Browsing by Author "Alzheimer's Disease Neuroimaging Initiative"

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    The Alzheimer's Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans
    (Elsevier, 2015-07) Kang, Ju-Hee; Korecka, Magdalena; Figurski, Michal J.; Toledo, Jon B.; Blennow, Kaj; Zetterberg, Henrik; Waligorska, Teresa; Brylska, Magdalena; Fields, Leona; Shah, Nirali; Soares, Holly; Dean, Robert A.; Vanderstichele, Hugo; Petersen, Ronald C.; Aisen, Paul S.; Saykin, Andrew J.; Weiner, Michael W.; Trojanowski, John Q.; Shaw, Leslie M.; Alzheimer's Disease Neuroimaging Initiative; Department of Radiology and Imaging Sciences, School of Medicine
    INTRODUCTION: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aβ1-42), t-tau, and p-tau181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. METHODS: Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aβ1-42, t-tau, and p-tau181 data. RESULTS: CSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies. DISCUSSION: Further studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials.
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    Building a Surface Atlas of Hippocampal Subfields from MRI Scans using FreeSurfer, FIRST and SPHARM
    (Institute of Electrical and Electronics Engineers, 2014-08) Cong, Shan; Rizkalla, Maher; Du, Eliza Y.; West, John; Risacher, Shannon; Saykin, Andrew J.; Shen, Li; Alzheimer's Disease Neuroimaging Initiative; Department of Medicine, IU School of Medicine
    The hippocampus is widely studied with neuroimaging techniques given its importance in learning and memory and its potential as a biomarker for brain disorders such as Alzheimer's disease and epilepsy. However, its complex folding anatomy often presents analytical challenges. In particular, the critical hippocampal subfield information is usually ignored by hippocampal registration in detailed morphometric studies. Such an approach is thus inadequate to accurately characterize hippocampal morphometry and effectively identify hippocampal structural changes related to different conditions. To bridge this gap, we present our initial effort towards building a computational framework for subfield-guided hippocampal morphometry. This initial effort is focused on surface-based morphometry and aims to build a surface atlas of hippocampal subfields. Using the FreeSurfer software package, we obtain valuable hippocampal subfield information. Using the FIRST software package, we extract reliable hippocampal surface information. Using SPHARM, we develop an approach to create an atlas by mapping interpolated subfield information onto an average surface. The empirical result using ADNI data demonstrates the promise and good reproducibility of the proposed method.
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    Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype
    (Elsevier, 2013) Thambisetty, Madhav; An, Yang; Nalls, Michael; Sojkova, Jitka; Swaminathan, Shanker; Zhou, Yun; Singleton, Andrew B.; Wong, Dean F.; Ferrucci, Luigi; Saykin, Andrew J.; Resnick, Susan M.; Baltimore Longitudinal Study of Aging; Alzheimer's Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
    Background: The rs3818361 single nucleotide polymorphism in complement component (3b/4b) receptor-1 (CR1) is associated with increased risk of Alzheimer's disease (AD). Although this novel variant is associated with a small effect size and is unlikely to be useful as a predictor of AD risk, it might provide insights into AD pathogenesis. We examined the association between rs3818361 and brain amyloid deposition in nondemented older individuals. Methods: We used (11)C-Pittsburgh Compound-B positron emission tomography to quantify brain amyloid burden in 57 nondemented older individuals (mean age 78.5 years) in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging. In a replication study, we analyzed (11)C-Pittsburgh Compound-B positron emission tomography data from 22 cognitively normal older individuals (mean age 77.1 years) in the Alzheimer's Disease Neuroimaging Initiative dataset. Results: Risk allele carriers of rs3818361 have lower brain amyloid burden relative to noncarriers. There is a strikingly greater variability in brain amyloid deposition in the noncarrier group relative to risk carriers, an effect explained partly by APOE genotype. In noncarriers of the CR1 risk allele, APOE ε4 individuals showed significantly higher brain amyloid burden relative to APOE ε4 noncarriers. We also independently replicate our observation of lower brain amyloid burden in risk allele carriers of rs3818361 in the Alzheimer's Disease Neuroimaging Initiative sample. Conclusions: Our findings suggest complex mechanisms underlying the interaction of CR1, APOE, and brain amyloid pathways in AD. Our results are relevant to treatments targeting brain Aβ in nondemented individuals at risk for AD and suggest that clinical outcomes of such treatments might be influenced by complex gene-gene interactions.
