Microstructural mapping of dentate gyrus pathology in Alzheimer’s disease: A 16.4 Tesla magnetic resonance imaging study

Abstract

AbstractBackgroundThe dentate gyrus (DG) is an important part of the hippocampal structure and it comprises the molecular (ML), granular cell (GCL), and polymorphic layers (PL). Impaired DG is associated with Alzheimer’s disease (AD) pathology. MRI provides general structural information for the clinical diagnosis, but assessing subtle cellular pathological changes still requires histological observation. Here, we performed ultra‐high‐resolution MRI to investigate the correlation between MRI signals in DG and histological measurements of AD pathology.MethodPostmortem hippocampi tissues were used (5 cognitive normal, 5 AD; from USC ADRC). Approximately 2 cm3 of tissue dissected from the anterior hippocampus was scanned using 16.4T MRI, the adjacent tissue was processed for immunohistochemistry. Quantitative ex vivo MRI were acquired at 50 µm3 (T2, T2* and SWI). Multi‐shell diffusion MRI were acquired at 150 µm3 (scan time=72hrs). ITK‐SNAP was used to delineate ML, GCL, and PL regions of the DG; and Fiji software to divide histological images of ML, GCL, and PL into twenty equally sized regions of interest (Figure1A), guided by the Allen human brain atlas. Quantitative and morphometric features of DG subregions were calculated from MRI. Histological data was analyzed to measure cell count from H&E slides, neurofilament density and tau pathology from NF160 and AT8 stained slides, respectively (Figure1B).ResultT2‐map (Figure1C) was positively correlated with neurofilament density in ML (R=0.66, p=0.038), PL (R=0.75, p=0.033) and negatively correlated with p‐tau density (ML:R=−0.60, p=0.064; PL:R=−0.61, p=0.062). R2‐map (ML:R=−0.78, p=0.008; PL:R=−0.67, p=0.032 ) and SWI (ML:R=−0.79, p=0.006; PL:−0.80, p=0.005) was negatively correlated with neurofilament. R2 also had positive correlations with p‐tau density (ML:R=0.70, p=0.02; PL:R=0.6, p=0.068). Finally, diffusion decay rate was significantly correlated with neurofilament in PL (R=0.76; p=0.012).ConclusionResults suggest that quantitative MRI is sensitive to subtle neurite changes within the hippocampal formation, which could be used to assess the connectivity changes in the course of AD. This could also provide insight about the mechanism of AD progression if translated in vivo. The quantitative measurement of the connectivity alteration could also have early diagnosis value, given that recent studies have shown that connectivity changes precede cortical atrophy in AD.