Alzheimer's disease neuroimaging Initiative: episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects

Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
Brain (Impact Factor: 9.2). 12/2008; 132(Pt 5):1310-23. DOI: 10.1093/brain/awn320
Source: PubMed


Although beta-amyloid (Abeta) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via 'Pittsburgh Compound-B' (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Abeta and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Abeta deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Abeta deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Abeta-induced hippocampus atrophy.

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    • "On top of this, the debate also affects potential brain alterations in cognitively healthy subjects harboring amyloid pathology, i.e., in the preclinical stage of AD (Chetelat et al., 2013; Fjell et al., 2014). Again, although some cross-sectional studies found that amyloid-positive nondemented subjects show decreased hippocampal volumes (Bourgeat et al., 2010; Dickerson et al., 2009; Mormino et al., 2009; Storandt et al., 2009), some others did not find significant differences in the hippocampus (Jack et al., 2010; Vemuri et al., 2009) but did find in whole-brain volume (Fagan et al., 2009), parietal, posterior cingulate cortex, and precuneus (Becker et al., 2011; Fortea et al., 2014) or even increased volume in temporal regions including the hippocampus (Chetelat et al., 2010b). Previous studies have also reported an association between the reduction of cortical thickness and Ab deposition, before clinically evident cognitive impairment, in the parietotemporal and posterior cingulate regions extending into the precuneus (Becker et al., 2011; Fortea et al., 2011). "
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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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    • "This finding is consistent with the early accumulation of tau-related pathology in the mesial temporal regions in AD compared to the relatively diffuse deposition of A␤ [7]. In a previous study, Mormino and colleagues reported that the relationship between cortical A␤ deposition and memory function was mediated by hippocampal volume [18]. Although a direct measure of tau-related pathology was not included in their study, the authors speculated that hippocampal volume might have acted as an indirect measure of NFT load. "
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    ABSTRACT: Alzheimer’s disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifying therapeutic trials.
    Journal of Alzheimer's disease: JAD 05/2015; 47(4):965-975. DOI:10.3233/JAD-142643 · 4.15 Impact Factor
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    • "Decline in memory performance , particularly episodic memory, is a major characteristic of dementia, particularly in early-middle stages. However, it is also well established that there is normal aging-associated decline of episodic memory in the absence of dementia (Mormino et al., 2009). Therefore, with aging populations, it is not only important to investigate strategies to delay dementia onset, but also to increase resistance to aging-related cognitive decline. "
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    ABSTRACT: Inter-individual variability in memory performance has been suggested to result, in part, from genetic differences in the coding of proteins involved in long-term potentiation (LTP). The present study examined the effect of a single-nucleotide polymorphism (SNP) in the KIBRA gene (rs1707045) on episodic memory performance, using multiple measures of verbal and visual episodic memory. A total of 256 female and 130 male healthy, older adults (mean age = 60.86 years) were recruited from the Tasmanian Healthy Brain Project, undergoing both neuropsychological and genetic testing. The current study showed no significant effect of the KIBRA polymorphism on performance on the Rey Auditory Verbal Learning Task, Logical Memory test, Paired Associates Learning test or Rey Complex Figure Task. The results suggest there is little to no functional significance of KIBRA genotype on episodic memory performance, regardless of modality.
    Frontiers in Aging Neuroscience 10/2014; 6. DOI:10.3389/fnagi.2014.00270 · 4.00 Impact Factor
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