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Synthesis of Methyl-t-Butyl Ether from Methanol and Isobutene Using a Clay Catalyst
- J. M. Adams, D. E. Clement, S. H. Graham
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- Clays and Clay Minerals / Volume 30 / Issue 2 / April 1982
- Published online by Cambridge University Press:
- 02 April 2024, pp. 129-134
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The acid-catalyzed reaction between methanol and isobutene to give methyl-t-butyl ether may be carried out using a cation-exchanged smectite as the catalyst. In 1,4-dioxan solvent at 60°C smectites exchanged with Al3+, Fe3+, or Cr3+ give yields of ∼60% after 4 hr, whereas smectites exchanged with Cu2+, Pb2+, Ni2+, Co2+, Ca2+, and Na+ give less than ∼8% yield. The reaction is efficient only when certain solvents are used, e.g., with Al3+-smectite the yield is ∼5% when using 1,2-dimethoxyethane, diethyleneglycol diethylether, n-pentane, tetrahydropyran, N-methylmorpholine, or tetrahydrofuran solvents compared with ∼60% using 1,4-dioxan solvent (4 hr). Moreover, the effective solvents depend somewhat on the clay interlayer cation. The use of tetrahydrofuran and tetrahydropyran gives ∼35% yields at 60°C (4 hr) with Fe3+- or Cr3+-smectites but ∼4% yield with Al3+-smectite.
Reactions of Alcohols with Alkenes over an Aluminum-Exchanged Montmorillonite
- J. M. Adams, D. E. Clement, S. H. Graham
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- Clays and Clay Minerals / Volume 31 / Issue 2 / April 1983
- Published online by Cambridge University Press:
- 02 April 2024, pp. 129-136
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The reaction of 2-methyl pent-2-ene with primary alcohols (C1-C18) at 95°C over an Al-montmorillonite gave yields of 20–90% of ethers of the type R-O-C(CH3)2C3H7. Lower yields were produced if secondary alcohols were employed, and tertiary alcohols gave only a trace of this ether. When a variety of alkenes was reacted with butan-1-ol at 95°C over a similar catalyst, no reaction occurred unless the alkene was capable of forming a tertiary carbonium ion immediately upon protonation. In this case the product was the tertiary ether t-R-O-nC4H9. However, at a reaction temperature of 150°C a variety of products were formed including (1) ether by the attack of butanol on the carbonium ions produced either directly from protonation of the alkenes or by hydride shift from such an ion, (2) alkenes by the attack of n-C4H9+ ions (derived from protonation and dehydration of butanol) on the alkene, (3) di-(but-1-yl) ether by dehydration of the butanol, and (4) small amounts of alcohol by hydration of the alkene. The differences in reactivity below and above 100°C are related directly to the amount of water present in the interlayer space of the clay and the degree of acidity found there. Although the clay behaves as an acid catalyst, the reactions are far cleaner (more selective) than comparable reactions catalyzed by sulfuric acid.
A comprehensive hierarchical comparison of structural connectomes in Major Depressive Disorder cases v. controls in two large population samples
- Gladi Thng, Xueyi Shen, Aleks Stolicyn, Mark J. Adams, Hon Wah Yeung, Venia Batziou, Eleanor L. S. Conole, Colin R. Buchanan, Stephen M. Lawrie, Mark E. Bastin, Andrew M. McIntosh, Ian J. Deary, Elliot M. Tucker-Drob, Simon R. Cox, Keith M. Smith, Liana Romaniuk, Heather C. Whalley
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- Psychological Medicine , First View
- Published online by Cambridge University Press:
- 18 March 2024, pp. 1-12
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Background
The brain can be represented as a network, with nodes as brain regions and edges as region-to-region connections. Nodes with the most connections (hubs) are central to efficient brain function. Current findings on structural differences in Major Depressive Disorder (MDD) identified using network approaches remain inconsistent, potentially due to small sample sizes. It is still uncertain at what level of the connectome hierarchy differences may exist, and whether they are concentrated in hubs, disrupting fundamental brain connectivity.
MethodsWe utilized two large cohorts, UK Biobank (UKB, N = 5104) and Generation Scotland (GS, N = 725), to investigate MDD case–control differences in brain network properties. Network analysis was done across four hierarchical levels: (1) global, (2) tier (nodes grouped into four tiers based on degree) and rich club (between-hub connections), (3) nodal, and (4) connection.
ResultsIn UKB, reductions in network efficiency were observed in MDD cases globally (d = −0.076, pFDR = 0.033), across all tiers (d = −0.069 to −0.079, pFDR = 0.020), and in hubs (d = −0.080 to −0.113, pFDR = 0.013–0.035). No differences in rich club organization and region-to-region connections were identified. The effect sizes and direction for these associations were generally consistent in GS, albeit not significant in our lower-N replication sample.
ConclusionOur results suggest that the brain's fundamental rich club structure is similar in MDD cases and controls, but subtle topological differences exist across the brain. Consistent with recent large-scale neuroimaging findings, our findings offer a connectomic perspective on a similar scale and support the idea that minimal differences exist between MDD cases and controls.
