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Title of Journal: Acta Neuropathol

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Abbravation: Acta Neuropathologica

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Springer-Verlag

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DOI

10.1002/asna.18480271402

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1432-0533

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Neuropathologically defined subtypes of Alzheimer’

Authors: Nicholas J Janocko Kevin A Brodersen Alexandra I SotoOrtolaza Owen A Ross Amanda M Liesinger Ranjan Duara Neill R GraffRadford Dennis W Dickson Melissa E Murray
Publish Date: 2012/09/12
Volume: 124, Issue: 5, Pages: 681-692
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Abstract

Alzheimer’s disease AD can be classified based on the relative density of neurofibrillary tangles NFTs in the hippocampus and association cortices into three subtypes typical AD hippocampalsparing AD HpSp AD and limbicpredominant AD LP AD AD subtypes not only have pathologic but also demographic clinical and genetic differences Neurofibrillary tanglepredominant dementia NFTD a disorder with NFTs relatively restricted to limbic structures shares this feature with LP AD raising the possibility that NFTD is a variant of AD The objective criteria for pathologic diagnosis of NFTD are not available A goal of this study was to design a mathematical algorithm that could diagnose NFTD from NFT and senile plaque SP counts in hippocampus and association cortices analogous to that used to subtype AD Moreover we aimed to compare pathologic demographic clinical and genetic features of NFTD n = 18 with LP AD n = 19 as well as the other AD subtypes typical AD n = 52 and HpSp AD n = 17 Using digital microscopy we confirmed that burden of phosphotau CP13 and of an NFT conformational epitope Ab39 correlated with NFT densities and showed expected patterns across AD subtypes HpSp AD had the highest and LP AD had the lowest burden of cortical CP13 and Ab39 immunoreactivity On the other hand cortical βamyloid burden did not significantly differ between AD subtypes Semiquantitative assessment of SPs in the basal ganglia did show HpSp AD to have significantly more frequent presence of SPs compared to typical AD which was more frequent than LP AD Compared to LP AD NFTD had an older age at disease onset and shorter disease duration as well as lower Braak NFT stage NFTs and SPs on thioflavinS fluorescent microscopy as well as CP13 Ab39 and Aβ immunoreactivities were very low in the frontal cortex of NFTD differentiating NFTD from AD subtypes including LP AD MAPT H1H1 genotype frequency was high ~70  in NFTD and LP AD and similar to typical AD while APOE ε4 carrier state was low in NFTD While it shares clinical similarities with regard to female sex predominance onset in advanced age and a slow cognitive decline NFTD has significant pathologic differences from LP AD suggesting that it may not merely be a variant of ADThe project was supported by the Mayo ADRC Grant P50 AG16574 Mayo Clinic Study on Aging U01 AG06786 Florida ADRC P50 AG215711 Einstein Aging Study P01 AG03949 Mangurian Foundation and the State of Florida Alzheimer’s Disease Initiative MEM and this project were supported by a fellowship from the Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program and the Mayo ADRC Pilot Grant OAR and DWD were supported by the Mayo Clinic Udall Center P50 NS072187 OAR was partially supported by R01 NS078086 DWD was supported by the Robert E Jacoby Professorship for Alzheimer’s Research We thank the patients and their families who donated brains to help further our knowledge in neurodegeneration The authors would like to acknowledge the endless hours of commitment and teamwork offered by Linda G Rousseau Virginia R Phillips John Gonzalez and Monica CastanedesCasey Without the sampling design and procedures for thioflavinS fluorescent microscopy developed originally by Dr Robert D Terry 36 this study would not have been possibleAll research reported is on postmortem material which is considered exempt from human subject research All brains were acquired with appropriate ethical approval and the research described has approval from the Mayo Clinic Institutional Review Board

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