Browsing by Author "Bice, Paula J."

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    Aberrant GAP43 Gene Expression Is Alzheimer Disease Pathology-Specific
    (Wiley, 2023) Pyun, Jung-Min; Park, Young Ho; Wang, Jiebiao; Bice, Paula J.; Bennett, David A.; Kim, Sang Yun; Saykin, Andrew J.; Nho, Kwangsik; Radiology and Imaging Sciences, School of Medicine
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    Altered Cerebral Blood Flow in Older Adults with Alzheimer’s Disease: A Systematic Review
    (Springer, 2023) Swinford, Cecily G.; Risacher, Shannon L.; Wu, Yu-Chien; Apostolova, Liana G.; Gao, Sujuan; Bice, Paula J.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of Medicine
    The prevalence of Alzheimer’s disease is projected to reach 13 million in the U.S. by 2050. Although major efforts have been made to avoid this outcome, so far there are no treatments that can stop or reverse the progressive cognitive decline that defines Alzheimer’s disease. The utilization of preventative treatment before significant cognitive decline has occurred may ultimately be the solution, necessitating a reliable biomarker of preclinical/prodromal disease stages to determine which older adults are most at risk. Quantitative cerebral blood flow is a promising potential early biomarker for Alzheimer’s disease, but the spatiotemporal patterns of altered cerebral blood flow in Alzheimer’s disease are not fully understood. The current systematic review compiles the findings of 81 original studies that compared resting gray matter cerebral blood flow in older adults with mild cognitive impairment or Alzheimer’s disease and that of cognitively normal older adults and/or assessed the relationship between cerebral blood flow and objective cognitive function. Individuals with Alzheimer’s disease had relatively decreased cerebral blood flow in all brain regions investigated, especially the temporoparietal and posterior cingulate, while individuals with mild cognitive impairment had consistent results of decreased cerebral blood flow in the posterior cingulate but more mixed results in other regions, especially the frontal lobe. Most papers reported a positive correlation between regional cerebral blood flow and cognitive function. This review highlights the need for more studies assessing cerebral blood flow changes both spatially and temporally over the course of Alzheimer’s disease, as well as the importance of including potential confounding factors in these analyses.
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    BMI1 is associated with CS8F amyloid-β and rates of cognitive decline in Alzheimer's disease
    (Springer Nature, 2021-10-05) Kim, Jun Pyo; Kim, Bo‑Hyun; Bice, Paula J.; Seo, Sang Won; Bennett, David A.; Saykin, Andrew J.; Nho, Kwangsik; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
    Background: Accumulating evidence suggests that BMI1 confers protective effects against Alzheimer's disease (AD). However, the mechanism remains elusive. Based on recent pathophysiological evidence, we sought for the first time to identify genetic variants in BMI1 as associated with AD biomarkers, including amyloid-β. Methods: We used genetic, longitudinal cognition, and cerebrospinal fluid (CSF) biomarker data from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). First, we performed a gene-based association analysis of common single nucleotide polymorphisms (SNPs) (minor allele frequency (MAF) > 5%) located within ± 20 kb of the gene boundary of BMI1, an optimal width for including potential regulatory SNPs in the 5' and 3' untranslated regions (UTR) of BMI1, with CSF Aβ1-42 levels. Second, we performed cross-sectional and longitudinal association analyses of SNPs in BMI1 with cognitive performance using linear and mixed-effects models. We replicated association of SNPs in BMI1 with cognitive performance in an independent cohort (N=1084), Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Results: Gene-based genetic association analysis showed that BMI1 was significantly associated with CSF Aβ1-42 levels after adjusting for multiple testing using permutation (permutation-corrected p value=0.005). rs17415557 in BMI1 showed the most significant association with CSF Aβ1-42 levels. Participants with minor alleles of rs17415557 have increased CSF Aβ1-42 levels compared to those with no minor alleles. Further analysis identified and replicated the minor allele of rs17415557 as being significantly associated with slower cognitive decline rates in AD. Conclusions: Our findings provide fundamental evidence that BMI1 rs17415557 may serve as a protective mechanism related to AD pathogenesis, which supports the results of previous studies linking BMI1 to protection against AD.
