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.

Download full-text


Available from: Kim Celone Willment,
    • "The current findings are consistent with the results from two of our previous studies. Compared to non-carrier family members, we showed that young carriers had hyperactivation of the right anterior hippocampal activation during encoding of face-name paired-associates [15]. In another study [18], we found a similar pattern of hippocampal hyperactivation, in addition to an increase in activation in the parietal cortex, in a group of much younger carriers from the same kindred, even before evidence of amyloid accumulation as measured by CSF. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Brain regions critical to episodic memory are altered during the preclinical stages of Alzheimer's disease (AD). However, reliable means of identifying cognitively-normal individuals at higher risk to develop AD have not been established. Objective: To examine whether functional MRI can detect early functional changes associated with scene encoding in a group of presymptomatic presenilin-1 (PSEN1) E280A mutation carriers. Methods: Participants were 39 young, cognitively-normal individuals from an autosomal dominant early-onset AD kindred, located in Antioquia, Colombia. Participants performed a functional MRI scene encoding task and a post-scan subsequent memory test. Results: PSEN1 mutation carriers exhibited hyperactivation within medial temporal lobe regions (hippocampus, parahippocampal formation) during successful scene encoding compared to age-matched non-carriers. Conclusion: Hyperactivation in medial temporal lobe regions during scene encoding is seen in individuals genetically-determined to develop AD years before their clinical onset. Our findings will guide future research with the ultimate goal of using functional neuroimaging in the early detection of preclinical AD.
  • Source
    • "). In the years preceding AD diagnosis, a hyperactivity of the distributed memory network is often observed in those at risk for AD (Bookheimer et al. 2000; Bondi et al. 2005; Bassett et al. 2006; Filippini et al. 2009; Quiroz et al. 2010; Sperling et al. 2010). Although originally this hyperactivity was believed to serve a compensatory function for deteriorating circuitry (Bondi et al. 2005), more recent evidence suggests this hyperactivity may be indicative of excitotoxicity, could directly contribute to cognitive impairment, and may even be permissive for the development of AD (Mackenzie and Miller 1994; Kamenetz et al. 2003; Busche et al. 2008, Koh et al. 2010; Bakker et al. 2012; Vossel et al. 2013; Yamada et al. 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hyperexcitability of the hippocampus is a commonly observed phenomenon in the years preceding a diagnosis of Alzheimer's disease (AD). Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for amyotrophic lateral sclerosis (ALS) that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved performance in the water radial arm maze and the Morris water maze, associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus (DG), cornu ammonis 3(CA3), and cornu ammonis 1(CA1) regions of the hippocampus. Riluzole also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter (vGLUT1), which packages glutamate into vesicles and influences glutamate release; and the TauP301L-mediated decrease in hippocampal glutamate transporter 1 (GLT-1), the major transporter responsible for removing glutamate from the extracellular space. The TauP301L-mediated reduction in PSD-95 expression, a marker of excitatory synapses in the hippocampus, was also rescued by riluzole. Riluzole treatment reduced total levels of tau, as well as the pathological phosphorylation and conformational changes in tau associated with the P301L mutation. These findings open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2015; 135(2). DOI:10.1111/jnc.13230 · 4.28 Impact Factor
    • " ( 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"
    [Show abstract] [Hide abstract]
    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
Show more