Brain Advance Access originally published online on November 28, 2008
Brain 2009 132(5):1310-1323; doi:10.1093/brain/awn320
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Episodic memory loss is related to hippocampal-mediated β-amyloid deposition in elderly subjects
1 Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA 2 The Department of Molecular Imaging and Neuroscience, Lawrence Berkeley National Laboratory, Berkeley, CA, USA 3 Memory and Aging Center and Department of Neurology, University of California San Francisco, San Francisco, CA, USA 4 Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI, USA 5 Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA 6 Center for Imaging of Neurodegenerative Diseases, Department of Veterans Affairs Medical Center, San Francisco, CA, USA
Correspondence to: William Jagust, 132 Barker Hall, MC#3190, University of California, Berkeley, Berkeley, CA 94720 E-mail: jagust{at}berkeley.edu
Although β-amyloid (Aβ) 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 Aβ 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 Aβ deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Aβ deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Aβ-induced hippocampus atrophy.
Key Words: Pittsburgh Compound-B; magnetic resonance imaging; β-amyloid; hippocampus; preclinical Alzheimer's disease
Abbreviations: Aβ, β-amyloid; NC, normal controls; PIB, Pittsburgh compound-B; PET, positron emission tomography
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Received June 27, 2008. Revised September 30, 2008. Accepted November 3, 2008.
*Data used in the preparation of this article were obtained in part from the Alzheimer's; Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). As such the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. ADNI investigators are listed at www.loni.ucla.edu/ADNI/Collaboration/ADNI_Authorship_list.pdf
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