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Item C-reactive protein and risk of cognitive decline: The REGARDS study(PLOS, 2020-12-31) Rentería, Miguel Arce; Gillett, Sarah R.; McClure, Leslie A.; Wadley, Virginia G.; Glasser, Stephen P.; Howard, Virginia J.; Kissela, Brett M.; Unverzagt, Frederick W.; Jenny, Nancy S.; Manly, Jennifer J.; Cushman, Mary; Psychiatry, School of MedicineMarkers of systemic inflammation are associated with increased risk of cognitive impairment, but it is unclear if they are associated with a faster rate of cognitive decline and whether this relationship differs by race. Our objective was to examine the association of baseline C-reaction protein (CRP) with cognitive decline among a large racially diverse cohort of older adults. Participants included 21,782 adults aged 45 and older (36% were Black, Mean age at baseline 64) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. CRP was measured at baseline and used as a continuous variable or a dichotomous grouping based on race-specific 90th percentile cutoffs. Cognitive measures of memory and verbal fluency were administered every 2 years for up to 12 years. Latent growth curve models evaluated the association of CRP on cognitive trajectories, adjusting for relevant demographic and health factors. We found that higher CRP was associated with worse memory (B = -.039, 95% CI [-.065,-.014]) and verbal fluency at baseline (B = -.195, 95% CI [-.219,-.170]), but not with rate of cognitive decline. After covariate adjustment, the association of CRP on memory was attenuated (B = -.005, 95% CI [-.031,-.021]). The association with verbal fluency at baseline, but not over time, remained (B = -.042, 95% CI [-.067,-.017]). Race did not modify the association between CRP and cognition. Findings suggest that levels of CRP at age 45+, are a marker of cognitive impairment but may not be suitable for risk prediction for cognitive decline.Item The characterisation of subjective cognitive decline(Elsevier, 2020-03) Jessen, Frank; Amariglio, Rebecca E.; Buckley, Rachel F.; van der Flier, Wiesje M.; Han, Ying; Molinuevo, José Luis; Rabin, Laura; Rentz, Dorene M.; Rodriguez-Gomez, Octavio; Saykin, Andrew J.; Sikkes, Sietske A.M.; Smart, Colette M.; Wolfsgruber, Steffen; Wagner, Michael; Medical and Molecular Genetics, School of MedicineA growing awareness about brain health and Alzheimer's disease in the general population is leading to an increasing number of cognitively unimpaired individuals, who are concerned that they have reduced cognitive function, to approach the medical system for help. The term subjective cognitive decline (SCD) was conceived in 2014 to describe this condition. Epidemiological data provide evidence that the risk for mild cognitive impairment and dementia is increased in individuals with SCD. However, the majority of individuals with SCD will not show progressive cognitive decline. An individually tailored diagnostic process might be reasonable to identify or exclude underlying medical conditions in an individual with SCD who actively seeks medical help. An increasing number of studies are investigating the link between SCD and the very early stages of Alzheimer's disease and other neurodegenerative diseases.Item 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 MedicineINTRODUCTION: 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.Item International Cognition and Cancer Task Force Recommendations for Neuroimaging Methods in the Study of Cognitive Impairment in Non-CNS Cancer Patients(Oxford University Press, 2018-03) Deprez, Sabine; Kesler, Shelli R.; Saykin, Andrew J.; Silverman, Daniel H. S.; de Ruiter, Michiel B.; McDonald, Brenna C.; Radiology & Imaging Sciences, IU School of MedicineCancer- and treatment-related cognitive changes have been a focus of increasing research since the early 1980s, with meta-analyses demonstrating poorer performance in cancer patients in cognitive domains including executive functions, processing speed, and memory. To facilitate collaborative efforts, in 2011 the International Cognition and Cancer Task Force (ICCTF) published consensus recommendations for core neuropsychological tests for studies of cancer populations. Over the past decade, studies have used neuroimaging techniques, including structural and functional magnetic resonance imaging (fMRI) and positron emission tomography, to examine