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Browsing by Author "Risacher, Shannon L."
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Item [(11)C]PiB PET in Gerstmann-Sträussler-Scheinker disease(e-Century Publishing Corporation, 2016) Deters, Kacie D.; Risacher, Shannon L.; Yoder, Karmen K.; Oblak, Adrian L.; Unverzagt, Frederick W.; Murrell, Jill R.; Epperson, Francine; Tallman, Eileen F.; Quaid, Kimberly A.; Farlow, Martin R.; Saykin, Andrew J.; Ghetti, Bernardino; Department of Pathology & Laboratory Medicine, IU School of MedicineGerstmann-Sträussler-Scheinker Disease (GSS) is a familial neurodegenerative disorder characterized clinically by ataxia, parkinsonism, and dementia, and neuropathologically by deposition of diffuse and amyloid plaques composed of prion protein (PrP). The purpose of this study was to evaluate if [(11)C]Pittsburgh Compound B (PiB) positron emission tomography (PET) is capable of detecting PrP-amyloid in PRNP gene carriers. Six individuals at risk for GSS and eight controls underwent [(11)C]PiB PET scans using standard methods. Approximately one year after the initial scan, each of the three asymptomatic carriers (two with PRNP P102L mutation, one with PRNP F198S mutation) underwent a second [(11)C]PiB PET scan. Three P102L carriers, one F198S carrier, and one non-carrier of the F198S mutation were cognitively normal, while one F198S carrier was cognitively impaired during the course of this study. No [(11)C]PiB uptake was observed in any subject at baseline or at follow-up. Neuropathologic study of the symptomatic individual revealed PrP-immunopositive plaques and tau-immunopositive neurofibrillary tangles in cerebral cortex, subcortical nuclei, and brainstem. PrP deposits were also numerous in the cerebellar cortex. This is the first study to investigate the ability of [(11)C]PiB PET to bind to PrP-amyloid in GSS F198S subjects. This finding suggests that [(11)C]PiB PET is not suitable for in vivo assessment of PrP-amyloid plaques in patients with GSS.Item Age at Injury is Associated with the Long-Term Cognitive Outcome of Traumatic Brain Injuries(Elsevier, 2017) Li, Wei; Risacher, Shannon L.; McAllister, Thomas W.; Saykin, Andrew J.; Physician Assistant Studies Program, School of Health and Rehabilitation SciencesAbstract Introduction The association between age at injury (AAI) and long-term cognitive outcome of traumatic brain injuries (TBI) is debatable. Methods Eligible participants with a history of TBI from Alzheimer's Disease Neuroimaging Initiative were divided into a childhood TBI (cTBI) group (the AAI ≤ 21 years old) and an adult TBI (aTBI) group (the AAI > 21 years old). Results The cTBI group has a higher Everyday Cognition total score than the aTBI group. All perceived cognitive functions are worse for the cTBI group than for the aTBI group except memory. By contrast, the cTBI group has higher assessment scores on either the Boston Naming Test or Rey Auditory Verbal Learning Test than the aTBI group. Discussion The AAI is associated with the long-term cognitive outcomes in older adults with a history of TBI.Item Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome(Elsevier, 2019-01) MahmoudianDehkordi, Siamak; Arnold, Matthias; Nho, Kwangsik; Ahmad, Shahzad; Jia, Wei; Xie, Guoxiang; Louie, Gregory; Kueider‐Paisley, Alexandra; Moseley, M. Arthur; Thompson, J. Will; St John Williams, Lisa; Tenenbaum, Jessica D.; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Bhattacharyya, Sudeepa; Toledo, Jon B.; Schafferer, Simon; Klein, Sebastian; Koal, Therese; Risacher, Shannon L.; Kling, Mitchel Allan; Motsinger‐Reif, Alison; Rotroff, Daniel M.; Jack, John; Hankemeier, Thomas; Bennett, David A.; De Jager, Philip L.; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; van Duijn, Cornelia M.; Saykin, Andrew J.; Kastenmüller, Gabi; Kaddurah‐Daouk, Rima; Radiology and Imaging Sciences, School of MedicineIntroduction Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut‐brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). Methods Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD‐related genetic variants, adjusting for confounders and multiple testing. Results In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α‐dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response–related genes implicated in AD showed associations with BA profiles. Discussion We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut‐liver‐brain axis in the pathogenesis of AD.Item Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers(Elsevier, 2019-02) Nho, Kwangsik; Kueider-Paisley, Alexandra; MahmoudianDehkordi, Siamak; Arnold, Matthias; Risacher, Shannon L.; Louie, Gregory; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Kastenmüller, Gabi; Jia, Wei; Xie, Guoxiang; Ahmad, Shahzad; Hankemeier, Thomas; van