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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.
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PMID:Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. 887 72

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently identified cause of stroke and vascular dementia. It is a condition of mid-adulthood due to mutations of Notch 3 gene on chromosome 19. Whereas the disease was first reported in European families, since 1993 CADASIL has been observed in American, African and Asiatic pedigrees, suggesting that today, the disease probably still remains largely underdiagnosed. The pathological data first dealt with the white matter and the basal ganglia showing the features observed in Binswanger's subcortical arteriopathic encephalopathy; over the past few years, CADASIL has become appreciated as a systemic vascular disease with specific features. Here we have reviewed the literature from 1977 to the present for pathologically and genetically verified cases accompanied by relatively complete clinical descriptions so as to give the pathological features associated with this condition a clearer definition. The review will focus mainly on pathological studies and the pathophysiological mechanisms most likely to be involved in CADASIL.
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PMID:CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. 929 37

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited condition whose key features include recurrent subcortical ischemic events, migraine attacks and vascular dementia in association with diffuse white-matter abnormalities seen on neuroimaging. Pathologic examination shows multiple small deep cerebral infarcts, a leukoencephalopathy and a nonatherosclerotic nonamyloid angiopathy involving mainly the media of small cerebral arteries. To progress in understanding the pathophysiological mechanisms of this condition, we undertook the identification of the mutated gene. We mapped the CADASIL gene on chromosome 19p13.1. More than 120 families have been referred to our lab. Genetic linkage analysis of 33 of these families allowed us to reduce the size of the genetic interval to less than 1 cM and to demonstrate the genetic homogeneity of this condition. In the absence of any candidate gene, we undertook positional cloning of this gene. We identified, within the CADASIL critical region, the human Notch3 gene, whose sequence analysis revealed deleterious mutations in CADASIL families co-segregating with the affected phenotype. These data establish that this gene causes CADASIL. Identification of the CADASIL gene will provide a valuable diagnostic tool for clinicians and could be used to estimate the prevalence of this underdiagnosed condition. It should help in the understanding of pathophysiological mechanisms of CADASIL and vascular dementia.
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PMID:Notch3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a mendelian condition causing stroke and vascular dementia. 932 92

Some aspects of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are reviewed. The condition causes stroke and vascular dementia. Pathological examination reveals multiple small, deep infarcts, leukoencephalopathy, and non-atherosclerotic, non-amyloid angiopathy which mainly involve the small cerebral arteries where there are severe alterations in vascular smooth-muscle cells. In hereditary autosomal dominant stroke condition patients with mutations in the human Notch 3 gene on chromosome 19 have been identified. Skin and muscle biopsy may be useful for diagnosing this condition. No causal treatment is available. Hereditary autosomal dominant stroke condition has not been diagnosed in any Norwegian family to date.
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PMID:[Hereditary autosomal dominant brain infarction]. 966 25

This decade witnessed a resurgence of interest in vascular dementia (VaD) as an increasingly important cause of senile dementia. Although definitions of dementia in general, and of VaD in particular, are still controversial recent diagnostic criteria for VaD acknowledge that pathogenetic mechanisms different from multi-infarct dementia are important in dementia causation. These include subcortical strokes, mainly lacunes, global hypoxic-ischemic events during acute stroke, and ischemic periventricular white matter lesions of the Binswanger type. These lesions tend to be manifested primarily by alterations of frontal executive function control. The importance of these ischemic vascular lesions in the clinical expression of Alzheimer's disease (AD) in very old subjects has also been recognized. Clinically, VaD may present in two forms: Acute VaD includes large-vessel infarction, and lacunar dementia due to small-vessel disease, including thalamic and caudate strokes. Subacute VaD includes Binswanger's disease (BD), cerebral angiopathy with leukoencephalopathy and CADASIL. The discovery of CADASIL, a genetic form of VaD mapped to chromosome 19 as a mutation of the Notch 3 gene, opened research avenues into the pathogenesis of BD. Finally, epidemiological evidence suggests that it may be possible to prevent VaD--and perhaps degenerative senile dementia--by controlling hypertension and other vascular risk factors. These findings offer hope for prevention of this growing public health problem.
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PMID:Vascular dementia today. 1063 40

