Genetic Insights Into Hemorrhagic Stroke and Vascular Malformations: Pathogenesis and Emerging Therapeutic Strategies.

Brain arteriovenous malformations (AVMs), cerebral cavernous malformations (CCMs), and intracranial aneurysms are major causes of hemorrhagic stroke, yet noninvasive therapies to prevent growth or rupture are lacking. Understanding the genetic basis of these malformations is critical for uncovering underlying mechanisms, developing targeted prevention strategies, and identifying novel therapeutic targets. This review highlights the causal genes and signaling pathways in AVMs, CCMs, and intracranial aneurysms, noting both their commonalities and differences.

Exploring the Relationship Between Radiation-Induced Moyamoya Syndrome and Radiation Dose for Pediatric Patients Treated With Proton Radiation Therapy.

Purpose: The incidence and risk factors associated with radiation-induced moyamoya syndrome (RIMMS) in pediatric brain tumor patients treated with proton radiation therapy (PRT) remain poorly understood. The objective of this study was to determine the incidence of RIMMS in the setting of central nervous system PRT in a pediatric cohort and assess its relationship with dose to the circle of Willis (COW) or optic chiasm (OC).

Methods And Materials: We performed a retrospective review of pediatric brain tumor patients treated with intracranial PRT (1995-2021).

A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets.

Objective: X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.

Endovascular thrombectomy for childhood stroke (Save ChildS Pro): an international, multicentre, prospective registry study.

Background: Emerging evidence suggests that endovascular thrombectomy is beneficial for treatment of childhood stroke, but the safety and effectiveness of endovascular thrombectomy has not been compared with best medical treatment. We aimed to prospectively analyse functional outcomes of endovascular thrombectomy versus best medical treatment in children with intracranial arterial occlusion stroke.

Methods: In this prospective registry study, 45 centres in 12 countries across Asia and Australia, Europe, North America, and South America reported functional outcomes for children aged between 28 days and 18 years presenting with arterial ischaemic stroke caused by a large-vessel or medium-vessel occlusion who received either endovascular thrombectomy plus best medical practice or best medical treatment alone.

Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy.

Background: Cerebral adrenoleukodystrophy is a severe form of X-linked adrenoleukodystrophy characterized by white-matter disease, loss of neurologic function, and early death. Elivaldogene autotemcel (eli-cel) gene therapy, which consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing complementary DNA, is being tested in persons with cerebral adrenoleukodystrophy.

Methods: In a phase 2-3 study, we evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI).

Treatment of calcific arterial disease via enhancement of autophagy using GSK343.

Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown.

A novel mouse model of cerebral adrenoleukodystrophy highlights NLRP3 activity in lesion pathogenesis.

Objective: We sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate potential therapeutic targets such as fibrin, oxidative stress, and the NLRP3 inflammasome, in post-mortem human and murine brain tissues.

Background: ALD is caused by mutations in the gene encoding a peroxisomal transporter.

Monogenic Causes of Cerebrovascular Disease in Childhood: A Case Series.

Background: Despite an increase in the number of genes associated with pediatric stroke, imaging phenotypes in children have not been well reported. Guidelines are needed to facilitate the identification and treatment of patients with monogenic causes of cerebrovascular disorders.

Methods: We performed a retrospective review of imaging and medical records of patients aged zero to 21 years with monogenic causes of vascular malformations, small or large vessel disease, transient ischemic attacks, and/or ischemic or hemorrhagic stroke.

An Engineered Adeno-Associated Virus Capsid Mediates Efficient Transduction of Pericytes and Smooth Muscle Cells of the Brain Vasculature.

Neurodegeneration and cerebrovascular disease share an underlying microvascular dysfunction that may be remedied by selective transgene delivery. To date, limited options exist in which cellular components of the brain vasculature can be effectively targeted by viral vector therapeutics. In this study, we characterize the first engineered adeno-associated virus (AAV) capsid mediating high transduction of cerebral vascular pericytes and smooth muscle cells (SMCs).

Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy.

Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation.

Cerebral arteriopathy and ischemic stroke in a pediatric MYH11 patient.

