4.1. Abnormalities in activation of the medial temporal lobe memory system in AD and MCI
With respect to memory, a number of fMRI studies in patients with clinically diagnosed AD, using a variety of visually presented stimuli, have identified a lesser degree of activation in hippocampal and parahippocampal regions compared to control subjects during episodic encoding tasks [56
]. AD patients have also demonstrated increased activation in MTL regions to repeated or highly familiar stimuli, which may represent a failure of the normal repetition suppression response [42
]. Neocortical abnormalities in AD have also been demonstrated using fMRI, including decreased activation in temporal and prefrontal regions. In addition to AD-related differences in task-related blood-oxygen level dependent (BOLD) signal amplitude or spatial extent, the temporal dynamics of activation appear to be altered in patients with AD [88
]. And, as observed in other types of tasks, increased
activation in prefrontal and other regions has also been found in AD patients performing memory tasks [101
A recent quantitative meta-analysis [90
] of both fMRI and FDG-PET memory activation studies of AD identified several regions as consistently being more likely to show greater encoding-related activation in controls than in AD patients, including hippocampal formation, ventrolateral prefrontal cortex, precuneus, cingulate gyrus, and lingual gyrus. Controls were more likely to show greater retrieval-related activation than AD patients in frontopolar, medial prefrontal, superior parietal, precuneus, superior temporal, amygdala, and parahippocampal regions. Compared to controls, AD patients showed greater likelihood of encoding-related activation in ventrolateral prefrontal, orbitofrontal, dorsolateral prefrontal, superior temporal, and fusiform regions. Greater retrieval-related activation was more likely in AD patients than in controls in dorsolateral prefrontal, ventrolateral prefrontal, precuneus, and supramarginal gyri.
Although AD patients consistently demonstrated a lesser degree of MTL activity than controls, they consistently (across multiple studies) demonstrated some degree of right parahippocampal activation during encoding, indicating that MTL brain regions are not entirely unable to generate memory-related activity. Furthermore, there was consistent hypoactivation in frontopolar activation in AD compared to controls during both encoding and retrieval, but consistent hyperactivation in dorsolateral and ventrolateral prefrontal regions, suggesting the presence of both dysfunction and possibly compensation in functional brain networks in AD. Finally, regions of the cognitive control network (dorsolateral prefrontal, posterolateral parietal, anterior cingulate, frontoinsula) were not engaged as robustly in AD as in controls, indicating the contribution of dysfunction in other cortical networks to impaired memory function in AD.
Several groups have also reported alterations in the pattern of deactivation in AD patients [14
]. These alterations in deactivation occur in regions of the so-called default mode network [83
], which overlap substantially [14
] with brain regions in which fibrillar amyloid deposition is detected with Pittsburgh Compound B (PIB) in PET studies in AD [59
], as well as to the pattern of hypometabolism found on FDG PET studies of AD patients [1
] and subjects at-risk for AD [51
]; and of hypoperfusion on resting MR perfusion studies in AD [2
]. In addition, the default mode network has demonstrated alterations at rest and in block-design fMRI paradigms in aging and AD [44
It appears that alterations in hippocampal activation and parietal deactivation over the course of MCI and AD are strongly correlated [15
]. Similarly, resting state fMRI data has demonstrated alterations in parietal and hippocampal connectivity in MCI and AD [44
]. Thus, converging evidence suggests that a distributed memory network is disrupted by the pathophysiological process of AD, which includes both medial temporal lobe systems and medial and lateral parietal regions involved in default mode activity. Future studies to probe alterations in connectivity between these system, which combine fMRI with other techniques such as diffusion tensor imaging, may prove particularly valuable in elucidating the early functional alterations in AD [112
With respect to task-related activation in MCI, a handful of fMRI studies have been published to date and the results, thus far, have been variable, with some studies identifying a lesser degree of MTL activation in MCI compared to controls [55
]. Petrella et al. [80
] found no differences between MCI and controls in MTL activation during encoding, but observed hippocampal hypoactivation in MCI vs. controls during retrieval. Hippocampal hypoactivation in MCI was no longer seen when memory performance accuracy was included as a covariate in the analysis. Johnson et al. used a paradigm involving the repetitive presentation of faces to demonstrate that MCI patients do not show the same slope of decreasing hippocampal activation with face repetition that is seen in older controls, suggesting disruption of this “adaptive” response in the medial temporal lobe [53
Several studies have reported greater MTL activation in MCI patients compared to controls. We used an associative face-name encoding paradigm to compare MTL activation in very mild MCI, AD, and controls [34
]. Compared with controls, MCI subjects showed a greater extent of hippocampal activation and a trend toward greater entorhinal activation. Furthermore, there was minimal atrophy of the hippocampal formation or entorhinal cortex in this MCI group. The AD patients had smaller MTL volumes and a lesser degree of activation in these regions, and performed below controls on the post-scan memory test. Across all the subjects in the three groups, post-scan memory task performance correlated with extent of activation in both the entorhinal cortex and hippocampus.
