Functional magnetic resonance imaging (fMRI) was used to study memory-associated activation of medial temporal lobe (MTL) regions in 32 nondemented elderly individuals with mild cognitive impairment (MCI). Subjects performed a visual encoding task during fMRI scanning and were tested for recognition of stimuli afterward. MTL regions of interest were identified from each individual's structural MRI, and activation was quantified within each region. Greater extent of activation within the hippocampal formation and parahippocampal gyrus (PHG) was correlated with better memory performance. There was, however, a paradoxical relationship between extent of activation and clinical status at both baseline and follow-up evaluations. Subjects with greater clinical impairment, based on the Clinical Dementia Rating Sum of Boxes, recruited a larger extent of the right PHG during encoding, even after accounting for atrophy. Moreover, those who subsequently declined over the 2.5 years of clinical follow-up (44% of the subjects) activated a significantly greater extent of the right PHG during encoding, despite equivalent memory NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript performance. We hypothesize that increased activation in MTL regions reflects a compensatory response to accumulating AD pathology and may serve as a marker for impending clinical decline.Medial temporal lobe (MTL) structures are essential for memory function. These regions, particularly the hippocampal formation and entorhinal cortex, bear a heavy neuropathological burden very early in the course of Alzheimer's disease (AD), even before clinical diagnostic criteria for dementia are met. 1,2 Using volumetric magnetic resonance imaging (MRI), we can detect MTL atrophy in vivo in elderly individuals with memory impairment, and these measures correlate with memory task performance 3,4 and are useful for the identification of subgroups of persons who will progress to a clinical diagnosis of AD within a few years. [5][6][7][8][9][10] However, despite considerable data on the structural correlates of memory impairment in prodromal and very early AD, less is known about the effects of the neurodegenerative process on the functional capacity of these brain regions as measured by functional MRI (fMRI).fMRI paradigms have been developed that reliably activate MTL regions during memory tasks. [11][12][13][14][15] Most fMRI studies of AD have been performed in clinically diagnosed patients with mild-to-moderate dementia and have found decreased MTL activation when subjects attempt to learn new information. [16][17][18][19][20][21] It is not yet clear when in the course of prodromal AD functional activity in the MTL declines, or whether the slope of decline is linear across the range of impairment among individuals at risk for AD. A recent fMRI study of clinic patients with mild cognitive impairment (MCI) showed decreased MTL activation during a memory encoding task. 21 However, Small and colleagues 16 found that only a subgroup of subj...

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