Faculty Bibliography

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). In CTE, hyperphosphorylated tau (p-tau) aggregates are found in neurons at the depth of cortical sulci close to the gray matter/white matter (GM/WM) boundary. To date, CTE can only be diagnosed postmortem by neuropathological examination. Traumatic encephalopathy syndrome (TES) is the clinical syndrome purported to be associated with CTE pathology. The aim of this study is to investigate microstructural properties at the GM/WM boundary in individuals with a history of exposure to RHI and clinical features of CTE (i.e., TES). Diffusion magnetic resonance imaging (dMRI), TES diagnoses, and cerebrospinal fluid (CSF) biomarkers were acquired from 165 male former American football players (age: 57.29 ± 8.23 years) from the DIAGNOSE CTE Research Project, a multicenter, observational cohort study. Fractional anisotropy (FA) was measured at the GM/WM boundary of the whole brain. In addition, a widely used method (tract-based spatial statistics [TBSS]) was applied to measure FA of central WM. We used analyses of covariance to test associations between FA and TES. Furthermore, we used linear regressions to test associations between FA and nine CSF biomarkers (i.e., p-tau-181, -217, -231, total tau, amyloid β [Aβ]_1-40, Aβ_1-42, glial fibrillary acidic protein [GFAP], neurofilament light [NfL], and soluble triggering receptor expressed on myeloid cells-2 [sTREM2]). We report an association between higher FA at the GM/WM boundary and higher levels of certainty for CTE pathology (F(1, 147) = 5.781, 95% confidence interval (CI) = 0.0003-0.003, p = 0.035) as well as neurobehavioral dysregulation (F(1, 148) = 7.559, 95% CI = 0.001-0.009, p = 0.020), and functional dependence/dementia (F(1, 148) = 5.046, 95% CI = 0.0004-0.006, p = 0.039). In addition, we report an association between higher FA at the GM/WM boundary and higher CSF p-tau-181 (β = 0.272, 95% CI = 0.078-0.466, p = 0.029) and p-tau-217 (β = 0.295, 95% CI = 0.102-0.488, p = 0.027). FA of the central WM was not associated with TES diagnoses. Taken together, these findings suggest that dMRI at the GM/WM boundary could be used to investigate microstructural alterations suggestive of tau pathology-associated neurodegeneration in individuals with TES, the clinical presentation of CTE. Future studies are needed to validate this approach and to identify clinically useful cutoff values for dMRI metrics.

OBJECTIVE:People with migraine have a higher prevalence and severity of insomnia. We examined the relationship between insomnia severity and migraine-related disability (MIDAS) and migraine-specific quality of life (MSQv2.1). METHODS:We conducted a post-hoc analysis of a pilot randomized controlled study assessing the RELAXaHEAD application in those with insomnia and comorbid migraine. Descriptive statistics were used to summarize demographic and clinical characteristics. Linear mixed model analysis was conducted to evaluate Insomnia Severity Index (ISI) as a predictor of each MSQv2.1 domain and MIDAS. RESULTS:Forty-two participants completed baseline and at least one follow-up survey. Mean age was 43.8 years (SD 12.6) and the majority (85.7%) were female. Most participants (81.0%) had severe migraine-related disability (median baseline MIDAS, 32 (IQR 52)). Over half (54.8%) of participants had moderate clinical insomnia (mean baseline ISI, 18.5 (SD 4.6)). Baseline median MSQv2.1 scores were 44.3 (IQR 31.4) for Role Function-Restrictive (RFR), 65.0 (IQR 45.0) for Role Function-Preventive (RFP), and 46.7 (IQR 46.7) for Emotional Function (EF). The effect of ISI on MIDAS was statistically significant (rate ratio (RR)=1.10, p < 0.05, 95%CI [1.028, 1.171], meaning each one-point increase in ISI was associated with a 10% higher MIDAS score). Additionally, a 1-point increase in ISI was associated with a decrease of 1.2 points in MSQ-RFR (B=-1.205, p = 0.001),1.0 point in MSQ-RFP (B=-0.981, p = 0.020), and 1.4 points in MSQ-EF (B=-1.66, p = 0.001). CONCLUSIONS:Our study revealed significant associations between insomnia severity and migraine-related disability and quality of life, highlighting the importance of prevention and sleep intervention for patients with migraine.

BACKGROUND:The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. METHODS:We investigated associations of genetic susceptibility to type 2 diabetes (T2D), eight T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242,283 cases, 1,569,734 controls), T1D (18,942 cases, 501,638 controls), and PDAC (10,244 cases and 360,535 controls) in individuals of European ancestry. RESULTS:Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI 1.05-1.15), particularly the T2D obesity (OR = 1.28; 95% CI 1.15-1.42) and lipodystrophy (OR = 1.25; 95% CI 1.03-1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI 0.99-1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10-8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10-4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. CONCLUSIONS:Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

OBJECTIVE:To examine associations between oxidative stress and fetal weight across pregnancy. STUDY DESIGN/METHODS:Cohort study of pregnant participants from 2016-2021 in New York City with urinary lipid, protein, and DNA oxidative stress biomarkers (<18, 18-25, >25 weeks) and estimated fetal weight from ultrasound fetal biometry with the HadlockIII formula (20, 30, 36 weeks). RESULT/RESULTS:percentile. Oxidative stress biomarkers of protein damage were associated with larger estimated fetal weight at 20 (3.4 [95% CI: 1.2, 5.7]) and 36 weeks (16.5 [95% CI: 5.2, 27.8]). CONCLUSION/CONCLUSIONS:These findings advance our understanding of different oxidative stress pathways and their potential role in fetal growth.

