasks. About 15% go on to experience long-lasting cognitive problems from long-term chemotherapy treatment. Identifying the underlying cause of these cognitive deficits is a major step toward finding alternative agents, or modifying current ones, to reduce or eliminate these effects.
Further Reading
- Chemotherapy Disrupts Learning, Neurogenesis and Theta Activity in the Adult Brain.
- Cognitive Side Effects of Cancer Therapy Demonstrate a Functional Role for Adult Neurogenesis.
- Changing the Rate and Hippocampal Dependence of Trace Eyeblink Conditioning: Slow Learning Enhances Survival of New Neurons.