Using power analysis and spatial prioritization to evaluate the design of a forest bird monitoring programme
- Darren M. Southwell, Adam Smart, Samuel D. Merson, Katherine E. Selwood, Nicholas A. Macgregor
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- Oryx , First View
- Published online by Cambridge University Press:
- 01 February 2024, pp. 1-10
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Biodiversity monitoring programmes should be designed with sufficient statistical power to detect population change. Here we evaluated the statistical power of monitoring to detect declines in the occupancy of forest birds on Christmas Island, Australia. We fitted zero-inflated binomial models to 3 years of repeat detection data (2011, 2013 and 2015) to estimate single-visit detection probabilities for four species of concern: the Christmas Island imperial pigeon Ducula whartoni, Christmas Island white-eye Zosterops natalis, Christmas Island thrush Turdus poliocephalus erythropleurus and Christmas Island emerald dove Chalcophaps indica natalis. We combined detection probabilities with maps of occupancy to simulate data collected over the next 10 years for alternative monitoring designs and for different declines in occupancy (10–50%). Specifically, we explored how the number of sites (60, 128, 300, 500), the interval between surveys (1–5 years), the number of repeat visits (2–4 visits) and the location of sites influenced power. Power was high (> 80%) for the imperial pigeon, white-eye and thrush for most scenarios, except for when only 60 sites were surveyed or a 10% decline in occupancy was simulated over 10 years. For the emerald dove, which is the rarest of the four species and has a patchy distribution, power was low in almost all scenarios tested. Prioritizing monitoring towards core habitat for this species only slightly improved power to detect declines. Our study demonstrates how data collected during the early stages of monitoring can be analysed in simulation tools to fine-tune future survey design decisions.
Summary of Recommendations of Nomenclature Committees Relevant to Clay Mineralogy: Report of the Association Internationale Pour l’Etude Des Argiles (AIPEA) Nomenclature Committee for 2006
- S. Guggenheim, J. M. Adams, D. C. Bain, F. Bergaya, M. F. Brigatti, V. A. Drits, M. L. L. Formoso, E. Galán, T. Kogure, H. Stanjek
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- Clays and Clay Minerals / Volume 54 / Issue 6 / December 2006
- Published online by Cambridge University Press:
- 01 January 2024, pp. 761-772
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Helium as a Surrogate for Deuterium in LPI Studies
- Matthias Geissel, Adam J. Harvey-Thompson, Matthew R. Weis, Jeffrey R. Fein, David Ampleford, David E. Bliss, Aaron M. Hansen, Christopher Jennings, Mark W. Kimmel, Patrick Rambo, Jonathon E. Shores, Ian C. Smith, C. Shane Speas, John L. Porter, Fabrizio Consoli
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- Laser and Particle Beams / Volume 2023 / 2023
- Published online by Cambridge University Press:
- 01 January 2024, e2
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Helium or neopentane can be used as surrogate gas fill for deuterium (D2) or deuterium-tritium (DT) in laser-plasma interaction studies. Surrogates are convenient to avoid flammability hazards or the integration of cryogenics in an experiment. To test the degree of equivalency between deuterium and helium, experiments were conducted in the Pecos target chamber at Sandia National Laboratories. Observables such as laser propagation and signatures of laser-plasma instabilities (LPI) were recorded for multiple laser and target configurations. It was found that some observables can differ significantly despite the apparent similarity of the gases with respect to molecular charge and weight. While a qualitative behaviour of the interaction may very well be studied by finding a suitable compromise of laser absorption, electron density, and LPI cross sections, a quantitative investigation of expected values for deuterium fills at high laser intensities is not likely to succeed with surrogate gases.
Erratum to: Summary of recommendations of nomenclature committees relevant to Clay mineralogy: Report of the Association Internationale pour l’etude des argiles (AIPEA) Nomenclature Committee for 2006
- S. Guggenheim, J. M. Adams, D. C. Bain, F. Bergaya, M. F. Brigatti, V. A. Drits, M. L. L. Formoso, E. Galán, T. Kogure, H. Stanjek
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- Clays and Clay Minerals / Volume 55 / Issue 6 / December 2007
- Published online by Cambridge University Press:
- 01 January 2024, pp. 646-647
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3 Two Dominant Post-COVID Subtypes in Patients Seeking Treatment for “Brain Fog” Through a Post-COVID Treatment Clinic
- Kristine Lokken, Jamie Hansel Robinson, Richard Kennedy, David E Vance, Ronald M Lazar, Roy C Martin, Melissa J Greenfield, Pariya F Wheeler, Adam Gerstenecker
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- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 876-877
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Objective:
To examine patterns of cognitive function among a clinical sample of patients seeking treatment for Post-Acute Sequelae of COVID-19 (PASC).
Participants and Methods:One hundred nineteen patients each completed a baseline neuropsychological evaluation, including clinical diagnostic interview, cognitive assessments, and a comprehensive battery of self-report questionnaires. Patients had a mean age of 50 years (range:18 to 74, SD=10.1) and a mean of 15.5 years (SD=2.54) of formal education. Patients were primarily female (74%) and of White/Caucasian race (75%). Hierarchical agglomerative clustering was used to partition the data into groups based on cognitive performance. Euclidean distance was used as the similarity measure for the continuous variables and within-cluster variance was minimized using Ward’s method. The optimal number of clusters was determined empirically by fitting models with 1 to 15 clusters, with the best number of clusters selected using the silhouette index. All analyses were conducted using the NbClust package, an R package for determining the relevant number of clusters in a data set.
Results:Clustering yielded two distinct clusters of cognitive performance. Group 1 (n=57) performed worse than Group 2 (n=62) on most cognitive variables (including a brief cognitive screener and tests of attention/working memory, executive function, processing speed, learning and delayed recall). Of note, there were no significant differences between groups on an infection severity scale, hospitalizations/ICU admissions, initial or current COVID-19 symptoms, or prior comorbidities. Groups did not differ in age or gender, but Group 1 had a lower education level than Group 2 (M=14.7, SD=2.45 vs. M=16.2, SD=2.42; p=.001). Group 1 also had significantly more minorities than Group 2 (40% vs. 8%; p<.001). No other demographic differences (income, living arrangement, or marital status) were observed. In comparison to Group 2 patients, Group 1 patients self-reported significantly higher levels of anxiety and depression and functional impairment (Functional Activities Questionnaire: M=11.3, SD=8.33 vs. M=7.65, SD=7.97), perceived stress (Perceived Stress Scale: M=24.7, SD=7.90 vs. M=20.3, SD=7.89), insomnia (Insomnia Severity Index: M=16.0, SD=6.50 vs. M=13.1, SD=6.76), and subjective cognitive functioning (Cognitive Failures Questionnaire: M=58.8, SD=16.9 vs. M=50.3, SD=18.6; p’s<.05).
