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EARLY, BUT NOT ADVANCED, NEUROFIBRILLARY TANGLE PATHOLOGY OR AMYLOID-B PATHOLOGY SIGNIFICANTLY ASSOCIATES WITH ABNORMAL HIPPOCAMPAL SIZE IN COGNITIVELY NORMAL ELDERLY

      Background: Hippocampal volume (HCV) is a surrogate measure of underlying neurodegenerative disease. Tau pathology is known to associate with hippocampal volume, but what is unclear is the extent to which early versus advanced neurofibrillary tangle (NFT) pathology contributes to hippocampal volume in nondemented patients. Early neuritic, pretangle and mature NFT pathology (measurable by hyperphosphorylated tau [pTau] antibodies) precedes the formation of advanced mature and extracellular NFTs (measurable by a NFT conformational epitope [cNFT]). The purpose of this study was to examine the relationship between hippocampal volume and neuropathologic measures of early pTau, advanced cNFT, and amyloid- β pathology in nondemented elderly participants.
      Methods: We selected Mayo Clinic Study of Aging autopsied participants who had available 3T antemortem MRI and were nondemented within 2.0 years of death (14 women and 27 men, aged 73-101). FreeSurfer v4.5 was used to measure HCV and adjusted based on regression modeling that measures how different the expected volume (based on TIV) is to the actual volume. Using a 90% sensitivity in clinically diagnosed ADs, the cut-point was -0.69. Serial sections of posterior hippocampus were analyzed using digital microscopy (Aperio technologies) to measure % burden of early pTau (CP13-antibody), advanced cNFT (Ab39-antibody), and amyloid- β (33.1.1- antibody). An H&E stain was used to quantify pyramidal neuron density.
      Results: Of the 41 nondemented participants who met selection criteria, 18 (44%, median=-1.25) were below the abnormal HCV cutpoint and 23 (56%, median=-0.0389) were above the cutpoint. Four multiple linear regression models predicting HCV were adjusted for age at MRI, gender, and time from MRI to death. Smaller HCV was significantly associated with higher early pTau burden (p=0.017), but not advanced cNFT (p=0.299) nor amyloid- β burden (p=0.199). A lower density of pyramidal neurons was also associated with smaller HCV (p=0.012).
      Conclusions: Our data supports previous work describing associations between HCV and hippocampal tau pathology, but adds new information relative to the maturity of neurofibrillary tangle pathology in the hippocampus. Early pTau pathology was found to significantly associate with hippocampal volumes in nondemented persons, suggesting that there are distinct mechanisms involved in NFT accumulation that may have different pathophysiologic bases relevant to structural MRI.