Browsing by Author "Rowe, Christopher C."
Now showing 1 - 10 of 13
Results Per Page
Sort Options
Item APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies(Wiley, 2022) Wang, Tingting; Huynh, Kevin; Giles, Corey; Mellett, Natalie A.; Duong, Thy; Nguyen, Anh; Lim, Wei Ling Florence; Smith, Alex At; Olshansky, Gavriel; Cadby, Gemma; Hung, Joseph; Hui, Jennie; Beilby, John; Watts, Gerald F.; Chatterjee, Pratishtha; Martins, Ian; Laws, Simon M.; Bush, Ashley I.; Rowe, Christopher C.; Villemagne, Victor L.; Ames, David; Masters, Colin L.; Taddei, Kevin; Doré, Vincent; Fripp, Jürgen; Arnold, Matthias; Kastenmüller, Gabi; Nho, Kwangsik; Saykin, Andrew J.; Baillie, Rebecca; Han, Xianlin; Martins, Ralph N.; Moses, Eric K.; Kaddurah-Daouk, Rima; Meikle, Peter J.; Radiology and Imaging Sciences, School of MedicineIntroduction: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Discussion: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.Item Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume(Springer, 2022) Milicic, Lidija; Vacher, Michael; Porter, Tenielle; Doré, Vincent; Burnham, Samantha C.; Bourgeat, Pierrick; Shishegar, Rosita; Doecke, James; Armstrong, Nicola J.; Tankard, Rick; Maruff, Paul; Masters, Colin L.; Rowe, Christopher C.; Villemagne, Victor L.; Laws, Simon M.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Australian Imaging Biomarkers and Lifestyle (AIBL) Study; Medical and Molecular Genetics, School of MedicineThe concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer's Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer's disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.Item Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease(Springer Nature, 2022-06-06) Cadby, Gemma; Giles, Corey; Melton, Phillip E.; Huynh, Kevin; Mellett, Natalie A.; Duong, Thy; Nguyen, Anh; Cinel, Michelle; Smith, Alex; Olshansky, Gavriel; Wang, Tingting; Brozynska, Marta; Inouye, Mike; McCarthy, Nina S.; Ariff, Amir; Hung, Joseph; Hui, Jennie; Beilby, John; Dubé, Marie-Pierre; Watts, Gerald F.; Shah, Sonia; Wray, Naomi R.; Lim, Wei Ling Florence; Chatterjee, Pratishtha; Martins, Ian; Laws, Simon M.; Porter, Tenielle; Vacher, Michael; Bush, Ashley I.; Rowe, Christopher C.; Villemagne, Victor L.; Ames, David; Masters, Colin L.; Taddei, Kevin; Arnold, Matthias; Kastenmüller, Gabi; Nho, Kwangsik; Saykin, Andrew J.; Han, Xianlin; Kaddurah-Daouk, Rima; Martins, Ralph N.; Blangero, John; Meikle, Peter J.; Moses, Eric K.; Radiology and Imaging Sciences, School of MedicineWe integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10-3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.Item Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease(Nature, 2020-11-10) Huynh, Kevin; Lim, Wei Ling Florence; Giles, Corey; Jayawardana, Kaushala S.; Salim, Agus; Mellett, Natalie A.; Smith, Adam Alexander T.; Olshansky, Gavriel; Drew, Brian G.; Chatterjee, Pratishtha; Martins, Ian; Laws, Simon M.; Bush, Ashley I.; Rowe, Christopher C.; Villemagne, Victor L.; Ames, David; Masters, Colin L.; Arnold, Matthias; Nho, Kwangsik; Saykin, Andrew J.; Baillie, Rebecca; Han, Xianlin; Kaddurah-Daouk, Rima; Martins, Ralph N.; Meikle, Peter J.; BioHealth Informatics, School of Informatics and ComputingChanges to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation., The onset and pathology of Alzheimer’s disease (AD) is associated with changes to lipid metabolism. Here, the authors analysed 569 lipids from 32 classes and subclasses in two independent patient cohorts to identify key lipid pathways to link the plasma lipidome with AD and the future onset of AD.Item 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 MedicineDetermining 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.Item Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer disease: Phase 3 study(Elsevier, 2015) Sabri, Osama; Sabbagh, Marwan N.; Seibyl, John; Barthel, Henryk; Akatsu, Hiroyasu; Ouchi, Yasuomi; Senda, Kohei; Murayama, Shigeo; Ishii, Kenji; Takao, Masaki; Beach, Thomas G.; Rowe, Christopher C.; Leverenz, James B.; Ghetti, Bernardino; Ironside, James W.; Catafau, Ana M.; Stephens, Andrew W.; Mueller, Andre; Koglin, Norman; Hoffman, Anja; Roth, Katrin; Reininger, Cornelia; Schulz-Schaeffer, Walter J.; Department of Pathology and Laboratory Medicine, IU School of MedicineBackground Evaluation of brain β-amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias. Methods