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Posterior cingulate hypometabolism in early Alzheimer’s disease: what is the contribution of local atrophy and disconnection? Ga?l Chételat1, Nicolas Villain1, Béatrice Desgranges1, Francis Eustache1, Jean-Claude Baron2 1 Inserm-EPHE-Université de Caen/Basse-Normandie, Unité U923, GIP Cyceron, CHU C?te de Nacre, Caen, France 2 Department of Clinical Neurosciences, Neurology Unit, University of Cambridge, UK Correspondence and reprint request: Ga?l Chételat, Inserm-EPHE-Université de Caen/Basse-Normandie, Unité U923, GIP Cyceron, Bd H. Becquerel, BP 5229, 14074 Caen Cedex, France. Tel: +33 0 2 31 47 01 07; Fax: +33 0 2 31 47 02 75, E-mail: chetelat@cyceron.fr Sir, Garden et al. 2009 reported an important experimental study highlighting a potential mechanism for neuronal dysfunction distant from the site of damage, specifically a loss of synaptic plasticity in the retrosplenial/posterior cingulate cortex PCC after anterior thalamic lesion in the rat. In the discussion section of their article, they make the assumption that this phenomenon plays a role in the early episodic memory impairment characterizing Alzheimer’s disease: the PCC would be disconnected from the anterior thalamic nucleus - affected by early neuronal/synaptic loss - through disruption of the cingulum bundle. This would in turn lead to PCC hypometabolism, which occurs very early in Alzheimer’s disease and already at the stage of amnestic mild cognitive impairment Minoshima et al., 1997, Chételat et al., 2003a, b . The study by Garden et al. 2009 is therefore important for the understanding of the pathophysiology of the memory impairment that characterizes early Alzheimer’s disease as the proposed underlying synaptic mechanism could be amenable to specific pharmacological modulation. Garden et al. 2009 also allude to the current debate about the relative importance of disconnection versus local atrophy/direct neuronal damage in the PCC hypometabolism observed in amnestic mild cognitive impa