This study investigated the relationship between in vivo amyloid deposition and neural activity during memory formation in older persons without dementia or objective cognitive impairment. Similar to the pattern observed in AD patients, a substantial subset of non-demented older individuals demonstrated evidence of amyloid deposition in the default network, most prominently in key nodes of the network thought to be involved in successful memory function. Here for the first time in humans, we demonstrate that amyloid deposition in asymptomatic and minimally impaired older individuals is associated with aberrant neural activity in the default network, consistent with findings reported in AD patients. Our results support the hypothesis that amyloid pathology is related to disrupted synaptic activity in the networks supporting memory function, even prior to cognitive impairment.
Aberrant default network activity during both task fMRI and resting state, has been a consistent finding in patients with clinical AD and in subjects at high risk for AD. Multiple groups have confirmed impaired intrinsic functional connectivity in the default network during the resting state in MCI and AD (Bai et al., 2008
; Greicius et al., 2004
; Rombouts et al., 2005
; Sorg et al., 2007
), which appears to be over and above more general age-related disruption of large-scale networks (Andrews-Hanna et al., 2007
). Lustig et al. reported a similar observation of disrupted default network activity during memory tasks in AD subjects, showing a reversal of MR signal response that was strikingly similar to the present observation in PiB+ subjects (Lustig et al., 2003
). We have also previously seen this aberrant default network activity, that is, failure of task-induced deactivation, in late MCI and in mild AD patients using face-name block design fMRI paradigms (Celone et al., 2006
; Pihlajamaki et al., 2008
). Petrella and colleagues, using a similar face-name encoding paradigm, found that impaired deactivation in MCI subjects was predictive of subsequent cognitive decline into clinical AD (Petrella et al., 2007
). Two recent papers have also reported diminished deactivation in older subjects with genetic risk for AD (Persson et al., 2008
; Pihlajamaki et al., in press
). Our finding that cognitively intact and minimally impaired older individuals with high amyloid burden demonstrate disrupted default network activity, similar to the pattern found in AD, suggests that amyloid deposition may be responsible for dysfunction of brain networks supporting memory function, and suggests the possibility that these subjects may be indeed be in early (preclinical) stages of AD.
The mechanistic underpinnings of the aberrant default network activity remain to be elucidated. The PPC region typically demonstrates hypometabolism on FDG-PET and decreased perfusion in SPECT and arterial spin labeling (ASL) MRI in AD (Johnson et al., 1998
; Johnson et al., 2005
; Minoshima et al., 1997
). This region has also demonstrated abnormal metabolism and perfusion in subjects with MCI who go on to develop clinical AD, and even in normal older subjects with genetic risk factors for AD or who subsequently develop dementia (Jagust et al., 2006
; Johnson and Albert, 2000
; Reiman et al., 2001
). Thus, it is possible that abnormal PPC activity during memory encoding in these subjects might reflect the inability to modulate activity below an already decreased level of activity during the resting state. There have, however, also been reports of hyperperfusion in the PPC in very mildly impaired subjects, and it is possible that the paradoxical increase in MR signal reflects an abnormally increased level of activity at baseline (Sojkova et al., 2008
). Studies relating amyloid to FDG-PET and ASL MR perfusion, as well as intrinsic functional connectivity during the resting state in these older subjects with elevated PiB retention are ongoing, and we will eventually be able to relate fMRI activity to baseline perfusion, metabolism, and activity in these subjects.
Recent molecular and electrophysiological studies in amyloid precursor protein (APP) transgenic mouse models may be relevant to our findings of abnormally increased activity in regions with high amyloid burden. A recent mouse study suggests that the presence of amyloid plaques may result in abnormally increased neuronal activity in surrounding neurons (Busche et al., 2008
). Another study reported evidence of aberrant neuronal excitation that reached the level of non-convulsive seizure activity in mice overexpressing human APP (Palop et al., 2007
). Thus, our observation of paradoxically increased fMRI signal during memory encoding might reflect a local excitatory response to amyloid pathology, interfering with the normal inhibition of default network neurons during memory encoding. AD pathology has also been associated with loss of inhibitory neuronal function (Baig et al., 2005
; Hyman et al., 1992
), and it is possible that our findings are due to an imbalance of excitatory and inhibitory inputs related to amyloid pathology.
The PPC is of particular interest because of the convergence of this region's vulnerability to early amyloid deposition, and its critical role in memory function, both during encoding and retrieval. The PPC and lateral parietal cortices typically deactivate during successful memory encoding of novel information (Daselaar et al., 2004
; Duverne et al., 2008
) and then typically activate during successful memory retrieval (Wagner et al., 2005
), metamemory processes (Chua et al. 2006
) and during autobiographical recall (Svoboda et al., 2006
). As daily life involves a constant alternation between the processes of encoding of new information, retrieval of previously encountered information, and assessment as to whether information is novel or familiar, the PPC may be nearly continuously “toggling” between an activated and deactivated state, which may be particularly metabolically demanding. We have also recently noted that the PPC is a prominent “hub” in intrinsic cortical connectivity, and that the topography of hubs with high connectivity in young subjects overlapped the pattern of amyloid deposition in AD patients (Buckner et al., 2009
). Laboratory evidence suggests that neuronal activity may directly increase production of amyloid-beta peptides (Cirrito et al., 2005
). Thus, the critical role of the PPC in memory function and its heightened fluctuations in activity might serve to increase the production of amyloid β-protein in this region.
