Citations

Background The literature on dyslipidemia and cognitive trajectories among cognitively unimpaired (CU) persons remains inconclusive. Objective To investigate the association between baseline dyslipidemia and change in global and domain specific (i.e., memory, language, attention/executive function, and visuospatial skills) cognition in a population-based setting and whether the association differs by sex, age, or APOE ɛ4 carrier status. Methods We conducted a longitudinal study derived from the Mayo Clinic Study of Aging, involving 4236 CU persons aged ≥ 50 years. We ran linear mixed-effect models to examine baseline dyslipidemia in predicting longitudinal cognitive global and domain-specific z-scores adjusted for age, sex, education, medical comorbidity, repeated cognitive testing, and APOE ɛ4. We examined interactions among dyslipidemia, years since baseline, and separately by sex, age, and APOE ɛ4 carrier status. Results Over a median follow-up period of 6.4 years, CU individuals with dyslipidemia showed faster decline in z-scores of all domains, i.e., memory, language, attention/executive function, visuospatial and global cognition relative to CU individuals without dyslipidemia. Three-way interactions showed that dyslipidemia's effect on decline in z-scores of global cognition, attention and visuospatial skills was less pronounced in males than females. Higher age increased dyslipidemia's effect on decline in z-scores of attention but not global cognition or any other domain. APOE ɛ4 carrier status did not modify the effect of dyslipidemia on cognitive z-scores. Conclusions Dyslipidemia was associated with faster global and domain-specific cognitive decline over time in older community-dwelling individuals who were cognitively unimpaired at baseline. The effect of dyslipidemia on cognitive trajectories may be sex-influenced.

Abstract Disclosure: E.M. Lewiecki: Amgen Inc, Kyowa Kirin, Ultragenyx, Angitia, Radius Health, Inc, Ascendis. E. Kapoor: Fresenius Kabi USA Inc., Astellas Pharma, Estetra SRL, WellFound Inc., Exeltis. S. Hurtado: None. V.M. Navarro: Bayer, Inc. M. Torres: Bayer, Inc. J. Beau: Bayer, Inc. I. Gkioni: Syneos Health LLC (providing service to Bayer), AstraZeneca. K. Genga: Bayer, Inc.. Background: The neuropeptide substance-P and its receptor neurokinin-1 (SP-NK1R pathway) play a role in bone metabolism and remodelling. Pre-clinical evidence also points to a role of this pathway in energy homeostasis. NK-1R antagonists have been proposed as potential therapies in obesity and musculoskeletal disorders like osteoporosis. Elinzanetant (EZN) is a dual neurokinin-1 and -3 receptor antagonist in late-stage development for vasomotor symptoms (hot flashes) associated with menopause. This post hoc analysis evaluates potential benefits of EZN on the skeleton, body weight, and body composition in postmenopausal women. Methods: Data were gathered from exploratory endpoints of the 52-week (wk), placebo (PL)-controlled, OASIS-3 Phase 3 EZN efficacy and safety trial. Mean percentage (%) change in total bone mass (kg) (measured indirectly by bioelectrical impedance analysis at baseline (BL), wks 4, 8, 12, 18, 24, 36, 52); mean % change in bone mineral density (BMD, measured directly by dual-energy X-ray absorptiometry at BL, wks 24 and 52) in femoral neck, total hip, and lumbar spine; and mean % change in key bone turnover markers osteocalcin (OC) and procollagen 1N-terminal propeptide (P1NP) at BL, wks 4, 8, 12, 18, 24, 36, 52 were evaluated. Weight, body mass index (BMI: weight/height2), waist circumference (WC), fat mass index (FMI; fat mass/height2), lean mass index (LMI; lean mass/height2) and body water were measured to monitor body composition at BL and wks 4, 8, 12, 18, 24, 36, 52. A sub-analysis was performed based on FMI at baseline (FMI ≤9 normal fat mass; >9 excess fat mass). Descriptive statistics were used to evaluate all parameters and trends. Results: From BL to wk 52, increasing trends in bone mass were observed with EZN (mean [SD]: 2.81 [1.02] to 2.95 [1.96]) but not PL (mean [SD]: 2.87 [1.09] to 2.87 [1.13]). In parallel, lower BMD reductions were seen in EZN vs PL at all skeletal sites [EZN vs PL, mean % change from BL: femoral neck (0.00% vs -1.22%), total hip (-0.70% vs -1.37%), and lumbar spine (-0.57% vs -1.22%), with considerable variability in both groups (SD range 3.01 - 4.70)]. Lower levels of circulating OC and P1NP were consistently observed over 52 wks of EZN treatment, suggesting a lower rate of bone resorption with EZN vs PL. Trending reductions in weight, BMI, and WC, along with increases in LMI and body water were observed with EZN vs PL. Trends of higher LMI in patients with excess fat, or lower FMI in patients with normal fat at BL were observed with EZN, suggestive of a positive body re-composition with EZN. Conclusions: These data expand on EZN safety profile and further point to novel potential benefits for the skeleton and body composition of postmenopausal women. Further research is warranted to provide conclusive evidence of the benefits of EZN specifically in post-menopausal women with obesity/overweight status or osteoporosis. Sponsorship: Bayer U.S., Whippany, NJ, USA Presentation: Monday, July 14, 2025

