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Item Characterization of gene expression patterns in mild cognitive impairment using a transcriptomics approach and neuroimaging endophenotypes(Wiley, 2022) Bharthur Sanjay, Apoorva; Patania, Alice; Yan, Xiaoran; Svaldi, Diana; Duran, Tugce; Shah, Niraj; Nemes, Sara; Chen, Eric; Apostolova, Liana G.; Neurology, School of MedicineIntroduction: Identification of novel therapeutics and risk assessment in early stages of Alzheimer's disease (AD) is a crucial aspect of addressing this complex disease. We characterized gene-expression patterns at the mild cognitive impairment (MCI) stage to identify critical mRNA measures and gene clusters associated with AD pathogenesis. Methods: We used a transcriptomics approach, integrating magnetic resonance imaging (MRI) and peripheral blood-based gene expression data using persistent homology (PH) followed by kernel-based clustering. Results: We identified three clusters of genes significantly associated with diagnosis of amnestic MCI. The biological processes associated with each cluster were mitochondrial function, NF-kB signaling, and apoptosis. Cluster-level associations with cortical thickness displayed canonical AD-like patterns. Driver genes from clusters were also validated in an external dataset for prediction of amyloidosis and clinical diagnosis. Discussion: We found a disease-relevant transcriptomic signature sensitive to prodromal AD and identified a subset of potential therapeutic targets associated with AD pathogenesis.Item Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease(Elsevier, 2020) Dincer, Aylin; Gordon, Brian A.; Hari-Raj, Amrita; Keefe, Sarah J.; Flores, Shaney; McKay, Nicole S.; Paulick, Angela M.; Shady Lewis, Kristine E.; Feldman, Rebecca L.; Hornbeck, Russ C.; Allegri, Ricardo; Ances, Beau M.; Berman, Sarah B.; Brickman, Adam M.; Brooks, William S.; Cash, David M.; Chhatwal, Jasmeer P.; Farlow, Martin R.; la Fougère, Christian; Fox, Nick C.; Fulham, Michael J.; Jack, Clifford R., Jr.; Joseph-Mathurin, Nelly; Karch, Celeste M.; Lee, Athene; Levin, Johannes; Masters, Colin L.; McDade, Eric M.; Oh, Hwamee; Perrin, Richard J.; Raji, Cyrus; Salloway, Stephen P.; Schofield, Peter R.; Su, Yi; Villemagne, Victor L.; Wang, Qing; Weiner, Michael W.; Xiong, Chengjie; Yakushev, Igor; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L.S.; Neurology, School of MedicineDefining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the younger-onset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (nADRC = 381; nDIAN = 145), preclinical (nADRC = 153; nDIAN = 76), and cognitively impaired (nADRC = 54; nDIAN = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either 11C-Pittsburgh compound B or 18F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD.Item Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years(Wiley, 2022-01) Frangou, Sophia; Modabbernia, Amirhossein; Williams, Steven C.R.; Papachristou, Efstathios; Doucet, Gaelle E.; Agartz, Ingrid; Aghajani, Moji; Akudjedu, Theophilus N.; Albajes-Eizagirre, Anton; Alnæs, Dag; Alpert, Kathryn I.; Andersson, Micael; Andreasen, Nancy C.; Andreassen, Ole A.; Asherson, Philip; Banaschewski, Tobias; Bargallo, Nuria; Baumeister, Sarah; Baur-Streubel, Ramona; Bertolino, Alessandro; Bonvino, Aurora; Boomsma, Dorret I.; Borgwardt, Stefan; Bourque, Josiane; Brandeis, Daniel; Breier, Alan; Brodaty, Henry; Brouwer, Rachel M.; Buitelaar, Jan K.; Busatto, Geraldo F.; Buckner, Randy L.; Calhoun, Vincent; Canales-Rodríguez, Erick J.; Cannon, Dara M.; Caseras, Xavier; Castellanos, Francisco X.; Cervenka, Simon; Chaim-Avancini, Tiffany M.; Ching, Christopher R.K.; Chubar, Victoria; Clark, Vincent