Our findings may also help to elucidate a long-standing conundrum regarding the role of amyloid in memory impairment in AD patients. Memory impairment in AD was often attributed primarily to pathology in the medial temporal lobe, where tangle formation and neuronal loss predominate (Hyman et al., 1984
). Although transgenic mice show very high levels of amyloid deposition in the hippocampus, human autopsy series and PiB imaging studies have consistently found relatively low levels of amyloid plaques in the hippocampus and related medial temporal lobe regions, compared to the very high levels of amyloid pathology observed in heteromodal association cortices (Klunk et al., 2004
). Our findings suggest that amyloid deposition in the default network is associated with altered neural activity in multiple nodes of the distributed network supporting memory function.
Interestingly, our exploratory analyses also revealed a relationship between PiB in the PPC and fMRI activity in the hippocampus, which was primarily due to increased activation among the PiB + CDR 0.5 subjects. This finding is consonant with our previous studies and those of other groups reporting hippocampal hyperactivation in very mild MCI subjects (Celone et al., 2006
; Dickerson et al., 2005
; Kircher et al., 2007
; Miller et al., 2007
) and in subjects at genetic risk for AD (Bondi et al., 2005
; Bookheimer et al., 2000
). Given the reciprocal anatomic and functional connectivity between the PPC and the hippocampus through the entorhinal cortices, it is conceivable that amyloid deposition and abnormal activity in the default network contributes to synaptic dysfunction and eventual neuronal loss in the hippocampus and surrounding medial temporal cortices. Recent PiB and volumetric MRI studies suggest that cognitively normal older adults with high levels of amyloid deposition have reduced whole-brain (Fotenos et al., 2008
) and hippocampal volume (Mormino et al., 2008
), as well as selective cortical thinning (Dickerson et al., 2009
), relative to their amyloid-free peers. Taken together with our current findings, these studies suggest that amyloid deposition in the default network may have both local and remote effects on critical nodes in the distributed network supporting memory function.
The relationship of amyloid-related disruption to memory performance remains to be elucidated. The subjects included in this study did not have significant memory impairment, as we wanted to examine the relationship of amyloid pathology to memory network function prior to dementia, and thus it may not be surprising that we did not find a significant relationship between amyloid levels and task performance. It remains unclear whether the increased activity, particularly in the hippocampus, might be compensatory enabling these individuals to maintain memory performance. It is also possible that the increased hippocampal activation may also be indicative of impending memory failure, as suggested by our previous fMRI studies in MCI (Dickerson et al., 2004
; Miller et al., 2008b
). We are following these subjects longitudinally to determine if the combination of amyloid imaging and fMRI might be a sensitive predictor of subsequent cognitive decline.
There are several limitations to the current study. We have a relatively small sample of older subjects who fell in the PiB+ range of that seen in AD patients. Many of our analyses combined the CDR 0 and CDR 0.5 subjects to have adequate power to observe significant relationships on the whole brain map level, however, a significant difference in fMRI activity is observed among the CDR 0 group alone based on PiB status in the ROI analyses. We chose to focus on the PPC in this study because of its intriguing role in memory function, and the prominent early amyloid deposition in this region. While we found evidence that PPC amyloid deposition was associated with dysfunction in the PPC and multiple other regions comprising the default network, it is likely that amyloid deposition in other brain regions contribute to the altered functional activity observed in the default network. The issue of regional specificity may be difficult to fully elucidate given the high degree of colinearity among regional PiB levels. Furthermore, PiB binds selectively to fibrillar forms of amyloid β-protein, and recent evidence suggests that oligomeric forms may be the principal species responsible for impaired neural activity (Shankar et al., 2008
). Although it is likely that brain regions with high fibrillar amyloid deposition also harbor high levels of oligomeric A-β, perhaps in “toxic halos” surrounding plaques (Meyer-Luehmann et al., 2008
), we cannot yet image soluble forms of amyloid β-protein in living humans. It is also possible that the observed functional alterations are related to other pathophysiological alterations that may co-occur with amyloid deposition, such as tangle pathology and or neuronal loss. Most importantly, we do not yet have clinical follow-up on these subjects to determine if the presence of amyloid deposition and impairment of memory related fMRI activity are indeed predictors of subsequent cognitive decline and eventual progression to clinical AD.
In summary, our findings suggest that amyloid pathology in older humans is associated with aberrant neural responses during memory formation. Alterations in default network activity, similar to those observed in patients with clinical AD, were found even in asymptomatic and minimally impaired older individuals with high levels of amyloid deposition. Aberrant default network activity may be a sensitive indicator of amyloid-related synaptic toxicity that will eventually result in memory impairment. Longitudinal studies are clearly needed, but our findings are consistent with the premise that cognitively intact older individuals with amyloid pathology may already be in the prodromal stages of AD. This combination of molecular and functional imaging techniques may prove useful in monitoring disease progression prior to significant clinical symptomatology, as well as the response to amyloid-modifying agents in clinical trials of subjects at-risk for developing AD.