Importance The effect of cornea donor diabetes on endothelial cell density (ECD) and morphometry after Descemet membrane endothelial keratoplasty (DMEK) is not known. Objective To determine whether endothelial cell loss (ECL) and morphometric changes 1 year after successful DMEK are related to cornea donor’s diabetes status. Design, Setting, and Participants This was a multicenter, double-masked, randomized clinical trial conducted from February 2022 to July 2024 at 28 US clinical sites (46 surgeons) and 13 eye banks. Included in the trial were the eyes of recipients (some of whom received tissue from donors without diabetes and others who received tissue from donors with diabetes) who underwent successful DMEK, primarily for Fuchs endothelial corneal dystrophy, and had at least 1 analyzable postoperative endothelial image. Intervention DMEK performed with a cornea from a donor without or with diabetes, assigned using a minimization procedure to achieve an approximate 2:1 distribution. Main Outcomes and Measures ECD, ECL, coefficient of variation in cell area (CV), and percentage of hexagonal cells (HEX) at 1 year from eye bank and postoperative specular central endothelial images. Results A total 1274 eyes of 982 recipients (mean [SD] age, 70 [8] years; 569 female [57.9%]; 816 [64.1%] with tissue from donors without diabetes and 458 [35.9%] with tissue from donors with diabetes) were included in the study. Preoperatively, mean (SD) central ECD in tissue from donors without diabetes and with diabetes were 2676 (290) cells/mm 2 and 2671 (286) cells/mm 2 , respectively. At 1 year, mean (SD) ECL was 28.3% (16.1%) and 28.0% (17.0%), in the donor groups without and with diabetes, respectively (adjusted mean difference = −0.4%; 95% CI, −2.3% to 1.4%), resulting in a mean (SD) 1-year ECD of 1927 (498) cells/mm 2 and 1920 (496) cells/mm 2 , respectively (adjusted mean difference = 10 cells/mm 2 ; 95% CI, −36 to 56; P = .95). No difference in ECD at 1 year associated with diabetes severity was noted ( P = .97). Mean (SD) CV did not differ at 1 year between the 2 groups of eyes (31.5% [4.1%] vs 31.4% [4.1%]; adjusted mean difference = −0.4%; 95% CI, −0.9% to 0.1%; P = .51), and mean (SD) HEX did not differ at 1 year between the 2 groups of eyes (57.7% [5.8%] vs 57.2% [5.8%]; adjusted mean difference = 0.1%, 95% CI, −0.8% to 0.9%; P = .33). Conclusions and Relevance This randomized clinical trial found that ECL and morphometry 1 year after DMEK were not affected by cornea donor diabetes status. With comparable 1-year graft success with tissue from donors with and without diabetes demonstrated in this trial, these findings support the use of corneas from donors with diabetes for endothelial keratoplasty procedures. Trial Registration ClinicalTrials.gov Identifier: NCT05134480