Conclusions:Findings indicate two predominant subtypes of patients seeking treatment for PASC, with one group presenting as more cognitively impaired and reporting greater levels of anxiety, depression, insomnia, perceived stress, functional limitations, and subjective cognitive impairment. Future directions include follow-up assessments with these patients to determine cognitive trajectories over time and tailoring treatment adjuncts to address mood symptoms, insomnia, functional ability, and lifestyle variables. Understanding mechanisms of differences in cognitive and affective symptoms is needed in future work. Limitations to the study were that patients were referred for evaluation based on the complaint of “brain fog” and the sample was a homogenous, highly educated, younger group of individuals who experienced generally mild COVID-19 course.
53 2-Back Performance Does Not Differ Between Cognitive Training Groups in Older Adults Without Dementia
- Nicole D Evangelista, Jessica N Kraft, Hanna K Hausman, Andrew O’Shea, Alejandro Albizu, Emanuel M Boutzoukas, Cheshire Hardcastle, Emily J Van Etten, Pradyumna K Bharadwaj, Hyun Song, Samantha G Smith, Steven DeKosky, Georg A Hishaw, Samuel Wu, Michael Marsiske, Ronald Cohen, Gene E Alexander, Eric Porges, Adam J Woods
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- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 360-361
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Objective:
Cognitive training is a non-pharmacological intervention aimed at improving cognitive function across a single or multiple domains. Although the underlying mechanisms of cognitive training and transfer effects are not well-characterized, cognitive training has been thought to facilitate neural plasticity to enhance cognitive performance. Indeed, the Scaffolding Theory of Aging and Cognition (STAC) proposes that cognitive training may enhance the ability to engage in compensatory scaffolding to meet task demands and maintain cognitive performance. We therefore evaluated the effects of cognitive training on working memory performance in older adults without dementia. This study will help begin to elucidate non-pharmacological intervention effects on compensatory scaffolding in older adults.
Participants and Methods:48 participants were recruited for a Phase III randomized clinical trial (Augmenting Cognitive Training in Older Adults [ACT]; NIH R01AG054077) conducted at the University of Florida and University of Arizona. Participants across sites were randomly assigned to complete cognitive training (n=25) or an education training control condition (n=23). Cognitive training and the education training control condition were each completed during 60 sessions over 12 weeks for 40 hours total. The education training control condition involved viewing educational videos produced by the National Geographic Channel. Cognitive training was completed using the Posit Science Brain HQ training program, which included 8 cognitive training paradigms targeting attention/processing speed and working memory. All participants also completed demographic questionnaires, cognitive testing, and an fMRI 2-back task at baseline and at 12-weeks following cognitive training.
Results:Repeated measures analysis of covariance (ANCOVA), adjusted for training adherence, transcranial direct current stimulation (tDCS) condition, age, sex, years of education, and Wechsler Test of Adult Reading (WTAR) raw score, revealed a significant 2-back by training group interaction (F[1,40]=6.201, p=.017, η2=.134). Examination of simple main effects revealed baseline differences in 2-back performance (F[1,40]=.568, p=.455, η2=.014). After controlling for baseline performance, training group differences in 2-back performance was no longer statistically significant (F[1,40]=1.382, p=.247, η2=.034).
Conclusions:After adjusting for baseline performance differences, there were no significant training group differences in 2-back performance, suggesting that the randomization was not sufficient to ensure adequate distribution of participants across groups. Results may indicate that cognitive training alone is not sufficient for significant improvement in working memory performance on a near transfer task. Additional improvement may occur with the next phase of this clinical trial, such that tDCS augments the effects of cognitive training and results in enhanced compensatory scaffolding even within this high performing cohort. Limitations of the study include a highly educated sample with higher literacy levels and the small sample size was not powered for transfer effects analysis. Future analyses will include evaluation of the combined intervention effects of a cognitive training and tDCS on nback performance in a larger sample of older adults without dementia.
61 Network Segregation Predicts Processing Speed in the Cognitively Healthy Oldest-old
- Sara A Nolin, Mary E Faulkner, Paul Stewart, Leland Fleming, Stacy Merritt, Roxanne F Rezaei, Pradyumna K Bharadwaj, Mary Kathryn Franchetti, Daniel A Raichlen, Courtney J Jessup, Lloyd Edwards, G Alex Hishaw, Emily J Van Etten, Theodore P Trouard, David S Geldmacher, Virginia G Wadley, Noam Alperin, Eric C Porges, Adam J Woods, Ronald A Cohen, Bonnie E Levin, Tatjana Rundek, Gene E Alexander, Kristina M Visscher
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- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 367-368
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Objective:
Understanding the factors contributing to optimal cognitive function throughout the aging process is essential to better understand successful cognitive aging. Processing speed is an age sensitive cognitive domain that usually declines early in the aging process; however, this cognitive skill is essential for other cognitive tasks and everyday functioning. Evaluating brain network interactions in cognitively healthy older adults can help us understand how brain characteristics variations affect cognitive functioning. Functional connections among groups of brain areas give insight into the brain’s organization, and the cognitive effects of aging may relate to this large-scale organization. To follow-up on our prior work, we sought to replicate our findings regarding network segregation’s relationship with processing speed. In order to address possible influences of node location or network membership we replicated the analysis across 4 different node sets.
