Breaking News
February 23, 2019 - Study gives a snapshot of crocodile evolution
February 23, 2019 - Research finds steep rise in self-poisonings among young people
February 23, 2019 - American Gastroenterological Association announces “AGA Future Leaders Program”
February 23, 2019 - Scientists uncover new mechanisms regulating neural stem cells
February 23, 2019 - Combinations of certain insecticides turn out to be lethal for honeybees
February 23, 2019 - AHA News: Why Are Black Women at Higher Risk of Dying From Pregnancy Complications?
February 23, 2019 - NIMH » Anxiety Disorders
February 23, 2019 - Autistic people urgently need access to tailored mental health support
February 23, 2019 - Newly designed molecule could benefit people with Friedrich’s Ataxia
February 23, 2019 - Chinese CRISPR twins may have better cognition and memory
February 23, 2019 - Study finds new genetic clues associated with asthma in African ancestry populations
February 23, 2019 - Fetal signaling pathways may offer future opportunities to treat lung damage
February 23, 2019 - Early-stage osteoarthritis drug wins prestigious innovation award
February 23, 2019 - Researchers report positive findings with dasotraline for ADHD in children ages 6-12
February 23, 2019 - News study reanalyzes the effects of noncaloric sweeteners on gut microbiota
February 23, 2019 - New device allows scientists to reproduce blow effects on the heart in lab
February 23, 2019 - Holy herb identified as a potential treatment for Alzheimer’s disease
February 23, 2019 - New technology platform digitally counts growth factors in single cells
February 23, 2019 - Surgery and other treatments offer viable options for adult scoliosis
February 23, 2019 - Reduced antibody adaptability may make the elderly more vulnerable to influenza
February 23, 2019 - Neighborhood income, education associated with risk of disability progression in MS patients
February 23, 2019 - 2019 guidelines for management of patients with atrial fibrillation
February 23, 2019 - Surprise rheumatoid arthritis discovery points to new treatment for joint inflammation
February 23, 2019 - A just-right fix for a tiny heart
February 23, 2019 - UMass Amherst scientist explores role of citrus peel in decreasing gut inflammation
February 23, 2019 - Owlstone Medical and Shanghai Renji Hospital collaborate to initiate breath biopsy lung cancer trial
February 23, 2019 - AMSBIO’s comprehensive portfolio of knock-out cell lines and lysates
February 23, 2019 - New app reliably determines physicians’ skills in forming accurate, efficient diagnoses
February 23, 2019 - Peripheral nerve injury can trigger the onset and spread of ALS, shows study
February 23, 2019 - Researchers uncover mechanisms that prevent tooth replacement in mice
February 23, 2019 - Once-a-day capsule offers new way to reduce symptoms of chronic breathlessness
February 23, 2019 - FDA Adds Boxed Warning for Increased Risk of Death with Gout Medicine Uloric (febuxostat)
February 23, 2019 - Phone-based intervention aids rheumatoid arthritis care
February 23, 2019 - Opioid epidemic makes eastern inroads and targets African-Americans
February 23, 2019 - New identified biomarker predicts patients who might benefit from HER2-targeted agents
February 23, 2019 - Study offers new insights into mechanisms of changes in erythrocytes under stress
February 23, 2019 - Antipsychotic polypharmacy may be beneficial for schizophrenia patients
February 23, 2019 - Researchers investigate how marijuana and tobacco co-use affects quit attempts by smokers
February 23, 2019 - Patients with diabetes mellitus have high risk of stable ischemic heart disease
February 23, 2019 - Transparency on healthcare prices played key role in Arizona health system’s turnaround
February 23, 2019 - A comprehensive, multinational review of peppers around the world
February 23, 2019 - Study finds modest decrease in burnout among physicians
February 23, 2019 - A simple change can drastically reduce unnecessary tests for urinary tract infections
February 23, 2019 - Deep Learning-Enhanced Device Detects Diabetic Retinopathy
February 23, 2019 - Researchers discover new binding partner for amyloid precursor protein
February 23, 2019 - Modest decrease seen in burnout among physicians, researchers say | News Center
February 23, 2019 - Transplanting bone marrow of young mice into old mice prevents cognitive decline
February 23, 2019 - Mogrify to accelerate novel IP and cell therapies using $3.7m USD funding
February 23, 2019 - Johns Hopkins study describes cells that may help speed bone repair
February 23, 2019 - Scientists demonstrate influence of food odors on proteostasis
February 23, 2019 - Researchers unlock the secret behind reproduction of fish called ‘Mary’
February 23, 2019 - Acupuncture Could Help Ease Menopausal Symptoms
February 23, 2019 - Researchers use AI to detect early signs of Alzheimer’s
February 23, 2019 - On recovery, vulnerability and ritual: An exhibit in white | News Center
February 23, 2019 - Memory Stored in Unexpected Region of the Brain
February 23, 2019 - Several health experts worldwide gather at EUDONORGAN event
February 23, 2019 - Discovery of potent compound in native California shrub may lead to treatment for Alzheimer’s
February 22, 2019 - Researchers create new map of the brain’s own immune system
February 22, 2019 - ICHE’s reviews on surgical infections, unnecessary urine tests, and nurses’ role in antibiotic stewardship
February 22, 2019 - UK Research and Innovation invests £200 million to create new generation of AI leaders
February 22, 2019 - Takeda collaboration to boost fight against Alzheimer’s and other neurodegenerative diseases
February 22, 2019 - Heavy drinking may change DNA, leading to increased craving for alcohol
February 22, 2019 - U.S. opioid deaths jump fourfold in 20 years; epidemic shifts to Eastern states | News Center
February 22, 2019 - 5 Questions with William Turner on Diversity in Medicine
February 22, 2019 - HHS Finalizes Rule Seeking To Expel Planned Parenthood From Family Planning Program
February 22, 2019 - Researchers uncover biochemical pathway that may help identify drugs to treat Alzheimer’s
February 22, 2019 - Biologist uses new grant to find ways to eliminate schistosomiasis
February 22, 2019 - Bag-mask ventilation to help patients breathe during intubation prevents complications
February 22, 2019 - AbbVie Announces New Drug Application Accepted for Priority Review by FDA for Upadacitinib for Treatment of Moderate to Severe Rheumatoid Arthritis
February 22, 2019 - Nature versus nurture and addiction
February 22, 2019 - New website connects researchers with data experts, resources | News Center
February 22, 2019 - Today’s Concerns About Drug Prices Echo The Past
February 22, 2019 - CT and Doppler equipment have low accuracy in detecting cerebral vasospasm and ischemia
February 22, 2019 - Study finds out similarity in function between healthy retina cell and tumor cell
February 22, 2019 - CWRU awarded NIH grant to identify effective treatments for intimate partner violence
February 22, 2019 - Oncotype DX Not Cost-Effective for Low-Risk Breast Cancer
February 22, 2019 - Scientists discover new type of immune cells that are essential for forming heart valves
February 22, 2019 - Talk About Déjà Vu: Senators Set To Re-Enact Drug Price Hearing Of 60 Years Ago
February 22, 2019 - Genetic defect linked to pediatric liver disease identified
February 22, 2019 - New cellular atlas could provide a deeper insight into blinding diseases
‘Chemo brain’ caused by malfunction in three types of brain cells | News Center