Objectives: Mutations in the MYH11 gene result in smooth muscle cell dysfunction and are associated with familial thoracic aortic aneurysms and dissection. We describe a pediatric patient with a stroke and a pathogenic MYH11 IVS32G>A mutation, and a phenotype similar to ACTA2.

Methods: A proband girl with an acute ischemic stroke underwent genetic analysis and 7T high-resolution MRI.

The Genetic Landscape of Ischemic Stroke in Children - Current Knowledge and Future Perspectives.

Stroke in childhood has multiple etiologies, which are mostly distinct from those in adults. Genetic discoveries over the last decade pointed to monogenic disorders as a rare but significant cause of ischemic stroke in children and young adults, including small vessel and arterial ischemic stroke. These discoveries contributed to the understanding that stroke in children may be a sign of an underlying genetic disease.

Burden of Stroke and Population-Attributable Fractions of Risk Factors in Latin America and the Caribbean.

Background Stroke burden characterization studies in low- and middle-income countries are scarce. We estimated the burden of stroke and its risk factors in Latin America and the Caribbean (LAC). Methods and Results We extracted GBD (Global Burden of Disease) study 2019 data on overall stroke and 3 subtypes (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) for 20 LAC countries.

Cost-Effectiveness of Endovascular Thrombectomy in Childhood Stroke: An Analysis of the Save ChildS Study.

Background And Purpose: The Save ChildS Study demonstrated that endovascular thrombectomy (EVT) is a safe treatment option for pediatric stroke patients with large vessel occlusions (LVOs) with high recanalization rates. Our aim was to determine the long-term cost, health consequences and cost-effectiveness of EVT in this patient population.

Methods: In this retrospective study, a decision-analytic Markov model estimated lifetime costs and quality-adjusted life years (QALYs).

The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive spinal cord axonopathy [adrenomyeloneuropathy (AMN)] to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. Leriglitazone is a recently developed brain penetrant full PPARγ agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased adenosine 5'-triphosphate concentration, and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long chain fatty acid-induced toxicity simulating X-ALD.

Neurofilament light chain as a potential biomarker for monitoring neurodegeneration in X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD), the most frequent monogenetic disorder of brain white matter, is highly variable, ranging from slowly progressive adrenomyeloneuropathy (AMN) to life-threatening inflammatory brain demyelination (CALD). In this study involving 94 X-ALD patients and 55 controls, we tested whether plasma/serum neurofilament light chain protein (NfL) constitutes an early distinguishing biomarker. In AMN, we found moderately elevated NfL with increased levels reflecting higher grading of myelopathy-related disability.

Cerebrovascular Disease Progression in Patients With Arg179 Pathogenic Variants.

Objective: To establish progression of imaging biomarkers of stroke, arterial steno-occlusive disease, and white matter injury in patients with smooth muscle dysfunction syndrome caused by mutations in the gene, we analyzed 113 cerebral MRI scans from a retrospective cohort of 27 patients with Arg179 pathogenic variants.

Methods: Systematic quantifications of arterial ischemic strokes and white matter lesions were performed on baseline and follow-up scans using planimetric methods. Critical stenosis and arterial vessel diameters were quantified applying manual and semiautomated methods to cerebral magnetic resonance angiograms.

Clinical Diffusion Mismatch to Select Pediatric Patients for Embolectomy 6 to 24 Hours After Stroke: An Analysis of the Save ChildS Study.

Objective: To determine whether thrombectomy is safe in children up to 24 hours after onset of symptoms when selected by mismatch between clinical deficit and infarct.

Methods: A secondary analysis of the Save ChildS Study (January 2000-December 2018) was performed, including all pediatric patients (<18 years) diagnosed with arterial ischemic stroke who underwent endovascular recanalization at 27 European and United States stroke centers. Patients were included if they had a relevant mismatch between clinical deficit and infarct.

Clinical and radiographic course of arrested cerebral adrenoleukodystrophy.

Objective: To gain insight into the natural history of arrested cerebral adrenoleukodystrophy (CALD) by quantifying the change in Neurologic Function Score (NFS) and Loes Score (LS) over time in patients whose cerebral lesions spontaneously stopped progressing.

Methods: We retrospectively reviewed a series of 22 patients with arrested CALD followed longitudinally over a median time of 2.4 years (0.