Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer's disease: Insights from functional MRI studies
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.
Section snippets
Functional MRI as a tool to probe brain activity in MCI and AD
Since functional neuroimaging tools assess inherently dynamic processes that may change over short time intervals in relation to a host of factors, these measures have unique characteristics that may offer both strengths and weaknesses as potential biomarkers of neurologic disease. Functional neuroimaging measures may be affected by transient brain and body states at the time of imaging, such as arousal, attention, sleep deprivation, sensory processing of irrelevant stimuli, or the effects of
fMRI in MCI and AD
Functional MRI has been used to investigate abnormalities in patterns of regional brain activation during a variety of cognitive tasks in patients diagnosed with mild AD compared to control subjects. It is important to keep in mind that the particular abnormalities found in an fMRI study of an AD or other patient group are heavily dependent on the type of behavioral task used in the study—if the task does not engage a particular circuit, functional abnormalities will not likely be observed.
Conclusions
fMRI is a particularly attractive method for studying cognitive task-related patterns of brain activation in MCI and AD. Despite the relative infancy of the field, there have already been a number of promising fMRI studies in AD, MCI, and related disorders which highlight the potential uses of fMRI in both basic and clinical spheres of investigation. fMRI may provide novel insights into the neural correlates of memory and other cognitive abilities, and how they are altered in AD and MCI.
Acknowledgements
Supported by grants from the NIA (K23-AG22509), the NINDS (K23-NS02189), and the Beeson Scholars in Aging Program (American Federation of Aging Research).
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