Citations

Background/Objectives: White matter (WM) tract detection is critical in the presurgical planning of tumor resection. However, standard-of-care imaging techniques including T1-weighted, T2-weighted, and Diffusion Tensor Imaging (DTI) often fail to identify WM tracts within edematous regions. In T1/T2-weighted imaging, edema increases extracellular water and reduces tissue contrast, and in diffusion-weighted imaging, edema elevates isotropic diffusion, reducing sensitivity to anisotropic diffusion along WM tracts. Advanced biophysical diffusion modeling techniques such as Neurite Orientation Dispersion and Density Imaging (NODDI) and the Standard Model (SM) address this limitation by compartmentalizing the diffusion signal into free-water, intra-neurite, and extra-neurite contributions. Here, we test if biophysical multi-compartment models can robustly identify WM tracts and recover tractography streamlines within edematous regions. Methods: In this study, we use multi-shell diffusion-weighted MRI data obtained from patients with meningiomas—a pathology allowing for isolation of the effects of edema without the confounding effects of tumor cell invasion. We compared FA from standard and free-water-corrected DTI, the orientation dispersion index (ODI) from NODDI, and P2 (a scalar descriptor of fiber orientation coherence) from the SM fODF in edematous and unaffected contralateral WM regions. As a proof of concept, we visually evaluated the tractography performance across models. Results: Our results show that (1 − ODI) and P2 values in edema remained close to within-subject contralateral measurements, contrasting with substantial reductions in FA and FW-FA. (1 − ODI) showed a small but statistically significant increase in edema (~8%, p = 0.02), while P2 was unchanged. Conclusions: These results highlight the potential of biophysical diffusion models for preoperative mapping in edema.

ABSTRACT Background Long‐term outcome data for stiff person spectrum disorder (SPSD) remain limited and sustained response to treatment varies. Methods In this retrospective cohort study, we included patients with probable or definite SPSD (Mayo Clinic criteria), evaluated at Mayo Clinic (12/1995‐07/2024) with ≥ 5 years of follow‐up after diagnosis. Primary outcome measures included the modified Rankin scale (mRS) and use of gait aids. Results Fifty‐four patients were included, 41 (76%) were female; median age at onset was 45 years (16–78). Most were antibody‐positive (51 [94%]), with high‐titer (serum, ≥ 20 nmol/L) GAD65‐IgG in 45 (83%). Nine patients had a stiff‐limb presentation (17%). The median interval from onset to diagnosis was 2 years (0–34), and median follow‐up was 9 years (5–26). Most patients (46 [85%]) received immune therapy; 37 (82%) reported improvement. All patients had significant impairment (mRS ≥ 2) at nadir, with 31 (57%) losing functional independence (mRS ≥ 3) and 40 (75%) requiring bilateral gait assistance. The median time from onset to nadir was 6 years (0–39). At last follow‐up, most (37 [69%]) were functionally independent (mRS ≤ 2), including 8 (15%) with minimal restrictions (mRS ≤ 1). Bilateral gait assistance was needed in 22 (41%). Among 40 patients with ≥ 10 years of follow‐up, 22 (56%) had an mRS ≤ 2 and 25 (63%) required a gait aid at last follow‐up. Poor outcome in this population was associated with bilateral gait assistance at nadir and older age ( p < 0.05). Conclusions Although over half of SPSD patients lose functional independence at disease nadir, many regain independence and achieve well‐controlled symptoms.

Abstract We describe early experience with beta-lactam therapeutic drug monitoring (TDM) in a high-volume outpatient parenteral antimicrobial therapy program. In selected patients, TDM informed dose optimization and toxicity mitigation. Illustrative cases highlight feasibility and emerging lessons supporting beta-lactam TDM in outpatient care.

