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

The case of a 72-year-old demented woman having episodes of strokes without any risk factors for cardiovascular disease is reported. Her elder brother and sister have also had stroke episodes since their middle age. She experienced hallucinations, delusions, and recurrent headaches since the age of 55. She has gradually developed gait disturbance and cognitive impairment. Brain MRI revealed extensive leukoaraiosis and multiple lacunar infarcts in the deep white matter and brainstem. Repeated MRI incidentally disclosed fresh hemorrhage in the dorsal subcortical temporal lobe, which appeared to be asymptomatic. Anti-platelet agents were not used during disease progression. We detected G975C mutation of the Notch3 gene and diagnosed our patient's disease as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This report suggests that arteriopathy of CADASIL could cause a hemorrhagic process, indicating that, in such a case, routine administration of anti-platelet agent to prevent recurrent ischemic stroke is not recommended.
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PMID:[Case of CADASIL showing spontaneous subcortical hemorrhage with a novel mutation of Notch3 gene]. 1726 Aug 7

Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and Leukoencephalopathy (CADASIL) is the most prominent known cause of inherited stroke and vascular dementia in human adult. The disease gene, NOTCH3, encodes a transmembrane receptor primarily expressed in arterial smooth muscle cells (SMC). Pathogenic mutations lead to an odd number of cysteine residues within the NOTCH3 extracellular domain (NOTCH3(ECD)), and are associated with progressive accumulation of NOTCH3(ECD) at the SMC plasma membrane. The murine homolog, Notch3, is dispensable for viability but required post-natally for the elaboration and maintenance of arteries. How CADASIL-associated mutations impact NOTCH3 function remains a fundamental, yet unresolved issue. Particularly, whether NOTCH3(ECD) accumulation may titrate the ligand and inhibit the normal pathway is unknown. Herein, using genetic analyses in the mouse, we assessed the functional significance of an archetypal CADASIL-associated mutation (R90C), in vivo, in brain arteries. We show that transgenic mouse lines expressing either the wild-type human NOTCH3 or the mutant R90C human NOTCH3, at comparable and physiological levels, can rescue the arterial defects of Notch3-/- mice to similar degrees. In vivo assessment of NOTCH3/RBP-Jk activity provides evidence that the mutant NOTCH3 protein exhibits normal level of activity in brain arteries. Remarkably, the mutant NOTCH3 protein remains functional and does not exhibit dominant negative interfering activity, even when NOTCH3(ECD) accumulates. Collectively, these data suggest a model that invokes novel pathogenic roles for the mutant NOTCH3 protein rather than compromised NOTCH3 function as the primary determinant of the CADASIL arteriopathy.
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PMID:The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo. 1733 78

Proteins of the Notch family are cell surface receptors that transduce signals between neighbouring cells. The Notch signalling pathway is highly evolutionarily conserved and critical for cell fate determination during embryonic development, including many aspects of vascular development. The interaction of Notch receptors with ligands leads to cleavage of the Notch intracellular domain (NICD) which then translocates to the nucleus and activates the transcription factor CBF1/JBP-Jkappa, regulating downstream gene expression. To date four Notch receptors have been found in mammals. Of these, Notch3 is predominantly expressed in adult arterial smooth muscle cells in human. NOTCH3 gene mutations cause the autosomal dominant condition, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoecephelopathy (CADASIL), an inherited early stroke syndrome leading to dementia due to systemic vascular degeneration. This suggests that Notch3 plays a critical role in maintaining the phenotypic stability of vascular smooth muscle cells (VSMCs). Recent publications indicate that Notch3 is involved in vascular injury and is a determinant of VSMC survival, but its exact function is unknown. The molecular mechanisms underlying CADASIL pathology are therefore intriguing. Investigation of CADASIL mutant Notch3 shows that the majority of mutations do not change CBF1/JBP-Jkappa mediated classic Notch activation, so the pathological consequences of NOTCH3 mutations in CADASIL patients can not be simply explained by loss- or gain-of-function in the classic Notch signalling pathway. This suggests that a novel Notch3-mediated signalling pathway may be present in VSMCs, or cross-regulation of Notch3 to other signalling pathway(s) may play a critical role on VSMCs survival. Alternatively, the mutant Notch3 may gain a novel or toxic function in VSMCs. This review will focus on recent findings of Notch3 in vascular development and in regulating the VSMC behaviour and phenotype, and will use findings on investigating the molecular pathology of the single gene disorder CADASIL to understand the function of Notch3 in VSMCs.
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PMID:An overview of Notch3 function in vascular smooth muscle cells. 1785 69

