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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiovascular risk factors are present in 85% of patients with stroke. However, up to 6%-15% of patients have a stroke secondary to unusual reasons such as systemic diseases, coagulation disorders, etc., and, in some cases, no reason can be identified even after performing an extensive study. This usually happens in young people. In this regard, the diagnostic screening must consider hereditary causes of stroke. CADASIL, an autosomal dominant brain white matter angiopathy, is emerging as a not uncommon cause of stroke with diverse clinical manifestations. Its clinical diagnosis is controversial because of the diverse role of the brain imaging study, the biopsy of the vessels of skin or other tissues and the DNA study.
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PMID:[Clinical variability and diagnostic controversies in CADASIL]. 1747 82

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is an inherited small vessel disease causing migraine, early strokes, cognitive impairment and premature death. The disease is caused by NOTCH3 gene puntiform mutations on one of the exons coding for the epidermal-growth factor (EGF)-like repeats of the extracellular domain of the NOTCH3 receptor. Mutations have been reported with higher frequency on some exons, and never on 6 out of a total of 23. We report for the first time a mutation (c.3471C>G) on exon 21 of the NOTCH3 gene that leads to a cysteine substitution (p.1131C>W) in the EGF-like repeat 29 of the NOTCH3 receptor extracellular domain, and that is responsible for CADASIL in a functionally independent elderly man who came to our attention at the age of 79 because of a minor stroke. CADASIL suspicion aroused only from the finding of severe white matter changes extended to the temporopolar region on cerebral magnetic resonance imaging. This case report underlines that, when CADASIL is suspected, molecular analysis should be performed on all the NOTCH3 exons coding for EGF-like repeats and not be limited to those where mutations have been found with higher frequency, and that the disease may be encountered also in mildly symptomatic elderly patients. The newly reported mutation might sustain a milder expressivity of the disease.
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PMID:A pathogenic mutation on exon 21 of the NOTCH3 gene causing CADASIL in an octogenarian paucisymptomatic patient. 1802 98

Numerous epidemiologic observations reporting high prevalence of migraine among young individuals with stroke as well as dysfunction of cerebral arteries during migraine attacks prompt speculation on the existence of a comorbidity between the two disorders. The recent finding of silent infarct-like brain lesions in migraineurs reinforced this hypothesis and raised questions on whether migraine may be a progressive disorder rather than simply an episodic disorder. Stroke can occur during the course of migraine attacks with aura, supporting the assumption of a causal relation between the two diseases. Migraine may accentuate other existing risk factors for stroke, and both jointly increase the risk of cerebral ischemia outside of migraine attacks. In this regard, the role of migraine might be that of predisposing condition for cerebral ischemia. Migraine and ischemic stroke may be the end phenotype of common pathogenic mechanisms. Evidence of a migraine-stroke relation in cases of specific disorders, such as CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), strongly supports this concept. Finally, acute focal cerebral ischemia can trigger migraine attacks, and, thus, migraine may be the consequence of stroke. In this paper, we will review contemporary epidemiologic studies, discuss potential mechanisms of migraine-induced stroke and comorbid ischemic stroke, and pose new research questions.
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PMID:Migraine and ischemic stroke: a debated question. 1846 Oct 80

Notch signaling is critically important for proper architecture of the vascular system, and mutations in NOTCH3 are associated with CADASIL, a stroke and dementia syndrome with vascular smooth muscle cell (VSMC) dysfunction. In this report, we link Notch signaling to platelet-derived growth factor (PDGF) signaling, a key determinant of VSMC biology, and show that PDGF receptor (PDGFR)-beta is a novel immediate Notch target gene. PDGFR-beta expression was upregulated by Notch ligand induction or by activated forms of the Notch receptor. Moreover, upregulation of PDGFR-beta expression in response to Notch activation critically required the Notch signal integrator CSL. In primary VSMCs, PDGFR-beta expression was robustly upregulated by Notch signaling, leading to an augmented intracellular response to PDGF stimulation. In newborn Notch3-deficient mice, PDGFR-beta expression was strongly reduced in the VSMCs that later develop an aberrant morphology. In keeping with this, PDGFR-beta upregulation in response to Notch activation was reduced also in Notch3-deficient embryonic stem cells. Finally, in VSMCs from a CADASIL patient carrying a NOTCH3 missense mutation, upregulation of PDGFR-beta mRNA and protein in response to ligand-induced Notch activation was significantly reduced. In sum, these data reveal a hierarchy for 2 important signaling systems, Notch and PDGF, in the vasculature and provide insights into how dysregulated Notch signaling perturbs VSMC differentiation and function.
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PMID:Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells. 1856 9

CADASIL is an early onset small vessel disease and genetic variant of pure subcortical ischemic vascular dementia (SIVD). The condition has been invaluable in defining the profile and neuroimaging correlates of cognitive deficits in pure SIVD. The recent completion of a randomized trial in cognitively impaired CADASIL patients has illustrated the feasibility of targeted therapeutic trials in narrowly defined subtypes of vascular cognitive impairment. This article highlights some of the advances on cognition in CADASIL.
Stroke 2009 Mar
PMID:Cognition in CADASIL. 1906 78

