Alzheimer's Disease Neuroimaging Initiative (2009): Automated 3D mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's disease, mild cognitive impairment, and elderly controls

Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, Los Angeles, California 90095-1769, USA.
Human Brain Mapping (Impact Factor: 5.97). 09/2009; 30(9):2766-88. DOI: 10.1002/hbm.20708
Source: PubMed


We used a new method we developed for automated hippocampal segmentation, called the auto context model, to analyze brain MRI scans of 400 subjects from the Alzheimer's disease neuroimaging initiative. After training the classifier on 21 hand-labeled expert segmentations, we created binary maps of the hippocampus for three age- and sex-matched groups: 100 subjects with Alzheimer's disease (AD), 200 with mild cognitive impairment (MCI) and 100 elderly controls (mean age: 75.84; SD: 6.64). Hippocampal traces were converted to parametric surface meshes and a radial atrophy mapping technique was used to compute average surface models and local statistics of atrophy. Surface-based statistical maps visualized links between regional atrophy and diagnosis (MCI versus controls: P = 0.008; MCI versus AD: P = 0.001), mini-mental state exam (MMSE) scores, and global and sum-of-boxes clinical dementia rating scores (CDR; all P < 0.0001, corrected). Right but not left hippocampal atrophy was associated with geriatric depression scores (P = 0.004, corrected); hippocampal atrophy was not associated with subsequent decline in MMSE and CDR scores, educational level, ApoE genotype, systolic or diastolic blood pressure measures, or homocysteine. We gradually reduced sample sizes and used false discovery rate curves to examine the method's power to detect associations with diagnosis and cognition in smaller samples. Forty subjects were sufficient to discriminate AD from normal and correlate atrophy with CDR scores; 104, 200, and 304 subjects, respectively, were required to correlate MMSE with atrophy, to distinguish MCI from normal, and MCI from AD.

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Available from: Paul Thompson, Oct 04, 2015
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    • "With respect to APOE genotype, we were somewhat surprised that we did not find any significant effect of e4 carrier status on hippocampal and subfield volume and only trend-level relationships (10% FDR) with respect to shape. Our findings align with some groups [Morra et al., 2009], but not with others [Mueller and Weiner, 2009]. In addition, some studies have shown age-dependent effects of e4 status across the adult lifespan [Felsky and Voineskos , 2013; Nichols et al., 2012]. "
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    ABSTRACT: Newer approaches to characterizing hippocampal morphology can provide novel insights regarding cognitive function across the lifespan. We comprehensively assessed the relationships among age, hippocampal morphology, and hippocampal-dependent cognitive function in 137 healthy individuals across the adult lifespan (18-86 years of age). They underwent MRI, cognitive assessments and genotyping for Apolipoprotein E status. We measured hippocampal subfield volumes using a new multiatlas segmentation tool (MAGeT-Brain) and assessed vertex-wise (inward and outward displacements) and global surface-based descriptions of hippocampus morphology. We examined the effects of age on hippocampal morphology, as well as the relationship among age, hippocampal morphology, and episodic and working memory performance. Age and volume were modestly correlated across hippocampal subfields. Significant patterns of inward and outward displacement in hippocampal head and tail were associated with age. The first principal shape component of the left hippocampus, characterized by a lengthening of the antero-posterior axis was prominently associated with working memory performance across the adult lifespan. In contrast, no significant relationships were found among subfield volumes and cognitive performance. Our findings demonstrate that hippocampal shape plays a unique and important role in hippocampal-dependent cognitive aging across the adult lifespan, meriting consideration as a biomarker in strategies targeting the delay of cognitive aging. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 05/2015; 36(8). DOI:10.1002/hbm.22825 · 5.97 Impact Factor
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    • "The hippocampus plays a central role in early memory loss in AD patients [5]. The earliest neuropathological changes in AD are consistently observed in the medial temporal lobe (entorhinal cortex and hippocampus) [6], and hippocampal volume loss is the best established diagnostic marker for AD and highly predictive of disease progression [7]. Early deficits in hippocampal memory performance and synaptic plasticity have been established in various animal models of AD, before neuropathological changes are observed and in the absence of neurodegeneration [8,9]. "
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    ABSTRACT: Alzheimer’s disease is caused by increased production or reduced clearance of amyloid-β, which results in the formation amyloid-β plaques and triggers a cascade of downstream events leading to progressive neurodegeneration. The earliest clinical symptoms of Alzheimer’s disease, i.e., memory loss, are however poorly understood from a molecular and cellular perspective. Here we used APPswe/PS1dE9 (APP/PS1) transgenic mice to study the early pre-pathological effects of increased amyloid-β levels on hippocampal synaptic plasticity and memory. Using an unbiased proteomics approach we show that the early increase in amyloid-β levels in APP/PS1 mice at three months of age coincides with a robust and significant upregulation of several protein components of the extracellular matrix in hippocampal synaptosome preparations. This increase in extracellular matrix levels occurred well before the onset of plaque formation and was paralleled by impairments in hippocampal long-term potentiation and contextual memory. Direct injection into the hippocampus of the extracellular matrix inactivating enzyme chondroitinase ABC restored both long-term potentiation and contextual memory performance. These findings indicate an important role for the extracellular matrix in causing early memory loss in Alzheimer’s disease. Electronic supplementary material The online version of this article (doi:10.1186/s40478-014-0076-z) contains supplementary material, which is available to authorized users.
    06/2014; 2(1):76. DOI:10.1186/PREACCEPT-1259006781131998
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    • "The most pronounced atrophy in AD has been found in the anterior hippocampus (as well as posterior parahippocampal gyrus and the precuneus) compared to age-matched controls (Raji et al., 2009). Moreover, hippocampal head (anterior) atrophy has been reported as a predictive marker of conversion to AD (Csernansky et al., 2005; Apostolova et al., 2006; Morra et al., 2009a; Costafreda et al., 2011). Costafreda et al. identified more pronounced changes in the right lateral and medial aspects of hippocampal head in individuals that later converted to AD and his results correspond with previous reports of anterior CA1 (Csernansky et al., 2005; Apostolova et al., 2006; Costafreda et al., 2011). "
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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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