Ultrahigh-resolution microstructural diffusion tensor imaging reveals perforant path degradation in aged humans in vivo

Abstract

The perforant path (PP) undergoes synaptic changes in the course of aging and dementia. Previous studies attempting to assess the integrity of the PP in humans using diffusion tensor imaging (DTI) were limited by low resolution and the inability to identify PP fibers specifically. Here we present an application of DTI at ultrahigh submillimeter resolution that has allowed us to successfully identify diffusion signals unique to the PP and compare the intensity of these signals in a sample of young adults and older adults. We report direct evidence of age-related PP degradation in humans in vivo. We find no evidence of such loss in a control pathway, the alveus, suggesting that these findings are not evidence for a global decline. We also find no evidence for specific entorhinal gray matter atrophy. The extent of PP degradation correlated with performance on a word-list learning task sensitive to hippocampal deficits. We also show evidence for gray matter diffusion signals consistent with pyramidal dendrite orientation in the hippocampus and cerebral cortex. Ultrahigh-resolution microstructural DTI is a unique biomarker that can be used in combination with traditional structural and functional neuroimaging methods to enhance detection of Alzheimer disease in its earliest stages, test the effectiveness of new therapies, and monitor disease progression.

Fig. 1.

(A) Circuit figure of hippocampal connectivity showing the PP. EC2, entorhinal cortex layer II; EC3, entorhinal cortex layer III; EC deep, entorhinal cortex deep layers; DG, dentate gyrus; Sub, subiculum. The broken red line emphasizes that this pathway is degraded with aging. (B) A retrograde tracer diagram of the PP [Reproduced with permission from ref. (Copyright John Wiley and Sons, 1991)]. (C) Schematized illustration of PP connectivity in the hippocampus [Adapted with permission from ref. (Copyright 1986, John Wiley and Sons)]. (D) Single hippocampal DTI slice clearly showing the tensor orientation of the PP fibers (the slice used here for tensor visualization is approximately twice as thick as the slices used in the main quantification analyses). (Inset) Structural MRI scan showing the position of this slice and the magnified location. The tensor map is overlaid on an FA map that is modulated by the grayscale anatomical image.

Fig. 2.

Sample measurements from two young (s1, s2) and two old (s3, s4) subjects (two from each hemisphere). (A) Coronal slice anatomical location where the measurement was conducted. Red boxes indicate the approximate location of the zoomed-in view in B. This view is a close-up of the anatomy with the blue dots defining a line parallel to the entorhinal cortex sheet (green dots are 1 voxel in each direction) and the red line is the direction perpendicular to it (the actual PP direction). The hippocampus (HIPP) and the entorhinal cortex (EC) are labeled on each slice. (C) One-dimensional plots of the PPproj value clearly show a peak consistent with the position of the PP. (D) The 2D plots of the PPproj value in the entire volume shown in B are color-coded so “hot” colors (red/yellow) are greater PPproj values (i.e., larger diffusion signal along the PP direction) and “cold” colors (blue/purple) are lower PPproj values (i.e., smaller diffusion signal along the PP direction). The hot spots in the middle of each spot represent the PP on that particular slice.

Fig. 3.

(A) Average PP signal curves from young and old subjects show a significant group difference between young and old subjects in AUC. (B) Average alveus signal curves from young and old subjects show no significant difference between groups in AUC.

Fig. 4.

Significant correlation between PP AUC and delayed recall performance on the RAVLT in older adults.