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Query: UMLS:C0038454 (stroke)
 147,016 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

The transgenic technique allows specific genetic alterations to be made in all cells of an animal and this has greatly improved our understanding of how the embryonic and adult central nervous system (CNS) develop. The CNS originates from the neuroectoderm in the neural plate on the dorsal side of the embryo and after closure of the neural tube the cells of the neuroepithelium, i.e. the CNS stem cells, transiently proliferate to generate neurons and glial cells. Here we review our attempts to gain insights into the control of CNS development. We have identified a gene, nestin, which is predominantly expressed in embryonic and adult CNS stem cells. In addition to its normal expression in the CNS stem cells, nestin is reexpressed in CNS tumors and in the adult spinal cord and brain after CNS injury. By using the lacZ reporter gene assay in transgenic mice, we have identified regulatory regions (enhancer) in the nestin gene required for expression in embryonic CNS stem cells and in the adult spinal cord after injury. In a second project, we have cloned and characterized the Notch gene family (the Notch 1, 2 and 3 genes) in mouse and man. These genes encode trans-membrane receptors, which appear to be key regulatory molecules for proliferation and differentiation both in the developing CNS and in other tissues. Expression of an activated form of the Notch 3 receptor from the nestin promoter in transgenic mice leads to a lethal, exencephaly-like phenotype in the embryo, probably as a result of excess proliferation of the CNS stem cells. The recent finding that the Notch 3 gene is the genetic cause for familial stroke is discussed in the context of current models for Notch function.
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PMID:Transgenic analysis of central nervous system development and regeneration. 924 56

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

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

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be considered as a new disease predominantly affecting the small vessels of the brain with an autosomal dominant transmission linked to chromosome 19. This review includes an historical perspective showing how the disease was identified from the spectrum of vascular leukoencephalopathies. More than two hundred patients have now been described, belonging to at least 30 unrelated pedigrees in Europe, America and Asia. The clinical features include four major neurological presentations associated in variable degrees during the course of the disease: migraine with or without aura, strokes or stroke-like episodes, major psychiatric symptoms and dementia. The patients are free of the classical vascular risk factors. The disease has a progressive or stepwise course with age at onset in the forties and a mean duration of 13.6 +/- 10.7 years. Death occurs in the fifties in a characteristic condition associating a pseudo-bulbar syndrome and subcortical dementia. Cerebral magnetic resonance imaging (MRI) is highly contributive to the diagnosis, showing a diffuse leukoencephalopathy with subcortical infarcts in the basal ganglia and white matter. Pathological data show macroscopic lesions similar to Binswanger's disease but different lesions of the small vessels including thickening of the media, characteristic PAS+ granular material and narrowing of the lumen. Skin biopsy may be a valuable diagnostic tool, showing ultrastructural alterations of skin vessels similar to those of brain vessels. The disease is highly homogeneous on a genetic basis and the identification of the gene Notch 3 on chromosome 19 has opened new avenues for research and genetic counselling. The pathogenesis of the disease has still to be elucidated. A definite diagnosis relies on genetical or pathological data. Diagnostic criteria are proposed to recognize the disease on clinical and imaging parameters. So far, no treatment has been reported to be successful for CADASIL. Copyright Lippincott-Raven Publishers
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PMID:CADASIL: a review with proposed diagnostic criteria. 1021 Aug 36

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) begins with migraine with aura in approximately one-third of the patients. More severe symptoms of recurrent strokes usually appear at 30-50 years of age. However, well before the first stroke, CADASIL may be diagnosed on the basis of characteristic hyperintensities in T2-weighted magnetic resonance images. Multiple lacunar infarcts located mainly in the basal ganglia and frontal white matter lead to a cognitive decline and finally to dementia. These infarcts result from a thickening and fibrosis of the walls of the small and medium-sized penetrating arteries with consequent obliteration and/or thrombosis. Although the symptoms are almost exclusively neurological, the arteriopathy is generalized. Thus, basophilic, periodic acid-Schiff-positive and, in electron microscopy, osmiophilic material accumulates between degenerating smooth muscle cells. This occurs even in dermal arteries, which renders skin a useful target for diagnostic biopsy. Presently, no specific therapy is available. CADASIL is caused by missense point mutations in the Notch3 gene, which encodes a transmembrane receptor protein. Each gene defect leads to either a gain or loss of a cysteine residue in the extracellular, N-terminal domain of the molecule, which most probably results in conformational alteration. The function of Notch3 in adults and the pathogenesis of CADASIL are still unknown.
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PMID:CADASIL: hereditary disease of arteries causing brain infarcts and dementia. 1047 42

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease that is characterized by recurrent stroke episodes and focal neurologic deficits progressing to pseudobulbar palsy and dementia. The causative gene is the Notch3 gene on chromosome 19, and 22 missense mutations have been identified in Caucasian patients to date. To perform mutational analysis of the Notch3 gene, we identified its exon intron boundaries and prepared sets of primers for amplification of each exon. Using these primers, we determined the Notch3 gene in a Japanese family with CADASIL symptoms and found a missense mutation (Arg133Cys) in exon 4. The mutation was heterozygous and cosegregated with the disease. Thus, the Notch3 gene is responsible for CADASIL in patients across different ethnic groups.
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PMID:Identification of a Notch3 mutation in a Japanese CADASIL family. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. 1060 71

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

Mutations in Notch3 cause CADASIL (cerebral autosomal dominant adult onset arteriopathy), which leads to stroke and dementia in humans. CADASIL arteriopathy is characterized by major alterations of vascular smooth muscle cells and the presence of specific granular osmiophilic deposits. Patients carry highly stereotyped mutations that lead to an odd number of cysteine residues within EGF-like repeats of the Notch3 receptor extracellular domain. Such mutations may alter the processing or the trafficking of this receptor, or may favor its oligomerization. In this study, we examined the Notch3 expression pattern in normal tissues and investigated the consequences of mutations on Notch3 expression in transfected cells and CADASIL brains. In normal tissues, Notch3 expression is restricted to vascular smooth muscle cells. Notch3 undergoes a proteolytic cleavage leading to a 210-kDa extracellular fragment and a 97-kDa intracellular fragment. In CADASIL brains, we found evidence of a dramatic and selective accumulation of the 210-kDa Notch3 cleavage product. Notch3 accumulates at the cytoplasmic membrane of vascular smooth muscle cells, in close vicinity to but not within the granular osmiophilic material. These results strongly suggest that CADASIL mutations specifically impair the clearance of the Notch3 ectodomain, but not the cytosolic domain, from the cell surface.
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PMID:The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. 1071 25

CADASIL, an autosomal dominant arteriopathy responsible for stroke and dementia, is caused by strongly stereotyped mutations in the Notch3 gene. We report a patient with a condition strongly suggestive of CADASIL (migraine, stroke, and white matter abnormalities), except that this patient did not have any first-degree relatives with similar symptoms. This patient carried a heterozygous Arg182Cys mutation in the Notch3 gene; this mutation was absent in his two biological parents. These data demonstrate the occurrence of a de novo noninherited mutation in the Notch3 gene, which indicates that CADASIL should not be rejected in the absence of a family history. Therefore, our finding suggests that CADASIL may be more frequent than anticipated.
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PMID:De novo mutation in the Notch3 gene causing CADASIL. 1071 63


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