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35 The Effect of Diagnostic Method on Racial Disparities in Mild Cognitive Impairment and Dementia Diagnosis Using the NACC Database.
- Jennifer L Nosker, Stephen L Aita, Nicholas C Borgogna, Tina Jimenez, Keenan A Walker, Tasha Rhoads, Janelle M Eloi, Zachary J Resch, Victor A Del Bene
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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. 909-910
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Objective:
Population studies have shown that Black individuals are at higher risk for MCI and dementia than White individuals but are more likely to be underdiagnosed or misdiagnosed. Although multiple contributory factors have been identified in relation to neurocognitive diagnostic disparities among persons of color, few studies have investigated race-associated differences in MCI and dementia classification across diagnostic methods. The current study examined the agreement of cognitive classification made via semi-structured interview and neuropsychological assessment.
Participants and Methods:Only participants assigned normal cognitive status or cognitive impairment with presumed Alzheimer’s etiology were included in the study. Baseline visit data in the National Alzheimer’s Coordinating Center (NACC) dataset was collected to compare correspondence of cognitive classification (normal cognition, MCI, dementia) via semi-structured interview (Clinical Dementia Rating; CDR) with formal NACC diagnostic determination. NACC diagnostic determination was further separated by single clinician and consensus diagnostic methods. Inter-rater agreement was evaluated using chi-squared tests, and respective analyses were stratified for race (Black vs White), ethnicity (Hispanic vs Non-Hispanic), and education (<12 years vs. >12 years).
Results:The sample size included 4,739 Black and 26,393 White participants across 43 Alzheimer’s Disease Research Centers (ADRCs). Inter-rater analyses between CDR (semi-structured interview) versus single-clinician and formal consensus NACC diagnostic methods showed strong (all (pc>.70) consistency in cognitive diagnoses overall, irrespective of race, ethnicity, and education. The percentage of agreement between diagnostic methods was nearly 100% for those categorized as cognitively normal or with dementia. However, the agreement for MCI was considerably lower (ranging from 28-74%) and revealed a disparity in diagnostic method between Black and White individuals. White individuals diagnosed with MCI via CDR (CDR total =0.5) were more likely to be labeled as having dementia regardless of NACC diagnostic method. However, Black individuals diagnosed with MCI via CDR were equally likely to be diagnosed as cognitively normal or with dementia via the formal consensus method.
Conclusions:Irrespective of race and other demographic variables, diagnostic methods had high agreement for groups labeled with normal cognition and dementia. Agreement was consistently lower for the group labeled with MCI, with Black individuals having greater variability in diagnostic differentials when diagnosed via formal consensus method. The results of the study suggest that neuropsychological assessment continues to be an integral component of diagnosing individuals with MCI, reducing possible sources of bias.
309 MYC Inhibition Overcomes IMiD Resistance in Heterogeneous Multiple Myeloma Populations
- Lorraine Davis, Zachary J. Walker, Denis Ohlstrom, Brett M. Stevens, Peter A. Forsberg, Tomer M. Mark, Craig T. Jordan, Daniel W. Sherbenou
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- Journal:
- Journal of Clinical and Translational Science / Volume 6 / Issue s1 / April 2022
- Published online by Cambridge University Press:
- 19 April 2022, p. 54
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OBJECTIVES/GOALS: Immunomodulatory drugs (IMiDs) are critical to multiple myeloma (MM) disease control. IMiDs act by inducing Cereblon-dependent degradation of IKZF1 and IKZF3, which leads to IRF4 and MYC downregulation (collectively termed the “Ikaros axis”). We therefore hypothesized that IMiD treatment fails to downregulate the Ikaros axis in IMiD resistant MM. METHODS/STUDY POPULATION: To measure IMiD-induced Ikaros axis downregulation, we designed an intracellular flow cytometry assay that measured relative protein levels of IKZF1, IKZF3, IRF4 and MYC in MM cells following ex vivo treatment with the IMiD Pomalidomide (Pom). We established this assay using Pom-sensitive parental and dose-escalated Pom-resistant MM cell lines before assessing Ikaros axis downregulation in CD38+CD138+ MM cells in patient samples (bone marrow aspirates). To assess the Ikaros axis in the context of MM intratumoral heterogeneity, we used a 35-marker mass cytometry panel to simultaneously characterize MM subpopulations in patient samples. Lastly, we determined ex vivo drug sensitivity in patient samples via flow cytometry. RESULTS/ANTICIPATED RESULTS: Our hypothesis was supported in MM cell lines, as resistant lines showed no IMiD-induced decrease in any Ikaros axis proteins. However, when assessed in patient samples, Pom treatment caused a significant decrease in IKZF1, IKZF3 and IRF4 regardless of IMiD sensitivity. Mass cytometry in patient samples revealed that individual Ikaros axis proteins were differentially expressed between subpopulations. When correlating this with ex vivo Pom sensitivity of MM subpopulations, we observed that low IKZF1 and IKZF3 corresponded to Pom resistance. Interestingly, most of these resistant populations still expressed MYC. We therefore assessed whether IMiD resistant MM was MYC dependent by treating with MYCi975. In 88% (7/8) of patient samples tested, IMiD resistant MM cells were sensitive to MYC inhibition. DISCUSSION/SIGNIFICANCE: While our findings did not support our initial hypothesis, our data suggest a mechanism where MYC expression becomes Ikaros axis independent to drive IMiD resistance, and resistant MM is still dependent on MYC. This suggests targeting MYC directly or indirectly via a mechanism to be determined may be an effective strategy to eradicate IMiD resistant MM.