Faculty Bibliography

Neuroimaging-based subtyping is increasingly used to explain heterogeneity in psychiatric disorders. However, the clinical utility of these subtyping efforts remains unclear, and replication has been challenging. Here we examined how the choice of neuroimaging measures influences the derivation of neuro-subtypes and the consequences for clinical delineation. On a clinically heterogeneous dataset (total n = 566) that included controls (n = 268) and cases (n = 298) of psychiatric conditions, including individuals diagnosed with post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), and comorbidity of both (PTSD&TBI), we identified neuro-subtypes among the cases using either structural, resting-state, or task-based measures. The neuro-subtypes for each modality had high internal validity but did not significantly differ in their clinical and cognitive profiles. We further show that the choice of neuroimaging measures for subtyping substantially impacts the identification of neuro-subtypes, leading to low concordance across subtyping solutions. Similar variability in neuro-subtyping was found in an independent dataset (n = 1642) comprised of major depression disorder (MDD, n = 848) and controls (n = 794). Our results suggest that the highly anticipated relationships between neuro-subtypes and clinical features may be difficult to discover.

Ovarian cancer remains low in prevalence but has the highest mortality of all gynecologic malignancies. Population-based screening for ovarian cancer remains a topic of interest in contemporary practice, given that the majority of cancers encountered are high-grade aggressive malignancies, for which favorable survival is encountered in the setting of early-stage disease. This document summarizes a review of the available data from randomized and observational trials that have evaluated the role of imaging for ovarian cancer screening in average-risk and high-risk patients. When considering screening using pelvic ultrasound in average-risk patients, we found insufficient published evidence to recommend ovarian cancer screening. Randomized controlled trials have not demonstrated a mortality benefit in this setting. Screening with pelvic ultrasound may be appropriate for select patients at high risk, although the existing data remain limited as large, randomized trials have not been performed in this setting. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

BACKGROUND:Despite the need, care partners of persons living with mild cognitive impairment (MCI) use supportive services less. The unique needs of care partners to persons living with MCI are not well described. This study explores how care partners support the inner strength of persons newly diagnosed with MCI. METHODS:Nine dyads of persons living with MCI and their care partners completed semi-structured interviews, analyzed according to the Listening Guide methodology. RESULTS:Care partners described supporting inner strengths of persons living with MCI by carrying the cognitive load and being reliable. Reconceptualizing identity was foundational. Across themes, care partners needed simultaneous support for themselves. DISCUSSION/CONCLUSIONS:This study represents the perspectives of a well-defined group of care partners to persons living with MCI. Eliciting the perspectives of underrepresented care partners and equitable access to MCI diagnosis are essential for future research. Dyadic supportive services tailored for MCI using a strengths-based approach are needed. HIGHLIGHTS/CONCLUSIONS:Care partners to persons living with mild cognitive impairment (MCI) are unique. Care partners support inner strength of persons living with MCI and need simultaneous support. Care partners reconceptualize their identities, are reliable, and carry cognitive load. Methods for eliciting perspectives of underrepresented care partners are needed. Supportive services tailored for MCI using a strengths-based approach are needed.

INTRODUCTION/BACKGROUND:Results from the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) trial suggest hearing intervention may not reduce 3-year cognitive decline in all older adults with hearing loss but may be beneficial in certain groups. This secondary analysis investigated if participants with multiple risk factors for cognitive decline received greater benefits. METHODS:We used a sample of dementia-free participants (N = 2692) from the Atherosclerosis Risk in Communities (ARIC) cohort to develop a predictive model for cognitive decline. The model was applied to baseline measures of ACHIEVE participants (N = 977) to estimate predicted risk. We tested an interaction between predicted risk and randomization to hearing intervention or health education control. RESULTS:Among ACHIEVE participants in the top quartile of predicted risk, 3-year cognitive decline in the hearing intervention was 61.6% (95% confidence interval [CI]: 33.7%-94.1%) slower than the control. DISCUSSION/CONCLUSIONS:The effect of hearing intervention on reducing 3-year cognitive decline was greatest among individuals with multiple baseline risk factors associated with faster cognitive decline. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier: NCT03243422 HIGHLIGHTS: The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) trial tested the effect of hearing intervention on cognitive decline. Participants were recruited from the Atherosclerosis Risk in Communities (ARIC) cohort or de novo from the local community. A 48% reduction in cognitive decline was observed in ARIC cohort participants. In this secondary analysis, there was an interaction between hearing intervention and predicted risk of cognitive decline. Among participants in the top quartile of predicted risk of cognitive decline, hearing intervention slowed cognitive decline by 62%.