OBJECTIVE Intramedullary spinal cord tumors (IMSCTs) are typically treated with maximal safe resection, during which neurosurgeons often monitor for neurological injury using muscle motor evoked potential (mMEP) and direct wave (D-wave) neuromonitoring. The predictive value of changes in D-waves for identifying motor outcomes is underexplored. This study evaluated the utility of D-waves for predicting postoperative motor deficits. METHODS Patients who underwent resection of a primary IMSCT with mMEP neuromonitoring from 2003 to 2023 at a tertiary care hospital were identified. Patients who underwent D-wave monitoring in addition to mMEP monitoring were compared to those who underwent mMEP monitoring alone using the Mann-Whitney U-test, chi-square test, and Fisher’s exact test. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of D-wave and mMEP monitoring for identifying new neurological deficits immediately postoperatively and at 1 month, 6 months, and last follow-up were calculated. RESULTS After matching, 125 patients were included (median age 42.0 years; 57.6% male; median follow-up 34.0 months), of whom 88 had both mMEP and D-wave data. The most common pathologies were ependymoma (64.0%) and astrocytoma (17.6%). Patients who did and did not undergo D-wave neuromonitoring had similar preoperative neurological function, primary pathology, tumor grade, and tumor location. D-wave use was associated with increased gross-total resection (88.6% vs 64.9%, p = 0.002) and reduced mortality (5.7% vs 24.3%, p = 0.007), length of stay (5.0 vs 6.0 days, p = 0.033), and 30-day readmission (2.3% vs 13.5%, p = 0.013) and reoperation (1.1% vs 10.8%, p = 0.012). At the 6-month follow-up, D-wave monitoring alone was superior to mMEP and combination monitoring for detecting new motor deficits. D-wave monitoring had peak sensitivity (77.8%) and NPV (96.5%) at 6 months and peak specificity (95.8%) and PPV (76.9%) in the immediate postoperative period. CONCLUSIONS D-wave monitoring was associated with reduced mortality and was more accurate than mMEP monitoring alone or combination monitoring for detecting new postoperative neurological deficits. Further prospective studies are needed to validate these results.

OBJECTIVE The objective was to evaluate the trajectories of hematoma resolution and functional improvement after middle meningeal artery embolization (MMAE) for chronic subdural hematoma (cSDH), model the temporal pattern of cSDH resolution, and identify factors associated with favorable outcomes. METHODS This real-world multicenter retrospective study included cSDH patients treated with MMAE at 24 centers between 2019 and 2024. Hematoma thickness was measured at baseline and at follow-up intervals (1–4 weeks, 1–3 months, 3–6 months, 6–12 months, and > 12 months after embolization). Resolution patterns were modeled using exponential decay functions. Modified Rankin Scale (mRS) scores assessed functional outcomes. Good functional outcome was defined as mRS score ≤ 2. Resolution patterns were modeled using exponential decay functions to estimate time to 50% and 80% reduction. Patients were categorized as complete resolution (≥ 99%) or by quartile of the remaining distribution (substantial [73%–98%], moderate [53%–73%], partial [27%–53%], minimal [< 27%]). The primary outcome was good functional status (mRS score ≤ 2). RESULTS The authors analyzed a total of 1781 patients with 2295 cSDHs who underwent MMAE. The mean ± SD age was 72.8 ± 12.4 years and 68.1% of patients were male. The initial mean hematoma thickness was 15.31 ± 6.53 mm, decreasing to 5.24 ± 5.91 mm at final follow-up (mean reduction 64.3% ± 42.1%). Resolution followed an exponential decay pattern, with an estimated time to 50% reduction of 1.8 months and to 80% reduction of 8.9 months. Complete resolution occurred in 1031 of 2224 patients (46.4%) with complete follow-up. The median (IQR) mRS score improved from 1 (0–3) at baseline to 0 (0–2) at > 12 months. Good functional outcomes were more common in patients with complete versus minimal resolution (68.9% vs 35.0%, p < 0.001). Achieving ≥ 73% resolution within 90 days was associated with better outcomes (good outcome in 76.9% of those with ≥ 73% resolution vs 67.3% in those without, p < 0.001). Neurological deterioration was the strongest predictor of lack of good outcome (23.7% in patients with neurological deterioration vs 82.4% without, p < 0.001). CONCLUSIONS After MMAE for cSDH, reduction in hematoma thickness follows a predictable exponential decay pattern. Greater extent (≥ 80%) and faster timing (within 90 days) of resolution are valuable prognostic indicators. Functional outcomes improve progressively through 6–12 months after the procedure. The relationship between resolution extent and functional outcomes provides quantitative benchmarks for evaluating treatment response.