Strong epidemiological evidence indicates that migraine, especially migraine with aura, is associated with increased risk of ischemic stroke. However, the precise mechanisms of such a relation are currently not fully elucidated and are still a matter of speculation. Migraine may directly cause an ischemic event (i.e, migrainous infarct), by inducing cerebral microcirculatory vasoconstriction (cortical spreading depression-related oligemia), intracerebral large vessels spasm, and vascular endothelium-related hypercoagulability. On the other hand, migraine may predispose to cerebral ischemia outside of a migraine attack by affecting endothelial function, alone or in combination with traditional vascular risk factors, or by interacting with pre-existent stroke susceptibility conditions (i.e, patent foramen ovale). At least theoretically, the migraine-stroke link may be the consequence of the unfavourable effect of migraine-specific drugs (i.e, triptans or ergot alkaloids). Finally, migraine and ischemic vascular events may be linked via genetic pathways, certain genes playing a role on both diseases and influencing their relation. The coexistence of ischemic stroke and migraine in the context of specific syndromes (i.e, CADASIL) characterized by peculiar phenotype, proven inherited background and chronic alterations of the wall of cerebral small vessel arteries suggests that migraine and ischemic stroke may be the end phenotype of common pathogenic mechanisms. How to identify those migraineurs at highest risk of ischemic stroke and whether stroke can be prevented by specific therapeutic strategies are the goals of future research.
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PMID:The migraine-ischemic stroke connection: potential pathogenic mechanisms. 1927 30

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. Clinical and neuroimaging features resemble those of sporadic small-artery disease, although patients with CADASIL have an earlier age at onset of stroke events, an increased frequency of migraine with aura, and a slightly variable pattern of ischaemic white-matter lesions on brain MRI. NOTCH3 (Notch homolog 3), the gene involved in CADASIL, encodes a transmembrane receptor primarily expressed in systemic arterial smooth-muscle cells. Pathogenetic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, which accumulates in small arteries of affected individuals. Functional and imaging studies in cultured cells, genetically engineered mice, and patients with CADASIL have all provided insights into the molecular and vascular mechanisms underlying this disease. A recent multicentre trial in patients with cognitive impairment emphasises the feasibility of randomised trials in patients with CADASIL. In this Review, we summarise the current understanding of CADASIL, a devastating disorder that also serves as a model for the more common forms of subcortical ischaemic strokes and pure vascular dementia.
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PMID:Cadasil. 1953 36

Polyamines are small cationic molecules that in adult brain are connected to neuronal signaling by regulating inward-rectifier K(+)-channels and different glutamate receptors. Antizyme inhibitors (AZINs) regulate the cellular uptake of polyamines and activate ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine synthesis. Elevated levels of ODC activity and polyamines are detected in various brain disorders including stroke and Alzheimer's disease (AD). We originally reported a novel brain- and testis-specific AZIN, called AZIN2, the distribution of which we have now studied in normal and diseased human brain by in situ hybridization and immunohistochemistry. We found the highest accumulation of AZIN2 in a pearl-on-the-string-like distribution along the axons in both the white and gray matter. AZIN2 was also detected in a vesicle-like distribution in the somas of selected cortical pyramidal neurons. Double-immunofluorescence staining revealed co-localization of AZIN2 and N-methyl D-aspartate-type glutamate receptors (NMDARs) in pyramidal neurons of the cortex. Moreover, we found accumulation of AZIN2 in brains affected by AD, but not by other neurodegenerative disorders (CADASIL or Lewy body disease). ODC activity is mostly linked to cell proliferation, whereas its regulation by AZIN2 in post-mitotically differentiated neurons of the brain apparently serves different purposes. The subcellular distribution of AZIN2 suggests a role in vesicular trafficking.
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PMID:Brain neurons express ornithine decarboxylase-activating antizyme inhibitor 2 with accumulation in Alzheimer's disease. 1983 40

In younger patients with stroke, cerebral vasculitis and hereditary small vessel diseases should be considered as important differential diagnoses. Since the clinical course of cerebral vasculitis is highly variable, diagnostic workup, which includes laboratory tests, CSF analysis, cranial magnetic resonance imaging and biopsy, is often challenging. Therapy should be initiated on an interdisciplinary basis and includes immunosuppressive induction and maintenance regimes. Hereditary small vessel diseases, e.g. CADASIL or Fabry's disease, can mimic clinical features of cerebral vasculitis. Their diagnosis which is based on family history, typical clinical features and genetic analysis often has implications for treatment and genetic counselling.
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PMID:[Vasculitis and hereditary small vessel diseases]. 1983 57

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a rare autosomal dominant genetic disease characterized with recurrent stroke, migrainous headache, cognitive deficits, and psychiatric symptoms associated with mutations in the NOTCH 3 gene on chromosome 19. Here, we report a case of CADASIL who presented with migrainous headache, behavioral disorder, and familial history of stroke and the diagnosis was established by the findings of head magnetic resonance images revealing characteristic white matter lesions and a mutation in the NOTCH 3 gene.
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PMID:A case report about CADASlL: mutation in the NOTCH 3 receptor. 2032 94


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