0761

Intra-Hippocampal Connectivity Differences in Cognitively Normal Subjects with/without Genetic Risk for Alzheimer’s Disease
Devon K. Overson1,2, Sasha Hakhu3, Scott C. Beeman3, Allen W. Song1,2, and Trong-Kha Truong1,2
1Brain Imaging and Analysis Center, Duke University, Durham, NC, United States, 2Medical Physics Graduate Program, Duke University, Durham, NC, United States, 3School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, United States

Synopsis

Keywords: Structural Connectivity, Brain Connectivity, Hippocampus, APOE4, Streamlines

Motivation: Microstructural changes within the hippocampus, which may occur well before cognitive decline in Alzheimer’s disease (AD), could serve as an early diagnosis biomarker in pre-symptomatic subjects.

Goal(s): We assessed differences in intra-hippocampal connectivity between cognitively normal carriers and non-carriers of the APOE4 allele, a genetic risk factor for AD.

Approach: We segmented the hippocampus into 12 subfields per hemisphere and performed fiber tractography on multi-shell diffusion tensor imaging data to determine the number of streamlines connecting each subfield pair.

Results: 22 subfield pairs had a significantly lower connectivity in the APOE4 carrier group compared to the APOE4 non-carrier group.

Impact: Our analysis shows differences in intra-hippocampal connectivity between cognitively normal subjects with and without a genetic risk factor for Alzheimer’s disease, which could potentially serve as a more definitive biomarker for its early diagnosis and treatment in pre-symptomatic subjects.

Introduction

Neurodegeneration leading to Alzheimer’s disease (AD) starts long before the onset of cognitive decline1, but is not uniformly distributed throughout the brain. Pre-symptomatic AD biomarkers, such as beta-amyloid and tau protein levels or volumetric changes derived from structural MRI, are not sufficiently specific to detect these early microstructural changes2. The hippocampus is especially vulnerable to early neurodegeneration in AD3. Previous studies have used diffusion tensor imaging (DTI) and fiber tractography to investigate the structural connectivity between the hippocampus and other brain regions in vivo4,5, or between different subfields of the hippocampus ex vivo6,7 but few studies have done so in subjects with/at risk for AD or investigated the intra-hippocampal connectivity in vivo.

In this study, we assess differences in intra-hippocampal connectivity between age-matched groups of cognitively normal carriers and non-carriers of the apolipoprotein ε4 allele (termed APOE4+ and APOE4-, respectively), a well-established genetic risk factor for developing AD8. Such a non-invasive imaging biomarker could potentially enable the early diagnosis of AD in pre-symptomatic subjects, when the neurodegeneration may be delayed by treatments.

Methods

3T MRI data from 32 APOE4- (21 females, age: 68.9±3.1) and 16 APOE4+ (13 females, age: 67.2±2.7) subjects were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data repository (adni.loni.usc.edu)9. T1-weighted anatomical images (1.05 x 1.05 x 1.2 mm) were upsampled to 1-mm isotropic resolution with Freesurfer10 and used to generate 12 hippocampal subfields per hemisphere with HA Segmentation11 (Figure 1a,b). Raw DTI data (2 mm isotropic, 127 volumes with 13x b=0, 6x b=500, 48x b=1000, and 60x b=2000 s/mm2) were pre-processed to correct for susceptibility artifacts, motion, and eddy currents with the synthesized b0 for diffusion distortion correction (Synb0-DISCO)12 algorithm and FSL’s eddy13. After brain extraction with FSL14, the b0 images were registered to the anatomical images with bbregister15 and the inverse of the registration matrix was applied to the hippocampal subfields to transform them to the DTI domain (Figure 1c).

To quantify the intra-hippocampal connectivity, the whole-brain response function was calculated16, and fiber orientation distributions (Figure 1d) and streamlines (Figure 1e) were generated within the hippocampal subfields with MRtrix317/iFOD218. The number of streamlines connecting each pair of subfields was calculated with spherical-deconvolution informed filtering of tractograms (SIFT)19 and normalized by the volume of each subfield pair to remove any volumetric bias, resulting in a 12x12 connectivity matrix (Figure 1f).