Duijn, Cornelia M.; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; Saykin, Andrew J.; Kaddurah-Daouk, Rima; Radiology and Imaging Sciences, School of MedicineINTRODUCTION: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-β deposition. METHOD: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET). RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ1-42 ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05). DISCUSSION: This is the first study to show serum-based BA metabolites are associated with "A/T/N" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.Item 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 MedicineThe 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.Item Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline(American Academy of Neurology, 2017-11-21) Risacher, Shannon L.; Anderson, Wesley H.; Charil, Arnaud; Castelluccio, Peter F.; Shcherbinin, Sergey; Saykin, Andrew J.; Schwarz, Adam J.; Radiology and Imaging Sciences, School of MedicineOBJECTIVE: To test the hypothesis that cortical and hippocampal volumes, measured in vivo from volumetric MRI (vMRI) scans, could be used to identify variant subtypes of Alzheimer disease (AD) and to prospectively predict the rate of clinical decline. METHODS: Amyloid-positive participants with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 and ADNI2 with baseline MRI scans (n = 229) and 2-year clinical follow-up (n = 100) were included. AD subtypes (hippocampal sparing [HpSpMRI], limbic predominant [LPMRI], typical AD [tADMRI]) were defined according to an algorithm analogous to one recently proposed for tau neuropathology. Relationships between baseline hippocampal volume to cortical volume ratio (HV:CTV) and clinical variables were examined by both continuous regression and categorical models. RESULTS: When participants were divided categorically, the HpSpMRI group showed significantly more AD-like hypometabolism on 18F-fluorodeoxyglucose-PET (p < 0.05) and poorer baseline executive function (p < 0.001). Other baseline clinical measures did not differ across the 3 groups. Participants with HpSpMRI also showed faster subsequent clinical decline than participants with LPMRI on the Alzheimer's Disease Assessment Scale, 13-Item Subscale (ADAS-Cog13), Mini-Mental State Examination (MMSE), and Functional Assessment Questionnaire (all p < 0.05) and tADMRI on the MMSE and Clinical Dementia Rating Sum of Boxes (CDR-SB) (both p < 0.05). Finally, a larger HV:CTV was associated with poorer baseline executive function and a faster slope of decline in CDR-SB, MMSE, and ADAS-Cog13 score (p < 0.05). These associations were driven mostly by the amount of cortical rather than hippocampal atrophy. CONCLUSIONS: AD subtypes with phenotypes consistent with those observed with tau neuropathology can be identified in vivo with vMRI. An increased HV:CTV ratio was predictive of faster clinical decline in participants with AD who were clinically indistinguishable at baseline except for a greater dysexecutive presentation.Item Amyloid and Tau Pathology are Associated with Cerebral Blood Flow in a Mixed Sample of Nondemented Older Adults with and without Vascular Risk Factors for Alzheimer’s Disease(Elsevier, 2023) Swinford, Cecily G.; Risacher, Shannon L.; Vosmeier, Aaron; Deardorff, Rachael; Chumin, Evgeny J.; Dzemidzic, Mario; Wu, Yu-Chien; Gao, Sujuan; McDonald, Brenna C.; Yoder, Karmen K.; Unverzagt, Frederick W.; Wang, Sophia; Farlow, Martin R.; Brosch, Jared R.; Clark, David G.; Apostolova, Liana G.; Sims, Justin; Wang, Danny J.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineIdentification of biomarkers for the early stages of Alzheimer's disease (AD) is an imperative step in developing effective treatments. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. CBF deviates as the disease process and symptoms progress. However, further characterization of the relationships between CBF and AD risk factors and pathologies is still needed. We assessed the relationships between CBF quantified by arterial spin-labeled magnetic resonance imaging, hypertension, APOEε4, and tau and amyloid positron emission tomography in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension or APOEε4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD.Item Analysis of the Inverse Association between Cancer and Alzheimer’s Disease: Results from the Alzheimer’s Disease Neuroimaging Initiative Cohort(Office of the Vice Chancellor for Research, 2014-04-11) Nudelman, Kelly N. H.; Risacher, Shannon L.; West, John D.; Nho, Kwangsik; Ramanan, Vijay K.; McDonald, Brenna C.; Shen, Li; Foroud, Tatiana M.; Schneider, Bryan P.; Saykin, Andrew J.Although a number of studies support a reciprocal inverse association between diagnoses of cancer and Alzheimer’s disease (AD), to date there has not been any systemic