Participants and Methods:Data were acquired as part of a multi-center study of 85+ cognitively normal individuals, the McKnight Brain Aging Registry (MBAR). For this analysis, we included 146 community-dwelling, cognitively unimpaired older adults, ages 85-99, who had undergone structural and BOLD resting state MRI scans and a battery of neuropsychological tests. Exploratory factor analysis identified the processing speed factor of interest. We preprocessed BOLD scans using fmriprep, Ciftify, and XCPEngine algorithms. We used 4 different sets of connectivity-based parcellation: 1)MBAR data used to define nodes and Power (2011) atlas used to determine node network membership, 2) Younger adults data used to define nodes (Chan 2014) and Power (2011) atlas used to determine node network membership, 3) Older adults data from a different study (Han 2018) used to define nodes and Power (2011) atlas used to determine node network membership, and 4) MBAR data used to define nodes and MBAR data based community detection used to determine node network membership.
Segregation (balance of within-network and between-network connections) was measured within the association system and three wellcharacterized networks: Default Mode Network (DMN), Cingulo-Opercular Network (CON), and Fronto-Parietal Network (FPN). Correlation between processing speed and association system and networks was performed for all 4 node sets.
Results:We replicated prior work and found the segregation of both the cortical association system, the segregation of FPN and DMN had a consistent relationship with processing speed across all node sets (association system range of correlations: r=.294 to .342, FPN: r=.254 to .272, DMN: r=.263 to .273). Additionally, compared to parcellations created with older adults, the parcellation created based on younger individuals showed attenuated and less robust findings as those with older adults (association system r=.263, FPN r=.255, DMN r=.263).
Conclusions:This study shows that network segregation of the oldest-old brain is closely linked with processing speed and this relationship is replicable across different node sets created with varied datasets. This work adds to the growing body of knowledge about age-related dedifferentiation by demonstrating replicability and consistency of the finding that as essential cognitive skill, processing speed, is associated with differentiated functional networks even in very old individuals experiencing successful cognitive aging.
13 Regional White Matter Hyperintensities are Associated with Cognition in Prospective Alzheimer’s Clinical Trial Participants
- Clarissa D. Morales, Dejania Cotton-Samuel, Kay C. Igwe, Patrick J. Lao, Julia F. Chang, Amirreza Sedaghat, Mohamad J. Alshikho, Rafael Lippert, Kelsang C. Bista, Kacie Deters, Molly E. Zimmerman, Adam M. Brickman
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- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 224-225
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Objective:
Previous research established that white matter hyperintensities (WMH), a biomarker of small vessel cerebrovascular disease, are strong predictors of cognitive function in older adults and associated with clinical presentation of Alzheimer’s disease (AD), particularly when distributed in posterior brain regions. Secondary prevention clinical trials, such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study, target amyloid accumulation in asymptomatic amyloid positive individuals, but it is unclear the extent to which small vessel cerebrovascular disease accounts for performance on the primary cognitive outcomes in these trials. The purpose of this study was to examine the relationship between regional WMH volume and performance on the Preclinical Alzheimer Cognitive Composite (PACC) among participants screened for participation in the A4 trial. We also determined whether the association between WMH and cognition is moderated by amyloid positivity status.
Participants and Methods:We assessed demographic, amyloid PET status, cognitive screening, and raw MRI data for participants in the A4 trial and quantitated regional (by cerebral lobe) WMH volumes from T2-weighted FLAIR in amyloid positive and amyloid negative participants at screening. Cognition was assessed using PACC scores, a z-score sum of four cognitive tests: The Mini-Mental State Examination (MMSE), the Free and Cued Selective Reminding Test, Logical Memory Test, and Digit Symbol Substitution Test. We included 1329 amyloid positive and 329 amyloid negative individuals (981 women; mean age=71.79 years; mean education=16.58 years) at the time of the analysis. The sample included Latinx (n=50; 3%), non-Latinx (n=1590; 95.9%), or unspecified ethnicity (n=18; 1.1%) individuals who identified as American Indian/Alaskan Native (n=7; 0.4%), Asian (n=38; 2.3%), Black/African American (n=41; 2.5%), White (n=1551 ; 93.5%), or unspecified (n=21; 1.3%) race. We first examined the associations of total and regional WMH volume and amyloid positivity on PACC scores (the primary cognitive outcome measure for A4) using separate general linear models and then determined whether amyloid positivity status and regional WMH statistically interacted for those WMH regions that showed significant main effects.
Results:Both increased WMH, in the frontal and parietal lobes particularly, and amyloid positivity were independently associated with poorer performance on the PACC, with similar magnitude. In subsequent models, WMH volume did not interact with amyloid positivity status on PACC scores.
Conclusions:Regionally distributed WMH are independently associated with cognitive functioning in typical participants enrolled in a secondary prevention clinical trial for AD. These effects are of similar magnitude to the effects of amyloid positivity on cognition, highlighting the extent to which small vessel cerebrovascular disease potentially drives AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered explicitly when evaluating outcomes in trials, both as potential effect modifiers and as possible targets for intervention or prevention. The findings from this study cannot be generalized widely, as the participants are not representative of the overall population.