Using a visual object encoding paradigm, Hamalainen et al. found that MCI subjects had greater activation (than controls) of caudal hippocampal formation, parahippocampal gyrus, and fusiform cortex [47
]. Based on MMSE and neuropsychological data, the MCI subjects in this study were on the relatively more impaired end of the MCI spectrum (although CDR-SB was still mildly impaired), yet the group performed the fMRI memory paradigm relatively well – better than the AD group – although not as well as controls. In the first event-related subsequent memory study of MCI, Kircher et al. used an item-based task with words and found that MCI subjects activated rostral left hippocampal and surrounding cortical regions to a greater degree than controls [57
]. MMSE scores from these MCI participants suggested that the group was at the more impaired end of the MCI spectrum, but neuropsychological data indicated milder impairment – in fact, delayed verbal recall scores were minimally impaired relative to controls, with scores for the MCI participants ranging as high as 14 items freely recalled after a 20 minute delay in this 15-item test. In addition, the MCI participants performed similarly to controls on the fMRI memory paradigm. In an event-related verbal memory retrieval task, Heun and colleagues also found evidence of increased activation in MCI subjects compared to normal older controls when specifically examining successful retrieval trials [50
The variability in fMRI data from MCI subjects probably relates, at least in part, to the complex relationships between the severity of the subjects’ clinical impairment and to their ability to perform the memory task employed as the fMRI paradigm. In addition, the particular fMRI memory paradigms, scanning techniques, and analytic approaches likely contribute to this variability. These issues are discussed in detail elsewhere [30
Despite all the caveats, there is replicated evidence to support the hypothesis that there may be a phase of increased MTL activation in MCI. This increase, which also may be present in cognitively intact carriers of the APOE-e4 allele (for review, see [112
]), may represent an attempted compensatory response to AD neuropathology, given that some MCI individuals with smaller hippocampal volume perform similarly on memory tasks to MCI individuals with larger hippocampal volume but have relatively greater MTL activation [33
]. Additional studies employing event-related fMRI paradigms [32
] will be very helpful in determining whether increased MTL activation in MCI patients is specifically associated with successful memory, as opposed to a general effect that is present regardless of success (possibly indicating increased effort). It is possible that MTL hyperactivation reflects cholinergic or other neurotransmitter upregulation in MCI patients [26
]. Alternatively, increased regional brain activation may be a marker of the pathophysiologic process of AD itself, such as aberrant sprouting of cholinergic fibers [49
] or inefficiency in synaptic transmission [104
]. It is important, however, to acknowledge that multiple non-neural factors may confound the interpretation of changes in the hemodynamic response measured by BOLD fMRI, such as age- and disease-related changes in neurovascular coupling [12
], AD-specific alterations in vascular physiology [75
], and resting hypoperfusion and metabolism in MCI and AD [37
], which may result in an amplified BOLD fMRI signal during activation [18
]. Further research to determine the specificity of hyper-activation with respect to particular brain regions and behavioral conditions will be valuable to better characterize this phenomenon.
4.2. MTL hyperactivation as a predictive biomarker in MCI
We recently extended a preliminary analysis of fMRI as a predictor of dementia in MCI [33
]. Over a follow-up interval of more than 5 years after fMRI scanning in 25 MCI subjects some showed no change and others progressed to dementia (change in CDR-Sum-of-Boxes ranged from 0 to 4.5). The degree of cognitive decline was predicted by hippocampal activation at the time of baseline scanning, with greater hippocampal activation predicting greater decline [71
]. This finding was present even after controlling for baseline degree of impairment (CDR-SB), age, education, and hippocampal volume. These data suggest that fMRI may provide a physiologic imaging biomarker useful for identifying the subgroup of MCI individuals at highest risk of cognitive decline for potential inclusion in disease-modifying clinical trials.
If, in fact, the “inverse U-shaped curve” of hyper-activation that we hypothesize takes place early in the course of prodromal AD (at the clinical stage of MCI) is confirmed by future longitudinal studies, then the use of fMRI as a physiologic imaging biomarker will have to grapple with the problem of “pseudonormalization” of activation when individuals with MCI demonstrate progressive decline that results in the loss of hyperactivation. It may be possible to use a combination of clinical (e.g., CDR Sum-of-Boxes), neuropsychologic (e.g., memory tasks), anatomic (e.g., hippocampal and/or entorhinal volume), and molecular (e.g., FDG-PET) measures to assist in the determination of where an individual is along the inverse U-shaped curve of MTL activation. That is, moderate hyperactivation in the setting of minimal clinical and memory impairment and relatively little MTL atrophy would be consistent with the upgoing phase of the hyperactivation curve while the same level of hyperactivation in the setting of more prominent clinical and memory impairment and MTL atrophy would be consistent with the downgoing phase of the curve. In the end, it will be critical to perform longitudinal studies to determine whether this model of the physiologic, anatomic, and behavioral progression of MCI is supported by trajectories in individuals and groups of subjects.
We have recently completed longitudinal fMRI studies in a group of 51 older individuals, across a range of cognitive impairment, imaged with alternate forms of the face-name paradigm at baseline and two-year follow-up [102
]. Preliminary analyses indicate that subjects who remained cognitively normal over the 2 years demonstrated no evidence of change in activation, whereas the subjects who demonstrated significant cognitive decline demonstrated a decrease in activation, specifically in the right hippocampal formation. Interestingly, we again observed that those subjects who declined had greater hippocampal activation at baseline, and that the amount of hyperactivation at baseline correlated with both loss of hippocampal signal and amount of clinical decline over two years. Thus, although we have hypothesized that hippocampal hyperactivation may be compensatory, it may also be a harbinger of impending hippocampal failure.