Importance If the success of Descemet membrane endothelial keratoplasty (DMEK) is not affected by whether the donor has diabetes, then the donor pool should expand. Objective To determine whether the 1-year DMEK success rate is affected by the presence of diabetes in the donor. Design, Setting, and Participants This was a multicenter, double-masked, randomized clinical trial conducted from February 2022 to July 2025 at 28 clinical sites (46 surgeons), with donor corneas provided by 13 eye banks in the US. Included in the study were individuals undergoing low to moderate risk DMEK (95% for Fuchs endothelial corneal dystrophy). Study data were analyzed from April to September 2025. Intervention DMEK performed with a cornea from a donor without or with diabetes, assigned using a minimization procedure (comparable with randomization) to achieve an approximate 2:1 distribution, respectively. Main Outcomes and Measures Graft success at 1 year Results A total of 1097 individuals (1421 study eyes; median [IQR] age, 71 [66-76] years; 631 female [57.5%]) were included in the study. The 1-year cumulative probability of graft success was 96.3% (95% CI, 95.0%-97.5%) among 912 study eyes (64.2%) receiving tissue from donors without diabetes and 97.1% (95% CI, 95.5%-98.4%) among 509 study eyes (35.8%) receiving tissue from donors with diabetes (difference between groups = 0.7 percentage points; 95% CI, −1.2 to 2.6; P = .63). The 1-year cumulative probability of graft success was 96.5% (95% CI, 93.6%-98.9%) in the mild donor diabetes severity subgroup (n = 173) and 97.3% (95% CI, 95.4%-98.8%) in the moderate to severe donor diabetes severity subgroup (n = 336), using a diabetes severity rating scale based on medical history. The rates of primary donor failure, early failure related to surgical complications, and subsequent failure were as follows: 2.5% (23 of 912), 0.7% (6 of 912), and 0.3% (3 of 912), respectively, in recipients of tissue from a donor without diabetes, and 2.6% (13 of 509), 0.4% (2 of 509), and 0%, respectively, among recipients of tissue from a donor with diabetes. There were no failures due to graft rejection. Conclusions and Relevance The 1-year success rate in eyes undergoing DMEK with successfully prepared tissue was very high regardless of donor diabetes status. These results, supported by the separately reported finding that endothelial cell loss and cornea morphometry after 1 year were not affected by donor diabetes status, provide strong support for having no restrictions on the use of tissue from donors with diabetes for DMEK. Trial Registration ClinicalTrials.gov Identifier: NCT05134480

Abstract Objective The objective of this study was to summarize the available evidence regarding the clinical value and trend over time of lumbar cerebrospinal fluid (CSF) opening pressure utilization to diagnose spontaneous intracranial hypotension (SIH). Background CSF opening pressure obtained via lumbar puncture is one of the diagnostic criteria for SIH based on the International Criteria for Headache Disorders, 3rd Edition (ICHD‐3), but it has questionable utility as an initial investigation for diagnosing SIH. Methods The authors performed a systematic literature review and meta‐analysis. PubMed/MEDLINE, Scopus, and Cochrane Library were searched from inception to October 2022. Original studies and case series in English reporting three or more patients with suspected or known SIH and CSF pressure measurement were included. Meta‐analyses and meta‐regression were used to calculate pooled estimates and examine the impact of age, sex, and publication year on outcomes, including CSF pressure < 60 mm CSF, orthostatic headache, and positive findings on brain magnetic resonance imaging (MRI), spinal imaging, and radionuclide studies. Results For every 1‐year increase in the year of publication, the odds of reporting low CSF pressure decreased by 6.20% (adjusted odds ratio [aOR] = 0.94, aOR 95% confidence interval [CI] = [0.90, 0.97], p = 0.001), the odds of reporting a positive brain MRI increased by 4.67% (aOR = 1.05, aOR 95% CI = [1.01, 1.09], p = 0.026), and the odds of reporting orthostatic headache increased by 9.13% (aOR = 1.09, aOR 95% CI = [1.03, 1.15], p = 0.002). Each 1% increase in the percentage of patients with orthostatic headache was associated with a 3.13% increase in the odds of low CSF pressure (aOR = 1.03, aOR 95% CI = [1.01, 1.05], p = 0.003). Similarly, as the percentage of patients with low CSF pressure increased by 1%, there was a 2.53% increase in the odds of orthostatic headache (aOR = 1.03, aOR 95% CI = [1.01, 1.04], p = 0.005). It was estimated that 31.9% of patients with SIH had normal opening pressure (95% CI = [24.0%, 40.8%], prediction interval = [5.0%, 80.5%]). Every 1% increase in the percentage of patients with positive brain MRI was associated with a 5.25% increase in the odds of positive spinal imaging (aOR = 1.05, aOR 95% CI = [1.00, 1.11], p = 0.047). Age and positive radionuclide study did not significantly impact the outcomes measured. The corresponding I 2 for each outcome was reduced by controlling for study‐wide covariates believed to impact the prevalence of each outcome. Sensitivity analyses did not reveal discrepancies in results when studies requiring outcomes of interest were removed. Conclusion Our analysis found that recent studies indicate a reduced reliance on opening pressure for diagnosing SIH. Rather, results suggest an increasing reliance on contrast‐enhanced brain MRI, spine imaging, and clinical features for SIH diagnosis.