2 Higher White Matter Hyperintensity Load Adversely Affects Pre-Post Proximal Cognitive Training Performance in Healthy Older Adults
- Emanuel M Boutzoukas, Andrew O’Shea, Jessica N Kraft, Cheshire Hardcastle, Nicole D Evangelista, Hanna K Hausman, Alejandro Albizu, Emily J Van Etten, Pradyumna K Bharadwaj, Samantha G Smith, Hyun Song, Eric C Porges, Alex Hishaw, Steven T DeKosky, Samuel S Wu, Michael Marsiske, Gene E Alexander, Ronald Cohen, Adam J Woods
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- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 671-672
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Objective:
Cognitive training has shown promise for improving cognition in older adults. Aging involves a variety of neuroanatomical changes that may affect response to cognitive training. White matter hyperintensities (WMH) are one common age-related brain change, as evidenced by T2-weighted and Fluid Attenuated Inversion Recovery (FLAIR) MRI. WMH are associated with older age, suggestive of cerebral small vessel disease, and reflect decreased white matter integrity. Higher WMH load associates with reduced threshold for clinical expression of cognitive impairment and dementia. The effects of WMH on response to cognitive training interventions are relatively unknown. The current study assessed (a) proximal cognitive training performance following a 3-month randomized control trial and (b) the contribution of baseline whole-brain WMH load, defined as total lesion volume (TLV), on pre-post proximal training change.
Participants and Methods:Sixty-two healthy older adults ages 65-84 completed either adaptive cognitive training (CT; n=31) or educational training control (ET; n=31) interventions. Participants assigned to CT completed 20 hours of attention/processing speed training and 20 hours of working memory training delivered through commercially-available Posit Science BrainHQ. ET participants completed 40 hours of educational videos. All participants also underwent sham or active transcranial direct current stimulation (tDCS) as an adjunctive intervention, although not a variable of interest in the current study. Multimodal MRI scans were acquired during the baseline visit. T1- and T2-weighted FLAIR images were processed using the Lesion Segmentation Tool (LST) for SPM12. The Lesion Prediction Algorithm of LST automatically segmented brain tissue and calculated lesion maps. A lesion threshold of 0.30 was applied to calculate TLV. A log transformation was applied to TLV to normalize the distribution of WMH. Repeated-measures analysis of covariance (RM-ANCOVA) assessed pre/post change in proximal composite (Total Training Composite) and sub-composite (Processing Speed Training Composite, Working Memory Training Composite) measures in the CT group compared to their ET counterparts, controlling for age, sex, years of education and tDCS group. Linear regression assessed the effect of TLV on post-intervention proximal composite and sub-composite, controlling for baseline performance, intervention assignment, age, sex, years of education, multisite scanner differences, estimated total intracranial volume, and binarized cardiovascular disease risk.
Results:RM-ANCOVA revealed two-way group*time interactions such that those assigned cognitive training demonstrated greater improvement on proximal composite (Total Training Composite) and sub-composite (Processing Speed Training Composite, Working Memory Training Composite) measures compared to their ET counterparts. Multiple linear regression showed higher baseline TLV associated with lower pre-post change on Processing Speed Training sub-composite (ß = -0.19, p = 0.04) but not other composite measures.
Conclusions:These findings demonstrate the utility of cognitive training for improving postintervention proximal performance in older adults. Additionally, pre-post proximal processing speed training change appear to be particularly sensitive to white matter hyperintensity load versus working memory training change. These data suggest that TLV may serve as an important factor for consideration when planning processing speed-based cognitive training interventions for remediation of cognitive decline in older adults.
36 Regional Amyloid and Memory in Amyloid Positive and Negative Older Adults
- Kyla G. Cummings, Clarissa D. Morales, Dejania Cotton-Samuel, Patrick J. Lao, Kacie D. Deters, Molly E. Zimmerman, Adam M. Brickman
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- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 346-347
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Objective:
Alzheimer’s disease (AD) pathophysiology, including β-amyloid (Aβ), can be appreciated with molecular PET imaging. Among older adults, the distribution of Aβ standard uptake value ratios (SUVR) is typically bimodal and a diagnostic cut is applied to define those who are amyloid ‘positive’ and ‘negative’. However, it is unclear whether the dynamic range of SUVRs in amyloid positive and negative individuals is meaningful and associated with cognition. Previous work by Insel and colleagues (2020) used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) trial to demonstrate subtle associations between a cortical summary SUVR and cognition, particularly on the Free and Cued Selective Reminding Test (FCSRT). We followed up this study to determine the extent to which regional SUVR is associated with performance on the FCSRT in amyloid positive and negative participants screened for participation in the A4 study.
Participants and Methods:We accessed regional Aβ SUVR, including anterior cingulate, posterior cingulate, parietal, precuneus, temporal, and medial/orbital frontal regions, along with FCSRT15 and demographic data from 4492 A4 participants at screening. Participants were coded as amyloid positive (n=1329; 30%) or amyloid negative (n=3169; 70%) based on a summary SUVR of greater than or equal to 1.15. We used separate general linear models to examine the association of total or regional SUVR, amyloid positivity status, and the interaction of SUVR and amyloid status with FCSRT scores. We compared model fits across regions with the Akaike Information Criterion (AIC). We ran post hoc correlational analyses examining the relationship between SUVR and FCSRT scores stratified by amyloid status in the case of significant interactions. Results were similar with and without demographic adjustment.
Results:There was a significant interaction of summary and all regional SUVR with FCSRT scores in addition to main effects of amyloid positivity. In all models, there were small negative associations between SUVR and memory in amyloid positive individuals. For amyloid negative individuals, there was a significant and very small negative association between SUVR and FCSRT scores only in the parietal lobes and precuneus regions. Model fits were generally similar across the different analyses.