ABSTRACT Background Anemia is an established marker of cardiovascular disease severity and risk which leads to elevations in resting myocardial blood flow (MBF) and impaired myocardial flow reserve (MFR) in patients without obstructive coronary artery disease (CAD). Anemia can potentially be detected opportunistically from blood pool density changes on computed tomography (CT) imaging. Objectives We evaluated relationships between chamber density measurements with hemoglobin, positron emission tomography (PET) findings, and cardiovascular events. Methods We included 33460 patients from 13 sites in the REFINE-PET who underwent PET and 24368 patients undergoing lung cancer screening chest CT. A deep learning model segmented cardiac chambers from CT images, then quantified chamber density. We evaluated the relationship between chamber density measures with resting MBF and MFR, as well as associations with death or myocardial infarction (MI). Results We included a total of 57,828 patients. A higher density in myocardium compared to left ventricle blood pool was associated with reduced MFR (adjusted odds ratio 3.02 per SD increase, 95% confidence interval[CI] 2.72 – 3.38) and an increased risk of death or MI in (adjusted hazard ratio[HR] 1.38 per SD increase, 95% CI 1.26-1.51). Having myocardial density higher than blood pool density was also associated with cardiovascular death in patients undergoing low-dose chest CT (adjusted HR 1.73, 95% CI 1.20-2.52). Conclusions In a large multimodality dataset, lower cardiac chamber density is associated with impaired MFR and independently associated with cardiovascular events. These biomarkers can be automatically extracted from CT to provide physiologic insights and potentially guide patient care. CONDENSED ABSTRACT Anemia is an important marker of cardiovascular disease severity and predictor of cardiovascular events. We utilized deep learning to measure cardiac chamber density on computed tomography imaging as a surrogate for anemia in 57,828 patients from two large multicenter studies. A higher density in myocardium compared to left ventricle blood pool was associated with reduced MFR and an increased risk of death or MI in patients undergoing positron emission tomography, and an increased risk of cardiovascular death in patients undergoing low-dose computed tomography. These biomarkers can provide additionally physiologic insights which could be used to guide patient care.

Abstract INTRODUCTION To examine the generalizability of Alzheimer's disease (AD) biomarker models in real‐world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics. METHODS We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community‐recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics. RESULTS Elevated β‐amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk. DISCUSSION The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.

Abstract Rationale Pulmonary Fibrosis is characterized by excessive accumulation of extracellular matrix (ECM), primarily collagen I, leading to progressive lung scarring and loss of function. Many anti-fibrotic compounds have been found to attenuate collagen deposition. However, identifying compounds that stimulate collagen I degradation, a necessary step in fibrosis clearance, is less common. To identify such compounds, we developed in vitro and ex vivo assays to quantify extracellular collagen I and collagen I degradation products. Methods Primary lung fibroblasts (passage 1-3, N = 5) from patients with idiopathic pulmonary fibrosis (IPF) were cultured in DMEM/F12 with 2% FBS, 2 ng/mL TGF-β, and 50 µg/mL ascorbic acid for 72 hours to generate collagen-rich cell-derived ECM. Cells were then treated with test compounds for 24 hours in the same media. Nuclear labeling with Hoechst 33342 was used to quantify cell numbers by automated microscopy. Decellularization was then performed with a solution containing 20 mM ammonium hydroxide and 0.5% Triton X-100. Cell-derived ECM was then fixed, stained with anti-Collagen I antibody, and quantified by automated microscopy. Collagen I degradation was further assessed by measuring type I collagen C-telopeptide (ICTP) via ELISA in cell culture media. To investigate the role of matrix metalloproteinase-13 (MMP-13) in collagen degradation, we used T26-C, a selective MMP-13 inhibitor, or transfected cells with MMP-13 siRNA. Ex vivo validation of collagen-degrading activity was conducted by measuring type I collagen N-terminal telopeptide (NTX-I) in the culture media of human precision-cut lung slices (PCLS, N = 3) generated from upper and lower lobes of IPF tissue and stimulated with select compounds. Results Thirty-four candidate compounds (metabolic, epigenetic, and cAMP modulators) were tested for their ability to reduce collagen I levels in cell-derived ECM. Six hits and two positive controls were then validated using ICTP ELISAs. In total five compounds were found to stimulate collagen degradation: EGCG (1 μM), Nintedanib (0.25 μM), SB431542 (1 μM), and two dopamine receptor agonists, A68930 (10 μM) and Dihydrexidine (10 µM). MMP-13 inhibition or knockdown prevented collagen degradation by all five compounds. In human IPF PCLS, collagen degradation was confirmed in response to EGCG, Nintedanib and SB431542 but not Dihydrexidine, with much greater responses seen in PCLS from upper lobes than lower lobes. Conclusion Collagen degradation can be stimulated in cultured fibroblasts and IPF PCLS. These systems will assist in uncovering mechanisms and regulators of collagen degradation and may pave the way to better fibrosis-resolving therapies. This abstract is funded by: NIH U01 HL152967