Abstract INTRODUCTION Increased white matter hyperintensity (WMH) volume is a common but non‐specific finding in AD. This study investigates the effect of baseline WMH volume and APO E ε4 on magnetic resonance imaging (MRI)‐visible hemorrhagic lesion emergence. METHODS We included A4 participants with 0/1 hemorrhagic lesion at baseline and >1 post‐baseline MRI. We examined age, sex, amyloid, WMH, APOE ε4, and cardiovascular risk as predictors of whether people would accrue ≥2 hemorrhagic lesions by their last MRI. RESULTS Among 1097 individuals with 0/1 baseline lesion, 120 had at least two hemorrhagic lesions on their last MRI. Elevated baseline WMH (odds ratio [OR] = 2.3, p = 0.002) and APOE ɛ4/ɛ4 (OR = 4.8, p < 0.001) independently predicted membership to this group. Both hetero‐ and homozygous APOE ɛ4 carriers with low WMH volume had a low risk of accumulating hemorrhagic lesions. DISCUSSION These results support the independent consideration of WMH and APOE ɛ4 in the natural history of hemorrhagic lesion accumulation and suggest that individuals with low WMH volume have a low short‐term risk, irrespective of APOE genotype. Trial Registration : NCT02008357 Highlights Elevated baseline white matter lesion volume is related to the risk of ARIA‐H emergence. The effects of white matter lesion volume and APOE ɛ4 on ARIA‐H are independent. APOE ɛ4 carriers with low white matter lesion volume had a low risk of ARIA‐H emergence.

A 49-year-old woman presented with a dorsal column-predominant sensory myelopathy secondary to superficial siderosis. She had Marfan syndrome and was found to have dural ectasia. Superficial siderosis results from subpial haemosiderin deposition due to chronic subarachnoid space bleeding, often from a dural pathology, such as a tear. Dural ectasia is common in Marfan syndrome, but superficial siderosis is not. Gait ataxia, often with hearing impairment, is a common clinical presentation of superficial siderosis. Patients may develop myelopathy, here being a pure sensory myelopathy with predominant dorsal column deficit. Meningeal diverticulae and superficial siderosis are both associated with cerebrospinal fluid (CSF) leaks. This patient had dural ectasia and meningeal diverticulae, but the CT myelogram found no CSF leak. Superficial siderosis should be considered in patients with sensory myelopathy. Lumbosacral dural ectasia, or less likely CSF leak, can cause superficial siderosis in people with Marfan syndrome.

Study Design: Retrospective cohort analysis. Objective: To determine the effect of long-segment posterior cervical decompression and fusion (PCDF) on perioperative changes in vertebral Hounsfield Units (HUs) and the impact of these changes on radiographic outcomes and fusion status. Summary of Background Data: Low preoperative CT HUs have been associated with adverse outcomes after spinal fusion, including hardware complications and reoperation. No existing studies have investigated the preoperative to postoperative change in HUs after cervical spinal fusion. Stress shielding may decrease bone quality within the fusion construct. Whereas, altered junctional loading and increased segmental mobility may precipitate bony hypertrophy in the terminal and adjacent levels. Methods: All adult patients who underwent C2-T2 PCDF for myelopathy/ myeloradiculopathy at an academic center between 2013 and 2020 were retrospectively identified. Preoperative and postoperative HUs were assessed on axial CT images in the cranial, middle, and caudal C2, C6, T2, and T3 vertebral bodies, outside of the region of instrumentation and artifact by 2 independent reviewers. Paired t test compared preoperative to postoperative changes in HUs. Preoperative and long-term postoperative cervical alignment, fusion, and revision rates were assessed. Univariate and regression analysis compared patient factors and outcomes between groups with perioperative increase versus decrease in vertebral HUs. Results: One hundred patients were included. The average preoperative to postoperative change in HUs in the C2, C6, T2, and T3 vertebral bodies were −19.80 (P=0.008), −52.63 (P<0.001), 15.15 (P=0.014), and 9.41 (P=0.346), respectively. Perioperative increase in C2 HUs was predictive of increased postoperative distal junctional angle (β=3.41, P=0.048) and increased T1–T4 kyphosis (β=6.50, P=0.003). Perioperative increase in C6 HU predicted pseudoarthrosis (fusion odds ratio: 0.19, P=0.007). Conclusions: Significant perioperative decreases in C6 HUs within a long-fused construct may demonstrate stress shielding. The significant association between greater distal kyphosis and an increase in C2 HUs may be attributed to a stress riser effect. Level of Evidence: Level III.

The treatment landscape of B-cell lymphomas has significantly evolved in recent years with approval of novel targeted therapies. CD3 × CD20 bispecific antibodies and CD19-directed monoclonal antibodies and antibody–drug conjugates have demonstrated efficacy in relapsed/refractory follicular lymphoma (FL). Bruton tyrosine kinase (BTK) inhibitor–based regimens are emerging as effective treatment options for patients with TP53-mutated classical mantle cell lymphoma (MCL). Results from ongoing clinical trials suggest that the addition of CD3 × CD20 bispecific antibodies to chemoimmunotherapy improves outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, MCL, and DLBCL.