Conclusions:In this sample of individuals screened for a secondary prevention trial of AD, there were consistent associations between Aβ SUVR in all regions and memory for those considered amyloid positive. However, for individuals considered amyloid negative, there were only very small associations between SUVR and memory in parietal and precuneus regions. We conclude that the dynamic range of amyloid may be relevant among those with diagnostic evidence of amyloidosis, but that subtle Aβ accumulation in posterior regions may relate to declining memory in “subthreshold” states.
6 Adjunctive Transcranial Direct Current Stimulation and Cognitive Training Alters Default Mode and Frontoparietal Control Network Connectivity in Older Adults
- Hanna K Hausman, Jessica N Kraft, Cheshire Hardcastle, Nicole D Evangelista, Emanuel M Boutzoukas, Andrew O’Shea, Alejandro Albizu, Emily J Van Etten, Pradyumna K Bharadwaj, Hyun Song, Samantha G Smith, Eric S Porges, Georg A Hishaw, Samuel Wu, Steven DeKosky, Gene E Alexander, Michael Marsiske, Ronald A Cohen, Adam J Woods
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- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 675-676
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Objective:
Aging is associated with disruptions in functional connectivity within the default mode (DMN), frontoparietal control (FPCN), and cingulo-opercular (CON) resting-state networks. Greater within-network connectivity predicts better cognitive performance in older adults. Therefore, strengthening network connectivity, through targeted intervention strategies, may help prevent age-related cognitive decline or progression to dementia. Small studies have demonstrated synergistic effects of combining transcranial direct current stimulation (tDCS) and cognitive training (CT) on strengthening network connectivity; however, this association has yet to be rigorously tested on a large scale. The current study leverages longitudinal data from the first-ever Phase III clinical trial for tDCS to examine the efficacy of an adjunctive tDCS and CT intervention on modulating network connectivity in older adults.
Participants and Methods:This sample included 209 older adults (mean age = 71.6) from the Augmenting Cognitive Training in Older Adults multisite trial. Participants completed 40 hours of CT over 12 weeks, which included 8 attention, processing speed, and working memory tasks. Participants were randomized into active or sham stimulation groups, and tDCS was administered during CT daily for two weeks then weekly for 10 weeks. For both stimulation groups, two electrodes in saline-soaked 5x7 cm2 sponges were placed at F3 (cathode) and F4 (anode) using the 10-20 measurement system. The active group received 2mA of current for 20 minutes. The sham group received 2mA for 30 seconds, then no current for the remaining 20 minutes.
Participants underwent resting-state fMRI at baseline and post-intervention. CONN toolbox was used to preprocess imaging data and conduct region of interest (ROI-ROI) connectivity analyses. The Artifact Detection Toolbox, using intermediate settings, identified outlier volumes. Two participants were excluded for having greater than 50% of volumes flagged as outliers. ROI-ROI analyses modeled the interaction between tDCS group (active versus sham) and occasion (baseline connectivity versus postintervention connectivity) for the DMN, FPCN, and CON controlling for age, sex, education, site, and adherence.
Results:Compared to sham, the active group demonstrated ROI-ROI increases in functional connectivity within the DMN following intervention (left temporal to right temporal [T(202) = 2.78, pFDR < 0.05] and left temporal to right dorsal medial prefrontal cortex [T(202) = 2.74, pFDR < 0.05]. In contrast, compared to sham, the active group demonstrated ROI-ROI decreases in functional connectivity within the FPCN following intervention (left dorsal prefrontal cortex to left temporal [T(202) = -2.96, pFDR < 0.05] and left dorsal prefrontal cortex to left lateral prefrontal cortex [T(202) = -2.77, pFDR < 0.05]). There were no significant interactions detected for CON regions.
Conclusions:These findings (a) demonstrate the feasibility of modulating network connectivity using tDCS and CT and (b) provide important information regarding the pattern of connectivity changes occurring at these intervention parameters in older adults. Importantly, the active stimulation group showed increases in connectivity within the DMN (a network particularly vulnerable to aging and implicated in Alzheimer’s disease) but decreases in connectivity between left frontal and temporal FPCN regions. Future analyses from this trial will evaluate the association between these changes in connectivity and cognitive performance post-intervention and at a one-year timepoint.
45 The Impact of Loneliness on Amyloid Burden, Cerebrovascular Disease, Neurodegeneration, and Memory Performance in a Community-Based Sample of Older Adults
- Bayardo E Lacayo, Clarissa Morales, Aine Montgomery, Kiana Chan, Stephanie Cosentino, Adam M Brickman, Jennifer Manly, Nicole Schupf, Richard Mayeux, Patrick Lao
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 455-456
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Objective:
The current research framework recommends using biomarkers to further understand Alzheimer’s disease (AD) pathogenesis, including other contributing factors like cerebrovascular disease. In longitudinal studies of people with neuropathological examination after death, baseline loneliness was associated with lower cognition, faster cognitive decline, and future AD risk, independent of AD pathology. Examination of memory impairment along with AD and cerebrovascular biomarkers, could aid risk reduction efforts earlier in the lifecourse and among populations with more exposure to loneliness. We hypothesized that loneliness is associated with amyloid, vascular, and neurodegeneration biomarkers; with worse memory; and that loneliness increases the susceptibility to biomarker-related memory impairment.
Participants and Methods:A subset of cognitively unimpaired older adults with available amyloid PET, vascular MRI (white matter hyperintensity volume, WMH), structural MRI (cortical thickness in AD signature regions), neuropsychological testing (memory factor score), dichotomized loneliness data (one item from CES-D), and relevant medical data were drawn from the community-based Washington Heights-Inwood Columbia Aging Project (WHICAP; n=169; covariates included age=81±6 years; 63% women; 49/31/20% Non-Hispanic Black/Non-Hispanic White/Hispanic; education=13±4 years; 32% APOE-e4 carriers). General linear models in the overall sample and stratified by race and ethnicity tested the association between loneliness and AD and cerebrovascular biomarkers, loneliness and memory, and the interaction of loneliness and biomarkers on memory, adjusting for covariates.