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    Circulating lipid profiles are associated with cross-sectional and longitudinal changes of central biomarkers for Alzheimer's disease
    (medRxiv, 2023-06-21) Kim, Jun Pyo; Nho, Kwangsik; Wang, Tingting; Huynh, Kevin; Arnold, Matthias; Risacher, Shannon L.; Bice, Paula J.; Han, Xianlin; Kristal, Bruce S.; Blach, Colette; Baillie, Rebecca; Kastenmüller, Gabi; Meikle, Peter J.; Saykin, Andrew J.; Kaddurah-Daouk, Rima; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Metabolomics Consortium; Radiology and Imaging Sciences, School of Medicine
    Investigating the association of lipidome profiles with central Alzheimer's disease (AD) biomarkers, including amyloid/tau/neurodegeneration (A/T/N), can provide a holistic view between the lipidome and AD. We performed cross-sectional and longitudinal association analysis of serum lipidome profiles with AD biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort (N=1,395). We identified lipid species, classes, and network modules that were significantly associated with cross-sectional and longitudinal changes of A/T/N biomarkers for AD. Notably, we identified the lysoalkylphosphatidylcholine (LPC(O)) as associated with "A/N" biomarkers at baseline at lipid species, class, and module levels. Also, GM3 ganglioside showed significant association with baseline levels and longitudinal changes of the "N" biomarkers at species and class levels. Our study of circulating lipids and central AD biomarkers enabled identification of lipids that play potential roles in the cascade of AD pathogenesis. Our results suggest dysregulation of lipid metabolic pathways as precursors to AD development and progression.
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    Correction to: BMI1 is associated with CSF amyloid-β and rates of cognitive decline in Alzheimer’s disease
    (BMC, 2022-01-20) Kim, Jun Pyo; Kim, Bo‑Hyun; Bice, Paula J.; Seo, Sang Won; Bennett, David A.; Saykin, Andrew J.; Nho, Kwangsik; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
    Erratum for: BMI1 is associated with CS8F amyloid-β and rates of cognitive decline in Alzheimer's disease. Kim JP, Kim BH, Bice PJ, Seo SW, Bennett DA, Saykin AJ, Nho K; Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Res Ther. 2021 Oct 5;13(1):164. doi: 10.1186/s13195-021-00906-4. PMID: 34610832
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    CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET
    (Springer Nature, 2024-09-20) Nho, Kwangsik; Risacher, Shannon L.; Apostolova, Liana G.; Bice, Paula J.; Brosch, Jared R.; Deardorff, Rachael; Faber, Kelley; Farlow, Martin R.; Foroud, Tatiana; Gao, Sujuan; Rosewood, Thea; Kim, Jun Pyo; Nudelman, Kelly; Yu, Meichen; Aisen, Paul; Sperling, Reisa; Hooli, Basavaraj; Shcherbinin, Sergey; Svaldi, Diana; Jack, Clifford R., Jr.; Jagust, William J.; Landau, Susan; Vasanthakumar, Aparna; Waring, Jeffrey F.; Doré, Vincent; Laws, Simon M.; Masters, Colin L.; Porter, Tenielle; Rowe, Christopher C.; Villemagne, Victor L.; Dumitrescu, Logan; Hohman, Timothy J.; Libby, Julia B.; Mormino, Elizabeth; Buckley, Rachel F.; Johnson, Keith; Yang, Hyun-Sik; Petersen, Ronald C.; Ramanan, Vijay K.; Ertekin-Taner, Nilüfer; Vemuri, Prashanthi; Cohen, Ann D.; Fan, Kang-Hsien; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Ali, Muhammad; Benzinger, Tammie; Cruchaga, Carlos; Hobbs, Diana; De Jager, Philip L.; Fujita, Masashi; Jadhav, Vaishnavi; Lamb, Bruce T.; Tsai, Andy P.; Castanho, Isabel; Mill, Jonathan; Weiner, Michael W.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI); Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN); Australian Imaging, Biomarker & Lifestyle Study (AIBL); Saykin, Andrew J.; Radiology and Imaging Sciences, School of Medicine
    Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.
