04 Aug 2009

By now, the curious detection of brain Aβ deposits in some healthy seniors has become commonplace among amyloid imaging practitioners. Whether this amyloid portends future dementia isn’t so clear, but a report in the July 30 Neuron puts meat and bones on the hunch that it does. “I think this is the first time we have strong evidence that amyloid is associated with brain dysfunction prior to symptoms,” said first author Reisa Sperling, Massachusetts General Hospital, Boston, in an interview with ARF. A team led by her and husband-colleague Keith Johnson, also at MGH, has found that brain Aβ pathology correlates with abnormal activity in memory networks of non-demented elders. The skewed network signals, picked up by functional magnetic resonance imaging (fMRI), were “very similar to what’s been observed in patients with mild cognitive impairment (MCI) and early stages of Alzheimer disease (AD),” Sperling said. “This, to me, is evidence that the process of AD does indeed begin many years before you get symptoms and that these individuals with amyloid really might be in the prodromal stages.”

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

Comments

- Reisa Sperling
  Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School
- Posted: 04 Aug 2009
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.

References:

Miller SL, Celone K, DePeau K, Diamond E, Dickerson BC, Rentz D, Pihlajamäki M, Sperling RA. Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2181-6. PubMed.

Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR, Bi W, Cohen AD, Lopresti BJ, Dekosky ST, Halligan EM, Klunk WE. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008 Nov;65(11):1509-17. PubMed.

Jack CR, Lowe VJ, Senjem ML, Weigand SD, Kemp BJ, Shiung MM, Knopman DS, Boeve BF, Klunk WE, Mathis CA, Petersen RC. 11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. Brain. 2008 Mar;131(Pt 3):665-80. PubMed.

Jack CR, Lowe VJ, Weigand SD, Wiste HJ, Senjem ML, Knopman DS, Shiung MM, Gunter JL, Boeve BF, Kemp BJ, Weiner M, Petersen RC, . Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain. 2009 May;132(Pt 5):1355-65. PubMed.

Roe CM, Mintun MA, D'Angelo G, Xiong C, Grant EA, Morris JC. Alzheimer disease and cognitive reserve: variation of education effect with carbon 11-labeled Pittsburgh Compound B uptake. Arch Neurol. 2008 Nov;65(11):1467-71. PubMed.

Lustig C, Snyder AZ, Bhakta M, O'Brien KC, McAvoy M, Raichle ME, Morris JC, Buckner RL. Functional deactivations: change with age and dementia of the Alzheimer type. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14504-9. PubMed.

Petrella JR, Prince SE, Wang L, Hellegers C, Doraiswamy PM. Prognostic value of posteromedial cortex deactivation in mild cognitive impairment. PLoS One. 2007;2(10):e1104. PubMed.

Pihlajamäki M, O' Keefe K, Bertram L, Tanzi RE, Dickerson BC, Blacker D, Albert MS, Sperling RA. Evidence of altered posteromedial cortical FMRI activity in subjects at risk for Alzheimer disease. Alzheimer Dis Assoc Disord. 2010 Jan-Mar;24(1):28-36. PubMed.

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References

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Paper Citations

Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4637-42. PubMed.
Rombouts SA, Barkhof F, Goekoop R, Stam CJ, Scheltens P. Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: an fMRI study. Hum Brain Mapp. 2005 Dec;26(4):231-9. PubMed.
Filippini N, Macintosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, Matthews PM, Beckmann CF, Mackay CE. Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7209-14. PubMed.
Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci. 2005 Aug 24;25(34):7709-17. PubMed.
Miller SL, Celone K, DePeau K, Diamond E, Dickerson BC, Rentz D, Pihlajamäki M, Sperling RA. Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2181-6. PubMed.
Lustig C, Snyder AZ, Bhakta M, O'Brien KC, McAvoy M, Raichle ME, Morris JC, Buckner RL. Functional deactivations: change with age and dementia of the Alzheimer type. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14504-9. PubMed.
Petrella JR, Prince SE, Wang L, Hellegers C, Doraiswamy PM. Prognostic value of posteromedial cortex deactivation in mild cognitive impairment. PLoS One. 2007;2(10):e1104. PubMed.
Jagust W. Mapping brain beta-amyloid. Curr Opin Neurol. 2009 Aug;22(4):356-61. PubMed.

BOLD New Look—Aβ Linked to Default Network Dysfunction

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