Hippocampal Hyperactivation in Presymptomatic Familial Alzheimer's Disease

Department of Psychology, Center for Memory and Brain, Boston University, Boston, MA, USA.
Annals of Neurology (Impact Factor: 9.98). 12/2010; 68(6):865-75. DOI: 10.1002/ana.22105
Source: PubMed


The examination of individuals who carry fully penetrant genetic alterations that result in familial Alzheimer's disease (FAD) provides a unique model for studying the early presymptomatic disease stages. In AD, deficits in episodic and associative memory have been linked to structural and functional changes within the hippocampal system. This study used functional MRI (fMRI) to examine hippocampal function in a group of healthy, young, cognitively-intact presymptomatic individuals (average age 33.7 years) who carry the E280A presenilin-1 (PS1) genetic mutation for FAD. These PS1 subjects will go on to develop the first symptoms of the disease around the age of 45 years. Our objective was to examine hippocampal function years before the onset of clinical symptoms.
Twenty carriers of the Alzheimer's-associated E280A PS1 mutation and 19 PS1-negative control subjects participated. Both groups were matched for age, sex, education level, and neuropsychological test performance. All participants performed a face-name associative encoding task while in a Phillips 1.5T fMRI scanner. Analysis focused on the hippocampal system.
Despite identical behavioral performance, presymptomatic PS1 mutation carriers exhibited increased activation of the right anterior hippocampus during encoding of novel face-name associations compared to matched controls.
Our results demonstrate that functional changes within the hippocampal memory system occur years before cognitive decline in FAD. These presymptomatic changes in hippocampal physiology in FAD suggest that hippocampal fMRI patterns during associative encoding may also provide a preclinical biomarker in sporadic AD.

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Available from: Kim Celone Willment, Oct 03, 2015
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    • " ( CLU ) allele that recently was identified as a risk factor for AD ( Harold et al . , 2009 ; Lambert et al . , 2009 ) show higher activity levels in the frontal and posterior cingulate cortex and the hippocampus , particularly during working memory tasks , compared with subjects with the protective allele ( Lancaster et al . , 2011 ) . Finally , Quiroz et al . ( 2010 ) compared hip - pocampal activation in young healthy carriers of the E280A muta - tion in the presenilin 1 gene ( PSEN1 ) with matched controls . The presymptomatic PS1 mutation carriers performed equally well as the control group on an encoding task , but this was associated with an increased activation of the right anterior hippocamp"
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    ABSTRACT: Neuronal activity directly promotes the production and secretion of amyloid β (Aβ). Interestingly, neuronal hyperactivity can be observed in presymptomatic stages of both sporadic and familial Alzheimer's disease (AD) and in several AD mouse models. In this review, we will highlight the recent evidence for neuronal hyperactivity before or during the onset of cognitive defects in mild cognitive impairment. Furthermore, we review specific molecular mechanisms through which neuronal hyperactivity affects Aβ production and degradation. With these data, we will provide more insight into the 2-faced nature of neuronal hyperactivity: does enhanced neuronal activity during the presymptomatic stages of AD provide protection against the earliest disease processes or is it a pathogenic contributor to AD? Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 09/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.08.014 · 5.01 Impact Factor
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    • "It has been reported that during memory tasks individuals with mild AD show reduced hippocampal activity, whereas aMCI and MCI patients exhibit hyperactivity in the hippocampus/parahippocampal region (Hämäläinen et al., 2007; Miller et al., 2008; O’Brien et al., 2010; Yassa et al., 2010; Putcha et al., 2011). Task-related hyperactivity has been described in asymptomatic carriers of AD pathological mutations during associative encoding task (right anterior hippocampus; Quiroz et al., 2010); in asymptomatic offspring of autopsy-confirmed AD patients (Bassett et al., 2006); in cognitively intact young and old carriers of APOE4 (Bookheimer et al., 2000; Dickerson et al., 2005; Filippini et al., 2009) and in low-performing clinically healthy aged individuals (Miller et al., 2008). Conversely, individuals at late aMCI stage and early AD already express the hippocampal hypoactivity pattern (Hämäläinen et al., 2007). "
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    ABSTRACT: The hippocampus is one of the earliest affected brain regions in Alzheimer's disease (AD) and its dysfunction is believed to underlie the core feature of the disease-memory impairment. Given that hippocampal volume is one of the best AD biomarkers, our review focuses on distinct subfields within the hippocampus, pinpointing regions that might enhance the predictive value of current diagnostic methods. Our review presents how changes in hippocampal volume, shape, symmetry and activation are reflected by cognitive impairment and how they are linked with neurogenesis alterations. Moreover, we revisit the functional differentiation along the anteroposterior longitudinal axis of the hippocampus and discuss its relevance for AD diagnosis. Finally, we indicate that apart from hippocampal subfield volumetry, the characteristic pattern of hippocampal hyperactivation associated with seizures and neurogenesis changes is another promising candidate for an early AD biomarker that could become also a target for early interventions.
    Frontiers in Cellular Neuroscience 03/2014; 8:95. DOI:10.3389/fncel.2014.00095 · 4.29 Impact Factor
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    • "In most of these studies, the focus was on greater MTL activity in higher risk adults, which most frequently occurred in the right hemisphere [Bassett et al., 2006; Bondi et al., 2005; Filippini et al., 2009; Han et al., 2007; Quiroz et al., 2010]. However, three of these studies also found, as we did, that lower AD risk related to greater left hippocampal and/or parahippocampal activity [Bassett et al., 2006; Bondi et al., 2005; Quiroz et al., 2010], and two additional "
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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.
    Human Brain Mapping 12/2013; 34(12). DOI:10.1002/hbm.22141 · 5.97 Impact Factor
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