Citations

Abstract The apolipoprotein E ε4 ( APOE4 ) allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet the mechanistic underpinnings by which it alters human microglial function remain poorly understood. Here, we utilize CRISPR/Cas9-engineered isogenic human induced pluripotent stem cell-derived microglia-like cells (iMGs) expressing APOE3 or APOE4 to systematically interrogate genotype-dependent effects on microglial proteomes and their secreted extracellular vesicles (EVs) under basal and fibrillar amyloid-β (fAβ)-challenged conditions. Quantitative proteomics revealed that APOE4 iMGs exhibit downregulated RNA processing, impaired phagocytosis, and exacerbated pro-inflammatory signaling, particularly upon fAβ exposure. Functionally, APOE4 iMGs demonstrated increased NF-κB activation, enhanced neuronal apoptosis and tau pathology in 2D and 3D co-culture systems. Interestingly, APOE4 iMGs released greater amount of EVs enriched in proteasomal components over APOE3 iMG. Integrated proteomic analyses further highlighted APOE4 -specific selective packaging of EV cargo linked to neuron-glia communication, inflammatory signaling, and proteostasis dysregulation, suggesting a potent, non-cell-autonomous mechanism driving neuronal damage. Consistently, these APOE4 iMGEVs were preferentially internalized by neurons, leading to disrupted neuronal proteostasis, impaired neuronal firing, and increased tau phosphorylation, particularly under pathological stress. Notably, pharmacologic inhibition of NF-κB in APOE4 iMGs reduced EV cargo-loading of proteasomal molecules and mitigated iMGEV-driven neuronal dysfunction and tau pathology. These findings establish a mechanistic link between APOE4 , dysregulated microglial homeostasis, and microglial EV-mediated propagation of proteostatic dysfunction and neurodegeneration, advancing our understanding of how APOE4 contributes to AD pathogenesis.

PURPOSE Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era. METHODS The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database). RESULTS We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH -wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH -wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH -mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], P interaction < .001). In IDH -wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/–10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH -mutant glioma. CONCLUSION In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

ABSTRACT Background and Aims Nonsystemic vasculitic neuropathy classically presents as a painful asymmetric axonal neuropathy, multiple mononeuropathies or radiculoplexus neuropathy. Demyelinating electrophysiologic features are rare and may lead to misdiagnosis. We describe a patient with biopsy‐proven vasculitic neuropathy presenting as a severe symmetric demyelinating polyradiculoneuropathy. Methods Clinical, electrophysiologic, imaging, laboratory, and histopathologic findings are presented. Results A 57‐year‐old man developed acute ascending weakness, sensory loss, facial weakness, and areflexia following a febrile illness, with initial improvement before developing recurrent neurological decline 6 weeks after initial symptom onset despite treatment with intravenous immunoglobulin and plasma exchange. Cerebrospinal fluid protein was elevated. Nerve conduction studies demonstrated prolonged distal motor latencies, slowed conduction velocities, conduction block, and prolonged blink reflex latencies, fulfilling 2021 European Academy of Neurology/Peripheral Nerve Society electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). MRI demonstrated mild but diffuse lumbosacral plexus enlargement and T2 hyperintensity. Sural nerve biopsy ultimately demonstrated evidence of epineurial inflammation and microvasculitis with ischemic nerve injury, accompanied by both increased rates of axonal degeneration (12%) and segmental demyelination (9%) on teased fiber analysis. Treatment with corticosteroids and rituximab resulted in complete neurological recovery. Interpretation Vasculitic neuropathy may closely mimic CIDP clinically, radiologically, and electrophysiologically. Clues to the vasculitis diagnosis were prominent neuropathic pain, dense denervation on electrophysiology, and poor response to typical CIDP treatment. Peripheral nerve biopsy remains a critical tool in the evaluation of atypical or treatment‐refractory inflammatory neuropathies.

