Poster No:
215
Submission Type:
Abstract Submission
Authors:
Min Soo Byun1,2, Dahyun Yi3, Joon Sik Park4, Gihwan Byeon5, Hyejin Ahn6, Gijung Jung3, Yen-Ning Huang7, Yu Kyeong Kim8,1, Yun-Sang Lee1, Jun-Young Lee8,1, Koung Mi Kang2,1, Chul-Ho Sohn2,1, Andrew Saykin7, Kwangsik Nho7, Jaeseok Park4, Dong Young Lee1,2
Institutions:
1Seoul National University College of Medicine, Seoul, Korea, Republic of, 2Seoul National University Hospital, Seoul, Korea, Republic of, 3Seoul National University Medical Research Center, Seoul, Korea, Republic of, 4Sungkyunkwan University, Suwon, Korea, Republic of, 5Kangwon National University Hospital, Chuncheon, Korea, Republic of, 6Seoul National University College of Humanities, Seoul, Korea, Republic of, 7Indiana University School of Medicine, Indianapolis, IN, 8SMG-SNU Boramae Medical Center, Seoul, Korea, Republic of
First Author:
Min Soo Byun
Seoul National University College of Medicine|Seoul National University Hospital
Seoul, Korea, Republic of|Seoul, Korea, Republic of
Co-Author(s):
Dahyun Yi
Seoul National University Medical Research Center
Seoul, Korea, Republic of
Gihwan Byeon
Kangwon National University Hospital
Chuncheon, Korea, Republic of
Hyejin Ahn
Seoul National University College of Humanities
Seoul, Korea, Republic of
Gijung Jung
Seoul National University Medical Research Center
Seoul, Korea, Republic of
Yu Kyeong Kim
SMG-SNU Boramae Medical Center|Seoul National University College of Medicine
Seoul, Korea, Republic of|Seoul, Korea, Republic of
Yun-Sang Lee
Seoul National University College of Medicine
Seoul, Korea, Republic of
Jun-Young Lee
SMG-SNU Boramae Medical Center|Seoul National University College of Medicine
Seoul, Korea, Republic of|Seoul, Korea, Republic of
Koung Mi Kang
Seoul National University Hospital|Seoul National University College of Medicine
Seoul, Korea, Republic of|Seoul, Korea, Republic of
Chul-Ho Sohn
Seoul National University Hospital|Seoul National University College of Medicine
Seoul, Korea, Republic of|Seoul, Korea, Republic of
Andrew Saykin
Indiana University School of Medicine
Indianapolis, IN
Kwangsik Nho
Indiana University School of Medicine
Indianapolis, IN
Jaeseok Park
Sungkyunkwan University
Suwon, Korea, Republic of
Dong Young Lee
Seoul National University College of Medicine|Seoul National University Hospital
Seoul, Korea, Republic of|Seoul, Korea, Republic of
Introduction:
Previous research has showed that blood-brain barrier (BBB) dysfunction has a role in the pathogenesis of Alzheimer's disease (AD). However, the geographical pattern of BBB degradation in early Alzheimer's disease and its genetic basis are poorly understood. We looked at the relationship between BBB permeability and beta-amyloid (Aβ) deposition, and its connection with known AD-related single nucleotide polymorphisms (SNPs) in older persons using high-resolution 3-dimensional (3D) dynamic contrast-enhanced (DCE) MRI.
Methods:
Participants were recruited from the Korean Brain Aging Study of the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort (1) and dementia clinic of Seoul National University Hospital. Both cognitively normal (CN) and cognitively impaired (CI) older adults consisted of mild cognitive impairment and AD dementia were included in this study. A total 91 participants underwent comprehensive clinical and neuropsychological assessments. In addition, [11C] Pittsburgh Compound B (PiB) PET for measurement of cerebral Aβ deposition, high-resolution DCE- and T1-weighted-MRI scans were obtained from all participants, which were used to classify the participants into Aβ-positive or negative groups. After preprocessing of the high-resolution 3D DCE imaging, we calculated BBB permeability index (Ktrans) for the whole brain, incorporating FreeSurfer-based (v6.0) segmentation of T1 scans in order to exclude non-brain voxels such as that of ventricles. Next, voxel-wise whole brain analyses were conducted to demonstrate regional changes of the Ktrans map between two groups using SPM12 implemented in MATLAB 2018b. Apolipoprotein E (APOE) genotyping was done for all participants. Additionally, total of 38 AD-related SNPs with genetic evidence compiled by the AD Sequencing Project (ADSP) (minor allele frequency [MAF] > 1%, except APOE) were extracted from TOPMed-based imputed GWAS genotyping data in KBASE in a subset of participants (n=74). Comparison of Ktrans values between carriers and noncarriers of candidate SNPs were performed.
Results:
First, we observed greater BBB damage in multiple cerebral regions including the precuneus, posterior cingulate, and temporal regions in the Aβ-positive CN compared to Aβ-negative CN in a voxel-wise analysis of Ktrans map (cluster-wise FDR corrected p < 0.05). We then extracted the Ktrans value from the region-of-interests (ROIs) including the abovementioned regions for further analysis. Genetic susceptibility analysis of APOE4 revealed that APOE4 carriers showed increased Ktrans value in this ROI compared to noncarriers after adjusting age and sex (F(2,72) = 6.49, p = 0.013), indicative of greater breakdown of BBB in the carriers. Furthermore, we found increased Ktrans of the ROI in the carriers of rs7401792, located in Solute Carrier Family 24 Gene Member 4 (SLC24A4) compared to non-carriers after controlling the effect of age and sex (F(2,72) = 5.08, p = 0.027). This association remained significant after we additively controlled the effect of APOE4 carrier status (F(2,71) = 4.68, p = 0.034).
Conclusions:
We found that BBB breakdown is associated with Aβ accumulation in AD early on, before clinical symptoms appear. Furthermore, in older individuals, regional BBB damage is associated with genetic risks such as APOE4 and rs7401792 in SLC24A4; and, the genetic risk effect of SLC24A4 remains significant even after correcting for the effects of APOE4. More research is needed to explain the intricate interplay between these genes' biochemical pathways in connection to BBB integrity and AD.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Genetics:
Genetic Association Studies
Novel Imaging Acquisition Methods:
Multi-Modal Imaging
Imaging Methods Other 2
Keywords:
Other - Alzheimer's disease; Blood-brain barrier; Beta-amyloid; DCE-MRI; genetic variant
1|2Indicates the priority used for review
Provide references using author date format
(1) Byun et al. (2017), 'Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease: Methodology and Baseline Sample Characteristics', Psychiatry Investigation, vol. 14, no. 6, pp. 851-863