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    Dysregulated expression levels of APH1B in peripheral blood are associated with brain atrophy and amyloid-β deposition in Alzheimer's disease
    (BMC, 2021-11-03) Park, Young Ho; Pyun, Jung‑Min; Hodges, Angela; Jang, Jae‑Won; Bice, Paula J.; Kim, SangYun; Saykin, Andrew J.; Nho, Kwangsik; Radiology and Imaging Sciences, School of Medicine
    Background: The interaction between the brain and periphery might play a crucial role in the development of Alzheimer's disease (AD). Methods: Using blood transcriptomic profile data from two independent AD cohorts, we performed expression quantitative trait locus (cis-eQTL) analysis of 29 significant genetic loci from a recent large-scale genome-wide association study to investigate the effects of the AD genetic variants on gene expression levels and identify their potential target genes. We then performed differential gene expression analysis of identified AD target genes and linear regression analysis to evaluate the association of differentially expressed genes with neuroimaging biomarkers. Results: A cis-eQTL analysis identified and replicated significant associations in seven genes (APH1B, BIN1, FCER1G, GATS, MS4A6A, RABEP1, TRIM4). APH1B expression levels in the blood increased in AD and were associated with entorhinal cortical thickness and global cortical amyloid-β deposition. Conclusion: An integrative analysis of genetics, blood-based transcriptomic profiles, and imaging biomarkers suggests that APH1B expression levels in the blood might play a role in the pathogenesis of AD.
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    Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4
    (Frontiers, 2018-12-04) Spence, John Paul; Reiter, Jill L.; Qiu, Bin; Gu, Hao; Garcia, Dawn K.; Zhang, Lingling; Graves, Tamara; Williams, Kent E.; Bice, Paula J.; Zou, Yi; Lai, Zhao; Yong, Weidong; Liang, Tiebing; Medicine, School of Medicine
    Humans show sex differences related to alcohol use disorders (AUD). Animal model research has the potential to provide important insight into how sex differences affect alcohol consumption, particularly because female animals frequently drink more than males. In previous work, inbred strains of the selectively bred alcohol-preferring (P) and non-preferring (NP) rat lines revealed a highly significant quantitative trait locus (QTL) on rat chromosome 4, with a logarithm of the odds score of 9.2 for alcohol consumption. Recently, interval-specific congenic strains (ISCS) were developed by backcrossing the congenic P.NP line to inbred P (iP) rats to further refine the chromosome 4 QTL region. Two ISCS sub-strains, ISCS-A and ISCS-B, were obtained with a narrowed QTL, where the smallest region of overlap consisted of 8.9 Mb in ISCS-B. Interestingly, we found that females from both ISCS lines consumed significantly less alcohol than female iP controls (p < 0.05), while no differences in alcohol consumption were observed between male ISCS and iP controls. RNA-sequencing was performed on the nucleus accumbens of alcohol-naïve female ISCS-B and iP rats, which revealed differentially expressed genes (DEG) with greater than 2-fold change and that were functionally relevant to behavior. These DEGs included down-regulation of Oxt, Asb4, Gabre, Gabrq, Chat, Slc5a7, Slc18a8, Slc10a4, and Ngfr, and up-regulation of Ttr, Msln, Mpzl2, Wnt6, Slc17a7, Aldh1a2, and Gstm2. Pathway analysis identified significant alterations in gene networks controlling nervous system development and function, as well as cell signaling, GABA and serotonin receptor signaling and G-protein coupled receptor signaling. In addition, β-estradiol was identified as the most significant upstream regulator. The expression levels of estrogen-responsive genes that mapped to the QTL interval and have been previously associated with alcohol consumption were measured using RT-qPCR. We found that expression of the Adcyap1r1 gene, encoding the pituitary adenylate cyclase-activating polypeptide type 1 (PAC1) receptor, was upregulated in female ISCS-B compared to female iP controls, while no differences were exhibited in males. In addition, sequence variants in the Adcyap1r1 promoter region showed a differential response to estrogen stimulation in vitro. These findings demonstrate that rat chromosome 4 QTL contains genetic variants that respond to estrogen and are associated with female alcohol consumption.
