Mind jumble: Understanding chemo brain (Stanford Medicine):
Sarah Liu was treated for leukemia as a teenager. She attended her high school graduation on a four-hour pass from Lucile Packard Children’s Hospital Stanford and was bald under her white graduation cap, her arm bandaged where she’d been receiving chemotherapy drugs.
Liu survived cancer and the ordeal of her treatment, and for many years she thrived. But today, at 53, she struggles to remember the names of all the Stanford oncologists who helped her, though she reveres them for saving her life. Many years later, her childhood cancer treatments — chemotherapy and radiation — have left her brain muddled…She’s among the legions of cancer survivors suffering from chemo brain, a neurological disorder formally known as chemotherapy-related cognitive impairment…
Two of the major cancer treatments, radiation and chemotherapy, can lead to cognitive difficulties, though the impacts of cranial radiation tend to be more severe and to progress more rapidly … The majority of patients who overcome cancer experience the condition, which is marked by mental fogginess, slowed thinking, memory problems, inability to multitask and sometimes anxiety, said neuro-oncologist Michelle Monje, MD, PhD, an associate professor of neurology and neurological sciences at Stanford.
Monje’s latest studies, published in 2018 in Cell and last year in Neuron, have uncovered a cascade of cellular events caused by the common chemotherapy drug methotrexate that can disrupt brain function and cognitive abilities. Moreover, she and her colleagues have identified two molecules that can forestall the damage and restore normal brain processing, at least in mice.
- Summary: Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment.
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