‘Chemo brain’ caused by malfunction in three types of brain cells | News Center

image_pdfDownload PDFimage_print

More than half of cancer survivors suffer from cognitive impairment from chemotherapy that lingers for months or years after the cancer is gone. In a new study explaining the cellular mechanisms behind this condition, scientists at the Stanford University School of Medicine have demonstrated that a widely used chemotherapy drug, methotrexate, causes a complex set of problems in three major cell types within the brain’s white matter.

The study, which was published online Dec. 6 in Cell, also identifies a potential remedy. A drug now in clinical trials for other indications reversed symptoms of “chemo brain,” as the condition is known, in a mouse model, the researchers found.

Chemo brain is becoming more common as cancer therapies increasingly allow patients to live many years beyond their diagnoses. There are 15.5 million cancer survivors alive today in the United States, a figure expected to reach 20 million by 2026, according to the National Cancer Institute. But the cognitive side effects of cancer treatment can be debilitating and prolonged: Adults may be unable to return to work, and children often struggle in school.

“It’s wonderful that they’re alive, but their quality of life is really suffering,” said the study’s lead author, Erin Gibson, PhD, a research scientist at Stanford. “If we can do anything to improve that, there is a huge population that could benefit.”

Scientists have long known that drugs like methotrexate impair all of the body’s rapidly dividing cells, but how such drugs affect the function of brain cells has been poorly understood.

“Cognitive dysfunction after cancer therapy is a real and recognized syndrome,” said Michelle Monje, MD, PhD, associate professor of neurology and neurological sciences and the study’s senior author. “In addition to existing symptomatic therapies — which many patients don’t know about — we are now homing in on potential interventions to promote normalization of the disorders induced by cancer drugs. There’s real hope that we can intervene, induce regeneration and prevent damage in the brain.”

Chemo brain is especially severe in childhood cancer patients, Monje added, and children have the most to gain from better remedies.  

Inside the white matter

In addition to neurons, which transmit nerve impulses, the brain’s white matter contains other cells that help the neurons function. The research focused on three types of those cells: oligodendrocytes, which produce and maintain myelin, the fatty insulating sheath around nerve fibers; astrocytes, which link neurons to their blood supply, promote proper connections between neurons and maintain the neurons’ environment; and microglia, immune cells that can engulf and destroy foreign invaders in the brain, as well as sculpt neural circuitry.

