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The Journal of Neuroscience, June 11, 2008, 28(24):6174-6181; doi:10.1523/JNEUROSCI.1392-08.2008
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Neurobiology of Disease
Relationships between Hippocampal Atrophy, White Matter Disruption, and Gray Matter Hypometabolism in Alzheimer's Disease
Nicolas Villain,1 Béatrice Desgranges,1 Fausto Viader,1,2 Vincent de la Sayette,1,2 Florence Mézenge,1 Brigitte Landeau,1 Jean-Claude Baron,3 Francis Eustache,1 andGaël Chételat1 1Institut National de la Santé et de la Recherche Médicale–Ecole Pratique des Hautes Etudes–Université de Caen/Basse-Normandie, Unité U923, Groupement d'Intérêt Public Cyceron, Centre Hospitalier Universitaire (CHU) Côte de Nacre, 14074 Caen, France, 2Département de Neurologie, CHU Côte de Nacre, 14033 Caen Cedex, France, and 3Department of Clinical Neurosciences, Neurology Unit, University of Cambridge, Cambridge CB2 2SP, United Kingdom
Correspondence should be addressed to Dr. Gaël Chételat, Institut National de la Santé et de la Recherche Médicale–Ecole Pratique des Hautes Etudes–Université de Caen/Basse-Normandie, Unité U923, Groupement d'Intérêt Public Cyceron, Boulevard H. Becquerel, BP 5229, 14074 Caen Cedex, France. Email: chetelat{at}cyceron.fr
In early Alzheimer's disease (AD), the hippocampal region is the area most severely affected by cellular and structural alterations, yet glucose hypometabolism predominates in the posterior association cortex and posterior cingulate gyrus. One prevalent hypothesis to account for this discrepancy is that posterior cingulate hypometabolism results from disconnection from the hippocampus through disruption of the cingulum bundle. However, only partial and indirect evidence currently supports this hypothesis. Thus, using structural magnetic resonance imaging and 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography in 18 patients with early AD, we assessed the relationships between hippocampal atrophy, white matter integrity, and gray matter metabolism by means of a whole-brain voxel-based correlative approach. We found that hippocampal atrophy is specifically related to cingulum bundle disruption, which is in turn highly correlated to hypometabolism of the posterior cingulate cortex but also of the middle cingulate gyrus, thalamus, mammillary bodies, parahippocampal gyrus, and hippocampus (all part of Papez's circuit), as well as the right temporoparietal associative cortex. These results provide the first direct evidence supporting the disconnection hypothesis as a major factor contributing to the early posterior hypometabolism in AD. Disruption of the cingulum bundle also appears to relate to hypometabolism in a large connected network over and above the posterior cingulate cortex, encompassing the whole memory circuit of Papez (consistent with the key location of this white matter tract within this loop) and also, but indirectly, the right posterior association cortex.
Key words: Alzheimer's disease; hippocampus; white matter; deafferentation; morphometry; PET; positron emission tomography
Received Jan. 31, 2008; accepted April 30, 2008.
Correspondence should be addressed to Dr. Gaël Chételat, Institut National de la Santé et de la Recherche Médicale–Ecole Pratique des Hautes Etudes–Université de Caen/Basse-Normandie, Unité U923, Groupement d'Intérêt Public Cyceron, Boulevard H. Becquerel, BP 5229, 14074 Caen Cedex, France. Email: chetelat{at}cyceron.fr
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