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.

Introduction

Alzheimer's disease (AD) is the most common cause of dementia (Kukull & Bowen, 2002). Typically, the symptoms of the disease begin with mild memory difficulties after the sixth decade of life and progress slowly toward significant impairment in memory, executive function, visuospatial abilities, language, and other domains of cognition. Eventually, impaired cognitive abilities interfere with complex activities of daily life and ultimately result in the loss of independent function. Current treatments are symptomatic, in that clinical trials demonstrate short-term benefits in cognitive function but not a slowing of the rate of decline (Cummings, 2004). Increasing emphasis is being placed on the development of disease-modifying therapies to impede the underlying neurodegenerative process of AD and thereby slow the rate of cognitive decline.

By the time AD is typically diagnosed, substantial neuronal loss and neuropathologic change have damaged many brain regions. Although it may be possible to reverse some aspects of this damage, it would be ideal to initiate treatment with neuroprotective medications at a time when – or even before – AD is mildly symptomatic (DeKosky & Marek, 2003). To approach this goal, our capability needs to be improved to identify individuals with very mild symptoms prior to dementia (Dickerson & Sperling, 2005). Currently, individuals are classified as having mild cognitive impairment (MCI) when symptoms suggestive of AD are present but mild enough that traditional diagnostic criteria (which require functional impairment consistent with dementia) are not fulfilled. This gradual transitional state may last for a number of years, and diagnostic criteria have been developed (Petersen et al., 1999) and operationalized (Grundman et al., 2004). Efforts are currently underway by international groups of experts to revise the diagnostic criteria for AD with the goal of diagnosis prior to dementia—one proposed criteria set already makes explicit use of imaging and cerebrospinal fluid biomarkers (Dubois et al., 2007).

The cortex of the medial temporal lobe (MTL) subserves fundamental mnemonic functions, providing critical input from heteromodal association cortices to the hippocampal formation and receiving reciprocal afferents from the hippocampal formation (Van Hoesen and Pandya, 1975a, Van Hoesen and Pandya, 1975b; Van Hoesen, Pandya, & Butters, 1975). Even at a pre-dementia clinical stage of MCI, significant AD pathology is present in the MTL memory system. The entorhinal and perirhinal cortices are devastated by neurofibrillary pathology and cell loss very early in the course of AD, “disconnecting” the hippocampal formation from neocortical afferents and efferents, and the disease is thought to spread quickly to involve fields of the hippocampal formation (Braak & Braak, 1991; Gomez-Isla et al., 1996; Hyman, Van Hoesen, Damasio, & Barnes, 1984; Kordower et al., 2001; Price, Davis, Morris, & White, 1991; Van Hoesen, Augustinack, Dierking, Redman, & Thangavel, 2000).

Since an amnesic syndrome is typically the earliest symptom of AD, it is critical to further our understanding of abnormalities of the function of the medial temporal lobe memory system early in the course of AD. One promising technique for this purpose is functional magnetic resonance imaging (fMRI), which is thought to provide an in vivo correlate of neural activity. Given the growing body of evidence that alterations in synaptic function are present very early in the disease process, possibly long before the development of clinical symptoms and even significant neuropathology (Coleman, Federoff, & Kurlan, 2004; Selkoe, 2002), fMRI may be particularly useful for detecting alterations in brain function that may be present very early in the course of AD. In this article, we will review fMRI data regarding functional abnormalities of the medial temporal lobe memory system in MCI and AD.