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.
Comments
Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School
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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