Results:Loneliness was endorsed in 18% of participants, marginally associated with older age (2.1 [-0.2, 4.4], p=0.08), was more likely in those with untreated diabetes (13/0.1% lonely/not lonely, p=0.001), associated with lower cortical thickness (-0.05 [-0.09, -0.02], p=0.01), and associated with lower memory (0.3 [-0.6, -0.001], p=0.05). In Non-Hispanic White participants, loneliness was associated with greater WMH volume (0.5 [0.07, 0.82], p=0.03), while in Hispanic participants, loneliness was associated with lower cortical thickness (-0.16 [-0.24, -0.08], p=0.0006). In Non-Hispanic Black participants, loneliness was associated with lower memory (-13 [-26, -0.5], p=0.05), and the association between lower cortical thickness and lower memory was stronger in those that endorse loneliness (5 [0.2, 10], p=0.05). In Hispanic participants, loneliness was associated with higher memory (13 [4, 22], p=0.009), but the association between higher amyloid burden and lower memory was stronger in those that endorse loneliness (-12 [-20, -4], p=0.006); further, loneliness was marginally associated with lower memory (-0.7 [-1.4, 0.1], p=0.09), independently of WMH.
Conclusions:Associations between loneliness and biomarkers may relate to health seeking behavior, reported as treatment status for diabetes, for cerebrovascular burden and general neurodegeneration, but might be more complex for amyloid. The degree to which loneliness increased the susceptibility to amyloid and neurodegeneration-related, but not cerebrovascular-related, memory impairment, specifically, may suggest that domains beyond memory should be considered. Future work should be longitudinal to disentangle the effects of loneliness from related constructs like depression and anxiety, incorporate other AD biomarkers such as hyperphosphorylated tau, and incorporate biological mechanisms (e.g., stress, inflammation) into models of loneliness and AD pathogenesis. Older adults from all backgrounds may be more susceptible to loneliness, which was associated with lower memory; culturally-humble, social support-based interventions may reduce the risk of cognitive impairment.
9 Connecting memory and functional brain networks in older adults: a resting state fMRI study
- Jori L Waner, Hanna K Hausman, Jessica N Kraft, Cheshire Hardcastle, Nicole D Evangelista, Andrew O’Shea, Alejandro Albizu, Emanuel M Boutzoukas, Emily J Van Etten, Pradyumna K Bharadwaj, Hyun Song, Samantha G Smith, Steven T DeKosky, Georg A Hishaw, Samuel S Wu, Michael Marsiske, Ronald Cohen, Gene E Alexander, Eric C Porges, Adam J Woods
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 527-528
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Objective:
Nonpathological aging has been linked to decline in both verbal and visuospatial memory abilities in older adults. Disruptions in resting-state functional connectivity within well-characterized, higherorder cognitive brain networks have also been coupled with poorer memory functioning in healthy older adults and in older adults with dementia. However, there is a paucity of research on the association between higherorder functional connectivity and verbal and visuospatial memory performance in the older adult population. The current study examines the association between resting-state functional connectivity within the cingulo-opercular network (CON), frontoparietal control network (FPCN), and default mode network (DMN) and verbal and visuospatial learning and memory in a large sample of healthy older adults. We hypothesized that greater within-network CON and FPCN functional connectivity would be associated with better immediate verbal and visuospatial memory recall. Additionally, we predicted that within-network DMN functional connectivity would be associated with improvements in delayed verbal and visuospatial memory recall. This study helps to glean insight into whether within-network CON, FPCN, or DMN functional connectivity is associated with verbal and visuospatial memory abilities in later life.
Participants and Methods:330 healthy older adults between 65 and 89 years old (mean age = 71.6 ± 5.2) were recruited at the University of Florida (n = 222) and the University of Arizona (n = 108). Participants underwent resting-state fMRI and completed verbal memory (Hopkins Verbal Learning Test - Revised [HVLT-R]) and visuospatial memory (Brief Visuospatial Memory Test - Revised [BVMT-R]) measures. Immediate (total) and delayed recall scores on the HVLT-R and BVMT-R were calculated using each test manual’s scoring criteria. Learning ratios on the HVLT-R and BVMT-R were quantified by dividing the number of stimuli (verbal or visuospatial) learned between the first and third trials by the number of stimuli not recalled after the first learning trial. CONN Toolbox was used to extract average within-network connectivity values for CON, FPCN, and DMN. Hierarchical regressions were conducted, controlling for sex, race, ethnicity, years of education, number of invalid scans, and scanner site.
Results:Greater CON connectivity was significantly associated with better HVLT-R immediate (total) recall (ß = 0.16, p = 0.01), HVLT-R learning ratio (ß = 0.16, p = 0.01), BVMT-R immediate (total) recall (ß = 0.14, p = 0.02), and BVMT-R delayed recall performance (ß = 0.15, p = 0.01). Greater FPCN connectivity was associated with better BVMT-R learning ratio (ß = 0.13, p = 0.04). HVLT-R delayed recall performance was not associated with connectivity in any network, and DMN connectivity was not significantly related to any measure.
Conclusions:Connectivity within CON demonstrated a robust relationship with different components of memory function as well across verbal and visuospatial domains. In contrast, FPCN only evidenced a relationship with visuospatial learning, and DMN was not significantly associated with memory measures. These data suggest that CON may be a valuable target in longitudinal studies of age-related memory changes, but also a possible target in future non-invasive interventions to attenuate memory decline in older adults.
