Citations

Background New antiamyloid therapies (AAT) for treating patients with early Alzheimer disease (AD) have become available in the past 3 years. Although AAT can be beneficial in slowing progression of AD, they also come with potentially serious side effects, particularly for patients requiring anticoagulation or thrombolysis for cardiovascular conditions. Given that most patients with AD are older and likely to have cardiovascular risk factors, there is urgent need for additional guidance for clinicians about potential risks and benefits associated with AAT for patients with cardiovascular comorbidities, best practices for management of these patients, and special considerations with respect to emergency evaluation and treatment of patients on AAT who develop acute neurological symptoms. Methods The American Heart Association convened 75 multidisciplinary experts for the Amyloid‐Related Imaging Abnormalities Summit: Cardiovascular and Stroke Considerations for β‐Amyloid Immunotherapy in AD in July 2025. These experts were divided into 8 work groups to evaluate the current evidence related to AAT usage in patients with cardiovascular risk factors and conditions and develop consensus‐based guidance for clinicians. Results This statement outlines the outcomes of the Summit, including considerations for prescribers, primary care professionals, emergency personnel, and health care system stakeholders. These considerations are intended to improve identification of patients as appropriate candidates for AAT, management of patients with co‐occurring AD and cardiovascular conditions, and their emergency evaluation and treatment. The statement also includes guidance for shared decision‐making, implementation of system changes for improving dementia care, and recommendations for future research and data collection to add to the body of evidence for treating patients with concomitant AD and cardiovascular conditions. Conclusions Building on lessons learned from the establishment of stroke systems of care, the consensus‐based considerations outlined in this document can serve as a foundation for AD systems of care aimed at ensuring optimal use of these ground‐breaking therapies.

Abstract Since its introduction in 2002, left atrial appendage closure (LAAC) has rapidly expanded as an alternative to anticoagulation in patients with atrial fibrillation at high risk of stroke. Harmonized processes for data collection, analysis, and reporting in LAAC trials are essential to enhance research quality and improve clinical practice. The Left Atrial Appendage Academic Research Consortium (LAARC) initiative is an independent collaboration of academic research organizations, cardiology and neurology experts, clinical trialists, and regulatory authorities from the USA, Europe, and Asia. The consortium engaged clinical experts, regulators—including the US Food and Drug Administration (FDA), European Notified Bodies, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA)—and industry leaders to define standardized study elements and endpoints for LAAC trials. Key considerations included alignment with prior Academic Research Consortium initiatives, procedural and mechanistic insights, and clinical relevance. Consensus definitions were proposed for mortality, stroke, bleeding, and device performance, along with composite endpoints for safety and effectiveness. The proposed LAARC consensus definitions aim to standardize endpoint reporting, improve comparability across studies, and support regulatory and clinical trial applications for this evolving therapy through broad dissemination in the peer-reviewed literature.

ABSTRACT Background Patients with hypertrophic obstructive cardiomyopathy (HOCM) were excluded from all major trials for transcatheter aortic valve replacement (TAVR). “Suicide left ventricle” occurring after TAVR is postulated to occur as a result of chronic pressure overload from fixed obstruction that is acutely relieved after the valve deployment resulting in worsening left ventricular outflow tract obstruction. Aims The aim of this study was to determine the clinical and readmission outcomes in HOCM patients undergoing TAVR. Methods Data was extracted from the National Inpatient and National Readmission 2016−2020 Databases. We performed multivariable Logistic regression analysis to determine the odds of in‐hospital mortality and other relevant clinical outcomes in patients undergoing TAVR with and without comorbid HOCM. Multivariable Cox regression analysis was used to assess 30‐day hospital readmission in HOCM patients undergoing TAVR. Results We identified 296,670 patients who underwent TAVR, of whom 534 (0.2%) had comorbid HOCM. The patients undergoing TAVR with comorbid HOCM had more than threefold higher risk of in‐hospital mortality (adjusted odds ratio: 3.47, 95% CI 1.37–8.81, p = 0.009) when compared to patients without HOCM. Additionally, patients undergoing TAVR with comorbid HOCM had a higher risk of atrioventricular blocks, cardiogenic shock, acute kidney injury, and the need for intubation. There was no difference in readmission outcomes post‐TAVR among patients with and without HOCM. Conclusion Our analysis of a large, real‐world cohort of patients undergoing TAVR showed that patients with HOCM have a significantly higher risk of in‐hospital mortality and procedural complications when compared to patients without HOCM.