Open-label, nonrandomized, multicenter, phase 3 study to validate the 18F-labeled β-amyloid tracer florbetaben by comparing in vivo PET imaging with post-mortem histopathology. Results Brain images and tissue from 74 deceased subjects (of 216 trial participants) were analyzed. Forty-six of 47 neuritic β-amyloid-positive cases were read as PET positive, and 24 of 27 neuritic β-amyloid plaque-negative cases were read as PET negative (sensitivity 97.9% [95% confidence interval or CI 93.8–100%], specificity 88.9% [95% CI 77.0–100%]). In a subgroup, a regional tissue-scan matched analysis was performed. In areas known to strongly accumulate β-amyloid plaques, sensitivity and specificity were 82% to 90%, and 86% to 95%, respectively. Conclusions Florbetaben PET shows high sensitivity and specificity for the detection of histopathology-confirmed neuritic β-amyloid plaques and may thus be a valuable adjunct to clinical diagnosis, particularly for the exclusion of AD.Item Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study(SNM, 2016-06) Seibyl, John; Catafau, Ana M.; Barthel, Henryk; Ishii, Kenji; Rowe, Christopher C.; Leverenz, James B.; Ghetti, Bernardino; Ironside, James W.; Takao, Masaki; Akatsu, Hiroyasu; Murayama, Shigeo; Bullich, Santiago; Mueller, Andre; Koglin, Norman; Schulz-Schaeffer, Walter J.; Hoffmann, Anja; Sabbagh, Marwan N.; Stephens, Andrew W.; Sabri, Osama; Department of Pathology & Laboratory Medicine, IU School of MedicineTraining for accurate image interpretation is essential for the clinical use of β-amyloid PET imaging, but the role of interpreter training and the accuracy of the algorithm for routine visual assessment of florbetaben PET scans are unclear. The aim of this study was to test the robustness of the visual assessment method for florbetaben scans, comparing efficacy readouts across different interpreters and training methods and against a histopathology standard of truth (SoT). Methods: Analysis was based on data from an international open-label, nonrandomized, multicenter phase-3 study in patients with or without dementia (ClinicalTrials.gov: NCT01020838). Florbetaben scans were assessed visually and quantitatively, and results were compared with amyloid plaque scores. For visual assessment, either in-person training (n = 3 expert interpreters) or an electronic training method (n = 5 naïve interpreters) was used. Brain samples from participants who died during the study were used to determine the histopathologic SoT using Bielschowsky silver staining (BSS) and immunohistochemistry for β-amyloid plaques. Results: Data were available from 82 patients who died and underwent postmortem histopathology. When visual assessment results were compared with BSS + immunohistochemistry as SoT, median sensitivity was 98.2% for the in-person–trained interpreters and 96.4% for the e-trained interpreters, and median specificity was 92.3% and 88.5%, respectively. Median accuracy was 95.1% and 91.5%, respectively. On the basis of BSS only as the SoT, median sensitivity was 98.1% and 96.2%, respectively; median specificity was 80.0% and 76.7%, respectively; and median accuracy was 91.5% and 86.6%, respectively. Interinterpreter agreement (Fleiss κ) was excellent (0.89) for in-person–trained interpreters and very good (0.71) for e-trained interpreters. Median intrainterpreter agreement was 0.9 for both in-person–trained and e-trained interpreters. Visual and quantitative assessments were concordant in 88.9% of scans for in-person–trained interpreters and in 87.7% of scans for e-trained interpreters. Conclusion: Visual assessment of florbetaben images was robust in challenging scans from elderly end-of-life individuals. Sensitivity, specificity, and interinterpreter agreement were high, independent of expertise and training method. Visual assessment was accurate and reliable for detection of plaques using BSS and immunohistochemistry and well correlated with quantitative assessments.Item Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease(American Academy of Neurology, 2021-03-23) Joseph-Mathurin, Nelly; Wang, Guoqiao; Kantarci, Kejal; Jack, Clifford R., Jr.; McDade, Eric; Hassenstab, Jason; Blazey, Tyler M.; Gordon, Brian A.; Su, Yi; Chen, Gengsheng; Massoumzadeh, Parinaz; Hornbeck, Russ C.; Allegri, Ricardo F.; Ances, Beau M.; Berman, Sarah B.; Brickman, Adam M.; Brooks, William S.; Cash, David