Citations

Abstract Lower cerebral perfusion is associated with adverse outcomes, but risk factors are poorly understood. This study examined associations of cumulative systolic blood pressure [SBP], diabetes, and BMI from mid- to late-life with late-life cerebral perfusion, using whole-brain MRI Arterial Spin Labeling (ASL). Cumulative exposures were defined as either average continuous SBP or BMI across visits or number of years with diabetes, hypertension, or obesity. Multiple regression, adjusted for age and gender, estimated ASL (β: 95% CI) among participants without prevalent conditions at baseline in participants with ASL data from the Atherosclerosis Risk in Communities Study (ARIC; Jackson, MS; n = 100; age=81±3 years; 65% Female; 100% Black participants; 34 years retrospective risk factor assessments (1987-2021); pulsed ASL, 8/2021-1/2024) and the Mayo Clinic Study of Aging (MCSA; Rochester, MN; n = 537; age=71±13 years; 36.3% Female, 100% White participants; 18 years retrospective risk factor assessments (2005-2023); pseudo-continuous ASL 2/2023-3/2024). A 10 mmHg higher cumulative SBP was associated with a 0.04 lower ASL (MCSA β=-0.04; -0.01, -0.07; ARIC β=-0.04; -0.09, 0.01). A 10 kg/m2 higher cumulative BMI was associated with a 0.30 lower ASL (-0.51, -0.08) in ARIC and 0.03 lower ASL (-0.16, 0.10) in MCSA participants. Every five additional years of diabetes exposure was associated with a 0.03 (-0.06, -0.01) lower ASL in ARIC and 0.11 (-0.27, 0.05) lower ASL in MCSA participants. High BP, obesity, and diabetes may contribute to poor cerebral perfusion over extended exposures from midlife. Longer risk factor assessment periods and different ASL techniques may explain differences in the cohorts.

Abstract Extensive studies in rodents have shown that senescent cells accumulate across tissues and their clearance leads to improvements in healthspan and lifespan. Based on these studies, there is intense interest in translating these findings into humans. Based on ClinicalTrials.gov, there are currently 26 ongoing studies on “senolytics” and 32 on “fisetin”. However, to date, there are only 9 published clinical trials of senolytics, only 2 of which included a control group. Collectively, the initial findings from these trials have indicated possible biological efficacy of senolytics (dasatinib + quercitin) in improving biomarkers of healthspan in humans with no significant safety concerns. However, these initial studies also highlight the potential heterogeneity of aging mechanisms in humans and argue for a more personalized approach in future senolytic trials. Specifically, it is likely going to be critical to identify aging individuals with a sufficiently high burden of senescent cells that would result in a beneficial effect from the senolytic intervention.

Abstract As a group, family caregivers of people with dementia (PWDs) have substantially elevated levels of depression and anxiety, compared to same-aged non-caregiving adults. However, there is striking variation in mental health among individual caregivers. Previous research on predictors of the sources of these individual differences has focused on characteristics of individual caregivers and PWDs (rather than on the caregiver-PWD relationship), self-report measures (rather than behavioral measures), and negative emotion (rather than positive emotion). We examined 185 caregiver-PWD dyads who had an unrehearsed 10-minute conversation about an area of conflict in the laboratory. Video recordings were coded for Behavioral Indicators of Positivity Resonance (BIPR), which derives from Positivity Resonance Theory and assesses dyad-level behavioral expressions of positive affect, mutual warmth, and synchrony. Caregivers reported their level of depression, anxiety, and emotional well-being and PWDs underwent a comprehensive neurological and neuropsychological evaluation. Pearson’s correlations revealed that greater dyad-level BIPR was associated with caregivers’ higher emotional well-being (r(181) = .19, p = .008), lower depression (r(179) = -.17, p = .025), and lower anxiety (r(180) = -.15, p = .045). Regression analyses revealed that these associations were still obtained after controlling for caregiver age and sex and PWD dementia severity, cognitive impairment, and neuropsychiatric behavior (emotional well-being ß = .18, p = .012; depression ß = -.15, p = .039; anxiety ß = -.15, p = .044). Future studies should determine whether interventions that increase co-experienced positive emotions among caregiver-PWD dyads help buffer caregivers from adverse mental health consequences.

