The memory task we used in the current study is a modified version of the task we used previously (Miller et al., 2008). The Miller et al. paper utilized a pure event-related design, whereas the current paper uses a shorter mixed-block and event-related design that can be performed by more impaired subjects. So yes, one possibility for the lack of correlation with PIB and task performance is that the current task is not as difficult as the one in Miller et al., 2008. That one had 232 face-name pairs, whereas the Neuron task has only 84 novel face-name pairs. So we also may have less range of performance on the basis of task difficulty.

Several recent reports have also found no evidence of relationship between PIB and other memory measures among normal subjects (Aizenstein et al., 2008; Jack et al., 2008; Jack et al., 2009), so I am not too surprised that we didn't see a strong relationship,...  Read more

The memory task we used in the current study is a modified version of the task we used previously (Miller et al., 2008). The Miller et al. paper utilized a pure event-related design, whereas the current paper uses a shorter mixed-block and event-related design that can be performed by more impaired subjects. So yes, one possibility for the lack of correlation with PIB and task performance is that the current task is not as difficult as the one in Miller et al., 2008. That one had 232 face-name pairs, whereas the Neuron task has only 84 novel face-name pairs. So we also may have less range of performance on the basis of task difficulty.

Several recent reports have also found no evidence of relationship between PIB and other memory measures among normal subjects (Aizenstein et al., 2008; Jack et al., 2008; Jack et al., 2009), so I am not too surprised that we didn't see a strong relationship, either. There was a trend (p value of about .2). Also, we restricted this study sample to subjects without any objective memory impairment (within 1.5 SD), so we may have truncated the range even among a "generally normal" population.

We think cognitive reserve may have also played a role in allowing these subjects to perform well even with large amounts of amyloid deposition (see Roe et al., 2008). We are now conducting analyses to determine if cognitive reserve directly influences fMRI activity in the presence of amyloid.

Finally, we controlled for performance in this paper. That is, we only looked at successful encoding (High Confidence hits), because of our findings in Miller et al., 2008. We wanted to see if, controlling for performance, we still saw an effect of PIB on default network activity. If we had looked at all encoding trials, I suspect we would have again seen evidence of the relationship between deactivation and overall task performance.

Controlling for performance, we still found that the PIB+ subjects showed failure of deactivation even when they did encode the face-name pair successfully. Furthermore, at least in some subjects, we saw that successful encoding required increased hippocampal activity, which we speculate is compensatory, in the setting of both amyloid deposition and failure of default activity. I hypothesize that we will see evidence of memory decline in those subjects with high PIB retention and impaired default activity, but at least overall, at the time of this experiment, they were still performing pretty well. So at the moment, I would take our findings as evidence of early amyloid-related alterations that may convey vulnerability to eventual decline. It was striking how similar the pattern of paradoxical default network activation seen in the PIB+ adults was to previous reports in MCI and AD (Lustig et al., 2003; Petrella et al., 2007; Pihlajamaki et al., 2009), so I do think this is evidence that the memory systems are not working normally.

View all comments by Reisa Sperling

As is usually the case with work from Buckner, Sperling, and Johnson, this is very interesting and innovative work. It’s similar in some respects to the 2005 J. Neurosci paper comparing the topography of the default mode network to amyloid deposition. Indeed, many of the hubs lie in this region, and hub activity may be at the root of default mode activity and, in turn, may exacerbate Aβ deposition. It’s not completely clear to me whether this hub-vulnerability is simply a function of activity level (of any type) or whether it’s more a function of some form of connectivity and activity that is unique to hubs and may be less dependent on the actual level of activity (as might be measured by fMRI or FDG, for example).

The implications to this work appear rather ominous to me. If there is this arrangement of hubs, it’s highly likely that this architecture and its normal functioning are essential to normal cognition. Therefore, it may be very difficult to affect the hub network without bad consequences. However, it may be that some people have hyperactive hubs and they may...  Read more

As is usually the case with work from Buckner, Sperling, and Johnson, this is very interesting and innovative work. It’s similar in some respects to the 2005 J. Neurosci paper comparing the topography of the default mode network to amyloid deposition. Indeed, many of the hubs lie in this region, and hub activity may be at the root of default mode activity and, in turn, may exacerbate Aβ deposition. It’s not completely clear to me whether this hub-vulnerability is simply a function of activity level (of any type) or whether it’s more a function of some form of connectivity and activity that is unique to hubs and may be less dependent on the actual level of activity (as might be measured by fMRI or FDG, for example).

The implications to this work appear rather ominous to me. If there is this arrangement of hubs, it’s highly likely that this architecture and its normal functioning are essential to normal cognition. Therefore, it may be very difficult to affect the hub network without bad consequences. However, it may be that some people have hyperactive hubs and they may benefit from some downregulation without noticing any untoward effects.

One thing is sure: this is an elegant and innovative hypothesis and could suggest novel avenues of treatment that would be most welcome in our current efforts against AD.

View all comments by William Klunk

This paper takes the previous associations between brain function and β amyloid deposition a step further. These investigators have previously noted the interesting similarity between regions of β amyloid deposition and the default mode network. Using a different computational approach they defined hubs as brain regions with unusually high connectivity, and they find that it is these areas that are particularly predisposed to β amyloid accumulation. The idea essentially parallels molecular studies that have shown how neural activity stimulates Aβ production.

So basically, the idea is that persistent, high levels of neural activity may be responsible for Aβ deposition. This is an attractive argument as it explains not only why β amyloid tends to occur in some regions but not others, and also because it might explain age-dependence of the disease and its ubiquity. On the other hand, it is somewhat difficult to reconcile with epidemiological data showing that cognitive activity reduces the risk of AD. The data do not also seem to fully correspond to the deposition of β amyloid...  Read more

This paper takes the previous associations between brain function and β amyloid deposition a step further. These investigators have previously noted the interesting similarity between regions of β amyloid deposition and the default mode network. Using a different computational approach they defined hubs as brain regions with unusually high connectivity, and they find that it is these areas that are particularly predisposed to β amyloid accumulation. The idea essentially parallels molecular studies that have shown how neural activity stimulates Aβ production.

So basically, the idea is that persistent, high levels of neural activity may be responsible for Aβ deposition. This is an attractive argument as it explains not only why β amyloid tends to occur in some regions but not others, and also because it might explain age-dependence of the disease and its ubiquity. On the other hand, it is somewhat difficult to reconcile with epidemiological data showing that cognitive activity reduces the risk of AD. The data do not also seem to fully correspond to the deposition of β amyloid in subcortical structures and to some regions of prefrontal cortex. Nevertheless, as the authors point out, these data provide further testable approaches to exploring the pathogenesis of AD.

View all comments by William Jagust