P.; Conrod, Patricia; Conzelmann, Annette; Crespo-Facorro, Benedicto; Crivello, Fabrice; Crone, Eveline A.; Dale, Anders M.; Dannlowski, Udo; Davey, Christopher; de Geus, Eco J.C.; de Haan, Lieuwe; de Zubicaray, Greig I.; den Braber, Anouk; Dickie, Erin W.; Di Giorgio, Annabella; Doan, Nhat Trung; Dørum, Erlend S.; Ehrlich, Stefan; Erk, Susanne; Espeseth, Thomas; Fatouros-Bergman, Helena; Fisher, Simon E.; Fouche, Jean-Paul; Franke, Barbara; Frodl, Thomas; Fuentes-Claramonte, Paola; Glahn, David C.; Gotlib, Ian H.; Grabe, Hans-Jörgen; Grimm, Oliver; Groenewold, Nynke A.; Grotegerd, Dominik; Gruber, Oliver; Gruner, Patricia; Gur, Rachel E.; Gur, Ruben C.; Hahn, Tim; Harrison, Ben J.; Hartman, Catharine A.; Hatton, Sean N.; Heinz, Andreas; Heslenfeld, Dirk J.; Hibar, Derrek P.; Hickie, Ian B.; Ho, Beng-Choon; Hoekstra, Pieter J.; Hohmann, Sarah; Holmes, Avram J.; Hoogman, Martine; Hosten, Norbert; Howells, Fleur M.; Hulshoff Pol, Hilleke E.; Huyser, Chaim; Jahanshad, Neda; James, Anthony; Jernigan, Terry L.; Jiang, Jiyang; Jönsson, Erik G.; Joska, John A.; Kahn, Rene; Kalnin, Andrew; Kanai, Ryota; Klein, Marieke; Klyushnik, Tatyana P.; Koenders, Laura; Koops, Sanne; Krämer, Bernd; Kuntsi, Jonna; Lagopoulos, Jim; Lázaro, Luisa; Lebedeva, Irina; Lee, Won Hee; Lesch, Klaus-Peter; Lochner, Christine; Machielsen, Marise W.J.; Maingault, Sophie; Martin, Nicholas G.; Martínez-Zalacaín, Ignacio; Mataix-Cols, David; Mazoyer, Bernard; McDonald, Colm; McDonald, Brenna C.; McIntosh, Andrew M.; McMahon, Katie L.; McPhilemy, Genevieve; Meinert, Susanne; Menchón, José M.; Medland, Sarah E.; Meyer-Lindenberg, Andreas; Naaijen, Jilly; Najt, Pablo; Nakao, Tomohiro; Nordvik, Jan E.; Nyberg, Lars; Oosterlaan, Jaap; Ortiz-García de la Foz, Víctor; Paloyelis, Yannis; Pauli, Paul; Pergola, Giulio; Pomarol-Clotet, Edith; Portella, Maria J.; Potkin, Steven G.; Radua, Joaquim; Reif, Andreas; Rinker, Daniel A.; Roffman, Joshua L.; Rosa, Pedro G.P.; Sacchet, Matthew D.; Sachdev, Perminder S.; Salvador, Raymond; Sánchez-Juan, Pascual; Sarró, Salvador; Satterthwaite, Theodore D.; Saykin, Andrew J.; Serpa, Mauricio H.; Schmaal, Lianne; Schnell, Knut; Schumann, Gunter; Sim, Kang; Smoller, Jordan W.; Sommer, Iris; Soriano-Mas, Carles; Stein, Dan J.; Strike, Lachlan T.; Swagerman, Suzanne C.; Tamnes, Christian K.; Temmingh, Henk S.; Thomopoulos, Sophia I.; Tomyshev, Alexander S.; Tordesillas-Gutiérrez, Diana; Trollor, Julian N.; Turner, Jessica A.; Uhlmann, Anne; van den Heuvel, Odile A.; van den Meer, Dennis; van der Wee, Nic J.A.; van Haren, Neeltje E.M.; van't Ent, Dennis; van Erp, Theo G.M.; Veer, Ilya M.; Veltman, Dick J.; Voineskos, Aristotle; Völzke, Henry; Walter, Henrik; Walton, Esther; Wang, Lei; Wang, Yang; Wassink, Thomas H.; Weber, Bernd; Wen, Wei; West, John D.; Westlye, Lars T.; Whalley, Heather; Wierenga, Lara M.; Wittfeld, Katharina; Wolf, Daniel H.; Worker, Amanda; Wright, Margaret J.; Yang, Kun; Yoncheva, Yulyia; Zanetti, Marcus V.; Ziegler, Georg C.; Karolinska Schizophrenia Project (KaSP); Thompson, Paul M.; Dima, Danai; Radiology and Imaging Sciences, School of MedicineDelineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.Item Multiparameter cortical surface morphology in former amateur contact sport athletes(Oxford University Press, 2024) Recht, Grace; Hou, Jiancheng; Buddenbaum, Claire; Cheng, Hu; Newman, Sharlene D.; Saykin, Andrew J.; Kawata, Keisuke; Radiology and Imaging Sciences, School of MedicineThe lifetime effects of repetitive head impacts have captured considerable public and scientific interest over the past decade, yet a knowledge gap persists in our understanding of midlife neurological well-being, particularly in amateur level athletes. This study aimed to identify the effects of lifetime exposure to sports-related