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    Fine mapping and expression of candidate genes within the chromosome 10 QTL region of the high and low alcohol-drinking rats
    (ScienceDirect, 2010-09) Bice, Paula J.; Liang, Tiebing; Zhang, Lili; Graves, Tamara J.; Carr, Lucinda G.; Lai, Dongbing; Kimpel, Mark W.; Foroud, Tatiana; Medicine, School of Medicine
    The high and low alcohol-drinking (HAD and LAD) rats were selectively bred for differences in alcohol intake. The HAD/LAD rats originated from the N/Nih heterogeneous stock developed from intercrossing eight inbred rat strains. The HAD×LAD F2 were genotyped, and a powerful analytical approach, using ancestral recombination and F2 recombination, was used to narrow a quantitative trait loci (QTL) for alcohol drinking to a 2-cM region on distal chromosome 10 that was in common in the HAD1/LAD1 and HAD2/LAD2 analyses. Quantitative real-time PCR was used to examine mRNA expression of six candidate genes (Crebbp, Trap1, Gnptg, Clcn7, Fahd1, and Mapk8ip3) located within the narrowed QTL region in the HAD1/LAD1 rats. Expression was examined in five brain regions, including the nucleus accumbens, amygdala, caudate putamen, hippocampus, and prefrontal cortex. All six genes showed differential expression in at least one brain region. Of the genes tested in this study, Crebbp and Mapk8ip3 may be the most promising candidates with regard to alcohol drinking.
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    Genome-wide transcriptome analysis of Aβ deposition on PET in a Korean cohort
    (Wiley, 2024) Park, Tamina; Hwang, Jiyun; Liu, Shiwei; Chaudhuri, Soumilee; Han, Sang Won; Yi, Dahyun; Byun, Min Soo; Huang, Yen-Ning; Rosewood, Thea; Jung, Gijung; Kim, Min Jeong; Ahn, Hyejin; Lee, Jun-Young; Kim, Yu Kyeong; Cho, MinYoung; Bice, Paula J.; Craft, Hannah; Risacher, Shannon L.; Gao, Hongyu; Liu, Yunlong; Kim, SangYun; Park, Young Ho; Lee, Dong Young; Saykin, Andrew J.; Nho, Kwangsik; Radiology and Imaging Sciences, School of Medicine
    Introduction: Despite the recognized importance of including ethnic diversity in Alzheimer's disease (AD) research, substantial knowledge gaps remain, particularly in Asian populations. Methods: RNA sequencing was performed on blood samples from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) to perform differential gene expression (DGE), gene co-expression network, gene-set enrichment, and machine learning analyses for amyloid beta (Aβ) deposition on positron emission tomography. Results: DGE analysis identified 265 dysregulated genes associated with Aβ deposition and replicated three AD-associated genes in an independent Korean cohort. Network analysis identified two modules related to pathways including a natural killer (NK) cell-mediated immunity. Machine learning analysis showed the classification of Aβ positivity improved with the inclusion of gene expression data. Discussion: Our results in a Korean population suggest Aβ deposition-associated genes are enriched in NK cell-mediated immunity, providing a better understanding of AD molecular mechanisms and yielding potential diagnostic and therapeutic strategies. Highlights: Dysregulated genes were associated with amyloid beta (Aβ) deposition on positron emission tomography in a Korean cohort. Dysregulated genes in Alzheimer's disease were replicated in an independent Korean cohort. Gene network modules were associated with Aβ deposition. Natural killer (NK) cell proportion in blood was associated with Aβ deposition. Dysregulated genes were related to a NK cell-mediated immunity.