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PubMed2004

Histopathological abnormalities in ocular blood vessels of CADASIL patients.

PURPOSE: To assess histopathological findings in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). DESIGN: Case reports and histopathological evaluation of enucleated eyes. METHODS: Four eyes from two CADASIL patients were enucleated at autopsy and prepared for histopathological analysis using light and electron microscopy. RESULTS: Thickening of arterial walls with fibrosis, eosinophilic Periodic acid Schiff-positive basement membrane material and loss of vascular smooth muscle cells (VSMC) in the central retinal artery and its branches, the leptomeninges, the ocular adnexa, and the optic disk were observed. On electron microscopy, numerous deposits of granular, osmiophilic material in arterial walls as well as VSMC and pericyte degeneration were noted. In contrast to retinal vessels, the choroid was not affected. CONCLUSION: Our findings suggest a differential involvement of small blood vessels in CADASIL, depending on the angioarchitecture and support autopsy data of nervous tissue describing that loss of VSMCs is most pronounced in tissues depending on blood-tissue barriers.

Bruch Membrane↗
PubMed1999

White matter dementia in CADASIL.

Cerebral white matter disorders may be associated with profound neurobehavioral dysfunction. We report a 62-year-old man who had a slowly progressive 25-year history of personality change, psychosis, mood disorder, and dementia. Neurologic examination disclosed abulia, impaired memory retrieval, and preserved language, with only minimal motor impairment. Neuropsychological testing found a sustained attention deficit, cognitive slowing, impaired learning with intact recognition, and perseveration. Magnetic resonance imaging of the brain revealed extensive leukoencephalopathy. Right frontal brain biopsy showed ill-defined white matter pallor with hyaline narrowing of white matter arterioles. Granular osmiophilic material adjacent to vascular smooth muscle cells on electron microscopy of a skin biopsy, and an arginine for cysteine replacement at position 169 in the 4 EGF motif of the notch 3 region on chromosome 19q12 established the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This case illustrates that CADASIL can manifest as an isolated neurobehavioral disorder over an extended time period. The dementia associated with CADASIL closely resembles that which may occur with other white matter disorders, and represents an example of white matter dementia.

Brain↗
PubMed1995

Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain recently mapped to chromosome 19. We studied 148 subjects belonging to seven families by magnetic resonance imaging and genetic linkage analysis. 45 family members (23 males and 22 females) were clinically affected. Frequent signs were recurrent subcortical ischaemic events (84%), progressive or stepwise subcortical dementia with pseudobulbar palsy (31%), migraine with aura (22%), and mood disorders with severe depressive episodes (20%). All symptomatic subjects had prominent signal abnormalities on MRI with hyperintense lesions on T2-weighted images in the subcortical white-matter and basal ganglia which were also present in 19 asymptomatic subjects. The age at onset of symptoms was mean 45 (SD [10-6]) years, with attacks of migraine with aura occurring earlier in life (38.1 [8.03] years) than ischaemic events (49.3 [10.7] years). The mean age at death was 64.5 (10.6) years. On the basis of MRI data, the penetrance of the disease appears complete between 30 and 40 years of age. Genetic analysis showed strong linkage to the CADASIL locus for all seven families, suggesting genetic homogeneity. CADASIL is a hereditary cause of stroke, migraine with aura, mood disorders and dementia. The diagnosis should be considered not only in patients with recurrent small subcortical infarcts leading to dementia, but also in patients with transient ischaemic attacks, migraine with aura or severe mood disturbances, whenever MRI reveals prominent signal abnormalities in the subcortical white-matter and basal ganglia. Clinical and MRI investigations of family members are then crucial for the diagnosis which can be confirmed by genetic linkage analysis. The disease is probably largely undiagnosed.

Adult↗
PubMed2000

Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary microangiopathic condition causing stroke in young adults. The responsible gene has recently been identified as the Notch3 gene. Notch3 encodes a large transmembrane receptor with 34 extracellularly localised epidermal growth factor-like (EGF) repeat domains. We screened 71 unrelated CADASIL families for mutations in two exons coding for the first five EGF-like repeats and found mutations in 70% of the families (n = 50). Two types of mutations were identified: 48 families (96%) had missense mutations and two families (4%) had small in-frame deletions. Seven mutations occurred multiple times. All of them are C to T transitions that affect CpG dinucleotides, suggesting that their multiple occurrence is due to the hypermutability of this sequence. All mutations, including the two deletions, result in the gain or loss of a cysteine residue, thus substantiating the pivotal role of an uneven number of cysteine residues within EGF-like repeat domains of Notch3 in the pathogenesis of CADASIL. To study the potential effects of these mutations 3D homology models of the first six EGF domains were generated on the basis of NMR data from human fibrillin-1. These models predict domain misfolding for a subset of mutations.