In vertebrates Notch signaling regulates cell fate decisions and boundary formation and it underlies several murine and human diseases. Gene targeting experiments point to key roles of Notch receptors, ligands, modulators and downstream targets in somitogenesis, neurogenesis and vascular development. Here we report the embryonic expression of the hairy-related basic helix-loop-helix gene HeyL in wild-type and Notch pathway mutant mice. We show that HeyL is strongly expressed in the presomitic mesoderm, the somites, the peripheral nervous system and smooth muscle of all arteries. Loss of HeyL expression at the level of nascent somites in Notch1 and Delta-like1 knockout mutants implicates HeyL as a Notch effector during somite formation. Furthermore, HeyL expression in vascular smooth muscle cells and in the thymus strikingly overlaps with that of Notch3, mutations of which underlie the CADASIL vascular disorder.
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PMID:Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos. 1104 25

Recently identified in a french family, CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a generalised disease of small arteries, largely predominating in the brain. Its clinical manifestations start during mid-adulthood and include recurrent ischaemic subcortical events, attacks of migraine with aura, severe mood disorders, subcortical dementia, and, at magnetic resonance imaging, widespread leuko-encephalopathy. There is so far no specific treatment and the mean duration of the disease is 20 years. CADASIL is most frequently a familial disorder with an autosomal dominant mode of transmission. Its responsible gene, Notch 3, is located on Chromosome 19. By the identification of its gene, CADASIL, (which is now known to affect over 400 families worldwide) is a unique variety of cerebro-vascular disease, affecting mainly the subcortical white matter.
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PMID:[CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): clinical features and neuroimaging]. 1126 Dec 56

CADASIL, an autosomal dominant adult onset arteriopathy causing stroke and dementia in humans, is underlaid by a non atherosclerotic non amyloid angiopathy involving mainly the media of small cerebral arteries; it is characterized by major lesions of vascular smooth muscle cells. Using a positional cloning approach, we mapped CADASIL locus on chromosome 19 and identified the mutated gene as being Notch3. This gene, previously unknown in humans, encodes for a large transmembrane receptor belonging to the Notch/lin12 gene family which are known to be involved in cell fate specification during development. Genetic analysis of more than 120 CADASIL unrelated families allowed us to show that these mutations are highly stereotyped and affect only the extra cellular domain of the protein. On the basis of these data, a molecular diagnostic test has been set up and is now widely required by clinicians involved in the diagnosis of vascular leukoencephalopathies. Using this test, we recently showed that CADASIL can also occur in patients who do not have any affected relative due to the existence of notch3 de novo mutations. As a first step to investigate the molecular and cellular mechanisms leading from Notch3 mutations to CADASIL phenotype, we analyzed by in-situ hybridization and immunohistochemistry the pattern of expression of this gene. Notch3 expression is highly restricted to the vascular smooth muscle cell in normal human adults. In CADASIL tissues there is a dramatic accumulation of the extracellular domain of the protein which suggests that one of the main mechanisms of CADASIL involves anomalies in the proteolytical cleavage and clearance of this protein. These data provide important clues to the mechanisms of this condition and current work should lead in the next future to a complete understanding of CADASIL and set up the basis of a rational therapeutical approach of this condition.
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PMID:[CADASIL: genetics and physiopathology]. 1126 Dec 57

We describe a 45-year-old man with biopsy proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This patient demonstrated unique retinal findings, including arteriole narrowing and sheathing, irregular choroidal filling on fluorescein angiography, and patchy visual field loss. CADASIL is a hereditary, nonamyloid, nonathersclerotic microangiopathy. This disorder has been mapped to chromosome 19 with mutations in the Notch 3 gene. Deposits of granular osmiophilic material in the basal lamina of the smooth muscle cells of small vessels are considered pathognomonic for CADASIL and are typically seen only on electron microscopy. Although CADASIL is a systemic vascular disease affecting the entire arteriole tree, we are unaware of other reports describing the retinal findings observed in our patient.
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PMID:Retinal findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil). 1127 96

Mice with targeted mutations in genes required for Notch signal transduction die during embryogenesis, displaying overt signs of hemorrhage due to defects in their vascular development. Surprisingly, directed expression of a constitutively active form of Notch4 within mouse endothelial cells produces a similar vascular embryonic lethality. Moreover, patients with mutations in Notch3 exhibit the cerebral vascular disorder, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). These findings underscore the importance of Notch signaling in vascular development; however, they do not identify the specific functional defect. Here, we report that Notch1, Notch3, Notch4, Delta4, Jagged1 and Jagged2 are all expressed in arteries, but are not expressed by veins. These findings identify an aspect of Notch signaling that could contribute to the mechanism by which this pathway modulates vascular morphogenesis.
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PMID:Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. 1157 69


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