Brain Advance Access originally published online on February 27, 2009
Brain 2009 132(4):1067-1077; doi:10.1093/brain/awp007
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MRI of hippocampal volume loss in early Alzheimer's disease in relation to ApoE genotype and biomarkers
1 Department of Veterans Affairs Medical Center, San Francisco, CA, USA 2 Department of Radiology, University of California, San Francisco, CA, USA 3 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA 4 Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, Los Angeles, CA, USA 5 Mayo Clinic College of Medicine, Rochester, MN, USA
Correspondence to: Norbert Schuff, 4150 Clement St 114M, San Francisco, CA 94121, USA E-mail: norbert.schuff{at}ucsf.edu
Hippocampal volume change over time, measured with MRI, has huge potential as a marker for Alzheimer's disease. The objectives of this study were: (i) to test if constant and accelerated hippocampal loss can be detected in Alzheimer's disease, mild cognitive impairment and normal ageing over short periods, e.g. 6–12 months, with MRI in the large multicentre setting of the Alzheimer's Disease Neuroimaging Initiative (ADNI); (ii) to determine the extent to which the polymorphism of the apolipoprotein E (ApoE) gene modulates hippocampal change; and (iii) to determine if rates of hippocampal loss correlate with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, such as the β-amyloid (Aβ1–42) and tau proteins (tau). The MRI multicentre study included 112 cognitive normal elderly individuals, 226 mild cognitive impairment and 96 Alzheimer's disease patients who all had at least three successive MRI scans, involving 47 different imaging centres. The mild cognitive impairment and Alzheimer's disease groups showed hippocampal volume loss over 6 months and accelerated loss over 1 year. Moreover, increased rates of hippocampal loss were associated with presence of the ApoE allele 
4 gene in Alzheimer's disease and lower CSF Aβ1–42 in mild cognitive impairment, irrespective of ApoE genotype, whereas relations with tau were only trends. The power to measure hippocampal change was improved by exploiting correlations statistically between successive MRI observations. The demonstration of considerable hippocampal loss in mild cognitive impairment and Alzheimer's disease patients over only 6 months and accelerated loss over 12 months illustrates the power of MRI to track morphological brain changes over time in a large multisite setting. Furthermore, the relations between faster hippocampal loss in the presence of ApoE allele 4 and decreased CSF Aβ1–42 supports the concept that increased hippocampal loss is an indicator of Alzheimer's disease pathology and a potential marker for the efficacy of therapeutic interventions in Alzheimer's disease.
Key Words: MRI; mild cognitive impairment; ageing; human brain mapping; hippocampus
Abbreviations: ADAS-Cog, Alzheimer's disease Assessment Scale-Cognitive Subscale; ADNI, Alzheimer's Disease Neuroimaging Initiative; ApoE, apolipoprotein E; CDR, Clinical Dementia Rating; CSF, cerebrospinal fluid
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Received September 15, 2008. Revised November 24, 2008. Accepted December 31, 2008.
*Data used in the preparation of this article were obtained 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 include (complete listing available at www.loni.ucla.edu\ADNI\Collaboration\ADNI_Manuscript_Citations.pdf).
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