Amino Acid Sequence↗
PubMed1997

[CADASIL: 2 case reports of hereditary multi-infarct dementia].

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary stroke disease linked to chromosome 19 q 12. We report on two families affected by this disease, which is characterised by recurrent subcortical ischaemic strokes, progressive pseudobulbar palsy, and presenile dementia. Neuroimaging revealed multiple deep infarcts and diffuse leukoencephalopathy. Diagnosis of CADASIL based on the typical clinical feature without vascular risk factors, the neuroradiological signs of extensive leukoencephalopathy, and the autosomal dominant pattern of inheritance. CADASIL might be an underestimated cause of familial stroke and should be considered in the differential diagnosis of hereditary stroke.

Brain↗
PubMed2000

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): diagnostic skin biopsy changes determined by electron microscopy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial vascular disorder associated with migraines, recurrent ischemic strokes, and early-onset multiinfarct dementia. The diagnosis of CADASIL is made ultrastructurally by finding characteristic granular, electron-dense, osmiophilic material attached to vascular smooth muscle cells. These changes have been found in brain, skeletal muscle, nerve, and skin. We describe a woman with CADASIL diagnosed on the basis of brain and skin electronmicroscopic findings. Dermatologists and dermatopathologists need to be aware of this disorder because characteristic electronmicroscopic changes on a skin biopsy specimen are diagnostic.

Biopsy, Needle↗
PubMed2002

A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling.

Notch receptors are single transmembrane receptors that contain a large number of epidermal growth factor-like repeats (EGF repeats) in their extracellular domains. Mutations in the EGF repeats of the human Notch 3 receptor lead to the vascular dementia disease Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). The vast majority of CADASIL mutations are missense mutations removing or inserting cysteine residues in the EGF repeats, but it is not yet clear whether these mutations primarily affect receptor trafficking, maturation, andor signaling. To address this issue, we have generated and analyzed stable cell lines expressing either wild-type murine Notch 3 (mNotch 3) or the mutant mNotch 3(R142C), which corresponds to the prevalent CADASIL form of Notch 3, Notch 3(R141C) in humans. We find that a lower proportion of mNotch 3(R142C) is expressed in the site 1-cleaved configuration, and that reduced amounts of mNotch 3(R142C) appear at the cell surface, as compared with wild-type mNotch 3. This observation is accompanied by a higher propensity for mNotch 3(R142C) to form intracellular aggregates, which may be a result of increased accumulation or slowed transport in the secretory pathway. In contrast to the impaired cell surface expression, mNotch 3(R142C) signals equally well in response to Delta 1 and Jagged 1 as wild-type mNotch 3. Taken together, these data suggest that trafficking and localization rather than signaling of mNotch 3 are affected in mNotch 3(R142C).

3T3 Cells↗
PubMed2004

The influence of genetic and cardiovascular risk factors on the CADASIL phenotype.

The clinical phenotype in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), an autosomal dominant cerebral arteriopathy, is variable, but the reasons for this remain uncertain. Possible factors include the mutation site and the influence of additional modulating factors, which could include both epistatic interactions and interactions with cardiovascular risk factors known to cause sporadic small vessel disease. In a large prospectively recruited cohort of CADASIL subjects we determined relationships between phenotype and mutation site, the apoE genotype and cardiovascular risk factors. In addition to clinical features, disease severity was assessed by MRI lesion volume, measured both semiquantitatively (Scheltens scale) and quantitatively. One hundred and twenty-seven CADASIL cases from 65 families with 17 different mutations were studied. Site of mutation was not associated with the presence or age of onset of stroke, migraine, dementia, dependency or MRI lesion load. There was no evidence of intrafamilial clustering of particular phenotypes. Amongst subjects with stroke/transient ischaemic attack, smoking at the time of the event was independently associated with earlier age of onset (P = 0.01). There were no associations between age of onset or presence of stroke and other cardiovascular risk factors, including homocysteine. Homocysteine levels were higher in migraineurs [mean (SD) 12.8 (5.6) versus 9.8 (3.4) micromol/l, P = 0.02)] and elevated homocysteine was independently associated with an earlier age of onset of migraine (P = 0.01). No relationship was found between MRI lesion volume and risk factors, or between apoE genotype and phenotype. Our results show no notch 3 genotype-phenotype correlations. This implies that modulating factors influence phenotype. Smoking appears to increase the risk of stroke, while high homocysteine levels are associated with an increased risk of migraine.

Adult↗
PubMedDate not supplied

Identification of a Notch3 mutation in a Japanese CADASIL family. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

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.

Dementia, Multi-Infarct↗
PubMed2004

CADASIL or CADVaSIL?