Abstract Alveolar macrophages (AMs) are critical for host defense and immunity against Pneumocystis. Through surface-associated receptors, AMs recognize, phagocytose, and kill Pneumocystis organisms, producing cytokines that promote pathogen clearance but also contribute to lung inflammation and injury. The EphA2 receptor, a member of the receptor tyrosine kinase (RTK) family, contains an extracellular region that binds activating ligands (Ephrins) and, more recently, has been shown to bind fungal β-glucans, leading to activation of its intracellular tyrosine kinase domain. The EphA2 signaling pathway has important roles in cancer, angiogenesis, and inflammatory diseases such as atherosclerosis. EphA2 is highly expressed in epithelial and endothelial cells, and emerging evidence indicates that it serves as a critical regulator of host defense against bacterial, viral, and fungal pathogens. In oropharyngeal candidiasis, EphA2 was identified as a receptor for fungal β-glucans in oral epithelial cells, mediating proinflammatory signaling through signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) pathways. Our laboratory recently demonstrated that EphA2 on lung epithelial cells binds Pneumocystis organisms, and that β-glucans from these organisms activate downstream signaling leading to IL-6 release. However, the role of EphA2 signaling in AM immune responses during Pneumocystis pneumonia (PCP) remains unknown. To address this, we examined EphA2-deficient (EphA2−/−) AMs stimulated with Pneumocystis β-glucans. Compared to wild-type AMs, EphA2−/− AMs exhibited significantly decreased production of proinflammatory cytokines, including IL-6 and TNF-α. In CD4-depleted mouse models of PCP, EphA2−/− lungs displayed markedly reduced levels of inflammatory cytokines and increased organism burdens, indicating impaired immune activation but preserved fungal persistence. Importantly, in CD4-depleted mice undergoing standard trimethoprim-sulfamethoxazole (TMP/SMX) therapy, concurrent administration of the EphA2 small-molecule inhibitor ALW-II-41-27 significantly reduced lung TNF-α responses without evidence of toxicity. These findings demonstrate that EphA2 receptor signaling plays a critical role in regulating macrophage-mediated inflammatory responses to Pneumocystis. While EphA2 deficiency dampens pulmonary inflammation, it also compromises fungal clearance, highlighting a delicate balance between host defense and immunopathology. Our data suggest that targeted modulation of EphA2 signaling during anti-Pneumocystis therapy may provide a novel adjunctive approach to reduce detrimental lung inflammation associated with PCP, potentially improving outcomes in affected patients. This abstract is funded by: NIH R01 HL-62150

Abstract Rationale Pneumocystis pneumonia (PJP) remains a major opportunistic infection in immunocompromised hosts, with limited therapeutic options. Previous studies identified a conserved cysteine residue (C353) in Pneumocystisphosphoglucomutase (PGM), analogous to that found in other pathogenic fungi but absent in mammalian PGMs, suggesting an exploitable antifungal target. We aimed to define the functional significance and therapeutic potential of targeting Pneumocystis PGM. Methods Full-length P. jirovecii and P. murina PGM cDNAs were cloned into S. cerevisiae pgm2Δ yeast (deficient in PGM activity) using the pYES2.1 TOPO vector for heterologous expression. Recombinant yeast lysates were tested for PGM activity in the presence of the thiol-reactive inhibitor ISFP10 (0-200 μM). Parallel assays were performed using recombinant human PGM lacking C353. Yeast growth inhibition in these strains in the presence of ISFP10 was also measured over 72 hours. For in vitro and ex vivo assays, P. murina organisms were treated with ISFP10, and viability was quantified via qPCR of the mitochondrial 16S ribosomal copy number. Precision-cut lung slice (PCLS) ex vivo cultures from a murine PCP model and in vivo CD4-depleted mice were used to assess ISFP10 efficacy and toxicity. Results Both P. jirovecii and P. murina PGMs showed potent, dose-dependent inhibition of enzymatic activity by ISFP10 up to 12.5 μM, with no inhibition of human PGM at concentrations up to 200 μM. Yeast complementation assays confirmed that ISFP10 significantly reduced the growth of pgm2Δ yeast expressing Pneumocystis spp. PGM. In vitro incubation of P. murina with ISFP10 resulted in significant reductions in organismal 16S mitochondrial copy number, comparable to pentamidine. In ex vivo PCLS models, ISFP10 decreased P. murina burden without affecting uninfected tissue viability. In vivo, ISFP10 administration for seven days significantly reduced fungal burden in CD4-depleted mice with an acceptable safety profile. Conclusions These findings demonstrate that Pneumocystis PGM activity depends on a conserved cysteine residue that is selectively targetable by ISFP10. Pharmacologic inhibition of PGM impairs P. murina viability in vitro, ex vivo, and in vivo with minimal host toxicity. Collectively, these data establish PGM as a promising, fungus-specific antifungal target and support the further development of small-molecule inhibitors targeting Pneumocystis PGM. This abstract is funded by: NIH R01 HL-62150, R21 AI-181542