the underlying brain basis for cancer- and treatment-related cognitive declines. As yet, however, there have been no consensus recommendations to guide researchers new to this field or to promote the ability to combine data sets. We first discuss important methodological issues with regard to neuroimaging study design, scanner considerations, and sequence selection, focusing on concerns relevant to cancer populations. We propose a minimum recommended set of sequences, including a high-resolution T1-weighted volume and a resting state fMRI scan. Additional advanced imaging sequences are discussed for consideration when feasible, including task-based fMRI and diffusion tensor imaging. Important image data processing and analytic considerations are also reviewed. These recommendations are offered to facilitate increased use of neuroimaging in studies of cancer- and treatment-related cognitive dysfunction. They are not intended to discourage investigator-initiated efforts to develop cutting-edge techniques, which will be helpful in advancing the state of the knowledge. Use of common imaging protocols will facilitate multicenter and data-pooling initiatives, which are needed to address critical mechanistic research questions.Item Interventions Transformed Through Technology to Improve Cognitive Function in Heart Failure(Wolters Kluwer, 2019-11) Pressler, Susan J.; Jung, Miyeon; Haedtke, Christine; School of NursingItem Intrinsic brain activity changes associated with adjuvant chemotherapy in older women with breast cancer: a pilot longitudinal study(Springer, 2019-04-23) Chen, Bihong T.; Jin, Taihao; Patel, Sunita K.; Ye, Ningrong; Ma, Huiyan; Wong, Chi Wah; Rockne, Russell C.; Root, James C.; Saykin, Andrew J.; Ahles, Tim A.; Holodny, Andrei I.; Prakash, Neal; Mortimer, Joanne; Waisman, James; Yuan, Yuan; Li, Daneng; Sedrak, Mina S.; Vazquez, Jessica; Katheria, Vani; Dale, William; Radiology and Imaging Sciences, School of MedicinePurpose Older cancer patients are at increased risk of cancer-related cognitive impairment. The purpose of this study was to assess the alterations in intrinsic brain activity associated with adjuvant chemotherapy in older women with breast cancer. Methods Chemotherapy treatment (CT) group included sixteen women aged ≥ 60 years (range 60–82 years) with stage I-III breast cancers, who underwent both resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological testing with NIH Toolbox for Cognition before adjuvant chemotherapy, at time point 1 (TP1), and again within 1 month after completing chemotherapy, at time point 2 (TP2). Fourteen age- and sex-matched healthy controls (HC) underwent the same assessments at matched intervals. Three voxel-wise rs-fMRI parameters: amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo), were computed at each time point. The changes in rs-fMRI parameters from TP1 to TP2 for each group, the group differences in changes (the CT group vs. the HC group), and the group difference in the baseline rs-fMRI parameters were assessed. In addition, correlative analysis between the rs-fMRI parameters and neuropsychological testing scores was also performed. Results In the CT group, one brain region, which included parts of the bilateral subcallosal gyri and right anterior cingulate gyrus, displayed increased ALFF from TP1 to TP2 (cluster p-corrected=0.024); another brain region in the left precuneus displayed decreased fALFF from TP1 to TP2 (cluster level p-corrected=0.025). No significant changes in the rs-fMRI parameters from TP1 to TP2 were observed in the HC group. Although ALFF and fALFF alterations were observed only in the CT group, none of the between-group differences in rs-fMRI parameter changes reached statistical significance. Conclusions Our study results of ALFF and fALFF alterations in the chemotherapy-treated women suggest that adjuvant chemotherapy may affect intrinsic brain activity in older women with breast cancer.Item Neuropathological correlates and genetic architecture of microglial activation in elderly human brain(Springer Nature, 2019-01-24) Felsky, Daniel; Roostaei, Tina; Nho, Kwangsik; Risacher, Shannon L.; Bradshaw, Elizabeth M.; Petyuk, Vlad; Schneider, Julie A.; Saykin, Andrew; Bennett, David A.; De Jager, Philip L.; Radiology and Imaging Sciences, School of MedicineMicroglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. Here we report that