DIFFERENTIAL HIPPOCAMPAL SUBFIELD LOSS IN DIFFERENT PHENOTYPES OF YOUNG ONSET ALZHEIMER’S DISEASE

Abstract

Young onset Alzheimer's disease (YOAD - defined as symptom onset < 65 years) is notable for its degree of phenotypic heterogeneity. Total hippocampal volume is a key biomarker of Alzheimer's disease, and automated methods are now able to provide volumetric estimates of the histologically distinct subfields that contribute to total hippocampal volume. To what extent the volumes of individual hippocampal subfields change in YOAD and how this contributes to phenotypic heterogeneity is unclear. The aim of this analysis is to investigate the extent of hippocampal subfield loss in YOAD and how this relates to disease phenotype. 63 participants with volumetric T1-weighted MRI performed on the same 3T scanner were included in the analysis. This comprised 27 YOAD patients with a typical amnestic presentation; 12 patients with a visual symptom-led posterior cortical atrophy presentation; and 24 age-matched healthy controls. Volumetric estimates of hippocampal subfields for each participant were performed using Freesurfer version 6. This algorithm is based on a computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI and includes: CA1, CA2/3, CA4, fimbria, hippocampal fissure, presubiculum, subiculum, hippocampal tail, parasubiculum, the dentate gyrus, the molecular layer and the hippocampal amygdala transition area. Linear regression analyses comparing mean hippocampal subfield volumes between groups after adjustment for age, gender and total intracranial volume were performed. A threshold of p<0.004 for formal statistical significance was used following Bonferroni correction for comparison across the multiple regions of interest. Compared to healthy controls, amnestic YOAD patients showed strong evidence of widespread volume loss in all hippocampal subfields (p=<0.001), except the parasubiculum. In posterior cortical atrophy patients the strongest evidence for volume loss compared to controls was in: the fimbria (p<0.001), presubiculum (p=0.001), subiculum (p=0.001), dentate gyrus (p=0.001), molecular layer (p=0.001) and the hippocampal amygdala transition area (p=0.002). Comparing YOAD phenotypes, there was evidence of decreased volume in patients with an amnestic presentation compared to a posterior cortical atrophy presentation in CA1 (p=0.004) and the hippocampal tail (p=0.003). These data demonstrate evidence for differential hippocampal subfield loss in patients with YOAD relating to phenotypic presentation . Hippocampal formation subfields. Panel A: Diagram adapted from original drawing by Golgi(Golgi, 1903) depicting the hippocampal formation subfields (NB. does not include hippocampal amygdala transition area and hippocampal tail). Panel B: Example of segmentation of the left hippocampal formation into constituent subfields in the sagittal, axial, and coronal planes (NB. selected slices do not show the relatively smaller hippocampal amygdala transition area and parasubiculum.)