Abstract Introduction Patients with metastatic spine disease (MSD) present with varying degrees of systemic illness and frailty. Given the palliative intent of surgery and radiation treatment for MSD, treatment risks must be judiciously weighed against potential benefits. We sought to examine the impact of peroperative nutritional status as measured by the PG-SGA on survival in patients undergoing surgery and radiation for MSD. Methods This study involved an international, multicenter prospective, observational registry of patients with MSD: AO Knowledge Forum Tumor’s Metastatic Tumor Research and Outcomes Network (MTRON). Variables including baseline demographics, oncologic data, adverse events (medical adverse events and surgical complications), length of stay, and nutritional status were prospectively collected. The Patient-Generated Subjective Global Assessment (PG-SGA) was used to evaluate nutritional status. Results A total of 589 patients were included in this study; 469 (80%) of whom underwent surgery and radiation and 120 (20%) of whom underwent radiation alone. The majority of patients (362, 61%) were classified as well nourished, however, 68 patients (12%) were classified as severely malnourished. Among patients that underwent surgery and radiation, the median overall survival of well nourished patients was 491 days compared to 117 days in the severely malnourished patients (p &lt; 0.001). A multivariate analysis demonstrated severe malnourishment and ECOG performance status of 3 or 4 were associated with worse overall survival. Conclusion Malnutrition as measured by the PG-SGA demonstrated to be significantly and independently associated with perioperative survival in patients with MSD. Further studies that investigate optimal pre-treatment optimization for patients with MSD in order to mitigate morbidity and mortality risk are essential.

Abstract Introduction As the incidence of metastatic spine disease (MSD) increases, treatments to manage refractory pain, pathologic vertebral body fractures, and spinal cord compression are becoming increasingly common. Given the palliative nature of surgical intervention used to achieve tumor control and thus mitigate loss of neurologic function and compromised ambulatory function, it is essential to mitigate the risk of such procedures. Methods The AO Spine Knowledge Forum Tumor’s Metastatic Tumor Research and Outcomes Network (MTRON), an international, prospective registry for patients with spinal metastases, was used for this query. Prospective collection included baseline health and demographic information, oncologic data (including Spinal Instability Neoplastic Score (SINS) score and Bilksy epidural compression classification), and baseline functional status (preoperative American Spinal Injury Association (ASIA) and ECOG scores). Health related quality of life (HRQoL) data included Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ2.0) and Euro-QoL measures. Surgery related adverse events (AE’s) were collected using the Spine Adverse Events Severity (SAVES V2) framework. Kaplan-Meir curves were used to assess survival. Results The cohort consisted of 1267 patients, 701 male (55.3%). A total of 245 (19.3%) experienced at least one postoperative AE, the majority of which were considered minor (grade 3 or less). Among the most common were deep wound infections (3.2%), wound dehiscence (2.5%), and urinary infections (2.4%). A multivariate analysis demonstrated that age, smoking status, ECOG performance, prior radiotherapy, presence of multiple metastases at other sites, and multiple spine metastases were significant risk factors for a postoperative AE. Postoperative AE’s (p = 0.049) and major postoperative AE’s (p = 0.0038) were found to be related to survival as well as a significant change in HRQoL scores (p &lt; 0.001). Conclusion Postoperative AE’s are extremely relevant to the care of patients with MSD and impact both HRQoL and survival.

Objective Designation of a Medical Power of Attorney (MPOA) is a key component of advance care planning (ACP) that ensures patient preferences are honored when decision-making capacity is not present. This study aimed to quantify MPOA documentation rates and identify demographic and clinical factors associated with documentation presence. Methods We conducted a retrospective observational study using electronic health record data from 979 610 adult hospitalization encounters representing 459 365 unique patients within a large U.S. healthcare system from January 1, 2020, through December 31, 2021. All hospitalized patients aged ≥18 years were included. The primary outcome was MPOA documentation. Demographic and clinical variables were analyzed using multivariable logistic regression. Statistical significance was defined as P < .05. Results Among 979 610 encounters, 260 752 encounters (26.6%) had documented MPOA. Male sex, White race, older age (67.0 vs 54.3 years), and unmarried status were associated with a higher MPOA documentation rate (all, P < .001). In multivariable analyses, male sex (adjusted odds ratio [AOR], 1.07; 95% CI, 1.06-1.08) and unmarried status (AOR range, 1.41-1.75) were associated with higher odds of MPOA documentation. Dementia (AOR, 1.90; 95% CI, 1.86-1.93) and malignancy (AOR, 2.22; 95% CI, 2.19-2.25) were associated with higher odds, while discharge against medical advice was associated with lower odds (AOR, 0.91; 95% CI, 0.88-0.94) of MPOA documentation. Conclusions MPOA documentation rates were low, highlighting missed opportunities to identify alternate decision makers when a patient lacks capacity. Targeted interventions to promote surrogate decision-maker designation and documentation are needed, especially in inpatient care settings.

