Elsevier

NeuroImage

Volume 45, Issue 1, March 2009, Pages 181-190
NeuroImage

Functional imaging studies of episodic memory in Alzheimer's disease: a quantitative meta-analysis

https://doi.org/10.1016/j.neuroimage.2008.11.024Get rights and content

Abstract

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder, rapidly increasing in prevalence as the population ages. As the potential for disease-modifying therapy grows, a large body of literature has aimed at finding reliable, noninvasive biomarkers of AD, to allow for early intervention and sensitive tracking of therapeutic response. Task-related functional brain imaging techniques have been increasingly used to examine episodic memory function in AD. In the present study we completed a quantitative meta-analysis of this growing literature, to establish consensus and elucidate consistent patterns across this important research area. Results from encoding and retrieval paradigms were analyzed using the activation likelihood estimation (ALE) technique for patient and control groups. Second-level ALE analyses directly compared activation between these two groups. Results indicated a number of consistent findings across the included studies. Controls showed consistently greater activity than patients in a number of regions including the MTL and frontal pole across encoding and retrieval paradigms. Patients demonstrated increased activation likelihood in areas of the ventral lateral prefrontal cortex and other regions. Our findings quantitatively confirm the widely-cited deficits in MTL activity among AD patients, and also bring to light a pattern of differential prefrontal involvement, which may be implicated in compensatory changes occurring in AD. On the whole, this study quantitatively demonstrates that functional imaging studies show consistent, if complex, patterns of brain activation differences between patients and controls. These findings support the continued evaluation of functional neuroimaging for clinical use.

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting approximately 4.5 million people in the US alone, a number expected to triple by 2050 (Hebert et al., 2003). Pathology begins with the formation of neurofibrillary tangles in the medial temporal lobe (MTL) including entorhinal cortex and hippocampus. Association regions are eventually involved with the development of neuritic plaques and tangles, and neuronal death (Braak et al., 1999). Clinically, the earliest cognitive deficits in AD patients are noted in episodic memory, though the progressive nature of the disease means that all manner of cognition, motor function and personality are eventually affected (Braak et al., 1999).

With an increasing understanding of novel targets for disease-modifying therapy (Golde, 2006), the early detection of AD is of growing importance not only from a practical standpoint (e.g., life planning), but also to allow for potential slowing of the disease course. Additionally, a means for tracking endogenous response to therapy is lacking. To this end, a number of methodologies have been applied to the search for a clinically useful biomarker (Ewers et al., 2007, Pike et al., 2007, Ringman et al., 2007). While structural imaging of the MTL and other sites has been extensively studied (Ramani et al., 2006), there is evidence that functional imaging techniques may identify abnormal activation signatures before structural changes are seen (Mondadori et al., 2006, De Santi et al., 2001).

Positron emission tomography (PET) and blood-oxygenation-level-dependent functional MRI (BOLD fMRI) methods have the ability to measure local task-related changes in metabolism or oxygenation as surrogates for neural activity, and have enjoyed widespread use for investigating cognitive function in the intact brain. In recent years, these techniques have been applied to the hunt for dysfunction in neuropsychiatric disorders, including AD. Such work has been carried out across the spectrum of AD, from cognitively intact adults with increased risk (e.g., Bookheimer et al., 2000), to patients with mild cognitive impairment (MCI) at high risk of conversion to AD (e.g., Johnson et al., 2006a, Mandzia et al., 2007), to patients with clinically diagnosed probable AD. Across these studies, much attention has been focused on the MTL, given its established role in memory and its early pathological changes in the disease process. A number of studies have reported increased MTL activity during memory tasks in at-risk persons compared to controls (Bookheimer et al., 2000, Mondadori et al., 2006, Bassett et al., 2006, Fleisher et al., 2005). However, other studies have found the opposite pattern in this population (Trivedi et al., 2006, Lind et al., 2006). Such findings may be complicated by the interaction of ApoE genotype and family history risk factors in predicting activation abnormalities, which appear to be more complex than a simple additive relationship (Johnson et al., 2006b). Studies of MCI patients have also been inconsistent, with some authors showing increased MTL activity (Dickerson et al., 2004, Dickerson et al., 2005) and others reduced activity compared to age-matched controls (Machulda et al., 2003, Mandzia et al., 2007, Johnson et al., 2006a, Johnson et al., 2006b). These inconsistencies may result from the heterogeneous nature of MCI, such that a given sample of patients may show variable patterns of MTL dysfunction, depending on whether they will subsequently convert to AD. Indeed, it has been suggested that at least two subtypes of MCI may be classified based solely on their contrasting patterns of MTL activity (Small et al., 1999).