The capacity to sustain attention over time develops rapidly over early childhood and is associated with socioemotional and cognitive outcomes. However, sustained attention has largely been studied in either shared or independent contexts, leading to gaps in our understanding of how trade-offs between sustained attention to shared versus individual targets may predict later outcomes. We examined this question in a longitudinal sample of 1,290 children (49% female, 43% Black), living in predominately rural, low-income regions, using a naturalistic shared picture book reading task. Children's sustained attention to individual relative to shared targets during the book reading task was measured at 24 and 35 months. Using latent profile analysis, we identified four developmental profiles of children's attentional trajectories: three of the profiles differed in the extent that children' attention shifted toward more socially directed relative to individually directed attention; a fourth profile showed atypical decreases in both socially directed and individually directed attention across development. Importantly, heterogeneity in children's attentional profiles were associated with differences in executive functions at 48 months of age. Specifically, children who showed greater relative increases in socially directed attention had higher executive functions performance, whereas children with atypical decreases in attention showed substantial deficits in this domain. These findings reveal distinct longitudinal patterns of sustained attention in naturalistic contexts and show that heterogeneity in these patterns are robust predictors of subsequent executive functions. This person-centered approach provides novel insights into how quantitative and qualitative changes in attention may impact executive functions development and may help identify children at risk for nonnormative trajectories. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau₁₈₁:Aβ₄₂, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ⁺ and phosphorylated tau⁺ (A+T₁+) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T₁+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10^-4) and A+T₁+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10^-16) over a 15-year follow-up, adjusting for CSF pTau₁₈₁:Aβ₄₂, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.

Environmental exposures often exhibit temporal variability, prompting extensive research to understand their dynamic impacts on human health. There has been a growing interest in studying time-dependent exposure mixtures beyond a single exposure. However, current analytic methods typically assess each exposure individually or assume an additive relationship. This paper aims to fill the gap in method development for evaluating the joint effects of multiple time-dependent exposures on a scalar outcome. We introduce a dynamic single-index scalar-on-function model to characterize the exposure mixture's time-varying effect through a non-parametric bivariate exposure-time-outcome surface function. Utilizing B-spline tensor product bases to approximate the surface function, we propose a profiling algorithm for model estimation and establish large-sample properties for the resulting single-index estimators. In addition, we introduce a non-parametric hypothesis testing procedure to determine whether the surface function varies over time at each fixed mixture level and a model averaging solution to circumvent the issue of knot selection for spline approximations. The performance of our proposed methods is examined through extensive simulations and further illustrated using real-world applications.

