Using Pittsburgh compound B (PIB) and positron emission tomography (PET) to image fibrillar brain amyloid in vivo, scientists have found Aβ deposition in 10 to 40 percent of cognitively healthy seniors in various recent investigations, including the current one. Sperling and colleagues studied 18 young people (ages 18-30) and 35 older adults (ages 60-90). Thirteen of the older participants had subjective memory complaints and were thus classified with a Clinical Dementia Rating (CDR) of 0.5. However, none of these people demonstrated memory impairment on neuropsychological tests, nor did they meet MCI criteria. As such, the study population as a whole was considered “non-demented.” Among the older participants, regardless of CDR designation, roughly 30 percent came up PIB-positive—that is, they had brain amyloid loads within a range typical for AD patients.

The big issue, as Sperling put it, is the “black box between amyloid and the cognitive symptoms you see in AD.” Dating back decades to early autopsy studies in the field, amyloid plaques—despite being one of the best-characterized pathological hallmarks of AD—have correlated poorly with measures of brain function. There are people who have widespread amyloid deposits in their brains but show no signs of impairment. In an attempt to establish a functional link, Sperling’s team looked to the default network, a set of interconnected brain areas that fire up when the mind is at rest and tone down during focused mental tasks.

This network has risen to fame in AD research with reports of aberrant default mode activity in people with early AD (Greicius et al., 2004 and ARF related news story; ARF news story), in MCI patients challenged with visual and memory tasks (Rombouts et al., 2005), and in young adults carrying the AD risk allele ApoE4 (Filippini et al., 2009 and ARF related news story). What’s more, two brain areas most prone to Aβ deposition—the medial prefrontal cortex and precuneus/posterior cingulate—are both part of the default network (Buckner et al., 2005 and ARF related news story; see also ARF news story). And last year, Sperling and colleagues showed that the extent to which the brain areas of the default network tone down, or deactivate, during memory formation determines a person’s ability to recall that learned information later (Miller et al., 2008 and ARF related news story). In that study, the researchers measured blood-oxygen-level-dependent (BOLD) fMRI changes in young and old adults while they learned face-name pairs and while they recalled them a half hour later.

For the new work, the scientists used a modified version of that memory task and similar fMRI methods, but also included PIB-PET scans to determine if the people showing disrupted default network activity during the memory test were the ones who also had high levels of brain amyloid. In short, the answer was yes. Among the older participants, increased amyloid load associated with diminished deactivation in the precuneus/posterior cingulate. The correlation between amyloid burden and default mode deactivation held similarly in participants with and without subjective memory complaints. “It didn't make as much of a difference whether you were a CDR 0 or 0.5 as it did whether you had amyloid,” Sperling said. “Amyloid was what was associated with the abnormality.”

However, though amyloid load seemed to track with disrupted fMRI activity during the memory task, the researchers found no overall correlation between PIB retention and actual task performance. This “may not be surprising,” the authors write, given that all of the older participants were still performing in the normal range, i.e., did not show impairment in standard neuropsychological measures, which include memory components. In an e-mail to ARF, Sperling explained that the face-name task in the current paper was not as difficult as the one her lab had used previously (Miller et al., 2008). Her group speculates that cognitive reserve may also explain why subjects performed well despite having large amounts of brain amyloid. Analyses are ongoing to tease out this possibility (see full comment below).

Something more intriguing, perhaps, was that the PIB-positive seniors showed a net increase in fMRI activity while engaged in the memory task (as opposed to PIB-negative seniors, who just showed decreased deactivation but still a net decrease in fMRI activity).

One speculation is that their revved-up brain activity helps compensate for amyloid-related network disruptions. However, it “might be a sign that the system is starting to break down,” Sperling said, noting that this pattern of paradoxically increased fMRI activity is also seen in later stages of AD and in MCI (Lustig et al., 2003; Petrella et al., 2007 and ARF related news story). “That makes it less likely to be compensatory and more likely a marker that something’s about to fail,” she said.

Bill Jagust, University of California, Berkeley, author of a recent review on amyloid imaging (Jagust, 2009), appears on board with this line of thinking. In an accompanying review of the new study, he writes that it “adds a second phenotypic marker characteristic of AD to the first marker of Aβ deposition, supporting the view that those individuals with Aβ and functional alterations in the default mode network are in the early stages of AD despite normal cognition.”

Others are more hesitant about this conclusion. “To my mind, what they very elegantly show is that amyloid plaques affect BOLD signal,” said Scott Small of Columbia University, New York, in an interview with ARF. “I would probably be a little more cautious than they were in saying that Aβ affects underlying neural activity.” The problem with any form of fMRI is that it is only an indirect measure of neural activity, he said, noting that recent work supports “an alternative interpretation—that the effect plaques have on the BOLD response is independent of underlying ‘neural activity’ but rather reflects changes in baseline flow or vascular reactivity.” Sperling said that additional studies relating amyloid load to glucose metabolism and baseline tissue perfusion are underway and should help discern whether those properties are affecting BOLD signal in the current study. For now, though, “what I can say is that this finding is pretty specific to when people are performing the memory task well—when they are attempting to learn a face-name pair, and when they recall it successfully,” she said. To her, this makes it less likely that the fMRI measurements are skewed by baseline differences.

Assuming the BOLD changes do reflect brain dysfunction, Sperling said the most exciting application of the new data is the possibility of using fMRI or other functional measures, along with amyloid imaging, as biomarkers in clinical trials of amyloid-modifying drugs. “This study suggests to me that we really can link amyloid and memory impairment, and that we have markers to detect this before the point of irreversible damage,” she said, noting that continued longitudinal follow-up of the current participants is the only way to prove that brain Aβ in fact leads to memory impairment. In the meantime, the existing data already provide “evidence that we might be able to use markers like this in early drug trials,” she said. “Then we have a window in which to ask whether we are affecting the disease, without having to wait three years to see who develops cognitive impairment.”—Esther Landhuis.

References:
Sperling RA, LaViolette PS, O’Keefe K, O’Brien J, Rentz DM, Pihlajamaki M, Marshall G, Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA, Johnson KA. Amyloid Deposition Is Associated with Impaired Default Network Function in Older Persons without Dementia. 30 July 2009. Neuron 63:178-188. Abstract

Jagust W. Amyloid + Activation = Alzheimer’s? 30 July 2009. Neuron 63:141-143. Abstract