There is better consensus regarding MTL dysfunction during memory tasks in patients with AD. A number of studies have found reduced activation in comparison to controls (Golby et al., 2005, Pariente et al., 2005, Rémy et al., 2005, Rombouts et al., 2000, Machulda et al., 2003, Dickerson et al., 2005, Sperling et al., 2003). Such findings make intuitive sense given the evidence of pathological degeneration and memory dysfunction in AD. However, there is less of a consensus regarding the pattern of activity in neocortical areas. In some studies, MTL dysfunction is matched to concomitant increases in activity in prefrontal, parietal or other sites. This has led to the suggestion that such changes may represent compensatory increases as a result of pathology in core circuits (Becker et al., 1996, Grady et al., 2003, Pariente et al., 2005). Indeed, Grady et al. (2003) were first to demonstrate a direct relationship between such activation and task performance, while Pariente et al (2005) found that activity in these regions even correlated with MMSE scores, suggesting a relationship to general cognitive status. However, such findings are not universal (Rombouts et al., 2000, Kato et al., 2001, Hamalainen et al., 2007), and there is evidence that apparent compensatory increases may be largely accounted for by the greater difficulty patients have completing such tasks (Gould et al., 2005, Gould et al., 2006). Gould et al. (2005) found that when subjective difficulty was equated in a paired-associate learning task, AD patients showed a similar activation pattern to controls. These conflicting findings are reflected in the interpretations made by recent qualitative reviews (Krishnan et al., 2005, Prvulovic et al., 2005, Wierenga and Bondi, 2007).

Beyond the issue of controlling for task-performance effects, there are other challenges in imaging the AD patient. Fundamental questions about the validity of functional imaging results are based on evidence that the BOLD response may be altered in these patients (Rombouts et al., 2005, D'Esposito et al., 2003, Buckner et al., 2001), and that cortical atrophy may impact activation (Johnson et al., 2000). AD patients also show abnormal default-mode and resting activity, which may exaggerate task-related findings due to lower baseline activity in select regions (Greicius et al., 2004, Lustig et al., 2003). Any of these factors could lead to apparent signal change in brain regions which could be erroneously attributed to differences in task-related activity.

Despite the host of technical, pathological and psychological variables that make imaging with AD patients challenging, the current literature suggests that there is some agreement regarding memory-related activity across studies and laboratories. Further, it has recently been demonstrated that activation in some areas correlates well with commonly used measures of disease severity, strengthening the argument for functional imaging as a method for tracking decline or treatment response (Diamond et al., 2007).

Many of the inconsistencies noted between studies may reflect patient factors, the specific tasks employed, and statistical analysis protocols. Because no single paradigm can be completely sensitive to and specific for a given operation, it is difficult to draw conclusions about higher order functions from a single sample of patients with a single task. Meta-analyses in neuroimaging offer the opportunity to combine disparate studies which target the same higher level constructs, and to determine those regions of the brain which are consistently associated with these functions (Fox et al., 1998). A recently developed technique, Activation likelihood estimation (ALE; Turkletaub et al., 2002, Laird et al., 2005), describes the stereotactic coordinates of the brain most consistently active across studies. This method has been previously used to examine consistent activation associated with higher cognitive function in other populations (Achim and LePage, 2005, Glahn et al., 2005, Dickstein et al., 2006). Through its application here, we hope to summarize the state of consensus in functional imaging of AD. In doing so, we not only attempt to confirm generally accepted findings, but also aim to quantitatively elucidate patterns that may not be readily apparent from reading individual studies. In the present paper, we completed an ALE meta-analysis of episodic memory studies in AD patients and compared them to findings in age-matched controls, in an effort to tease out consistent findings in this important research area.

Section snippets

Literature collection and criteria

MEDLINE and PubMed searches were completed to collect functional imaging studies of episodic memory in AD patients. Reference lists of relevant papers were reviewed for inclusion of studies not retrieved in the original searches. Papers were included in the meta-analysis if they met the following criteria:

  • (1) Reported findings of episodic encoding and/or retrieval paradigms compared to some baseline task in patients with AD using PET or fMRI techniques. All papers were required to follow

Healthy controls

During encoding, healthy controls demonstrated elevated activation likelihood in a range of prefrontal, parietal and limbic sites. Within the frontal lobe, they showed elevated values in the bilateral precentral gyrus (BA4), medial surface (BA6), left rostrolateral prefrontal cortex (RL-PFC; BA10) and ventral lateral prefrontal cortex (VL-PFC; BA47, BA45), in addition to bilateral dorsolateral prefrontal cortex (DL-PFC; BA9). Increased activation likelihood in the parietal lobe was seen in the

Discussion

To our knowledge, this is the first meta-analysis of functional neuroimaging in Alzheimer's Disease. We chose to focus on papers examining episodic memory, currently the most extensively studied domain in task-related functional imaging of AD. Our results demonstrate that consistent patterns are found between patients and controls across studies and laboratories.

When healthy age-matched controls and patients were compared at encoding and retrieval, consistent differences between groups were

Acknowledgments

The authors wish to thank Dr. Cheryl Grady for thoughtful comments on an earlier version of the manuscript. GCS is supported by an MD/PhD scholarship from the Canadian Institutes of Health Research and the Mclaughlin Center for Molecular Medicine.

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