Vascular smooth muscle cells (SMCs) have been implicated in the pathophysiology of stroke, the third most common cause of death and the leading cause of long-term neurological disability in the world. However, there is little insight into the underlying cellular pathways that link SMC function to brain ischemia susceptibility. Using a hitherto uncharacterized knockout mouse model of Notch 3, a Notch signaling receptor paralogue highly expressed in vascular SMCs, we uncover a striking susceptibility to ischemic stroke upon challenge. Cellular and molecular analyses of vascular SMCs derived from these animals associate Notch 3 activity to the expression of specific gene targets, whereas genetic rescue experiments unambiguously link Notch 3 function in vessels to the ischemic phenotype.
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PMID:Linking Notch signaling to ischemic stroke. 1834 34

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

Most previously reported mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) result in an odd number of cysteine residues within the epidermal growth factor (EGF)-like repeats in Notch3. We report here R75P mutation in two Japanese CADASIL families not directly involving cysteine residues located within the first EGF-like repeats. Probands in both families had repeated episodes of stroke, depression, dementia as well as T2 high-intensity lesions in the basal ganglia and periventricular white matter, but fewer white matter lesions in the temporal pole on MRI. These families provide new insights into the diagnosis and pathomechanisms of CADASIL.
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PMID:Two Japanese CADASIL families exhibiting Notch3 mutation R75P not involving cysteine residue. 1904 63

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant vascular encephalopathy that has been mainly reported in Europe and the United States. Recently, this disease has been reported in Japan and the increasing number of reported cases has been attracting attention. Currently, the clinical diagnosis of CADASIL is based on the satisfaction of the following conditions: (1) development of the condition at a relatively young age (40-50 years), (2) no risk for stroke, (3) repeated attacks of lacunar infarction with gradual progression to pseudobulbar paralysis and dementia (migraine, emotional disturbance, cerebral infarction, and dementia in 30%, 20%, 85%, and 30-90% of patients, respectively), and (4) family members with similar symptoms (autosomal dominant inheritance). The diagnosis is also established on the basis of the following findings of imaging and laboratory studies: the presence of (1) leukoaraiosis and multiple small infarcts in the bilateral deep white matter, basal ganglia, thalamus, and pons revealed by MRI; (2) granular osmiophilic material (GOM) around the vascular smooth muscles in the brain, skeletal muscle, peripheral nerves, and skin demonstrated by electron microscopy; and (3) Notch3 mutations revealed by DNA analysis. Characteristics of CADASIL patients in Japan: Between 1997 and 2008, 38 CADASIL families have been reported in Japan. The age at onset of local neurological symptoms ranged from 15 to 71 years (mean 42. 3 +/- 11.4 years). All patients except one with borderline hypertension were normotensive or hypotensive. Out of 45 patients, 18 (40%) had migraine; 37 (82.2%) had repeated cerebral ischemic attacks including transient ischemic attacks (TIA); and 22 (48.9%), including borderline cases, had intellectual impairment. Nine of 38 patients (23.7%) had pseudobulbar paralysis. The retinal arteries were narrowed in 4 of 16 patients. The patients were distributed nationwide. Mutations in exon 4 have been reported in 22 of 31 families (71%). It is expected that an increase in the number of reported cases will lead to the discovery of other mutations associated with this condition. The mechanism of development of CADASIL due to Notch3 mutations is still unknown. However, a recent study has revealed that the Notch3 ectodomain is a major component of GOM. On binding to its ligand, Notch3 normally undergoes proteolytic cleavage, resulting in the clearance of the extracellular domain. However, in CADASIL, it accumulates as GOM and potentially inhibit the normal metabolism of smooth muscle cells.
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PMID:[CADASIL]. 1906 56

Mural cells are essential components of blood vessels and are necessary for normal development, homeostasis, and organ function. Alterations in mural cell density or the stable attachment of mural cells to the endothelium is associated with several human diseases such as diabetic retinopathy, venous malformation, and hereditary stroke. In addition mural cells are implicated in regulating tumor growth and have thus been suggested as potential antiangiogenic targets in tumor therapy. In recent years our knowledge of mural cell function and endothelial-mural cell signaling has increased dramatically, and we now begin to understand the mechanistic basis of the key signaling pathways involved. This is mainly thanks to sophisticated in vivo experiments using a broad repertoire of genetic technologies. In this review, we summarize the five currently best understood signaling pathways implicated in mural cell biology. We discuss PDGFB/PDGFRbeta- dependent pericyte recruitment, as well as the role of angiopoietins and Tie receptors in vascular maturation. In addition, we highlight the effects of sphingosine-1-phosphate signaling on adherens junction assembly and vascular stability, as well as the role of TGF-beta-signaling in mural cell differentiation. We further reflect recent data suggesting an important function for Notch3 signaling in mural cell maturation.
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PMID:Endothelial-mural cell signaling in vascular development and angiogenesis. 1916 13

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the Notch3 gene on chromosome 19. The condition manifests itself clinically typically in the third to fifth decade with migraine and recurrent episodes of stroke or transient ischaemic attacks. We report the case of an 11-year-old male with CADASIL resulting in stroke with right hemiparesis and dysphasia. Acute magnetic resonance imaging suggested infarction in the left hemisphere; magnetic resonance angiography revealed calibre variation of the intracerebral arteries. The patient suffered from common migraine with five to six attacks per month for 3 years 6 months before the stroke. Attacks occurred early in the morning with severe one-sided headache, photophobia, nausea, and vomiting. Antimigraine medications had no effect. The family history revealed more cases of CADASIL, with an autosomal dominant pattern. The diagnosis of CADASIL was confirmed by the finding of the known mutation of the Notch3 gene running in the family. With treatment in a neurorehabilitation centre the patient recovered most of his functions with only discrete fine-motor and cognitive sequelae. Our case report highlights the need for paediatricians to consider CADASIL in childhood stroke as well as in migraine patients.
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PMID:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy resulting in stroke in an 11-year-old male. 1920 99

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary stroke disorder. CADASIL is caused by missense point mutations or small deletions of the Notch3 gene, which encodes a large single-pass transmembrane receptor. Notch3 is essential for the normal maturation of blood vessels in both fetal and adult brains in mammals. Typical clinical manifestations are recurrent subcortical ischemic stroke, subcortical dementia, and migraine with aura. The age at the onset of stroke is approximately 40-50 years. Brain MRI shows a characteristic appearance with abnormalities, such as white matter hyperintensities in the anterior temporal lobes and subcortical lacunar lesions. Morphologically, CADASIL is characterized by the degeneration of vascular smooth muscle cells and accumulations of granular osmiophilic material(GOM) and the extracellular portion of Notch3. The progressive degeneration of smooth muscle cells in small blood vessels could be caused by an abnormal accumulation of the Notch3 ectodomain. Diagnostic criteria for CADASIL are the presence of mutations in the Notch3 gene and/or deposits of GOM or the Notch3 ectodomain in blood vessels. The most definitive diagnostic test is genetic testing for the mutated Notch3 gene. It has been shown that almost 70% of mutations can be found within exons 3-4 of the 33 exons making up the gene. Skin biopsies are usually used for the diagnosis, since pathomorphological changes in the small vessels are observed not only in the brain, but also in the skin. Recently, Notch3 immunostaining of skin biopsy specimens has been introduced as a simplified supportive test for the diagnosis of CADASIL.
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PMID:[Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)]. 1936 95


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