Outcomes after initial heart failure consultation in Fontan patients
- Sharon Chen, Muhammad F. Shezad, Angela Lorts, Amanda D. McCormick, Chad Y. Mao, Kathleen E. Simpson, Matthew J. O’Connor, Aliessa Barnes, Adam M. Lubert, Chesney Castleberry, Julie Schmidt, Katie Schroeder, Anna Joong, David W. Bearl, Ashwin K. Lal, Deepa Mokshagundam, Jennifer Conway, Ari Cedars, Kurt R. Schumacher
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- Journal:
- Cardiology in the Young , First View
- Published online by Cambridge University Press:
- 28 November 2023, pp. 1-8
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Background:
Patients with Fontan failure are high-risk candidates for heart transplantation and other advanced therapies. Understanding the outcomes following initial heart failure consultation can help define appropriate timing of referral for advanced heart failure care.
Methods:This is a survey study of heart failure providers seeing any Fontan patient for initial heart failure care. Part 1 of the survey captured data on clinical characteristics at the time of heart failure consultation, and Part 2, completed 30 days later, captured outcomes (death, transplant evaluation outcome, and other interventions). Patients were classified as “too late” (death or declined for transplant due to being too sick) and/or “care escalation” (ventricular assist device implanted, inotrope initiated, and/or listed for transplant), within 30 days. “Late referral” was defined as those referred too late and/or had care escalation.
Results:Between 7/2020 and 7/2022, 77 Fontan patients (52% inpatient) had an initial heart failure consultation. Ten per cent were referred too late (6 were too sick for heart transplantation with one subsequent death, and two others died without heart transplantation evaluation, within 30 days), and 36% had care escalation (21 listed ± 5 ventricular assist device implanted ± 6 inotrope initiated). Overall, 42% were late referrals. Heart failure consultation < 1 year after Fontan surgery was strongly associated with late referral (OR 6.2, 95% CI 1.8–21.5, p=0.004).
Conclusions:Over 40% of Fontan patients seen for an initial heart failure consultation were late referrals, with 10% dying or being declined for transplant within a month of consultation. Earlier referral, particularly for those with heart failure soon after Fontan surgery, should be encouraged.
Development of the data registry for the Cardiac Neurodevelopmental Outcome Collaborative
- Anjali Sadhwani, Erica Sood, Andrew H. Van Bergen, Dawn Ilardi, Jacqueline H. Sanz, J. William Gaynor, Michael Seed, Cynthia M. Ortinau, Bradley S. Marino, Thomas A. Miller, Michael Gaies, Adam R. Cassidy, Janet E. Donohue, Amy Ardisana, David Wypij, Caren S. Goldberg
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- Cardiology in the Young / Volume 34 / Issue 1 / January 2024
- Published online by Cambridge University Press:
- 19 May 2023, pp. 79-85
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Children with congenital heart disease (CHD) can face neurodevelopmental, psychological, and behavioural difficulties beginning in infancy and continuing through adulthood. Despite overall improvements in medical care and a growing focus on neurodevelopmental screening and evaluation in recent years, neurodevelopmental disabilities, delays, and deficits remain a concern. The Cardiac Neurodevelopmental Outcome Collaborative was founded in 2016 with the goal of improving neurodevelopmental outcomes for individuals with CHD and pediatric heart disease. This paper describes the establishment of a centralised clinical data registry to standardize data collection across member institutions of the Cardiac Neurodevelopmental Outcome Collaborative. The goal of this registry is to foster collaboration for large, multi-centre research and quality improvement initiatives that will benefit individuals and families with CHD and improve their quality of life. We describe the components of the registry, initial research projects proposed using data from the registry, and lessons learned in the development of the registry.
The People of Print
- Seventeenth-Century England
- Rachel Stenner, Kaley Kramer, Adam James Smith, Georgina E. M. Wilson, Joe Saunders, William Clayton, Jennifer Young, Alan B. Farmer, Benjamin Woodring, Michael Durrant, Verônica Calsoni Lima, Rosalind Johnson
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- 18 May 2023
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- 08 June 2023
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This collection profiles understudied figures in the book and print trades of the seventeenth century. With an equal balance between women and men, it intervenes in the history of the trades, emphasising the broad range of material, cultural, and ideological work these people undertook. It offers a biographical introduction to each figure, placing them in their social, professional, and institutional settings. The collection considers varied print trade roles including that of the printer, publisher, paper-maker, and bookseller, as well as several specific trade networks and numerous textual forms. The biographies draw on extensive new archival research, with details of key sources for further study on each figure. Chronologically organised, this Element offers a primer both on numerous individual figures, and on the tribulations and innovations of the print trade in the century of revolution.
361 WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma
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- Christopher Hubert, Kelly Mitchell, Samuel Sprowls, Sajina Shakya, Sonali Arora, Daniel J. Silver, Christopher M. Goins, Lisa Wallace, Gustavo Roversi, Rachel Schafer, Kristen Kay, Tyler E. Miller, Adam Lauko, John Bassett, Anjali Kashyap, J. D’Amato Kass, Erin E. Mulkearns-Hubert, Sadie Johnson, Joseph Alvarado, Jeremy N. Rich, Patrick J. Paddison, Anoop P. Patel, Shaun R. Stauffer, Christopher G. Hubert, Justin D. Lathia
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- Journal:
- Journal of Clinical and Translational Science / Volume 7 / Issue s1 / April 2023
- Published online by Cambridge University Press:
- 24 April 2023, p. 107
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OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.