Hippocampal Atrophy Is the Critical Brain Change in Patients With Hypoxic Amnesia M. Di Paola, 1 * C. Caltagirone, 2,3 L. Fadda, 2,3 U. Sabatini, 1,4 L. Serra, 1 and G.A. Carlesimo 2,3 ABSTRACT: Anoxia is considered a good model for studying amnesia. However, not all individuals who experience anoxic events develop memory problems. Moreover, the question still remains about whether, after anoxia, damage is limited to the hippocampus in patients with am- nesia and without other significant cognitive deficits. Here we investi- gated brain damage in a selected sample of adults affected exclusively by an amnesic syndrome after an anoxic episode. The cerebral MR images of these patients were submitted to visual inspection, volumetric measurements of the mesial temporal structures following manual seg- mentation, and to Voxel-Based Morphometry of the whole brain. We studied five anoxic patients and thirty-three well-matched healthy sub- jects. Our aim was to: (a) quantify regional atrophic changes associated with chronic anoxic damage compared to control subjects (Group Com- parison Analysis); (b) identify regions of common abnormality across all patients (Conjunction Analysis in the VBM); (c) investigate whether measures of regional volume reduction correlated with neuropsychologi- cal memory scores; (d) compare the results obtained with visual inspec- tion and ROI analyses with those obtained with VBM. We found that anoxic patients presented a significant reduction of gray matter volume in the hippocampus bilaterally compared to healthy subjects. The only common atrophic region across all patients was the hippocampus bilat- erally. Correlation analysis showed only a trend between the Prose im- mediate free recall test and the left hippocampus. Our findings confirm that the hippocampus is very sensitive to damage stemming from an- oxia. Patients with hypoxic amnesia may present damage in other brain regions, but only hippocampal atrophy is common in all of them. V V C 2008 Wiley-Liss, Inc. KEY WORDS: hippocampus; anterograde memory; Voxel-Based Mor- phometry; hypoxia; adults INTRODUCTION The most frequent cognitive sequalae of an anoxic event in humans are memory deficits, visuo-spatial, and visual-object recognition problems, impairment of executive functions and changes in personality and behav- ior (Caine and Watson, 2000). Although memory impairment is consid- ered one of the most consistent consequences of anoxia, it is noteworthy that an amnesic syndrome may be a rare neurological sequela of a hypoxic event. In fact, in a review of the literature on cognitive deficits due to a cerebral hypoxic event (Caine and Watson, 2000), only 13 out of 67 individual case reports (19.4%) and 4 out of 14 group studies (28.6%) reported memory impair- ments without any additional cognitive deficits. Very few studies have provided neuro-pathological descriptions of patients with post-hypoxic amnesia (Cummings et al., 1984; Zola-Morgan et al., 1986; Rempel-Clower et al., 1996; Gold and Squire, 2006). In all of these patients, a significant neuronal loss affected the hippocampi bilaterally, involving mainly the large pyramidal cells of the outer layers, while a normal neuronal density was noted at the level of ad- jacent structures in the mesial temporal lobes, such as the subiculum and the parahippocampal gyrus. Never- theless, all of these patients also presented post- hypoxic changes in other cerebral regions. For exam- ple, Cummings et al. (1984) reported small infarcts in the left thalamus and in the right fronto-parietal region, while Zola-Morgan et al. (1986) found gliotic areas in the left globus pallidus and internal capsula, in the right postcentral gyrus, and a significant neuro- nal loss in the cerebellar cortex. Contrasting data regarding the critical locus of brain damage in patients with hypoxic amnesia also emerged from ‘‘in vivo’’ studies based on the results of magnetic resonance imaging (MRI) investigation. Indeed, a num- ber of these studies reported that the atrophic changes in patients with hypoxic amnesia are confined to the hippocampi with the parahippocampal gyrus and the remaining temporal lobes substantially preserved (Henke et al., 1999; Cipolotti et al., 2001; Manns et al., 2003a,2003b; Bayley et al., 2005). In contrast, other studies reported evidence of structural or meta- bolic abnormalities in regions of the brain other than the mesial temporal lobe. In the case reported by Mar- kowitsch et al. (1997), the visual inspection of MR images only indicated non-specific cortical atrophy. Nevertheless, Positron Emission Tomography of the brain revealed a damage involving the mesial temporal lobes (MTL) and, even more, the thalami. The patients investigated by Allen et al. (2006) had significantly smaller hippocampal volumes than healthy controls. However, all of the other brain regions examined (fron- tal lobes, parietal lobes, temporal lobes, and amygdalae) were also smaller than in the healthy controls, even though the atrophic changes in these structures were less pronounced than in the hippocampi. These previous ‘‘in vivo’’ studies of anoxic adult patients were based on visual inspection of MR 1 Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Via Ardea- tina 306, Rome, Italy; 2 Department of Neurological Sciences, University of Rome ‘‘Tor Vergata’’, Italy; 3 Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Via Ardeatina 306, Rome, Italy; 4 Department of Radiology, IRCCS Santa Lucia Foundation, Via Ardea- tina 306, Rome, Italy *Correspondence to: Margherita Di Paola, Neuroimaging Laboratory, Fondazione Santa Lucia, IRCCS, Via Ardeatina 306, 00179 Rome, Italy. E-mail: m.dipaola@hsantalucia.it Accepted for publication 18 February 2008 DOI 10.1002/hipo.20432 Published online 29 April 2008 in Wiley InterScience (www.interscience. wiley.com). HIPPOCAMPUS 18:719–728 (2008) V V C 2008 WILEY-LISS, INC.