ArticleThe Journal of clinical investigation2022
CADASIL mutations sensitize the brain to ischemia via spreading depolarizations and abnormal extracellular potassium homeostasis.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 16 citations in OpenAlex.
- Activation of silent synapses driven by emerging technologies: mechanisms, disease associations, and prospects for clinical translation.Frontiers in synaptic neuroscience · 2026Review
- A theoretical model for oxygen transport to the cerebral cortex: effects of flow redistribution by penetrating arterioles.Microvascular research · 2025Article
- Genetic Architecture of Ischemic Stroke: Insights from Genome-Wide Association Studies and Beyond.Journal of cardiovascular development and disease · 2025Review
- The pathogenesis of cerebral small vessel disease and vascular cognitive impairment.Physiological reviews · 2025Review
- Signaling pathways and molecular mechanisms involved in the onset and progression of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); a focus on Notch3 signaling.The journal of headache and pain · 2025Review
- Is migraine a common manifestation of CADASIL? Arguments Pros.The journal of headache and pain · 2025Article
- Article
- Migraine is a dysfunction of neuronal potassium ion channels.Frontiers in neurology · 2025Review
- Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice.The Journal of clinical investigation · 2024Article
- Genetic Mechanisms of Migraine: Insights from Monogenic Migraine Mutations.International journal of molecular sciences · 2023Review
- The emerging role of the HTRA1 protease in brain microvascular disease.Frontiers in dementia · 2023Review
- Bibliometric Analysis of Research on Migraine-Stroke Association from 2013 to 2023.Journal of pain research · 2023Article
- Association between dietary potassium intake and severe headache or migraine in US adults: a population-based analysis.Frontiers in nutrition · 2023Article
Corrections and comments
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Authors and funding
17 authors at 2 institutions in 5 countries.
Funding
Abstract
Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic form of small vessel disease characterized by migraine with aura, leukoaraiosis, strokes, and dementia. CADASIL mutations cause cerebrovascular dysfunction in both animal models and humans. Here, we showed that 2 different human CADASIL mutations (Notch3 R90C or R169C) worsen ischemic stroke outcomes in transgenic mice; this was explained by the higher blood flow threshold to maintain tissue viability compared with that in wild type (WT) mice. Both mutants developed larger infarcts and worse neurological deficits compared with WT mice, regardless of age or sex after filament middle cerebral artery occlusion. However, full-field laser speckle flowmetry during distal middle cerebral artery occlusion showed comparable perfusion deficits in mutants and their respective WT controls. Circle of Willis anatomy and pial collateralization also did not differ among the genotypes. In contrast, mutants had a higher cerebral blood flow threshold, below which infarction ensued, suggesting increased sensitivity of brain tissue to ischemia. Electrophysiological recordings revealed a 1.5- to 2-fold higher frequency of peri-infarct spreading depolarizations in CADASIL mutants. Higher extracellular K+ elevations during spreading depolarizations in the mutants implicated a defect in extracellular K+ clearance. Altogether, these data reveal a mechanism of enhanced vulnerability to ischemic injury linked to abnormal extracellular ion homeostasis and susceptibility to ischemic depolarizations in CADASIL.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.