head impacts on brain morphology in retired, amateur athletes. This cross-sectional study comprised of 37 former amateur contact sports athletes and 21 age- and sex-matched noncontact athletes. High-resolution anatomical, T1 scans were analyzed for the cortical morphology, including cortical thickness, sulcal depth, and sulcal curvature, and cognitive function was assessed using the Dementia Rating Scale-2. Despite no group differences in cognitive functions, the contact group exhibited significant cortical thinning particularly in the bilateral frontotemporal regions and medial brain regions, such as the cingulate cortex and precuneus, compared to the noncontact group. Deepened sulcal depth and increased sulcal curvature across all four lobes of the brain were also notable in the contact group. These data suggest that brain morphology of middle-aged former amateur contact athletes differs from that of noncontact athletes and that lifetime exposure to repetitive head impacts may be associated with neuroanatomical changes.Item Neurocognitive markers of childhood abuse in individuals with PTSD: Findings from the INTRuST Clinical Consortium(Elsevier, 2020-02-01) Bomyea, Jessica; Simmons, Alan N.; Shenton, Martha E.; Coleman, Michael J.; Bouix, Sylvain; Rathi, Yogesh; Pasternak, Ofer; Coimbra, Raul; Shutter, Lori; George, Mark S.; Grant, Gerald; Zafonte, Ross D.; McAllister, Thomas W.; Stein, Murray B.; Psychiatry, School of MedicineTo date, few studies have evaluated the contribution of early life experiences to neurocognitive abnormalities observed in posttraumatic stress disorder (PTSD). Childhood maltreatment is common among individuals with PTSD and is thought to catalyze stress-related biobehavioral changes that might impact both brain structure and function in adulthood. The current study examined differences in brain morphology (brain volume, cortical thickness) and neuropsychological performance in individuals with PTSD characterized by low or high self-reported childhood maltreatment, compared with healthy comparison participants. Data were drawn from the INjury and TRaUmatic STress (INTRuST) Clinical Consortium imaging repository, which contains MRI and self-report data for individuals classified as PTSD positive (with and without a history of mild traumatic brain injury [mTBI]), individuals with mTBI only, and healthy comparison participants. The final sample included 36 individuals with PTSD without childhood maltreatment exposure (PTSD, n = 30 with mTBI), 31 individuals with PTSD and childhood maltreatment exposure (PTSD + M, n = 26 with mTBI), and 114 healthy comparison participants without history of childhood maltreatment exposure (HC). The PTSD + M and PTSD groups demonstrated cortical thinning in prefrontal and occipital regions, and poorer verbal memory and processing speed compared to the HC group. PTSD + M participants demonstrated cortical thinning in frontal and cingulate regions, and poorer executive functioning relative to the PTSD and HC groups. Thus, neurocognitive features varied between individuals with PTSD who did versus did not have exposure to childhood maltreatment, highlighting the need to assess developmental history of maltreatment when examining biomarkers in PTSD.Item Relationships between preoperative cortical thickness, postoperative electroencephalogram slowing, and postoperative delirium(Elsevier, 2021) White, Marissa F.; Tanabe, Sean; Casey, Cameron; Parker, Maggie; Bo, Amber; Kunkel, David; Nair, Veena; Pearce, Robert A.; Lennertz, Richard; Prabhakaran, Vivek; Lindroth, Heidi; Sanders, Robert D.; Medicine, School of MedicineBackground: It is unclear how preoperative neurodegeneration and postoperative changes in EEG delta power relate to