Several compounds, including somenon-steroidal anti-inflammatory drugs(NSAIDs), can promote amyloid-�(A�) 42 formation in vivo and maytherefore put people at greater risk ofAlzheimer’s disease (AD). Short-termstudies in mice have shown that twodrugs, fenofibrate and celecoxib, sub-stantially increased A�42 formation.

Previous studies have identifiedselect NSAIDs capable of loweringproduction of A�42 in vitro and invivo. However, recent studies by ToddE Golde and co-workers (Mayo Clinic,Jacksonville, FL, USA) have identifiedseveral compounds that increaseA�42 production, including cyclo-oxygenase-2 (COX-2) selectiveNSAIDs and derivatives of NSAIDs thatlower A�42 production. By use of cell-based screening, the researchersidentified only one compound thatdownregulated COX activity but alsolowered A�42 production. Manycompounds raised A�42, most ofwhich decreased the production ofA�38 and other shorter A� peptides.

The results of short-term in vivostudies showed that these compoundssignificantly increased amounts ofA�42 in mice.

Fenofibrate, an antilipidaemic agent,and celecoxib, a COX-2 selectiveNSAID, were among the more potentA�42-promoting drugs identifiedby Golde and co-workers (Nat Med2005; 11: 545–50). The compoundsseem to increase A�42 production bytargeting the �-secretase complex.“This effect mimics the effect ofmutations in the amyloid-� peptideprecursor and presenilin genes on A�production”, comments Golde. “Sincethese mutations cause AD, such datapotentially suggests that compounds(including ones produced as naturalmetabolites in the body) couldregulate A�42 production andpossibly alter risk for AD.”

The results point to the �-secretasecomplex as the target of boththe A�42-lowering and A�42-promoting agents, but suggest thatthey affect the complex in distinct

ways. According to Golde, theseresults re-inforce the notion that notall NSAIDs are equal; the secondaryeffects could be different for differentNSAIDs, which may mean that theyinfluence the AD phenotypedifferently.

Golde also stresses that the epi-demiological data support a protectiveand not necessarily a therapeutic rolefor traditional NSAIDs in AD. “All weknow is that at least two of thecompounds we identify can increaseA�42 in mice following oral dosing.”

Paul Aisen (Georgetown UniversityMedical Center, Washington, DC,USA) also advises caution whenextrapolating these results to humanbeings. “Doses used in humans maynot yield brain levels associatedwith significant A�42 changes”, hecomments. “While further investi-gation is warranted, it would bepremature to draw any clinicalconclusions from these findings.”

Stephanie Bartlett

A�42 formation: not all NSAIDs are equal

Newsdesk

A specific MRI technique canaccurately predict brain-tumourresponse after cancer treatment,according to a recent study byBradford A Moffat and colleagues(University of Michigan School of

Medicine, Ann Arbor, MI, USA). Non-invasive diffusion MRI, based on themotion of water molecules, can beused to assess the effectiveness ofradiotherapy or chemotherapy to treatbrain tumours 10 weeks earlier thantraditional testing methods.

Individuals with primary braintumours have high mortality rates andshort survival periods. Treatmenttailored to each patient is thereforeessential—these tumours are highlyheterogeneous (ie, composed ofdifferent cell types) making themdifficult to treat. First-line treatmentcommonly fails and therefore delayseffective treatment of the tumour.

Diffusion MRI was first usedsuccessfully in mice to analyse brain-tumour response. Moffat and co-workers have now used a similar

technique in patients after the start oftreatment (Proc Natl Acad Sci USA2005; 102: 5524–29). The techniqueis dependent on analysing thediffusion of water molecules intumours, which is determined by thedensity of tumour cells. Diffusionvalues can be calculated and displayedin a functional diffusion map fordigital image analysis.

The researchers investigatedwhether diffusion MRI could predicttumour response to treatment(chemotherapy, radiotherapy, orboth). They examined 20 patientswith unresectable, primary braintumours with standard and diffusionMRI before treatment. Patients thenunderwent another diffusion MRI3 weeks after treatment, and anotherstandard MRI after treatment had

334 http://neurology.thelancet.com Vol 4 June 2005

Diffusion MRI predicts response of brain tumours to treatment

Imaging the results of tumour treatment

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