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P153: The CIMA-Q and CompAS cohort studies on factors associated with Alzheimer's disease (AD): Exploring sociodemographic, health and neuropsychological profile of Subjective Cognitive Decline (SCD) participants from two culturally differentiated samples.
- Sonali Arora, Campos-Magdaleno Maria, Fátima Fernández-Feijoo, Alba Felpete, Samira Mellah, Sylvie Bellevile, Onésimo Juncos, Arturo X Pereiro, CIMA-Q
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- Journal:
- International Psychogeriatrics / Volume 35 / Issue S1 / December 2023
- Published online by Cambridge University Press:
- 02 February 2024, pp. 269-272
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Objective:
To explore commonalities and differences in the sociodemographic, health, and neuropsychological characteristics of participants with SCD recruited in two culturally differentiated cohort studies, namely CIMA-Q (Canada; Bellevile et al., 2019) and CompAS (Spain; Juncos et al., 2012).
Methods:Older adults with subjective cognitive complaints of the CompAS (N=251; 68.92% women; Control: 30.3%; SCD: 25.9%; MCI: 28.7%) and the CIMA-Q (N=179; 71.5% women; Control:16.1%; SCD: 36.8%; MCI:28.6%) were recruited, respectively, from primary care centers and memory clinics, excluding patients with dementia and other neurological or psychiatric disturbances. Cognitive complaints were assessed considering coincident items of the QAM and MFE questionnaires. Cut-off points for the 5%ile were calculated independently in both samples and according to this, participants were classified as SCD or controls (CompAS: N= 141; CIMA-Q: N=161) considering complaints relevance at baseline (Pereiro et al., 2021). Participants underwent neuropsychological assessment. Participants diagnosed as Mild Cognitive Impairment (MCI) were excluded from the analysis. Between cohort-studies and inter-group (control, SCD) differences were tested in the sociodemographic, health and neuropsychological measures considered. The Holm-Bonferroni correction was applied to reduce the probability of type I error (p<.003).
Results:Identical cut-off points for 5%ile were obtained in both samples though SCD prevalence was slightly higher in CIMA-Q. For both samples, equivalence between Control and SCD participants in sociodemographic, health, functionality, and neuropsychological measures was observed. Only complaints and depressive symptomatology was significantly higher in SCD participants than in controls in both CompAS and CIMA-Q studies.
Participants of the CIMA-Q, Controls and SCD, showed significantly higher age, cognitive reserve proxies, comorbidity, and better attentional performance than the CompAS participants (see Table 1). CompAS participants, Controls and SCD, showed more neuropsychiatric symptomatology than CIMA-Q participants (see Table 1).
Conclusions:Control and SCD participants showed equivalence on sociodemographic, health, functional, and neuropsychological measures in both studies. However, significant between-sample differences in the two groups, particularly in SCD participants, were observed in sociodemographic, health, cognitive reserve, behavioral and attentional measures. Identification of these factors are critical to analyze the transcultural validity of cognitive complaints in predicting progression to AD.
Table 1 Between group (control, SCD) and Between study (CIMA-Q, CompAS) differences in sociodemographic, health, and cognitive measures
CIMA-Q CompAS Between-studies differences Between-group differences Between-group differences Control SCD Sociodemographics Age NS NS CIMA-Q>CompAS; F(1,124)=22.78; p<.001 CIMA-Q>CompAS; F(1,172)=36.97; p<.001 Gender NS NS NS NS Schooling (years) NS NS NS CIMA-Q>CompAS; F(1,172)=20.74; p<.001 Prof. qualification NS NS CIMA-Q>CompAS; χ24=18.18; p=001 CIMA-Q>CompAS; χ24=33.95; p<001 Cognitive reserve (quartiles) NS NS CIMA-Q>CompAS; χ23=13.57; p=004 CIMA-Q>CompAS;χ23==42.56; p<001 Memory familiar antecedents NS NS NS CIMA-Q>CompAS; χ21==15.03; p<001 Neuropsychology Subjective complaints* SCD>Control; F(1,119)=147.17, p<.001) SCD>Control; F(1,177)=192.87, p<.001 NS NS Charlson Index* SCD>Control; F(1,115)=5.29, p=.023 NS CIMA-Q>CompAS; F(1,123)=394.96; p<.001 CIMA-Q>CompAS; F(1,168)=335.98; p<.001 General cognition NS (MoCA) NS (CAMCOG-R) -- -- GDS-15* SCD>Control; F(1,119)=8.60, p=.004 SCD>Control; F(1,176)=11.97, p<.001 NS NS TMT-A (secs.)* NS NS NS NS TMT-B (secs.)* NS NS CompAS>CIMA-Q; F(1,118)=12.56; p<.001 CompAS>CIMA-Q; F(1,163)=21.74; p<.001 Verbal fluency NS NS NS NS Semantic fluency NS NS NS NS Boston test NS NS NS NS NPI-Q NS NS CompAS>CIMA-Q; F(1,119)=16.68; p<.001 CompAS> CIMA-Q; F(1,162)=24.46; p<.001 Immediate recall (RAVL test) NS NS NS NS Short delay (RAVL test) NS NS NS NS Long delay(RAVL test) NS NS NS NS Intrusions (RAVL test) NS NS NS NS IAVD* NS NS NS NS Note: *On these measures, higher scores denote worse cognition or health condition. TMT: Trail Making Test (A and B forms); NPI-Q: Neuropsychiatric Inventory-Questionnaire; RAVL: Rey Auditory Verbal Learning; IAVD: Instrumental Activity of Daily Living.
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.