. Imaging the Abeta-related neurotoxicity of Alzheimer disease. Arch Neurol. 2007 Oct;64(10):1467-77. PubMed.

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  1. The major finding of Moreno et al. is that amyloid itself causes dysfunction in the absence of neuronal death or secondary tau aggregation, and that this dysfunction may be reversible with R-flurbiprofen (in the mice, anyway). This is provocative. I am not sure everyone will agree this proves quite yet that there was dysfunction in the absence of cell death. Unless I am misreading the paper, there was no pathology provided in the mice; instead this was inferred from previous studies of similarly aged animals. Likewise, the similarities between "mice and men" are used to imply that the amyloid dysfunction in the absence of death is operative in humans, too. This is possible, it’s interesting, and consistent with current thoughts about Aβ oligomers, and it’s a novel approach. But I do not think it can considered definitive at this point.

  2. Author Q&A with Scott Small. Questions by Gabrielle Strobel.

    Q: Brad Hyman's group showed years ago that people already have neuronal loss in the entorhinal cortex by the time they are diagnosed with AD (Gomez-Isla, 1996). How can you be sure that your 11 diagnosed AD patients have no neuronal loss in this area?
    A: In fact, we are sure that the patients have an admixture of cell loss, “cell sickness,” amyloid plaques, and neurofibrillary tangles. The mouse studies are the ones that show that CBV maps are sensitive enough to capture Aβ-related “cell sickness” (because they never develop cell loss). Thus, we can conclude that CBV mapping and other functional imaging variables are, in principle, sensitive enough to capture the cell sickness stage of AD. This is important because as we apply CBV techniques to people with the earliest stage of disease, these findings suggest that we might be able to detect early pathophysiology, that is, cell sickness. Furthermore, from a therapeutic perspective, capturing this stage is important, since it is easier to treat a “sick cell” than a dead cell.

    Q: In a nutshell, are you saying that while more is going on in the AD brain, the deficits your fMRI method visualizes are the piece that's due to Aβ synaptic toxicity?
    A: In a nutshell, we are saying that we now know that functional imaging is sensitive, in principle, to the cell sickness stage of AD. Previous studies in humans could not conclude this because of the point you raise above.

    Q: Floyd Bloom's group has characterized dendritic shrinkage in dentate gyrus early on in PDAPP mice (Wu et al., 2004) and hippocampal volume changes in 40-day-old PDAPP mice (Redwine et al., 2003). Have you imaged PDAPP mice to compare to the J20? How do these findings fit together?
    A: Good question. Actually, Redwine et al. showed retraction of presynaptic terminals in the dentate. These presynaptic terminals “belong” to entorhinal cortex neurons. Thus, at face value, their findings and ours agree that entorhinal cortex neurons are involved. The observation that the mice had reduced volume in the dentate is interesting. I should point out that no one really knows what volume changes mean at a neurobiological level. Furthermore, from my conversations with Jeffrey Redwine about his paper, i take it they never measured volume of the entorhinal cortex. This would have been interesting. In any case, I agree applying this technique to different models would be interesting and is important. As we point out in the paper, over time we do see CBV changes in all hippocampal subregions in the mice. However, when collapsed over time, the entorhinal cortex changes are the dominant ones.

    Q: Is your fMRI method of measuring the CBV variable, in mice and humans, highly specialized and bound to remain restricted to your academic center, or can it become widely available?
    A: In principle, it does not need special scanners or software. It can be done anywhere. The analysis side is a little sophisticated but can be done anywhere, as well.

    Q: I assume a goal is to make fMRI of CBV in entorhinal cortex a diagnostic tool of broad clinical value? What are the next steps in this direction?
    A: This is one goal. There are others. Diagnostics, as you know, requires large numbers of subjects. Because of this I am pleased that we just finished acquiring CBV maps in hundreds of healthy elders. This is an NIA-funded project headed up by Richard Mayeux. Now, we will wait and see whether we can predict who will progress to AD and who will not. Time will tell. Other utilities are trying to understand mechanism (why is entorhinal cortex vulnerable to AD and why is dentate gyrus vulnerable to normal aging—this line of questioning gave rise to our retromer findings), and for monitoring drug efficacy.

    Q: Do you think your method would make a better biomarker of drug response than, say, MRI volumetry or PIB PET, two imaging modalities that are gradually being incorporated in clinical trials for that purpose?
    A: Unsure. This is an empirical question.

    Q: Have you used the fMRI measure on people at risk, i.e., from two ApoE4 alleles, or a family history? Can you see the CBV change in them, too?
    A: Yes.... Interesting findings.... This is a work in progress.

    References:

    . Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer's disease. Ann Neurol. 1996 Jan;39(1):62-70. PubMed.

    . Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: digital morphometric analyses. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7141-6. PubMed.

    . Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: a magnetic resonance microscopy and stereologic analysis. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1381-6. PubMed.

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  1. Of Mice and Men—Functional Imaging of Aβ Toxicity, Early Pathology