Abstract Blood-based biomarkers show promise as a noninvasive method for measuring Alzheimer’s disease pathology and neurodegeneration throughout the lifecourse. However, the relationship between longitudinal changes in these biomarkers and late-life brain morphology in community-dwelling populations requires further investigation. Between 2011 and 2013, 1,977 participants from the Atherosclerosis Risk in Communities Study received underwent 3 Tesla magnetic resonance imaging scans. Whole-brain cortical thickness was quantified by Freesurfer. Stored plasma samples collected in midlife (1993-95, mean age 59.0 years) and late-life (2011-13, mean age 76.8 years) from a subsample of 1,515 participants (60.7% female, 25.5% Black adults) were assayed in 2022 using Quanterix SiMoA. The assay quantified amyloid-β (Aβ)42/40, phosphorylated tau at threonine 181 (p-Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models estimated the association of blood-based biomarkers from midlife, late-life, and the change from midlife to late-life with cortical thickness in late-life. In models adjusted for demographics, lifestyle factors, cardiovascular factors, and the presence of APOE ε4 alleles, higher midlife measures of p-Tau181 and increases from midlife to late-life in NfL and GFAP were associated with lower cortical thickness in late-life. Concurrent measures of p-Tau181, NfL, and GFAP were associated with lower cortical thickness in late-life and exhibited a stronger association among participants ≥75 years old compared to participants <75 years old. Additional longitudinal research is needed to determine whether blood-based biomarkers predict cortical thinning over time and may serve as an early indicator of accelerated brain atrophy.

ABSTRACT Immune checkpoint‐inhibitors (ICIs) have revolutionized and significantly improved cancer care through remarkable efficacy, but significant adverse effects have been observed. Among these, ICI‐induced myocarditis with myositis/myasthenia gravis overlap syndrome represents a life threatening, severe immune‐related adverse event that clinicians need to be aware of and be able to diagnose rapidly given its aggressive course. We present two patients who were treated with ICIs and subsequently developed said syndrome. Both patients experienced significant cardiac and neuromuscular manifestations and despite high‐dose intravenous steroids, intravenous immunoglobulin, and other adjunctive therapies, both patients rapidly deteriorated and elected to withdraw care. Additionally, we review the pathophysiology, diagnosis and management of ICI‐induced myocarditis with myositis/myasthenia gravis overlap syndrome. Overall, the overlap syndrome has a poor prognosis and high mortality rates requiring prompt recognition, discontinuation of ICIs and initiation of immunosuppressive therapies.

ABSTRACT Gain-of-function mutations in the transient receptor potential 6 (TRPC6) channel have recently been recognized as risk factors for both doxorubicin (DOX)-induced cardiomyopathy. Functional evaluation of TRPC6 missense variants is therefore important for cancer patients undergoing anthracycline treatment. However, traditional electrophysiological methods are labor-intensive and time-consuming. In this study, we compared the functional responses of TRPC6 missense variants to 1-oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC6 agonist, using molecular docking and patch clamp recording techniques. For the wild-type (WT) TRPC6 structure (PDB ID: 6UZ8), OAG exhibited a binding energy of -4.49 kcal/mol and a dissociation constant (Kd) of 0.511 mM. Twenty TRPC6 missense variants were identified from cancer patients in the Mayo Clinic database. Of these, fifteen variants had resolvable structures, nine of which displayed increased Kd values and six decreased Kd values compared to WT in molecular docking analysis. Patch clamp recordings revealed that TRPC6 WT and mutant channels were inactive at baseline but were activated upon 50 μM OAG stimulation, except two loss-of-function variants. Moreover, a 24-h treatment with 0.5 μM DOX significantly enhanced OAG-induced channel activation. All three variants identified in patients with heart failure demonstrated gain-of-function properties in both electrophysiological measurements and in-silico predictions. Importantly, the results obtained from molecular docking and patch clamp recordings were strongly correlated, showing an 82% concordance, higher than the predictions from AlphaMissense. These findings indicate that our computational analysis provides a rapid and reliable method for predicting the functional impact of TRPC6 missense variants, which may aid clinical decision-making in cancer patients receiving chemotherapy.

