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Annese J, Schenker-Ahmed NM, Bartsch H, Maechler P, Sheh C, Thomas N, Kayano J, Ghatan A, Bresler N, Frosch MP, Klaming R, Corkin S. Postmortem examination of patient H.M.'s brain based on histological sectioning and digital 3D reconstruction. Nat Commun. 2014;5:3122. PubMed.
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Columbia University
This is a fascinating paper, with three main points of interest: First, it is notable that H.M. has a near-complete ablation of the entorhinal cortex, yet there is remarkable preservation of many hippocampal regions (i.e., the dentate gyrus, the CA subfields, and the subiculum). The dentate gyrus receives nearly all its synaptic input from the entorhinal cortex. I am often asked how is it possible that the entorhinal cortex is affected first and foremost in Alzheimer's disease, yet the dentate gyrus is relatively preserved. This study suggests that the dentate gyrus can "survive" even without an entorhinal cortex.
Second, that the anterior hippocampus was excised more than the posterior hippocampus is interesting. As the authors point out, the monosynaptic connections of the anterior hippocampus support its role in mood and behavior. And this might account for H.M.’s affect, as described in the paper. At the same time, the anterior hippocampus has been implicated in schizophrenia, and H.M. clearly did not have psychotic symptoms. This agrees with the observations that in schizophrenia, the anterior hippocampus is hyperactive—a sort of “toxic” gain of function. Thus, one would not expect that H.M. should manifest psychotic symptoms. In fact, the extreme view would maintain that without an anterior hippocampus, he could not develop schizophrenia. One thing that is not commented on is whether H.M. has evidence of tau or amyloid pathology in the neocortex. If he does, this would suggest that tau pathology in AD does not all emanate from the entorhinal cortex, as suggested by some. Hopefully, the authors will be able to address this very important question in a future study.
IUPUI
H.M. was the poster child of the lesion method for studying brain-behavior relationships and cognitive sequelae. His death provides the scientific community an opportunity to take an excruciatingly detailed investigation of the role of the anterior hippocampus and the entorhinal cortex in brain function and examine what part these critical brain regions have played in cortical and subcortical remodeling and compensatory functionality.
What is even more fascinating for those of us in the dementia field is that H.M. was said to suffer from progressive cognitive decline in the later years of his life. It would be interesting to study the series of papers that will most certainly follow reporting the detailed immunohistochemical and stereological investigations of his brain. This is certainly one of the many significant publications that will result from in-depth investigation of H.M.'s famous brain. We will be tuned in for years to come.
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