Comparing postmortem frontal lobe brain tissue from children who had and had not received chemotherapy, the researchers showed that there were far fewer oligodendrocyte lineage cells in the brains of the chemotherapy-treated children. 

If we understand the cellular and molecular mechanisms that contribute to cognitive dysfunction after cancer therapy, that will help us develop strategies for effective treatment.

To figure out what was happening to these cells, the researchers injected young mice with methotrexate at levels designed to replicate human exposures during cancer treatment. The mice received three doses at weekly intervals. Four weeks later, the researchers compared the mice’s brains to those of mice that had not received the drug. 

Methotrexate chemotherapy was found to damage the brain’s populations of oligodendrocyte precursor cells. Normally, these cells can quickly divide to replace any that are lost, but after methotrexate was administered, this self-renewal process did not happen correctly. More precursor cells than normal were starting down the path of maturation to oligodendrocytes, but they were getting stuck in an intermediate, immature state. The same problem was seen in mice brains six months after methotrexate was administered.

Transmission electron microscopy of the mouse brains after methotrexate administration revealed deficiencies in the thickness of the myelin insulation around nerve fibers, similar to changes in the brains of humans who have received chemotherapy. Mice exposed to methotrexate also exhibited behavioral problems after four weeks that were similar to humans with chemo brain, including motor impairment (slower movement of their forepaws), signs of anxiety on an “open field” test used to assess how threatened the animal feels in an unsheltered environment, and impaired attention and short-term memory function, evidenced by the inability to discern between novel and familiar objects — a symptom that persisted for six months after methotrexate was given.

The researchers injected oligodendrocyte precursor cells from healthy animals into the brains of animals that had received methotrexate to see if the cells’ maturation problems were caused by some aspect of the brain environment after chemotherapy. The precursor cells still began maturing at higher-than-normal rates but did not get stuck partway through the maturation process, indicating that the brain environment was partly responsible for the cells’ abnormal maturation.

Microglial activation

Further study showed that microglia, the brain’s immune cells, were persistently activated after methotrexate exposure for at least six months. The activated microglia caused problems for astrocytes, the cells that help neurons get nutrients and function properly. Administering a drug that selectively depleted microglia to mice that had been treated with methotrexate reversed many of the cognitive symptoms of chemo brain and reversed the abnormalities in maturation of oligodendrocyte precursor cells, activation of astrocytes and myelin thickness.

“The biology of this disease really underscores how important intercellular crosstalk is,” Monje said. “Every major neural cell type is affected in this pathophysiology.” She suspects this type of complex dysfunction may also underlie other cognitive disorders. “I think that is probably more the rule than the exception,” she said.

More research is needed to understand exactly how the different cell types are signaling to each other, as well as when and how medications could be best deployed against chemo brain.

“If we understand the cellular and molecular mechanisms that contribute to cognitive dysfunction after cancer therapy, that will help us develop strategies for effective treatment,” Monje said. “It’s an exciting moment.” 

The study’s other Stanford co-authors are MD-PhD student Surya Nagaraja; undergraduate students Alfonso Ocampo, Lydia Tam, Andrea Goldstein, Praveen Pallegar and Jacob Greene; former medical student Lauren Wood, MD; postdoctoral scholar Anna Geraghty, PhD; research assistants Lijun Ni and Pamelyn Woo; the late Ben Barres, MD, PhD, professor of neurobiology, of developmental biology and of neurology and neurological sciences; former postdoctoral scholar Shane Liddelow, PhD; and Hannes Vogel, MD, professor of pathology and of pediatrics.

Monje is a member of Stanford Bio-X, the Stanford Maternal & Child Health Research Institute, the Stanford Institute for Stem Cell Biology and Regenerative Medicine, and the Wu Tsai Neurosciences Institute at Stanford. Monje and Vogel are both members of the Stanford Cancer Institute.

The research was funded by the California Institute for Regenerative Medicine, Unravel Pediatric Cancer, the McKenna Claire Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the National Institute of Neurological Disorders and Stroke (grant R01NS092597), the Stanford Medical Scientist Training Program, the Wu Tsai Neuroscience Institute, the Maternal & Child Health Research Institute, the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases, the Stanford Clinical and Translational Science Award (grant UL1RR025744), Stanford Bio-X, a Katharine McCormick fellowship, the Stanford MedScholars Program, the Christopher and Dana Reeve Foundation, the Novartis Institute for Biomedical Research, the JPB Foundation, the Cure Alzheimer’s Fund, the Glenn Foundation, the Esther B. O’Keeffe Charitable Foundation, the Australian National Health and the Medical Research Council. 

Stanford’s Department of Neurology and Neurological Sciences also supported the work.

Tagged with:

About author

Related Articles