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    Examining the role of repeated test exposure over 12 months across ADNI protocols
    (Wiley, 2022) Hammers, Dustin B.; Duff, Kevin; Apostolova, Liana G.; Alzheimer's Disease Neuroimaging Initiative; Neurology, School of Medicine
    Objective: Changes to study protocols during longitudinal research may alter cognitive testing schedules over time. Unlike in prior Alzheimer's Disease Neuroimaging Initiative (ADNI) protocols, where testing occurred twice annually, participants enrolled in the ADNI-3 are no longer exposed to cognitive materials at 6 months. This may affect their 12-month performance relative to earlier ADNI cohorts, and potentially confounds data harmonization attempts between earlier and later ADNI protocols. Method: Using data from participants enrolled across multiple ADNI protocols, this study investigated whether test exposure during 6-month cognitive evaluation influenced scores on subsequent 12-month evaluation. Results: No interaction effects were observed between test exposure group and time at 12 months on cognitive performance. No improvements, and limited declines, were seen between baseline and 12-month follow-up scores on most measures. Conclusions: The 6-month testing session had minimal impact on 12-month performance in ADNI. Collapsing longitudinal data across ADNI protocols in future research appears appropriate.
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    Frontolimbic atrophy is associated with agitation and aggression in mild cognitive impairment and Alzheimer's disease
    (Wiley, 2013) Trzepacz, Paula T.; Yu, Peng; Bhamidipati, Phani K.; Willis, Brian; Forrester, Tammy; Tabas, Linda; Schwarz, Adam J.; Saykin, Andrew J.; Alzheimer's Disease Neuroimaging Initiative; Psychiatry, School of Medicine
    Background: The neuroanatomy of agitation and aggression in Alzheimer's disease is not well understood. Methods: We analyzed 24 months of Alzheimer's Disease Neuroimaging Initiative data for patients with Alzheimer's disease, mild cognitive impairment-stable, and mild cognitive impairment-converter (n = 462) using the Neuropsychiatric Inventory Questionnaire Agitation and Aggression subscale. Magnetic resonance imaging regions of interest that correlated with Neuropsychiatric Inventory Questionnaire Agitation and Aggression subscale raw scores were included in mixed-model, repeated-measures analyses of agitation and aggression over time with age, sex, apolipoprotein E ε4 status, education, and Mini-Mental State Examination score as covariates. Results: Neuropsychiatric Inventory Questionnaire Agitation and Aggression subscale scores worsened in patients with Alzheimer's disease and in mild cognitive impairment-converter (P < .05; trend for mild cognitive impairment, P = .0518). Greater agitation and aggression severity was associated with greater atrophy of frontal, insular, amygdala, cingulate, and hippocampal regions of interest (P < .05). Mini-Mental State Examination score was significant in mixed-effect model repeated measures only in mild cognitive impairment-converters for posterior regions of interest. Demographics and apolipoprotein ε4 were not associated with agitation and aggression. Conclusions: Agitation and aggression in Alzheimer's disease and mild cognitive impairment is associated with neurodegeneration affecting the anterior salience network that may reduce capacity to process and regulate behaviors properly.