Background: Femoroacetabular impingement (FAI) is a common cause of hip pain in young, active athletes. American football players place high demands on the hip due to the sport's requirements for pivoting, cutting, and loading in deep flexion. Although arthroscopic treatment of FAI in professional National Football League (NFL) players has shown favorable outcomes, football-specific outcomes in non-NFL athletes remain limited. Purpose: To report the return-to-sport (RTS) rates and functional outcomes at a minimum 2-year follow-up for active American football players competing at multiple levels after primary hip arthroscopy for FAI. Study Design: Case series; Level of evidence, 4. Methods: An institutional database was queried to identify all active American football players who underwent primary hip arthroscopy with labral repair between 2010 and 2023. Demographic characteristics, radiographic parameters, procedure details, complications, and reoperations were collected. Follow-up was completed at a minimum of 2 years to obtain updated patient-reported outcome measures (PROMs) as well as football-specific data, including current participation and RTS status. PROMs were reported as mean ± standard deviation, and categorical variables, including RTS, were reported as frequencies. Pre- versus postoperative PROMs were compared using t tests or Mann-Whitney U tests to assess outcomes. Results: In total, 49 hips in 38 male football players (age, 18.1 years; range, 14-26 years) were included. Most athletes played at the high school (74%) or college level (21%). A total of 51% played as linemen. Labral repair was performed in all cases. At a mean 7.6 years, mean modified Harris Hip Score was 90 ± 13, Hip Outcome Score–Activities of Daily Living was 95 ± 7, and Hip Outcome Score–Sport was 89 ± 17. Overall mean surgery satisfaction was 8.7 ± 1.7 (out of 10). Significant postoperative improvements were observed in all PROMs ( P ≤ .002). Twelve players (32%) did not attempt RTS due to other nonmedical factors and were excluded from return to sport analysis. A total of 23 (88%) players achieved RTS, and 3 players (12%) did not. Two players (8%) cited other injuries, and 1 player (4%) continued to have hip limitations. Four hips (8%) underwent reoperation at a mean 4.9 years postoperative. Conclusion: Amateur American football players undergoing primary hip arthroscopy for FAI demonstrated excellent patient-reported outcomes and a high RTS rate of 88%, when excluding those who did not return for nonmedical reasons, at a mean 7.6-year follow-up. Notable positional differences were observed across multiple levels of play. Although outcomes were generally favorable, both medical and nonmedical factors could limit return to sport, particularly among high school and college athletes.

FRACTURE MRI demonstrated strong agreement with conventional radiography and CT in evaluating key bone tumor characteristics, including lesion type, location, and matrix content.

Abstract Multiple myeloma (MM) with t(11;14)(CCND1;IGH) remains the only subset sensitive to the BCL2 inhibitor venetoclax. However, not all patients with t(11;14)(CCND1;IGH) respond to treatment, and some progress early after initial response. To investigate this, we examined 44 whole-genome and whole-exome sequencing data samples from 34 patients with t(11;14) MM treated with venetoclax. The presence of mutations in the RAS pathway was strongly associated with shortened progression-free survival (PFS) and was validated in an independent cohort of 21 patients with MM. The presence of 1q gain was also associated with shorter PFS in patients without RAS mutations. In 10 patients with paired prevenetoclax and postvenetoclax treatment samples, postvenetoclax progression was recurrently driven by the selection of genomic events in the BCL2/MCL1 and RAS pathways and of high-risk features (eg, loss of TP53 and CDKN2C). Overall, our study shows that comprehensive genomic profiling can identify most mechanisms underlying resistance to BCL2 inhibition in t(11;14)(CCND1;IGH) MM.