Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer's disease: insights from functional MRI studies

Abstract

Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have begun to reveal abnormalities in memory circuit function in humans suffering from memory disorders. Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies, reviewed here, have focused on this region of the brain. By the time individuals are diagnosed clinically with AD dementia, the substantial memory impairments appear to be associated with not only MTL atrophy but also hypoactivation during memory task performance. Prior to dementia, when individuals are beginning to manifest signs and symptoms of memory impairment, the hippocampal formation and other components of the MTL memory system exhibit substantial functional abnormalities during memory task performance. It appears that, early in the course of MCI when memory deficits and hippocampal atrophy are less prominent, there may be hyperactivation of MTL circuits, possibly representing inefficient compensatory activity. Later in the course of MCI, when considerable memory deficits are present, MTL regions are no longer able to activate during attempted learning, as is the case in AD dementia. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, such as for use in clinical trials.

Figure 1

The localization, magnitude, and extent of abnormalities observed in fMRI studies of patients with neurologic diseases depend on both localization and severity of pathology and on functional networks engaged by the particular fMRI task, as well as participant performance on the task. In this illustration, regions of cortical thinning in Alzheimer’s disease from structural MRI (left, (Dickerson et al., 2007b)) are compared with cortical areas activated, as measured with fMRI, in normals during an event-related study of successful learning of new information that was able to later be freely recalled (right, (Dickerson et al., 2005a)). Analytic tools are emerging that enable the direct investigation of relationships between functional and structural abnormalities in MCI/AD and other disorders. Figure used with permission. (WE NEED TO REQUEST PERMISSION FROM NeuroRx, Elsevier—Dickerson BC, July 2007)

Figure 2

A phase of compensatory hyperactivation appears to occur in the medial temporal lobe (MTL) in very mild mild cognitive impairment, prior to AD dementia. Representative single subjects from each group, showing normal memory-related MTL activation measured with fMRI in Normal Older Controls, hyperactivation and very mild atrophy in MCI, and hypoactivation and more prominent atrophy in mild AD (Dickerson et al., 2005b). Color scale indicates p values of greater significance over threshold from red to orange to yellow. Figure used with permission. (WE NEED TO REQUEST PERMISSION FROM NeuroRx, Elsevier—Dickerson BC, July 2007)

Figure 3

A greater degree of hyperactivation of MTL regions is present in MCI individuals with a greater degree of MTL (hippocampal) atrophy, supporting the possible compensatory role of hyperactivation for AD pathology. Data shown here are taken from two separate studies, Dickerson et al. (Dickerson et al., 2004), left, and Hamalainen et al (Hamalainen et al., 2006), right. Analyses were performed differently in these studies so quantitative values on axes are not directly comparable, but represent conceptually similar measures (both are p<0.05).

Figure 4

Memory-related MTL activation as a predictive quantitative imaging biomarker. In a group of MCI patients, hippocampal activation at baseline (y axis) predicts degree of cognitive decline (change in CDR-SB, x axis) over four years after scanning (Miller et al., 2006) (p<0.05).

Figure 5

Reciprocal MTL-medial parietal memory network. MTL is hyperactivated in very mildly impaired MCI individuals compared to controls (top), while precuneus is hyper-deactivated (middle). Across a group including cognitively intact, MCI, and AD individuals, the degree of hippocampal activation (x axis) correlates with the degree of precuneus deactivation (y axis) (Celone et al., 2006) (p<0.0001).