CSF biomarker associations with change in hippocampal volume and precuneus thickness: Implications for the Alzheimer's pathological cascade

Psychology Service, VA Boston Healthcare System, Boston, MA, USA, .
Brain Imaging and Behavior (Impact Factor: 4.6). 05/2012; 6(4). DOI: 10.1007/s11682-012-9171-6
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ABSTRACT Neurofibrillary tangles (NFT) and amyloid plaques are hallmark neuropathological features of Alzheimer's disease (AD). There is some debate as to which neuropathological feature comes first in the disease process, with early autopsy studies suggesting that NFT develop first, and more recent neuroimaging studies supporting the early role of amyloid beta (Aβ) deposition. Cerebrospinal fluid (CSF) biomarkers of Aβ(42) and hyperphosphorylated tau (p-tau) have been shown to serve as in vivo proxy measures of amyloid plaques and NFT, respectively. The aim of this study was to examine the association between CSF biomarkers and rate of atrophy in the precuneus and hippocampus. These regions were selected because the precuneus appears to be affected early and severely by Aβ deposition, and the hippocampus similarly by NFT pathology. We predicted (1) baseline Aβ(42) would be related to accelerated rate of cortical thinning in the precuneus and volume loss in the hippocampus, with the latter relationship expected to be weaker, (2) baseline p-tau(181p) would be related to accelerated rate of hippocampal atrophy and cortical thinning in the precuneus, with the latter relationship expected to be weaker. Using all ADNI cohorts, we fitted separate linear mixed-effects models for changes in hippocampus and precuneus longitudinal outcome measures with baseline CSF biomarkers modeled as predictors. Results partially supported our hypotheses: Both baseline p-tau(181p) and Aβ(42) were associated with hippocampal atrophy over time. Neither p-tau(181p) nor Aβ(42) were significantly related to cortical thinning in the precuneus over time. However, follow-up analyses demonstrated that having abnormal levels of both Aβ(42) and p-tau(181p) was associated with an accelerated rate of atrophy in both the hippocampus and precuneus. Results support early effects of Aβ in the Alzheimer's disease process, which are less apparent than and perhaps dependent on p-tau effects as the disease progresses. However, amyloid deposition alone may be insufficient for emergence of significant morphometric changes and clinical symptoms.

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Available from: Hiroko Hayama Dodge, Sep 28, 2015
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    • "Cerebrospinal fluid (CSF) concentrations of Ab42 as well as total and phosphorylated tau (p-tau181p) have been shown to serve as in vivo proxy measures of the central neuropathological hallmarks of AD (Braak et al., 2013). Therefore, studying the relationship between CSF biomarkers and regional changes on structural and functional MRI may contribute to understanding the pathological mechanisms of AD (Stricker et al., 2012). "
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    ABSTRACT: The progression of Alzheimer's disease (AD) is characterized by complex trajectories of cerebral atrophy that are affected by interactions with age and apolipoprotein E allele ε4 (APOE4) status. In this article, we report the nonlinear volumetric changes in gray matter across the full biological spectrum of the disease, represented by the AD-cerebrospinal fluid (CSF) index. This index reflects the subject's level of pathology and position along the AD continuum. We also evaluated the associated impact of the APOE4 genotype. The atrophy pattern associated with the AD-CSF index was highly symmetrical and corresponded with the typical AD signature. Medial temporal structures showed different atrophy dynamics along the progression of the disease. The bilateral parahippocampal cortices and a parietotemporal region extending from the middle temporal to the supramarginal gyrus presented an initial increase in volume which later reverted. Similarly, a portion of the precuneus presented a rather linear inverse association with the AD-CSF index whereas some other clusters did not show significant atrophy until index values corresponded to positive CSF tau values. APOE4 carriers showed steeper hippocampal volume reductions with AD progression. Overall, the reported atrophy patterns are in close agreement with those mentioned in previous findings. However, the detected nonlinearities suggest that there may be different pathological processes taking place at specific moments during AD progression and reveal the impact of the APOE4 allele. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of aging 07/2015; 36(10). DOI:10.1016/j.neurobiolaging.2015.06.027 · 5.01 Impact Factor
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    • "In the cascade model [1] [2], the capacity of each biomarker to predict cognitive decline depends on the stage of AD disease process (e.g., normal, early mild cognitive impairment [MCI], late MCI, or AD), and whether biomarker baseline values or biomarker progressions are used. It is likely, for example, that brain beta amyloid burden is already high and probably plateaus by the time of AD diagnosis [3] [4], and although brain amyloid burden may distinguish among subjects with AD, MCI, and normal subjects cross-sectionally, continuing declines in cognitive functions at late MCI or AD stages will not be related to brain amyloid burden. Although baseline biomarker values are examined often in relation with subsequent longitudinal cognitive or functional trajectories, there is a paucity of data regarding biomarker progressions and their associations with cognitive or functional trajectories. "
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    ABSTRACT: Background It is unknown which commonly used Alzheimer disease (AD) biomarker values—baseline or progression—best predict longitudinal cognitive decline. Methods 526 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). ADNI composite memory and executive scores were the primary outcomes. Individual-specific slope of the longitudinal trajectory of each biomarker was first estimated. These estimates and observed baseline biomarker values were used as predictors of cognitive declines. Variability in cognitive declines explained by baseline biomarker values was compared with variability explained by biomarker progression values. Results About 40% of variability in memory and executive function declines was explained by ventricular volume progression among mild cognitive impairment patients. A total of 84% of memory and 65% of executive function declines were explained by fluorodeoxyglucose positron emission tomography (FDG-PET) score progression and ventricular volume progression, respectively, among AD patients. Conclusions For most biomarkers, biomarker progressions explained higher variability in cognitive decline than biomarker baseline values. This has important implications for clinical trials targeted to modify AD biomarkers.
    Alzheimer's and Dementia 11/2014; 10(6). DOI:10.1016/j.jalz.2014.04.513 · 12.41 Impact Factor
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    ABSTRACT: This article summarizes a special series of articles from The Advanced Psychometric Methods in Cognitive Aging Research conference, held in June, 2011 at Friday Harbor, Washington. This conference used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to address cognitive change associated with Alzheimer's disease (AD) and how it related to neuroimaging, genetic, and cerebrospinal fluid biomarkers. The 13 articles in this series present innovative approaches to measuring cognition and studying determinants of cognitive decline in AD.
    Brain Imaging and Behavior 12/2012; 6(4). DOI:10.1007/s11682-012-9211-2 · 4.60 Impact Factor
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