BACKGROUND: Anthracyclines are a widely used and effective class of chemotherapy. However, a major limitation for their use is cardiotoxicity, manifesting as systolic dysfunction, congestive heart failure, and arrhythmias. The objective of this study was to identify genes and genetic risk variants for doxorubicin-induced arrhythmia. METHODS: We performed genome-wide association studies and meta-analysis across 2 independent nonoverlapping, genetically homogenous data sets from the Molecular Epidemiology Resource (cases N=77, controls N=1184) and Tapestry (cases N=13, controls N=172). Doxorubicin-related arrhythmia was the primary cardiac outcome, followed by investigation of a broader phenotype of cardiac events. Effects of doxorubicin on top-associated genes were assessed by quantitative polymerase chain reaction on RNA extracted from human cardiomyocytes following treatment with doxorubicin and by echocardiography in a zebrafish model of doxorubicin-induced cardiomyopathy. RESULTS: In the meta-analysis, rs12151014 at the KCTD15 locus was associated with doxorubicin-related arrhythmia at the genome-wide significance (minor allele frequency in Molecular Epidemiology Resource cases 0.195 versus 0.069 in controls; Tapestry cases 0.192 versus 0.079 in controls) P =9.01×10 −9 ; odds ratio, 3.61. MMP 16 rs1094199 was associated with the broader phenotype of arrhythmia and heart failure (minor allele frequency in Molecular Epidemiology Resource cases 0.079 versus 0.019 in controls; Tapestry cases 0.038 versus 0.015) P =1.98×10 − 8 ; odds ratio=6.15. In human cardiomyocytes, MMP16 and KCTD15 gene expression was significantly downregulated by doxorubicin, and in a zebrafish MMP16 knockout was protective of doxorubicin-induced decline in left ventricular ejection fraction. CONCLUSIONS: Genetic variants at KCTD15 and MMP16 are associated with doxorubicin-related arrhythmia and cardiac events. MMP16 is a potential cardioprotective therapeutic target.

Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic progressive pulmonary fibrosis and high mortality. Genetic markers, summarized into a polygenic risk score (PRS), associate with IPF in well-phenotyped research cohorts. Objectives To evaluate the performance of the PRS using real-world data from routinely captured electronic healthcare records. Methods We conducted an observational study evaluating the association of a PRS for IPF with electronic healthcare record diagnosis of IPF as well as lung transplant-free survival in four independent cohorts; the Mass General Brigham Biobank (MGBB), Mayo Clinic Biobank (MCBB), Mayo Clinic Tapestry Cohort (Tapestry), and U.K. Biobank (UKBB). We used multivariable logistic regression and multivariable Cox proportional hazards models adjusting for age, gender, and principal components of ancestry. The cohorts then underwent fixed and random effects meta-analysis. Measurements and Main Results Of 37,709; 44,195; 43,202; and 447,422 participants from MGBB, MCBB, Tapestry and UKBB respectively, 1,015 (2.7%) 2,879 (6.5%), 1,310 (3.0%), and 2,742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis, OR 2.88 (95%CI 2.41-3.44) compared to all other individuals. A high-risk PRS also associated with the composite endpoint of mortality or lung transplant among those with an IPF diagnosis, HR 1.23(95%CI 1.11-1.35) compared to all other individuals. Conclusions A PRS can identify those at risk for an IPF diagnosis and mortality in biobank-scale data, which may have implications for clinical decisions. Further work is necessary to evaluate the utility of adding genetics in clinical settings.