In the present study, morphological examination of patients from two unrelated Polish families with CADASIL was performed. Using light microscopy, there were evident changes characteristic to the disease. On electron microscopy, deposits of granular osmiophillic material (GOM) were found not only in cerebral arteries and veins but also in cerebral capillaries and vessels of the internal organs. These findings indicate that pathological process in CADASIL is generalized and involves also small vessels devoid of smooth muscle cells. Therefore, we propose to consider a replacement for the name CADASIL that better reflects the morphological picture of the disease like, for example, cerebral autosomal dominant vasculopathy with subcortical infarcts and leukoencephalopathy (CADVaSIL) or, to preserve the commonly known acronym, cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy.

Adult↗
PubMed1998

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Neuropathological and in vitro studies of abnormal elastogenesis.

This study was performed on a family of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) subjects. Neuropathological alterations of small arteries consisting in thickening, reduplication and fragmentation of the internal elastic lamella, and granular periodic acid-Schiff-positive material deposited in the arterial media were demonstrated in 1 autopsy case by histochemistry and electron microscopy. This material reacted with a monoclonal antibody anti-elastin (aE), as demonstrated by immunohistochemistry and immunoelectron microscopy. Significant increases of aE-immunoreactivity and elastin mRNA expression were found in cultured skin fibroblasts from 5 family members genetically affected by CADASIL, but not genetically and clinically healthy members. These results suggest that alterations of the elastic apparatus are associated with CADASIL genotype and related to the clinical expression of the disease.

Adult↗
PubMed2004

Retinal abnormalities in CADASIL: a retrospective study of 18 patients.

BACKGROUND: CADASIL is an inherited small vessel disease related to Notch3 gene mutations. AIM: To report retinal findings in symptomatic CADASIL patients. METHODS: Assessment of visual acuity (VA), testing of visual fields (VF), funduscopic examination (FE), and fluorescein angiography (FA) were carried out in 18 symptomatic patients. RESULTS: No visual symptoms were presented by our patients. VA was normal in all. Ophthalmologic abnormalities were found in 8 patients. VF were normal except for a right hemianopia in one subject due to ischemic stroke. FE and FA revealed significant abnormalities in seven other subjects (mean age: 55 years; range: 39-74): nerve fibre loss (n = 4), cotton wool spots (n = 3), sheathed arteries (n = 1), and tortuous arteries (n = 1). Only one patient with both tortuous arteries and nerve fibre loss had multiple vascular risk factors, and another patient with cotton wool spots was a current smoker. DISCUSSION: FE and FA revealed silent retinal abnormalities in CADASIL patients with nerve fibre loss in 22% and cotton wool spots in 17%. The presence of these abnormal retinal findings does not seem related to the severity of the disorder but may be considered as peripheral markers of this genetic disease.

Adult↗
PubMed2003

Coexistence of CADASIL and Alzheimer's disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by point mutations in the Notch3 gene. Presenilins are proteins involved in the cleaving of both Notch and the amyloid precursor protein (APP). In cases of early onset Alzheimer's disease mutations of the presenilin genes (PSEN 1 and PSEN 2) and APP can be found. A 64 year old patient with CADASIL (R169C-mutation) is reported, who, in addition to subcortical infarcts and granular osmiophilic deposits, had numerous senile plaques and neurofibrillary tangles on pathological examination. Mutations in the APP, PSEN1, and PSEN2 genes were not identified. Neuropathological findings of Alzheimer's disease may be found in CADASIL patients.

Alzheimer Disease↗
PubMed1999

Clinical severity in CADASIL related to ultrastructural damage in white matter: in vivo study with diffusion tensor MRI.

BACKGROUND AND PURPOSE: CADASIL is a newly recognized cause of subcortical ischemic strokes that progressively leads to dementia associated with pseudobulbar palsy and severe motor disability. This deleterious progression and the severity of clinical presentation are widely variable among affected subjects. The exact role played by MRI white-matter abnormalities, a hallmark of the disease, in the severity of the clinical phenotype remains poorly understood. METHODS: To address this issue, we used diffusion tensor imaging (DTI), a new MRI technique highly sensitive to white-matter microstructural changes, in 16 symptomatic patients and 10 age-matched controls. Mean diffusivity and anisotropy of diffusion were measured within hyperintensities identified on T2-weighted images (T2WI) and outside these lesions on 4 slices at the level of centrum semiovale. RESULTS: We found a 60% increase of water mean diffusivity and a parallel loss of diffusion anisotropy in hyperintensities identified on T2WI. The same pattern of diffusion changes, but of lesser intensity, was found in the normal-appearing white matter on T2WI. Mean diffusivity in regions with increased signal on T2WI was higher in patients with severe clinical disability compared with those with no or mild deficit (1.33+/-0.11 versus 1.13+/-0.11 10(-3) mm(2)/s, P<0.01). Furthermore, diffusion measured within T2 hyperintensities correlated with both the Mini-Mental State Examination and Rankin scale scores. In patients with a severe clinical status, the increase of water diffusion in these regions exceeded 70% in comparison with values obtained in the normal white matter in control subjects. CONCLUSIONS: These results indicate that DTI is able to detect important ultrastructural changes in regions with increased signal on T2WI and within the normal-appearing white matter in CADASIL. The diffusion changes might be related to both neuronal loss and demyelination. The degree of the underlying ultrastructural alterations is related to the severity of the clinical status with a possible threshold level of white-matter damage above which severe neurological impairment may occur in this disease. DTI appears to be a promising technique for monitoring disease progression in CADASIL.

Adult↗
PubMed1999

The natural history of CADASIL: a pooled analysis of previously published cases.

BACKGROUND AND PURPOSE: Although numerous families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been reported, our understanding of the disease remains incomplete. Thus, we performed this study to investigate the phenotypic range and natural history of CADASIL. METHODS: We performed a pooled analysis of previously published cases. RESULTS: We identified 105 symptomatic patients in 33 families. Vascular risk factors were uncommon, with hypertension reported in only 8 patients. The mean age of symptom onset was 36. 7+/-12.9 years. Stroke or transient ischemic attack was an initial symptom in 45 patients, with a mean age of onset of 41.2+/-9.2 years. Migraine was also a common initial symptom, reported by 42 patients at a younger mean age of 28.3+/-11.7 years. Other initial symptoms included depression in 9 patients, cognitive impairment in 6 patients, and seizures in 3 patients. Regarding clinical course, 71 patients experienced a stroke or transient ischemic attack, and 52 of those patients had 1 or more recurrent ischemic events. Dementia was reported in 44 patients. Only 3 additional patients experienced migraine at a later time, while 13 additional patients developed depression. Six patients had seizures. Twenty-two of the 105 patients had died, with a mean age of death of 54.8+/-10.6 years. Nineteen of those 22 patients had experienced a stroke or transient ischemic attack and 19 patients were demented. CONCLUSIONS: CADASIL typically becomes evident in early or middle adulthood with migraine or an ischemic event, later manifests itself through recurrent subcortical ischemic strokes leading to a stepwise decline and dementia, and results in reduced survival.

Adolescent↗
PubMed2002

CADASIL imitating multiple sclerosis: the importance of MRI markers.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can mimic multiple sclerosis (MS), leading to diagnostic confusion. We report a family with CADASIL in which the index case and the daughter of the index case were initially erroneously diagnosed with MS. Relatively specific magnetic resonance imaging (MPI) markers of CADASIL include involvement of the anterior temporal lobes and external capsules and, as illustrated in this report, these MRI findings may aid in the differentiation of the two conditions.

Adult↗
PubMed1998

Patterns of MRI lesions in CADASIL.

OBJECTIVE: To investigate the location and severity of MRI signal abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). BACKGROUND: One hallmark of this arteriopathy due to mutations of Notch 3 gene is the presence of MRI signal abnormalities in both symptomatic and asymptomatic patients. METHODS: MRIs of 75 patients (43 with symptoms) were reviewed by a neuroradiologist masked to their clinical status. After assessing the presence of MRI lesions on T1- and T2-weighted images (T1-WI, T2-WI) in different subcortical regions, the severity of hyperintensities on T2-WI was scored using a global rating scale and a regional semiquantitative scale in the periventricular white matter (PV), deep white matter (WM), basal ganglia (BG), and infratentorial areas (IT). RESULTS: Sixty-eight patients (90%) had hyperintensities on T2-WI located in the white matter, more frequent in PV (96%) and WM (85%) than in the superficial white matter (25%). Hyperintensities also occurred in BG (60%) and brainstem (45%). Forty-seven patients (62%) presented with hypointensities on T1-WI. In one-third of the affected individuals, white matter hyperintensities occurred in the absence of small deep infarcts on T1-WI. The frequency and severity scores calculated for PV, WM, BG, or IT hyperintensities increase dramatically with age. These scores were higher in symptomatic compared with asymptomatic gene carriers. Dementia, Rankin score > 1, or both occurred only in the presence of diffuse white matter signal abnormalities. CONCLUSION: Our results suggest that different subcortical areas have different vulnerabilities to ischemia in CADASIL. The age effect we observed may show an accumulation of lesions with aging during the course of the disease. A prospective study is needed to investigate if the rating of MRI lesions is of prognostic value in CADASIL.

Adult↗
PubMed2001

NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL.

Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary angiopathy causing stroke and vascular dementia. All CADASIL mutations identified so far result in the loss or gain of one cysteine residue within epidermal growth factor (EGF)-like repeat domains. Here an in-frame deletion causing a loss of three cysteine residues within EGF repeat 6 is reported. These data are consistent with the hypothesis that the change toward an odd number of cysteine residues within a given EGF repeat and therefore an unpaired, reactive cysteine residue is the common and critical molecular event in CADASIL.

Adult↗