RATIONALE AND OBJECTIVES/OBJECTIVE:Prostate multiparametric magnetic resonance imaging (MRI) is recommended for prostate cancer detection, staging, and surveillance. Incidental bladder lesions are encountered on these studies but remain under-characterized in the literature. The patient characteristics associated with malignancy for these lesions are not well defined. We evaluated the prevalence, histopathologic outcomes, clinical characteristics, and associations with malignancy for incidental bladder lesions on prostate MRI. MATERIALS AND METHODS/METHODS:A retrospective review included 31,241 patients undergoing prostate MRI examinations from January 2013 to January 2023. Imaging reports and medical records were analyzed for incidental bladder lesions, demographic data, clinical symptoms, urinalysis findings, and histopathologic outcomes. Lesions were categorized based on biopsy results or negative clinical follow-up for bladder tumors in chart review. Logistic regression analysis and receiver operating characteristic analyses were performed. RESULTS:Incidental bladder lesions occurred in 0.74% (230/31,241) of examinations, with biopsy-confirmed bladder cancer in 0.11% of patients (34/31,241) or 14.8% (34/230) of cases with lesions. In multivariable analysis, gross hematuria had the strongest association with biopsy-proven bladder cancer (OR 9.26, 95% CI 4.12-20.79, p<0.001). A logistic regression model incorporating age, smoking status, and gross hematuria yielded area under the curve of 0.762 for bladder cancer. CONCLUSION/CONCLUSIONS:Incidental bladder lesions on prostate MRI may represent opportunities for early detection of bladder cancer, but also have potential for harms related to unnecessary procedures. Considering the presence of gross hematuria, possibly stated as part of the MRI referral or patient questionnaire, could improve risk stratification of encountered bladder lesions and early cancer detection.

The ACR Incidental Findings Committee presents recommendations for managing incidental pineal cysts on CT of the head or MRI of the brain. The Pineal Cyst Subcommittee is composed of neuroradiologists and a neurosurgeon who developed the algorithms presented. These recommendations represent a combination of current published evidence as well as expert experience and opinion and were finalized by a formal consensus-building process. The recommendations address commonly encountered incidental findings in the pineal gland and are not intended to be a comprehensive review of all pineal incidental findings. The goal is to improve the quality of care by providing guidance on management of incidentally detected pineal cysts.

Obesity has been associated with non-Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome-wide association studies of European ancestry (N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.18, 95% confidence interval (95% CI): 1.05-1.33, p = .005]. This finding was consistent with Mendelian randomization analyses, which demonstrated a similar increased risk of DLBCL with higher genetically determined BMI (OR_{per SD} = 1.12, 95% CI: 1.02-1.23, p = .03). No significant associations were observed with other NHL subtypes. Our study demonstrates a positive link between a genetically determined BMI and an increased risk of DLBCL, providing additional support for increased adiposity as a risk factor for DLBCL.

Standard genome-wide association studies (GWAS) and rare variant burden tests are essential tools for identifying trait-relevant genes¹. Although these methods are conceptually similar, by analysing association studies of 209 quantitative traits in the UK Biobank^2-4, we show that they systematically prioritize different genes. This raises the question of how genes should ideally be prioritized. We propose two prioritization criteria: (1) trait importance - how much a gene quantitatively affects a trait; and (2) trait specificity - the importance of a gene for the trait under study relative to its importance across all traits. We find that GWAS prioritize genes near trait-specific variants, whereas burden tests prioritize trait-specific genes. Because non-coding variants can be context specific, GWAS can prioritize highly pleiotropic genes, whereas burden tests generally cannot. Both study designs are also affected by distinct trait-irrelevant factors, complicating their interpretation. Our results illustrate that burden tests and GWAS reveal different aspects of trait biology and suggest ways to improve their interpretation and usage.

BACKGROUND:Uncontrolled hypertension (HTN) is a leading preventable cause of death. Interventions are needed that activate patients and motivate them to work with clinicians to control their blood pressure (BP). OBJECTIVE:To test whether mailing patients a letter including information about their hypertension and a summary of computerized algorithm-generated medication adjustment suggestions improves BP control processes and outcomes. DESIGN/METHODS:Randomized quality improvement trial. PARTICIPANTS/METHODS:We identified patients receiving primary care at a large academic medical center with diagnosed HTN and uncontrolled BP (> 140 mmHg systolic or > 90 mmHg diastolic) at both of their last 2 visits. INTERVENTIONS/METHODS:Participants were randomized into three groups. The BP Activate Letter group received a letter containing algorithm-generated BP medication adjustment suggestions, and a recommendation to discuss these suggestions with their provider; the Control Letter group received a letter that recommended they talk to their provider about their HTN, without specific medication suggestions; and the No Letter group received no mailed outreach. MAIN MEASURES/METHODS:The primary outcome was time to occurrence of either a BP medication intensification or documented achievement of BP control to < 140/< 90 mmHg using EHR data extracted 6 months after letters were mailed. KEY RESULTS/RESULTS:The primary outcome, which was time to medication intensification or achievement of BP control, did not occur more frequently in the BP Activate Letter group (hazard ratio = 0.86; 95% confidence interval [CI]: 0.65 to 1.14), or in the Control Letter group (0.78; 0.59 to 1.03) compared to the No Letter group, and we saw no evidence of significant improvement in any secondary outcome or subgroup. Time to medication intensification appeared to be significantly longer in the Control Letter compared to the No Letter group (0.50; 0.30 to 0.85). CONCLUSIONS:Mailing patients one letter with computerized BP medication adjustment suggestions to consider did not lead to effective patient activation.