investigation of the neurobiological impact of or genetic risk factors underlying this effect. To facilitate this goal, this study aimed to replicate the inverse association of cancer and AD using data from the NIA Alzheimer’s Disease Neuroimaging Initiative, which includes age-matched cases and controls with information on cancer history, AD progression, neuroimaging, and genomic data. Subjects included individuals with AD (n=234), mild cognitive impairment (MCI, n=542), and healthy controls (HC, n=293). After controlling for sex, education, race/ethnicity, smoking, and apolipoprotein E (APOE) e2/3/4 allele groups, cancer history was protective against baseline AD diagnosis (p=0.042), and was associated with later age of AD onset (p=0.001). Cancer history appears to result in a cumulative protective effect; individuals with more than one cancer had a later age of AD onset compared to those with only one cancer (p=0.001). Finally, a protective effect of AD was also observed in individuals who developed incident cancer after enrolling (post-baseline visit); 20 individuals with MCI and 9 HC developed cancer, while no AD patients had subsequent cancer diagnoses (p=0.013). This supports previous research on the inverse association of cancer and AD, and importantly provides novel evidence that this effect appears to be independent of APOE, the major known genetic risk factor for AD. Future analyses will investigate the neurobiological and genetic basis of this effect.Item APOE effect on Alzheimer's disease biomarkers in older adults with significant memory concern(Elsevier, 2015-12) Risacher, Shannon L.; Kim, Sungeun; Nho, Kwangsik; Foroud, Tatiana; Shen, Li; Peterson, Ronald C.; Jack Jr, Clifford R.; Beckett, Laurel A.; Aisen, Paul S.; Koeppe, Robert A.; Jagust, William J.; Shaw, Leslie M.; Trojanowski, John Q.; Department of Radiology and Imaging Sciences, IU School of MedicineINTRODUCTION: This study assessed apolipoprotein E (APOE) ε4 carrier status effects on Alzheimer's disease imaging and cerebrospinal fluid (CSF) biomarkers in cognitively normal older adults with significant memory concerns (SMC). METHODS: Cognitively normal, SMC, and early mild cognitive impairment participants from Alzheimer's Disease Neuroimaging Initiative were divided by APOE ε4 carrier status. Diagnostic and APOE effects were evaluated with emphasis on SMC. Additional analyses in SMC evaluated the effect of the interaction between APOE and [(18)F]Florbetapir amyloid positivity on CSF biomarkers. RESULTS: SMC ε4+ showed greater amyloid deposition than SMC ε4-, but no hypometabolism or medial temporal lobe (MTL) atrophy. SMC ε4+ showed lower amyloid beta 1-42 and higher tau/p-tau than ε4-, which was most abnormal in APOE ε4+ and cerebral amyloid positive SMC. DISCUSSION: SMC APOE ε4+ show abnormal changes in amyloid and tau biomarkers, but no hypometabolism or MTL neurodegeneration, reflecting the at-risk nature of the SMC group and the importance of APOE in mediating this risk.Item Associating Multi-modal Brain Imaging Phenotypes and Genetic Risk Factors via A Dirty Multi-task Learning Method(IEEE, 2020) Du, Lei; Liu, Fang; Liu, Kefei; Yao, Xiaohui; Risacher, Shannon L.; Han, Junwei; Saykin, Andrew J.; Shen, Li; Radiology and Imaging Sciences, School of MedicineBrain imaging genetics becomes more and more important in brain science, which integrates genetic variations and brain structures or functions to study the genetic basis of brain disorders. The multi-modal imaging data collected by different technologies, measuring the same brain distinctly, might carry complementary information. Unfortunately, we do not know the extent to which the phenotypic variance is shared among multiple imaging modalities, which further might trace back to the complex genetic mechanism. In this paper, we propose a novel dirty multi-task sparse canonical correlation analysis (SCCA) to study imaging genetic problems with multi-modal brain imaging quantitative traits (QTs) involved. The proposed method takes advantages of the multi-task learning and parameter decomposition. It can not only identify the shared imaging QTs and genetic loci across multiple modalities, but also identify the modality-specific imaging QTs and genetic loci, exhibiting a flexible capability of identifying complex multi-SNP-multi-QT associations. Using the state-of-the-art multi-view SCCA and multi-task SCCA, the proposed method shows better or comparable canonical correlation coefficients and canonical weights on both synthetic and real neuroimaging genetic data. In addition, the identified modality-consistent biomarkers, as well as the modality-specific biomarkers, provide meaningful and interesting information, demonstrating the dirty multi-task SCCA could be a powerful alternative method in multi-modal brain imaging genetics.