Growing research shows how two of the major cancer treatments, radiation and chemotherapy, can lead to long-term cognitive impairment

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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.

The Study:

Methotrex­ate Chemother­a­py Induces Per­sis­tent Tri-glial Dys­reg­u­la­tion that Under­lies Chemother­a­py-Relat­ed Cog­ni­tive Impair­ment (Cell)

  • 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.

The Study in Context: