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PubMed2006

A novel hereditary small vessel disease of the brain.

OBJECTIVE: Only few hereditary ischemic small vessel diseases of the brain (SVDB) have been reported so far. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent of them. Herein, we report a family affected by a SVDB distinct from CADASIL. METHODS: After the occurrence of a small deep infarct associated with white matter lesions both in a 46-year-old man and in his 52-year-old sister, clinical and neuroimaging investigations were conducted in 13 of their relatives originating from Portugal. Other investigations included (1) skin biopsy immunostaining with a Notch3 monoclonal antibody, (2) sequencing of the 23 exons encoding the epidermal growth factor-like domains of the NOTCH3 gene, and (3) a NOTCH3 locus haplotype analysis. RESULTS: Diffuse white matter hyperintensities were observed on T2-weighted magnetic resonance imaging (MRI) in six individuals. In contrast with MRI results in the father and paternal uncle of the proband who were hypertensive, white matter lesions were extensive in the mother who had no vascular risk factor. MRI data in four asymptomatic family members together with the results in the two initial cases were suggestive of an underlying hereditary small vessel disease of the brain. Skin biopsy and NOTCH3 gene mutation screening were negative. Haplotype analysis excluded the NOTCH3 locus. INTERPRETATION: These data strongly suggest that this family is affected by a novel hereditary small vessel disease of the brain and that the mutated gene is distinct from NOTCH3.

Brain Ischemia↗
PubMed2005

Cerebral small vessel diseases: cerebral microangiopathies.

PURPOSE OF REVIEW: Small vessel diseases of the brain are still clinically underrecognized whereas their burden is increasing steeply. The most frequent is acquired degenerative small vessel disease. Many hereditary or idiopathic small vessel diseases have also been identified, of which cerebral autosomal-dominant arteriopathy with stroke and ischaemic leukoencephalopathy (CADASIL) is the most prominent. In this review, we will highlight current evidence on pathophysiology and genetics, new imaging tools, and treatment options. RECENT FINDINGS: Recent imaging studies have stressed the disruption of white matter connections in the pathogenesis of cognitive impairment in acquired small vessel disease. Clinical trials suggest a therapeutic benefit of acetylcholinesterase inhibitors. CADASIL is caused by mutations in the Notch3 gene. Current basic research has identified Notch genes to be important for endothelial and smooth muscle cells to form arteries and veins. Diagnosis can now be made reliably by magnetic resonance brain imaging, skin biopsy, or genetic testing. The so-called retinocerebral vasculopathies share the involvement of both retinal, cerebral and cochlear arterioles (e.g. Susac's syndrome). Cerebral amyloid angiopathy, occurring either sporadically or as a cause of various gene mutations, predisposes to lobar haemorrhages caused by rupture of affected small cortical vessels. Other rare cerebral microangiopathies, such as mitochondrial cytopathies, Fabry's disease and toxemic vasculopathy, offer established or new therapeutic options. SUMMARY: Cerebral small vessel diseases are highly variable in their aetiopathogenesis and clinical course. Current pathophysiological insights will help develop better treatment modalities; new imaging tools will provide surrogate markers for monitoring disease progression and treatment effects.

CADASIL↗
PubMed2005

Shape and volume of lacunar infarcts: a 3D MRI study in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND AND PURPOSE: The shape and exact size of lacunar infarcts have been investigated only postmortem. Recent imaging techniques based on triangulation and connectivity can now be used for 3D segmentation of cerebral lesions. The shape and size of lacunar infarcts was investigated using these techniques in 10 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients. METHODS: We segmented 102 lacunar infarcts on T1-weighted images. The surface of the corresponding set of voxels was computed as a mesh of triangles. Thereafter, the shape of each lesion in 3D was visually analyzed by 2 investigators. RESULTS: The volume of lesions ranged from 10.5 to 1146 mm, with 93% of them having a volume <500 mm; 83% lacunar infarcts had a spheroid or ovoid shape, but 17% presented as sticks, slabs, or with a complex shape. Lesions with multiple components appeared larger than the others, and a tail extension was noticed in 13 of 102 lesions. CONCLUSIONS: These results suggest the following: (1) most lacunar infarcts in CADASIL have a volume far below one third of that of a sphere of 15 mm in diameter, the upper limit currently used for their identification on 2D imaging; (2) a significant proportion of lacunar infarcts have a shape distinct from the spheroid-ovoid morphology; and (3) lesions with a complex shape may result from the involvement of the largest small arteries, confluence of ischemic lesions, or secondary tissue degeneration. The segmentation of lacunar infarcts appears promising to better understand the pathophysiology of tissue lesions secondary to small vessel diseases.

Aged↗
PubMed1999

Distinguishing primary angiitis of the central nervous system from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: the importance of family history.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetically linked neurologic disease characterized by recurrent strokes and progressive or stepwise dementia, with or without migraine-like headaches, seizures, and pseudobulbar palsy. We describe a patient referred with a diagnosis of treatment-refractory primary angiitis of the central nervous system. Meningocortical and skin biopsies confirmed that the patient had CADASIL. Clinical and radiographic differences in these disorders may be subtle, but awareness of them is crucial if the patient is to avoid unnecessary exposure to potentially deleterious immunosuppressive therapy.

Dementia, Multi-Infarct↗
PubMed1996

Clinicopathological and genetic studies of two further Italian families with cerebral autosomal dominant arteriopathy.

We report on two Italian families with an early-adult onset autosomal dominant disorder, characterized by leukoencephalopathy, migraine, psychiatric disturbances, stroke and dementia. These findings fulfill the diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome. Moreover, to confirm the CADASIL gene location to 19p12, we performed a linkage analysis with four microsatellite markers. The results of the genetic study gave positive but not significant lod scores, indicating only weak evidence of a linkage with 19p12. In one autopsy case, we found extensive ischemic changes due to the selective involvement of the small muscular arteries of the cerebral white matter. The lesions consisted of a thickening of the media with deposition of granular eosinophilic material. Ultrastructural examination of the arterial walls showed graded damage to smooth muscle cells, mostly of the longitudinal layer, and an abnormal proliferation of basal lamina components. Immunocytochemical analysis showed strong reactivity using antibodies to collagen IV and smooth myosin proteins. The results suggest a primary involvement of the smooth muscle cells of small cerebral arteries, with a secondary alteration of basal lamina components and elastic tissue.

Adult↗
PubMed2002

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: phenotypic and mutational spectrum.

Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) an inherited small vessel disease leading to subcortical strokes and dementia. Since the vascular pathology is clearly defined, CADASIL may provide important insights into the mechanisms underlying lacunar infarcts, ischemic white matter changes, and vascular dementia. Evidence from different sources suggests a central role for vascular smooth muscle cells (VSMC) in the pathophysiology of the disease. This article gives a brief overview on the phenotypic spectrum of the disease and discusses some of the relevant disease mechanisms that lead from Notch3 mutations to ischemic infarcts.

Cognition Disorders↗
PubMed1997

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: study of two American families with predominant dementia.

Few European families have been reported with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We describe four patients from two independent American families. All four cases underwent comprehensive clinical, neuropsychological and pathological examination. Pathological data were correlated with clinical features. Dementia was a prominent and constant feature in all subjects. The families differed in phenotypical presentation and we analyzed possible pathological substrates that may account for the differences. Autopsy showed multiple ischemic infarcts in the white matter, abnormal vasculature with thickening and degeneration of the vessel wall. The clinical course in the first family was characterized by early dementia without stroke-like episodes; however, autopsy demonstrated strokes in the basal ganglia and thalamus. The members of the second family developed dementia later and had history of several clinically evident strokes. Pathological examination showed only widespread degeneration of the white matter. Our study of two American families with CADASIL suggests that involvement of the basal ganglia and thalamus is important for early development of dementia and clinically can present as a gradual dementia, resembling a neurodegenerative process. Selective damage of the white matter and central gray matter provides further insight to the pathogenesis of vascular dementia.

Adult↗
PubMed2003

Learning and memory deficits in Notch mutant mice.

Notch is a critical component of evolutionarily conserved signaling mechanisms that regulate development and may contribute to plasticity-related processes, including changes in neurite structure and maintenance of neural stem cells. Deficits in the Notch pathway are responsible for Alagille and Cadasil syndromes, which are associated with mental retardation and dementia. Additionally, in postmitotic neurons, Notch proteins interact with presenilins and with beta-amyloid precursor protein and could therefore have a role in the memory deficits associated with familial and sporadic Alzheimer's disease. To test if alterations in Notch signaling can lead to learning and memory deficits, we studied mice with mutations in this pathway. Here, we show that null heterozygous mutations in Notch1 result in deficits in spatial learning and memory without affecting other forms of learning, motor control, or exploratory activity. We also show that null heterozygous mutations in the downstream cofactor RBP-J result in similarly specific spatial learning and memory deficits. These data indicate that a constitutive decrease in Notch signaling can result in specific learning and memory deficits and suggest that abnormalities in Notch-dependent transcription may contribute to the cognitive deficits associated with Alzheimer's disease and Alagille and Cadasil syndromes.

Analysis of Variance↗
PubMed2002

Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis.

Mutations in the Notch3 receptor result in the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy (CADASIL) syndrome, a heritable arteriopathy predisposing to early onset stroke. Based upon clinical evidence that CADASIL arteriopathy results in degeneration and loss of vascular smooth muscle cells (VSMC) from the arterial wall, we postulated that Notch3 signaling is a critical determinant of VSMC survival. We initially established that both transient and constitutive Notch3 signaling promoted VSMC survival in response to the proapoptotic Fas ligand (FasL). Resistance to FasL-induced apoptosis was associated with the induction of c-FLIP, a primary inhibitor of the FasL signaling pathway. We determined that Notch3's regulation of c-FLIP was independent of the activity of the classical DNA-binding protein, RBP-Jk, but dependent upon cross-talk activation of the ERK/MAPK pathway. We extended our observations to the in vivo context by determining a coordinate regulation of Notch3 and c-FLIP within the arterial wall in response to injury. Furthermore, we defined that expression levels of Notch3 and c-FLIP are coordinately up-regulated within the neointima of remodeled arteries. Taken together, these findings provide initial evidence that Notch3 signaling may be a critical determinant of VSMC survival and vascular structure by modulating the expression of downstream mediators of apoptosis via signaling cross-talk with the ERK/MAPK pathway.

Animals↗
PubMed2006

Genetic variants of the NOTCH3 gene in migraine--a mutation analysis and association study.

Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Exons 3 and 4 are mutation hotspots. Migraine is a clinical hallmark of CADASIL. The objective of this study was to investigate whether genetic variants in exons 3 and 4 of the NOTCH3 gene are associated with migraine. Exons 3 and 4 of the NOTCH3 were analysed for mutations and polymorphisms by direct DNA sequencing in 97 migraineurs and the same number of control individuals. No mutations in exons 3 and 4 of the NOTCH3 gene were found in 97 patients with migraine. However, association analysis revealed significant association of the single nucleotide polymorphism (SNP) rs1043994 with migraine.

Adolescent↗
PubMed2006

Investigating the association between Notch3 polymorphism and migraine.

OBJECTIVE: The aim of the present study was to evaluate whether the functional Notch3 polymorphism T6746C, which is not causative for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), might be a risk factor for migraine. BACKGROUND: It has been recently demonstrated that migraine is characterized by subclinical brain infarctions and white matter lesions. Several genetic risk factors have been associated with migraine, but no study has unraveled a possible relationship between migraine and Notch3, which is involved in vascular damage. Mutations in Notch3 gene have been demonstrated to be pathogenetic for CADASIL, a small vessel disease of the brain characterized by migraine. METHODS: A total of 156 migraine patients and 128 nonheadache healthy volunteers entered the study. Demographic and clinical characteristics were carefully recorded, and a neurological work-up was performed. Moreover, each subject underwent a blood sampling for Notch3 genotype determination. RESULTS: Notch3 genotypes as well as allele frequencies did not differ in migraine patients compared to controls, even adjusting for the presence of possible confounds. No difference has been found either in migraine patients with aura or in those without aura. CONCLUSIONS: These findings support the view that functional polymorphism T6746C in Notch3 gene is not involved in increasing the risk of migraine or migraine subtypes.

Adult↗
PubMed2000

Skin biopsy value and leukoaraiosis.

In the field of leukoaraiosis, the identification of CADASIL and its link to Notch 3 mutation has shed light on the pathogenesis of white matter (WM) abnormalities related to small-vessel disease. Since 1993, its systemic vascular involvement allows skin biopsy diagnosis and research on tissues before postmortem examination. We received 160 skin biopsies from patients presenting subcortical dementia, recurrent strokes, behavioral disturbances or migraines, and suspected CADASIL. Almost all the patients lacked the well-known vascular risk factors. The ultrastructural study was systematically carried out looking at the vessel walls and the other components found in skin. In a third, we found endothelial changes, destruction of vascular smooth muscle cells (VSMCs), and characteristic granular osmiophilic material (GOM). In these cases, the genetic analysis confirmed the Notch 3 mutation. Curiously, the skin biopsies from the other two thirds presented marked alterations within the vessel walls. Such changes included destruction of VSMCs, lack of GOM, and replacement of these cells by an extracellular matrix. Frequently, we noticed endothelial pathological changes as well as other tissue impairments. By now, we are able to describe eight different groups of lesions according to either the prevalence of a lesion or the association of different lesions. The skin biopsy ultrastructural study seems to be highly informative given that we can observe vessel lesions and association of impairments in various tissues that might, in part, explain the brain vessel involvement and then the leukoaraiosis and probably some clinical symptoms. Moreover, these vessel lesions often belonged to young people (30-50 years old), and many of them seemed to run in families. These new data associated with early onset of clinical symptoms and leukoaraiosis would be extremely valuable in clarifying the wide field of leucoencephalopathy and might provide genetic research with new issues.

Adult↗
PubMed2002

Notch3 gene polymorphism and ischaemic cerebrovascular disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a type of hereditary stroke and dementia. More than 90% of patients with CADASIL have mutations in the Notch3 gene. All mutations either create or destroy a cysteine residue in the epidermal growth factor-like repeats. In addition, five polymorphisms, which lead to amino acid substitutions, have been identified within the Notch3 coding sequence. However, whether these polymorphisms affect Notch signalling or are involved in cerebrovascular diseases is unknown. In the present study, we investigated a possible association between a T6746C polymorphism in the Notch3 coding region and the occurrence of symptomatic ischaemic cerebrovascular disease (CVD) was investigated. Two hundred and thirty five patients with CVD, as confirmed by brain CT or MRI, and 315 age and sex matched control subjects were analyzed for genotype frequencies of the T6746C polymorphism in Notch3. The genotype distributions were: patients with CVD, C/C 14.0%, C/T 45.5%, and T/T 40.4%; controls, C/C, 14.3%; C/T, 47.9%; T/T, 37.8%. The Japanese population has a higher C allele frequency of the T6746C polymorphism than European populations. There was no significant difference between the T6746C polymorphism in patients with CVD and controls (chi(2)=0.414, p=0.813). This was confirmed by the results of multiple logistic regression analysis including established risk factors (chi(2) =4.65, p=0.311). In conclusion, the results indicate that T6746C polymorphism in the intracellular domain of the Notch3 gene is not associated with an increased risk for CVD.

Aged↗
PubMed1997

Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS).

We describe a Chinese American family with a hereditary syndrome consisting of retinopathy, nephropathy, and stroke, affecting 11 members spanning three generations. Ophthalmologic evaluations revealed macular edema with capillary dropout and perifoveal microangiopathic telangiectases. Several members had renal abnormalities with proteinuria and hematuria. Initial manifestations were visual impairment and renal dysfunction; neurologic deficits occurred in the third or fourth decade of life. Symptoms included migraine-like headache, psychiatric disturbance, dysarthria, hemiparesis, and apraxia. Neuroimaging consistently demonstrated contrast-enhancing subcortical lesions with surrounding edema. Ultrastructural studies showed distinctive multilaminated vascular basement membranes in the brain and in other tissues, including the kidney, stomach, appendix, omentum, and skin. Genetic analysis ruled out linkage to the CADASIL locus on chromosome 19. Distinct from CADASIL, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) is an autosomal dominant multi-infarct syndrome with systemic involvement.

Adult↗
PubMed2000

Migraine with aura and white matter abnormalities: Notch3 mutation.

The authors report on an Italian family with eight affected members who show autosomal dominant migraine with prolonged visual, sensory, motor, and aphasic aura. These symptoms are associated with white matter abnormalities on brain MRI. All living affected members carry a Notch3 mutation (Arg153Cys) previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). White matter abnormalities occur in a variable percentage of the general migraine population; CADASIL should be suspected in migraineurs with prolonged atypical aura and white matter abnormalities.

Brain↗
PubMed1999

Vascular dementia today.

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.

Acute Disease↗
PubMedDate not supplied

[Analysis of complex segregation in a large family with hereditary cerebrovascular disease in Antioquia, Colombia].

INTRODUCTION: Among different kinds of cerebrovascular diseases, few of them are caused by genetic disturbances, such as CADASIL (caused by Notch3 mutations), CARASIL, mitochondrial encephalopathy, MELAS and dementia typed Binswanger. However, to describe these type of cerebrovascular diseases related with genetic mutations could permit to determinate the causes of both hereditary and sporadic cerebrovascular diseases and then lead solutions. OBJECTIVE: To describe the genetic, environmental and cohort factors that determinate the presence of many affected people by a several cerebrovascular diseases in the pedigree of a large family from Antioquia (Colombia). PATIENTS AND METHODS: We performed one pedigree (268 individuals), through singular recruit and then complex segregation analysis with POINTER program. RESULTS: The model that more close to data is autosomal dominant mayor locus without influence of environmental factors. Frequency of allele of susceptibility to develop stroke or subcortical vascular dementia was 0.0006. Mayor gene is over epistatic effects or interactions with other gene. CONCLUSIONS: Described an autosomal dominant hereditary model through complex segregation analysis in a pedigree of patients with hereditary cerebral vascular diseases characterized by recurrent strokes, early onset subcortical dementia, hearing loss, antecedent of migraine and MRI signal abnormalities, subcortical infarcts and leukoencephalopathy. In this family the parameter calculated, autosomal dominant model, and clinical feature strongly support the diagnostic of CADASIL, linkage analysis and sequentiation will be performed to determinate if mutant gene is Notch3.

Adolescent↗