the proportion of morphologically activated microglia (PAM) in postmortem cortical tissue is strongly associated with β-amyloid, tau-related neuropathology, and the rate of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE ε4, the strongest genetic risk factor for Alzheimer's disease, and mediation models support an upstream role for microglial activation in Alzheimer's disease via accumulation of tau. Further, we identify a common variant (rs2997325) influencing PAM that also affects in vivo microglial activation measured by [11C]-PBR28 PET in an independent cohort. Thus, our analyses begin to uncover pathways regulating resident neuroinflammation and identify overlaps of PAM's genetic architecture with those of Alzheimer's disease and several other traits.Item The Nexus of Sensory Loss, Cognitive Impairment, and Functional Decline in Older Adults: A Scoping Review(Oxford Academic, 2022-10) Liu, Chiung-ju; Chang, Pei-Shiun; Griffith, Cheryl F; Hanley, Stephanie I; Lu, Yvonne; School of NursingBACKGROUND AND OBJECTIVES: The prevalence of cognitive impairment and sensory loss in hearing or vision increases with age. Based on the Information Processing Model, cognitive impairment coupled with sensory loss may exacerbate disability in late life. Yet this issue has not been systematically studied. The purpose of this scoping review was to examine the literature that studied the relationship between cognitive impairment, sensory loss, and activities of daily living in older adults. RESEARCH DESIGN AND METHODS: Two reviewers independently screened 1,410 studies identified from 5 electronic databases (Medline, EMBASE, PsycINFO, CINHAL, and Web of Science). The search was completed in June 2020. A study was eligible if it included measurements of cognitive function, vision or hearing, and activities of daily living. Additionally, the data analyses must address how cognitive impairment and sensory loss are related to the performance of activities of daily living. RESULTS: The final review included 15 studies. Findings show an additive effect of cognitive impairment and sensory loss on the activities of daily living. Cognitive impairment or vision loss independently relates to the decline in activities of daily living. Hearing loss relates to the decline only when the loss is severe, or if the daily task is hearing - specific. DISCUSSION AND IMPLICATIONS: Older adults with coexisting sensory loss and cognitive impairment have the highest risk or prevalence of disability, comparing to cognitive impairment or sensory loss alone. This finding highlights the importance of developing interventions to reduce the risk of disability for older adults experiencing multiple impairments.Item Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study(Oxford University Press, 2021-01-27) Van Dyk, Kathleen; Zhou, Xingtao; Small, Brent J.; Ahn, Jaeil; Zhai, Wanting; Ahles, Tim; Graham, Deena; Jacobsen, Paul B.; Jim, Heather; McDonald, Brenna C.; Nudelman Holohan, Kelly; Patel, Sunita K.; Rebeck, G. William; Root, James C.; Saykin, Andrew J.; Cohen, Harvey Jay; Mandelblatt, Jeanne S.; Carroll, Judith E.; Medical and Molecular Genetics, School of MedicineBackground: Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene ε4 polymorphisms. APOE ε4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas ε2 polymorphisms protect against AD. However, the effects of ε2 polymorphisms on CRCD have not been evaluated. Methods: We evaluated nonmetastatic breast cancer survivors (n = 427) and matched noncancer controls (n = 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an ε2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with ε2/ε4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any ε4 positivity. Results: There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta = 0.32, 95% confidence interval = 0.00 to 0.65); the chemotherapy group with an ε2 allele had higher scores at baseline and maintained higher scores over time compared with those without an ε2 allele, and this protective effect was not seen for other groups. There was no effect of ε2 on learning and memory domain scores. Conclusions: APOE ε2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.Item Reply: To PMID 25559091(Wiley Blackwell (John Wiley & Sons), 2015-11) Nho, Kwangsik; Farrer, Lindsay A.; Saykin, Andrew J.; Department of Radiology and Imaging Sciences, IU School of Medicine