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David Holtzman (Department ofNeurology, Molecular Biology, andPharmacology, Washington UniversitySchool of Medicine, St Louis, MO,USA) also believes the results advancethe study of AD substantially. “Theydemonstrate that the brain tissueenvironment, apart from where A� isgenerated, contributes to whether A�will aggregate into plaques. Thissuggests that alterations in the micro-environment of either the braininterstitial fluid drainage pathways, thetransport of A� from brain to blood, orthe brain extracellular matrix

contribute to plaque formation”, heexplains. The results are also en-couraging for the efforts to developdrugs and vaccines to promote A�clearance from the brain extracellularspace and also suggest that anabnormality in brain A� clearance withageing could be a mechanism of ADdevelopment. “Furthermore”, con-cludes Holtzman, “experiments to sortout exactly how A� is normally clearedfrom the extracellular space and howthis changes with ageing may lead tonew treatment strategies.”Kathryn Senior

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“Whether neurodegeneration inAlzheimer’s disease (AD) is related tointracellular A� generation or to itsextracellular deposition is key tounderstanding the pathobiology of thedisorder”, says Mathias Jucker(Department of Neuropathology,University of Basel, Switzerland), seniorauthor of a new study showing thatextracellular amyloid formation canlead to neurodegeneration in vivo.“Our experiments indicate that cerebralamyloid-� peptide (A�)-amyloidosisdoes not require locally generatedintracellular A� to initiate A�deposition; transport or diffusion of A�in the extracellular space in the braincan cause amyloid pathology aconsiderable distance away”, adds leadauthor Melanie Meyer-Luehmann.

The group investigated amyloiddeposition in vivo by transplantingtransgenic APP23 and wild-type B6embryonic neural cells into theneocortex and hippocampus of both B6and APP23 mice. APP23 transgenicmice develop robust cerebral amyloiddeposition with ageing, thus mimickinghuman AD. APP23 grafts into wild-type mice did not produce amyloiddeposits up to 20 months after graftingbut grafts of cells from both types ofmice produced plaques in APP23mice, in some cases by 3 months (NatNeurosci 2003; published online Feb 24,DOI: 10.1038/nn1022). Some of theamyloid deposits were associated withpathology similar to that previouslydescribed in ageing APP23 mice.

The results clearly suggest thatextracellular amyloid formation iscentral to AD pathogenesis, concludesJucker. “Our findings do not excludethe possibility that intracellular A�contributes to AD pathogenesis, butnobody has convincingly shown this invivo”, he adds. Sangram S Sisodia,Director of the Center for MolecularNeurobiology at the University ofChicago (IL, USA), comments that thisis an elegant demonstration thatextracellular deposition is critical for neurodegeneration. “This info-rmation dampens the notion held bymany that intracellular A�42

accumulation is responsible forneurological abnormalities”, he says.

Amyloid can attack neurons from the outside

Ephemeral signal in fMRI

Newsdesk

Observation of a short-lived signal infunctional MRI (fMRI) couldimprove the precision and power ofthis technique, according to researchpublished in Science in February(2003; 299: 1070–72). The “initialdip” in blood oxygenation is morelocalised to the region of neuralactivity than the subsequent blood-oxygen-level dependent (BOLD)signal that is normally used as anindicator of neural activity.

One of the problems with fMRI isthat it infers increased neuronalmetabolism from an influx ofoxygenated blood into areas of thebrain, implying that the neurons arehighly active in those areas. “In fMRIneural inferences are made”, saysresearcher Ralph D Freeman(University of California, Berkeley,USA). “However, our study providesa direct measurement of bothfunctions simultaneously in the sameregion of the cerebral cortex.” Theresearchers measured tissue oxygen-ation and single cell neuronal activityin the visual cortex of cats. “We finda clear correlation between neuraland metabolic activity”, saysFreeman.

Another problem with thetechnique is that the BOLD signalreflects changes over a large area ofarterioles relative to the number ofneurons that might actually be active.

Bob Turner of the Institute of Neurology, University College

London, UK, says that a furtherimportant discovery from Freeman’sresearch is that “increased oxygenuptake commences immediately afterneurons increase their activity, sorapidly in fact that tissue oxygenationcan drop before increased supplies ofoxygenated blood can arrive.”

This confirms the “initial dip”,which has been observed in previousfMRI studies. “fMRI may be used tolocalise activity within a relativelyfine area of the brain”, says Freeman.However, Turner suggests that“because the initial dip is small andtransient . . . it would be unfortunateif the prospects for high-resolutionfMRI were entirely dependent onsuch an unreliable phenomenon”.Turner continues: “differential fMRIexperiments with high spatialresolution have been able to demon-strate ocular dominance columns inthe human primary visual cortexusing data acquired in the steady state after blood flow had stabilised”.

Because of the indirectness of theBOLD signal as a measure for neuralactivity, the usefulness of fMRI hasbeen questioned. It is important towork out the existing problems, saysFreeman, since fMRI is relevant toboth basic research and has clinicalapplications. “There are neuraldisease processes that may bedetectable early and definitively byfMRI analysis.”Peter Hayward