BACKGROUND:Given the cardiovascular, renal, and survival benefits of GLP-1 receptor agonists for diabetes, these agents could be effective among kidney transplant recipients. However, kidney transplant recipients are distinct from GLP-1 receptor agonist trial participants, with longer diabetes duration and severity, greater end-organ damage, increased cardiovascular risk, and multimorbidity. We examined GLP-1 receptor agonist real-world effectiveness and safety in kidney transplant recipients with diabetes. METHODS:This USA-based retrospective cohort study included kidney transplant recipients with type 2 diabetes at transplantation and Medicare as their primary insurance from a national registry linked with Medicare claims. Post-transplantation GLP-1 receptor agonist use was identified through Medicare claims. Death-censored graft loss was estimated using the Fine-Gray sub-distribution hazard model and extended Cox models were used for mortality and safety endpoints. Models incorporated inverse probability of treatment weights. To further test whether bias could affect the main results, a cohort was created in which each GLP-1 receptor agonist user was matched with a kidney transplant recipient who had not started a GLP-1 receptor agonist, was alive with a functioning graft, and had accrued the same amount of post-transplant survival time. FINDINGS/RESULTS:Between Jan 1, 2013 and Dec 31, 2020, we identified 44 536 first time kidney transplant recipients with Medicare as primary payer in the 6 months before and at transplantation. 24 192 patients were excluded as they did not have type 2 diabetes. 2328 patients were ineligible (1916 had missing values and 412 used GLP-1 receptor agonists before transplantation). The primary cohort thus consisted of 18 016 kidney transplant recipients with diabetes. Of these patients, 1969 (10·9%) had at least one GLP-1 receptor agonist prescription filled post-transplant. Compared with patients who had not received a GLP-1 receptor agonist, GLP-1 receptor agonist users were younger (median age at transplant 57 years [IQR 49-64] vs 60 years [51-66], p<0·0001) and more likely to be female (786 [39·9%] vs 5645 [35·2%], p<0·0001). Among GLP-1 receptor agonist users, 552 [28·0%] were non-Hispanic White, 703 [35·7%] were non-Hispanic Black, and 568 [28·8%] were Hispanic. The 5-year unadjusted cumulative incidence of death-censored graft loss from a cohort matched on survival time before GLP-1 receptor agonist initiation was 6·0% for GLP-1 receptor agonist users and 10·7% for non-users (Gray's test p=0·004). The 5-year unadjusted cumulative incidence for mortality from a cohort matched on survival time before GLP-1 receptor agonist initiation was 17·0% for GLP-1 receptor agonist users and 25·8% for non-users (log-rank p=0·0006). The 5-year unadjusted cumulative incidence for mortality was 13·5% for GLP-1 receptor agonist users and 19·9% for non-users (log-rank p<0·0001). GLP-1 receptor agonist use was associated with a 49% lower incidence of death-censored graft loss (adjusted subhazard ratio [aSHR] 0·51, 95% CI 0·36-0·71; p=0·0001) and 31% lower mortality (adjusted hazard ratio [aHR] 0·69, 95% CI 0·55-0·86; p=0·001). Inferences were robust when matched on survival time (death-censored graft loss aSHR 0·53, 95% CI 0·37-0·75; p=0·0005; mortality aHR 0·70, 95% CI 0·55-0·88; p=0·003). Safety endpoints were rare and not associated with GLP-1 receptor agonists, with the exception of diabetic retinopathy (aHR 1·49, 1·11-2·00; p=0·008). INTERPRETATION/CONCLUSIONS:GLP-1 receptor agonists were associated with better graft and patient survival. Clinical trials are needed to confirm these findings. FUNDING/BACKGROUND:National Institutes of Health.

INTRODUCTION/BACKGROUND:Reasons for emergency department (ED) visits for persons with cognitive impairment are usually driven by unmet needs. METHODS:ED patients ≥ 75 years old with screener-detected cognitive impairment (Mini-Cog ≤ 3/5) or care partner tool (Informant Questionnaire on Cognitive Decline in the Elderly > 3.4), and care partners from New York and Indiana academically affiliated EDs, were randomly assigned to 6-month dementia care management or usual care. Nurses and paraprofessionals used principles of dementia care management informed by root cause analyses of participants' ED visits. We used logistic regression to compare ED revisit rates during the 6-month intervention. RESULTS:Of 642 dyads-320 intervention, 322 usual care-256 of 632 (40.5%) had at least one ED revisit within 6 months of index visit, but without between-group differences in revisit rates, care partner activation, or symptoms of depression or anxiety at 3 or 6 months. DISCUSSION/CONCLUSIONS:Using root cause analysis to inform dementia care management did not reduce ED revisits. HIGHLIGHTS/CONCLUSIONS:Cognitive screening during emergency department (ED) visits is feasible for quality improvement. ED cognitive screening alone may not identify dyads who need care management. Identifying root causes for ED visits could personalize post-visit care management. Root cause-informed care management did not reduce ED revisits. Need-based screening might better target ED patients with cognitive impairment.