Activation of brain regions vulnerable to Alzheimer's disease: The effect of mild cognitive impairment

Abstract

This study examined the functionality of the medial temporal lobe (MTL) and posterior cingulate (PC) in mild cognitive impairment amnestic type (MCI), a syndrome that puts patients at greater risk for developing Alzheimer disease (AD). Functional MRI (fMRI) was used to identify regions normally active during encoding of novel items and recognition of previously learned items in a reference group of 77 healthy young and middle-aged adults. The pattern of activation in this group guided further comparisons between 14 MCI subjects and 14 age-matched controls. The MCI patients exhibited less activity in the PC during recognition of previously learned items, and in the right hippocampus during encoding of novel items, despite comparable task performance to the controls. Reduced fMRI signal change in the MTL supports prior studies implicating the hippocampus for encoding new information. Reduced signal change in the PC converges with recent research on its role in recognition in normal adults as well as metabolic decline in people with genetic or cognitive risk for AD. Our results suggest that a change in function in the PC may account, in part, for memory recollection failure in AD.

Introduction

Amnestic mild cognitive impairment (MCI) is a condition in which patients display relative memory impairment beyond typical age-related declines, and unaccounted for by other medical conditions. Memory impairment is among the earliest symptoms of typical Alzheimer disease (AD), and amnestic MCI is a major risk factor for development of AD [44]. Brain volumetric studies using MRI in MCI have shown reductions in the medial temporal lobe (MTL) (e.g. [4], [23]) as well as the posterior cingulate (PC)[55]. Furthermore, F-18 fluoro-deoxy-glucose (FDG) positron emission tomography (PET) studies show reduced cerebral metabolic rate of glucose (CMRgl) in many of the areas affected by AD including the posterior cingulate and parietal lobes [40], and this is related to neuropsychological status [10]. Two studies have shown that reduced CMRgl in the PC of MCI patients predicts subsequent decline to AD [11], [16]. An in-vivo PET study of amyloid burden in AD has shown disproportionate aggregation of amyloid in the PC, among other areas [28], indicating that this region may be a primary site for AD neuropathology [29]. This same region of the brain has been found to be active during retrieval or recognition in functional MRI (fMRI) studies with healthy adults [9], [32], [57].

While CMRgl and structural MRI studies have shown some sensitivity to MCI, the use of fMRI has not been widely applied to this disorder. FMRI offers a method of examining memory-associated brain regions while those regions are functionally engaged in memory tasks. A small body of functional imaging studies suggest that the hippocampus is responsive to new information in controls more than MCI or early AD [26], [36], [59], [61]. One study showed that the extent of MTL activity in MCI was correlated with successful encoding, but paradoxically was also correlated with clinical impairment [15]. Some fMRI studies of mild AD and persons at genetic risk for AD have found greater activation associated with disease presence or risk, perhaps reflecting a compensatory response [5], [6], [53]. Further study is needed to resolve the discordant findings. The current study sought to mitigate this discrepancy by utilizing larger samples, a validated episodic memory task, regionally focused statistical analyses to protect against Type 1 error, and higher MRI field strength to increase signal sensitivity.

In the present study, we identify changes in fMRI activation in MCI patients during encoding and recognition. FMRI data were first acquired in a large reference group of healthy adult volunteers. This reference group was used to determine the areas of the brain normally active on the task, and guide the subsequent patient-control comparisons. The large sample size in the reference group provided sufficient statistical power and protection from spurious outliers influencing the functionally defined search regions [13]. The task was a variant of a well-known fMRI paradigm [14], [54], [64] in which participants distinguished between novel and previously learned items. The stimuli were line drawings of common nameable objects. The task was intentionally designed to be very simple, so that persons with memory impairment would be able to perform it at the same level as cognitively intact participants. We expected that the mesial temporal lobe would be more active to novel information [21], [67] and that this would be attenuated in persons with MCI. Given the accumulating findings of PC involvement in recollection in healthy adults [57], we hypothesized that the posterior cingulate would be responsive during recognition, but less so in MCI.