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    Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans
    (Elsevier, 2015-07) Saykin, Andrew J.; Shen, Li; Yao, Xiaohui; Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Ramanan, Vijay K.; Foroud, Tatiana M.; Faber, Kelly M.; Sarwar, Nadeem; Munsie, Leanne M.; Hu, Xiaolan; Soares, Holly D.; Potkin, Steven G.; Thompson, Paul M.; Kauwe, John S. K.; Kaddurah-Daouk, Rima; Green, Robert C.; Toga, Arthur W.; Weiner, Michael W.; Alzheimer's Disease Neuroimaging Initiative; Department of Radiology and Imaging Sciences, IU School of Medicine
    INTRODUCTION: Genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) have been crucial in advancing the understanding of Alzheimer's disease (AD) pathophysiology. Here, we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. METHODS: Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing data have been obtained and disseminated. RESULTS: ADNI genetic data have been downloaded thousands of times, and >300 publications have resulted, including reports of large-scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies used ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first whole exome and whole genome sequencing data sets and reports in healthy controls, mild cognitive impairment, and AD. DISCUSSION: Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multiomics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological processes. Fortunately, a broad swath of the scientific community has accepted this grand challenge.
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    Genome-wide association study identifies susceptibility loci of brain atrophy to NFIA and ST18 in Alzheimer's disease
    (Elsevier, 2021-06) Kim, Bo-Hyun; Nho, Kwangsik; Lee, Jong-Min; Alzheimer's Disease Neuroimaging Initiative; Radiology & Imaging Sciences, School of Medicine
    To identify genetic variants influencing cortical atrophy in Alzheimer's disease (AD), we performed genome-wide association studies (GWAS) of mean cortical thicknesses in 17 AD-related brain. In this study, we used neuroimaging and genetic data of 919 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, which include 268 cognitively normal controls, 488 mild cognitive impairment, 163 AD individuals. We performed GWAS with 3,041,429 single nucleotide polymorphisms (SNPs) for cortical thickness. The results of GWAS indicated that rs10109716 in ST18 (ST18 C2H2C-type zinc finger transcription factor) and rs661526 in NFIA (nuclear factor I A) genes are significantly associated with mean cortical thicknesses of the left inferior frontal gyrus and left parahippocampal gyrus, respectively. The rs661526 regulates the expression levels of NFIA in the substantia nigra and frontal cortex and rs10109716 regulates the expression levels of ST18 in the thalamus. These results suggest a crucial role of identified genes for cortical atrophy and could provide further insights into the genetic basis of AD.
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    Genome-wide association study of Alzheimer's disease
    (Springer Nature, 2012-05-15) Kamboh, M. I.; Demirci, F. Y.; Wang, X.; Minster, R. L.; Carrasquillo, M. M.; Pankratz, V. S.; Younkin, S. G.; Saykin, A. J.; Alzheimer's Disease Neuroimaging Initiative; Jun, G.; Baldwin, C.; Logue, M. W.; Buros, J.; Farrer, L.; Pericak-Vance, M. A.; Haines, J. L.; Sweet, R. A.; Ganguli, M.; Feingold, E.; DeKosky, S. T.; Lopez, O. L.; Barmada, M. M.; Radiology and Imaging Sciences, School of Medicine
    In addition to apolipoprotein E (APOE), recent large genome-wide association studies (GWASs) have identified nine other genes/loci (CR1, BIN1, CLU, PICALM, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and ABCA7) for late-onset Alzheimer's disease (LOAD). However, the genetic effect attributable to known loci is about 50%, indicating that additional risk genes for LOAD remain to be identified. In this study, we have used a new GWAS data set from the University of Pittsburgh (1291 cases and 938 controls) to examine in detail the recently implicated nine new regions with Alzheimer's disease (AD) risk, and also performed a meta-analysis utilizing the top 1% GWAS single-nucleotide polymorphisms (SNPs) with P<0.01 along with four independent data sets (2727 cases and 3336 controls) for these SNPs in an effort to identify new AD loci. The new GWAS data were generated on the Illumina Omni1-Quad chip and imputed at ~2.5 million markers. As expected, several markers in the APOE regions showed genome-wide significant associations in the Pittsburg sample. While we observed nominal significant associations (P<0.05) either within or adjacent to five genes (PICALM, BIN1, ABCA7, MS4A4/MS4A6E and EPHA1), significant signals were observed 69-180 kb outside of the remaining four genes (CD33, CLU, CD2AP and CR1). Meta-analysis on the top 1% SNPs revealed a suggestive novel association in the PPP1R3B gene (top SNP rs3848140 with P = 3.05E-07). The association of this SNP with AD risk was consistent in all five samples with a meta-analysis odds ratio of 2.43. This is a potential candidate gene for AD as this is expressed in the brain and is involved in lipid metabolism. These findings need to be confirmed in additional samples.