postoperative delirium severity. We sought to understand the relative relationships between neurodegeneration and delta power as predictors of delirium severity. Methods: We undertook a prospective cohort study of high-risk surgical patients (>65 yr old) to identify predictors of peak delirium severity (Delirium Rating Scale-98) with twice-daily delirium assessments (NCT03124303). Participants (n=86) underwent preoperative MRI; 54 had both an MRI and a postoperative EEG. Cortical thickness was calculated from the MRI and delta power from the EEG. Results: In a linear regression model, the interaction between delirium status and preoperative mean cortical thickness (suggesting neurodegeneration) across the entire cortex was a significant predictor of delirium severity (P<0.001) when adjusting for age, sex, and performance on preoperative Trail Making Test B. Next, we included postoperative delta power and repeated the analysis (n=54). Again, the interaction between mean cortical thickness and delirium was associated with delirium severity (P=0.028), as was postoperative delta power (P<0.001). When analysed across the Desikan-Killiany-Tourville atlas, thickness in multiple individual cortical regions was also associated with delirium severity. Conclusions: Preoperative cortical thickness and postoperative EEG delta power are both associated with postoperative delirium severity. These findings might reflect different underlying processes or mechanisms.Item Structural brain morphology in young adult women who have been choked/strangled during sex: A whole‐brain surface morphometry study(Wiley, 2023) Hou, Jiancheng; Huibregtse, Megan E.; Alexander, Isabella L.; Klemsz, Lillian M.; Fu, Tsung-Chieh; Rosenberg, Molly; Fortenberry, James Dennis; Herbenick, Debby; Kawata, Keisuke; Pediatrics, School of MedicineIntroduction: Being choked/strangled during partnered sex is an emerging sexual behavior, particularly prevalent among young adult women. Using a multiparameter morphometric imaging approach, we aimed to characterize neuroanatomical differences between young adult women (18-30 years old) who were exposed to frequent sexual choking and their choking naïve controls. Methods: This cross-sectional study consisted of two groups (choking [≥4 times in the past 30 days] vs. choking-naïve group). Participants who reported being choked four or more times during sex in the past 30 days were enrolled in the choking group, whereas those without were assigned to the choking naïve group. High-resolution anatomical magnetic resonance imaging (MRI) data were analyzed using both volumetric features (cortical thickness) and geometric features (fractal dimensionality, gyrification, sulcal depth). Results: Forty-one participants (choking n = 20; choking-naïve n = 21) contributed to the final analysis. The choking group showed significantly increased cortical thickness across multiple regions (e.g., fusiform, lateral occipital, lingual gyri) compared to the choking-naïve group. Widespread reductions of the gyrification were observed in the choking group as opposed to the choking-naïve group. However, there was no group difference in sulcal depth. The fractal dimensionality showed bi-directional results, where the choking group exhibited increased dimensionality in areas including the postcentral gyrus, insula, and fusiform, whereas decreased dimensionality was observed in the bilateral superior frontal gyrus and pericalcarine cortex. Conclusion: These data in cortical morphology suggest that sexual choking events may be associated with neuroanatomical alteration. A longitudinal study with multimodal assessment is needed to better understand the temporal ordering of sexual choking and neurological outcomes.