M.; Chhatwal, Jasmeer P.; Chui, Helena C.; Correia, Stephen; Cruchaga, Carlos; Farlow, Martin R.; Fox, Nick C.; Fulham, Michael; Ghetti, Bernardino; Graff-Radford, Neill R.; Johnson, Keith A.; Karch, Celeste M.; Laske, Christoph; Lee, Athene K.W.; Levin, Johannes; Masters, Colin L.; Noble, James M.; O’Connor, Antoinette; Perrin, Richard J.; Preboske, Gregory M.; Ringman, John M.; Rowe, Christopher C.; Salloway, Stephen; Saykin, Andrew J.; Schofield, Peter R.; Shimada, Hiroyuki; Shoji, Mikio; Suzuki, Kazushi; Villemagne, Victor L.; Xiong, Chengjie; Yakushev, Igor; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L.S.; Pathology and Laboratory Medicine, School of MedicineObjective: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD). Methods: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease. Results: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year). Conclusion: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.Item Polygenic scores for Alzheimer’s disease risk and resilience predict age at onset of amyloid‐β(Wiley, 2025-01-03) O’Brien, Eleanor K.; Porter, Tenielle; Fernandez, Shane; Cox, Timothy; Dore, Vincent; Bourgeat, Pierrick; Goudey, Benjamin; Doecke, James D.; Masters, Colin L.; Rowe, Christopher C.; Villemagne, Victor L.; Cruchaga, Carlos; Saykin, Andrew J.; Laws, Simon M.; ADOPIC Consortium (AIBL, ADNI, OASIS); Radiology and Imaging Sciences, School of MedicineBackground: Genome‐wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer’s disease (AD) risk, but genetic variation in the onset and progression of AD pathology is less understood. Accumulation of amyloid‐β (Aβ) in the brain is a key pathological hallmark of AD beginning 10 – 20 years prior to cognitive symptoms. We investigated the genetic basis of variation in age at onset (AAO) of brain Aβ by comparing the performance of polygenic scores (PGSs) based on AD risk and resilience with a Aβ‐AAO trait‐specific PGS. Method: 1122 participants from the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) study underwent genome‐wide SNP genotyping and assessment of brain Aβ using positron emission tomography (PET) imaging at two or more timepoints. AAO was the age at which participants were estimated to have crossed the 20 centiloid (CL) threshold for high Aβ. We utilised AD risk and resilience GWAS summary statistics and conducted a GWAS for AAO using a cross‐validation approach (10 test‐validation folds). We used PRSice to identify optimal PGSs for Aβ‐AAO for risk (PGSRisk), resilience (PGSResilience) and Aβ‐AAO (PGSAAO). Result: PGSRisk and PGSResilience were both significantly associated with Aβ‐AAO, such that higher PGSRisk and lower PGSResilience were associated with an earlier Aβ‐AAO. PGSRisk showed the strongest association and explained more variance in Aβ‐AAO than did PGSAAO. When stratified by APOE ε4 carriage, the strongest genetic risk factor for AD, the association of PGSRisk with Aβ‐AAO was stronger among ε4 non‐carriers, whilst PGSResilience, was more strongly associated with Aβ‐AAO in ε4 carriers. Conclusion: PGS based on genetic risk and resilience for AD are both significant predictors of the age at which people are estimated to cross the threshold for high brain Aβ burden. Predicting the age at which a person will pass this threshold would enable treatment at an earlier stage, when it may more effectively delay or prevent symptom onset.Item Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study(Elsevier, 2018-01) Kinnunen, Kirsi M.; Cash, David M.; Poole, Teresa; Frost, Chris; Benzinger, Tammie L. S.; Ahsan, R. Laila; Leung, Kelvin K.; Cardoso, M. Jorge; Modat, Marc; Malone, Ian B.; Morris, John C.; Bateman, Randall J.; Marcus, Daniel S.; Goate, Alison; Salloway, Stephen P.; Correia, Stephen; Sperling, Reisa A.; Chhatwal, Jasmeer P.; Mayeux, Richard P.; Brickman, Adam M.; Martins, Ralph N.; Farlow, Martin R.; Ghetti, Bernardino; Saykin, Andrew J.; Jack, Clifford R.; Schofield, Peter R.; McDade, Eric; Weiner, Michael W.; Ringman, John M.; Thompson, Paul M.; Masters, Colin L.; Rowe, Christopher C.; Rossor, Martin N.; Ourselin, Sebastien; Fox, Nick C.; Neurology, School of MedicineINTRODUCTION: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. METHODS: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. RESULTS: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. DISCUSSION: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.