One-tailed t-tests were performed with R20 between the APOE4- and APOE4+ groups on: 1) the connectivity for each subfield pair (66 per hippocampus) and 2) the connectivity between each subfield and all other subfields (11 per hippocampus).

Results & Discussion

There were 22 (out of 132) subfield pairs with a significantly lower, and 4 subfield pairs with a significantly higher, connectivity (p ≤ 0.05) for the APOE4+ group compared to the APOE4- group (Figures 2-3). Streamlines for the six subfield pairs with the most significant differences clearly show a lower intra-hippocampal connectivity in the median APOE4+ subjects compared to the median APOE4- subjects (Figure 4).

As for the connectivity between one subfield and all other subfields, there were 5 (out of 24) subfields with a significantly lower, and one subfield with a significantly higher, connectivity (p ≤ 0.05) for the APOE4+ group compared to the APOE4- group (Figure 5).

Among the subfields with a significant difference in connectivity to another subfield or to all other subfields, 18 (out of 26) and 4 (out of 6), respectively, included the head subiculum/presubiculum, head CA1, and hippocampal tail (subfields 1, 2, and 12). Streamlines in the anterior-posterior direction running through the length of the hippocampus showed the most striking difference between the APOE4- and APOE4+ subjects (green streamlines in Figures 4-5).

Such differences in intra-hippocampal connectivity could be detected even though no significant differences in hippocampal subfield volumes were measured between the APOE4- and APOE4+ groups (p > 0.05), showing the value of our diffusion MRI methodology compared to structural MRI.

Our study used multi-shell DTI data to resolve multiple fiber orientations per voxel, but with a 2-mm isotropic resolution. In contrast, previous similar studies in healthy and AD subjects21,22 used a higher 1-mm isotropic resolution to reduce partial volume effects, but with only a single shell due to the limited signal-to-noise ratio. Given this trade-off, the data acquisition/analysis could be further optimized to improve the assessment of the intra-hippocampal connectivity.

Conclusion

While a more comprehensive study including AD subjects is desirable, our analysis of intra-hippocampal connectivity between cognitively normal APOE4- and APOE4+ subjects shows potential to serve as an imaging biomarker for the early diagnosis and treatment of AD in high-risk pre-symptomatic subjects.

Acknowledgements

This work was in part supported by grants R01 EB028644 and S10 OD021480 from the National Institutes of Health. In addition, data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012).

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Figures

Figure 1: Overview of the analysis pipeline, showing the labeled hippocampal subfields (a) segmented from the T1-weighted anatomical images (b) and transformed to the DTI domain (c), the fiber orientation distributions (FODs) (d) and streamlines (e) generated within the hippocampal subfields, and the resulting connectivity matrix quantifying the intra-hippocampal connectivity for each subfield pair (f).

Figure 2: Matrices and graphs showing the pairs of hippocampal subfields with statistically significant (p ≤ 0.05) differences in connectivity between the APOE4- and APOE4+ groups. ML/HF: molecular layer/hippocampal fissure.

Figure 3: Box plots of the normalized number of streamlines for the pairs of hippocampal subfields with statistically significant (p ≤ 0.05) differences in connectivity between the APOE4- and APOE4+ groups.

Figure 4: Streamlines between hippocampal subfields from the median APOE4- and APOE4+ subjects for the six subfield pairs with the most significant differences in connectivity between the APOE4- and APOE4+ groups.

Figure 5: Left: box plots of the normalized number of streamlines for the hippocampal subfields with statistically significant (p ≤ 0.05) differences in connectivity to all other subfields between the APOE4- and APOE4+ groups. Right: streamlines between one of these subfields (left hippocampal tail) and all other subfields from the median APOE4- and APOE4+ subjects.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)
0761
DOI: https://doi.org/10.58530/2024/0761