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    Immunity gene IFITM3 variant: Relation to cognition and Alzheimer's disease pathology
    (Alzheimer’s Association, 2022-06-21) Pyun, Jung-Min; Park, Young Ho; Hodges, Angela; Jang, Jae-Won; Bice, Paula J.; Kim, SangYun; Saykin, Andrew J.; Nho, Kwangsik; AddNeuroMed Consortium; Alzheimer's Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
    Introduction: We investigated single-nucleotide polymorphisms (SNPs) in IFITM3, an innate immunity gene and modulator of amyloid beta in Alzheimer's disease (AD), for association with cognition and AD biomarkers. Methods: We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1565) and AddNeuroMed (N = 633) as discovery and replication samples, respectively. We performed gene-based association analysis of SNPs in IFITM3 with cognitive performance and SNP-based association analysis with cognitive decline and amyloid, tau, and neurodegeneration biomarkers for AD. Results: Gene-based association analysis showed that IFITM3 was significantly associated with cognitive performance. Particularly, rs10751647 in IFITM3 was associated with less cognitive decline, less amyloid and tau burden, and less brain atrophy in ADNI. The association of rs10751647 with cognitive decline and brain atrophy was replicated in AddNeuroMed. Discussion: This suggests that rs10751647 in IFITM3 is associated with less vulnerability for cognitive decline and AD biomarkers, providing mechanistic insight regarding involvement of immunity and infection in AD. Highlights: IFITM3 is significantly associated with cognitive performance.rs10751647 in IFITM3 is associated with cognitive decline rates with replication.rs10751647 is associated with amyloid beta load, cerebrospinal fluid phosphorylated tau levels, and brain atrophy.rs10751647 is associated with IFITM3 expression levels in blood and brain.rs10751647 in IFITM3 is related to less vulnerability to Alzheimer's disease pathogenesis.
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    Impact of the Alzheimer's Disease Neuroimaging Initiative, 2004 to 2014
    (Elsevier, 2015-07) Weiner, Michael W.; Veitch, Dallas P.; Aisen, Paul S.; Beckett, Laurel A.; Cairns, Nigel J.; Cedarbaum, Jesse; Donohue, Michael C.; Green, Robert C.; Harvey, Danielle; Jack, Clifford R.; Jagust, William; Morris, John C.; Petersen, Ronald C.; Saykin, Andrew J.; Shaw, Leslie; Thompson, Paul M.; Toga, Arthur W.; Trojanowski, John Q.; Alzheimer's Disease Neuroimaging Initiative; Department of Radiology and Imaging Sciences, IU School of Medicine
    INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) was established in 2004 to facilitate the development of effective treatments for Alzheimer's disease (AD) by validating biomarkers for AD clinical trials. METHODS: We searched for ADNI publications using established methods. RESULTS: ADNI has (1) developed standardized biomarkers for use in clinical trial subject selection and as surrogate outcome measures; (2) standardized protocols for use across multiple centers; (3) initiated worldwide ADNI; (4) inspired initiatives investigating traumatic brain injury and post-traumatic stress disorder in military populations, and depression, respectively, as an AD risk factor; (5) acted as a data-sharing model; (6) generated data used in over 600 publications, leading to the identification of novel AD risk alleles, and an understanding of the relationship between biomarkers and AD progression; and (7) inspired other public-private partnerships developing biomarkers for Parkinson's disease and multiple sclerosis. DISCUSSION: ADNI has made myriad impacts in its first decade. A competitive renewal of the project in 2015 would see the use of newly developed tau imaging ligands, and the continued development of recruitment strategies and outcome measures for clinical trials.