Abstract Background Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

ABSTRACT LYRM7‐associated mitochondrial complex III deficiency has classically been described in the literature as a childhood‐onset episodic leukoencephalopathy with neuroimaging findings of cavitating periventricular and subcortical white matter loss. We describe the heterogeneous clinical and neuroimaging profile of six individuals from south India with the specific homozygous pathogenic variant in the LYRM7 gene (c.2T>C, (p.Met1?)). This is a retrospective case series featuring six cases (four pediatric, one adult, and one adolescent‐onset) with the pathogenic start loss LYRM7 variant. The spectrum of neurologic manifestations and brain imaging findings documented over multiple clinic visits was analyzed and described. Vision loss and lactic acidosis were seen in all but one individual. A novel phenotype with adult‐onset isolated bilateral simultaneous optic neuropathy was noted. Characteristic cavitating leukoencephalopathy in supratentorial white matter was seen in the brain MRI of three out of six individuals. A comprehensive description of our cases along with the previously published cases is provided in the table highlighting the clinical and imaging variability and the disease course. The phenotype of adult‐onset isolated acute optic neuropathy can be a manifestation of LYRM7‐related mitochondrial disorder. LYRM7‐associated Mitochondrial Complex III deficiency should be considered in the differential diagnosis of para‐ and post‐infectious demyelinating/inflammatory disorders, especially if there is a background of variable developmental delay, recurrence of the episodes, family history, cystic changes in cerebral white matter on imaging, or poor response to immunomodulation. The case series also exemplifies the intra‐and inter‐familial variability seen with this rare disorder.

Background: Nurtec, a versatile migraine medication, has gained popularity. However, the awareness of migraine surgery remains uncertain. Methods: Following a descriptive approach, this cross-sectional study used Google Trends data as of December 1, 2023, to analyze internet search patterns. Approval from Vanderbilt University’s institutional review board and adherence to Strengthening the Reporting of Observational Studies in Epidemiology guidelines were confirmed. Monthly relative search volume (RSV) data for “migraine surgery,” “Nurtec,” and “Rimegepant” were collected from January 1, 2004, to November 11, 2023, within the United States. Statistical analysis involved determining mean monthly RSV values and percentage changes for critical periods. Results: For “Nurtec,” a significant surge in RSV occurred from March 2020 to April 2020 (344%). Additional peaks were observed from June 2020 to July 2020 (66%), October 2020 to December 2020 (169%), May 2021 to June 2021 (33%), and May 2023 to June 2023 (14%). “Migraine surgery” exhibited a notable 400% increase in RSV, from March 2005 to May 2005. However, post-2006, RSV for “migraine surgery” consistently remained low without noticeable peaks. Conclusions: The analysis of RSV trends for “Nurtec” and “migraine surgery” from 2004 to 2023 reveals the impact of pivotal events and marketing strategies on public interest. The distinct peaks in “Nurtec” RSV align with Food & Drug Administration approvals and marketing campaigns, highlighting the medication’s accessibility. Conversely, the consistently low RSV for “migraine surgery” indicates limited awareness, emphasizing the need for enhanced promotion and education regarding surgical interventions.

Abstract Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations of SMARCB1 or (rarely) SMARCA4 causing loss of nuclear SMARCB1 or SMARCA4 protein expression are characteristic features, but further recurrent genetic alterations are lacking. Most AT/RTs occur de novo, but secondary AT/RTs arising in other central nervous system tumors have been reported. Malignant gliomas, IDH-wildtype, arising in patients with Li-Fraumeni syndrome typically show somatic mutations of TP53 as well as complex copy number alterations, but little is known about loss of SMARCB1 or SMARCA4 protein expression in this context. Here we report two children, in whom malignant supratentorial brain tumors with SMARCB1-deficiency, complex copy number alterations and somatic TP53 mutations lead to the discovery of pathogenic/likely pathogenic TP53 variants in the germ line. Screening of the molecularneuropathology.org data set for cases with similar genetic and epigenetic alterations yielded another case with SMARCA4-deficiency in a young adult with Li-Fraumeni syndrome. In conclusion, SMARCB1- or SMARCA4-deficient malignant brain tumors with complex copy number alterations and somatic TP53 mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation for TP53 germline status.