Effects of Risk Genes on BOLD Activation in Presymptomatic Carriers of Familial Alzheimer's Disease Mutations during a Novelty Encoding Task

Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Cerebral Cortex (Impact Factor: 8.67). 04/2011; 21(4):877-83. DOI: 10.1093/cercor/bhq158
Source: PubMed


Prior functional magnetic resonance imaging (fMRI) studies have found increased activity-related blood oxygen level–dependent
(BOLD) signal in cognitively normal persons at genetic risk for Alzheimer's disease (AD). This has been interpreted as a compensatory
response to incipient AD pathology. We studied the effects of fully penetrant familial Alzheimer's disease (FAD) mutations
and apolipoprotein E (APOE) genotype on BOLD fMRI during a novelty encoding task in presymptomatic subjects. Twenty-three Mexican or Mexican-American
persons at-risk for inheriting FAD mutations performed a block design novelty encoding task, and activation exhibited by FAD
mutation carriers (MCs) was contrasted with that of noncarriers (NCs) and among APOE genotype groups. FAD MCs (n = 14) showed decreased BOLD activation in the anterior cingulate gyrus relative to 9 NCs. No increased activation was seen
in MCs relative to NCs. Four APOE ε3/4 carriers demonstrated increased BOLD signal compared with 14 ε3/3 carriers in the occipital and perisylvian cortices
bilaterally. There were no areas where ε3/3 carriers activated more than ε3/4 carriers. Our findings of increased fMRI activation
associated with APOE genotype but not with FAD mutations suggest that APOE exerts an effect on the BOLD signal that is not readily explained as a compensatory phenomenon.

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    • "In a prior novelty encoding study, we found no group hippocampal differences in an overlapping sample of FAD mutation carriers [Braskie et al., 2012; Ringman et al., 2011a], even when those subjects [Braskie et al., 2012] were reanalyzed to control for age and education across all subjects (R 2 [full model] ¼ 0.05; P [full model] ¼ 0.78). "
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    ABSTRACT: Rare autosomal dominant mutations result in familial Alzheimer's disease (FAD) with a relatively consistent age of onset within families. This provides an estimate of years until disease onset (relative age) in mutation carriers. Increased AD risk has been associated with differences in functional magnetic resonance imaging (fMRI) activity during memory tasks, but most of these studies have focused on possession of apolipoprotein E allele 4 (APOE4), a risk factor, but not causative variant, of late-onset AD. Evaluation of fMRI activity in presymptomatic FAD mutation carriers versus noncarriers provides insight into preclinical changes in those who will certainly develop AD in a prescribed period of time. Adults from FAD mutation-carrying families (nine mutation carriers, eight noncarriers) underwent fMRI scanning while performing a memory task. We examined fMRI signal differences between carriers and noncarriers, and how signal related to fMRI task performance within mutation status group, controlling for relative age and education. Mutation noncarriers had greater retrieval period activity than carriers in several AD-relevant regions, including the left hippocampus. Better performing noncarriers showed greater encoding period activity including in the parahippocampal gyrus. Poorer performing carriers showed greater retrieval period signal, including in the frontal and temporal lobes, suggesting underlying pathological processes. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
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    • "One study demonstrated early glucose fluorodeoxyglucose-PET hypometabolism in the posterior cingulate cortices, hippocampus and entorhinal cortices of presymptomatic carriers of ADAD mutations, which was present prior to significant atrophy in these regions [48]. Functional MRI techniques have demonstrated alterations in hippocampal activity during episodic memory tasks in presymptomatic ADAD carriers that appear to occur decades prior to dementia [49], similar to the observations in young apolipoprotein E ε4 carriers [50,51], however, this observation was not replicated in a larger population of ADAD mutation carriers in a study employing an implicit novelty encoding paradigm [52]. "
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    ABSTRACT: Although many Alzheimer's disease (AD) patients have a family history of the disease, it is rarely inherited in a predictable way. Functional magnetic resonance imaging (fMRI) studies of nondemented adults carrying familial AD mutations provide an opportunity to prospectively identify brain differences associated with early AD-related changes. We compared fMRI activity of 18 nondemented autosomal dominant AD mutation carriers with fMRI activity in eight of their noncarrier relatives as they performed a novelty encoding task in which they viewed novel and repeated images. Because age of disease onset is relatively consistent within families, we also correlated fMRI activity with subjects' distance from the median age of diagnosis for their family. Mutation carriers did not show significantly different voxelwise fMRI activity from noncarriers as a group. However, as they approached their family age of disease diagnosis, only mutation carriers showed increased fMRI activity in the fusiform and middle temporal gyri. This suggests that during novelty encoding, increased fMRI activity in the temporal lobe may relate to incipient AD processes.
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