Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts And Leucoencephalopathy Research Articles

Stem Cell Factor in Combination with Granulocyte Colony-Stimulating Factor reduces Cerebral Capillary Thrombosis in a Mouse Model of CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cerebral small vascular disease caused by NOTCH3 mutation-induced vascular smooth muscle cell (VSMC) degeneration, leading to ischemic stroke and vascular dementia. Our previous study has demonstrated that repeated treatment with a combination of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) reduces VSMC degeneration and cerebral endothelial cell (EC) damage and improves cognitive function in a mouse model of CADASIL (TgNotch3R90C). This study aimed to determine whether cerebral thrombosis occurs in TgNotch3R90C mice and whether repeated SCF+G-CSF treatment reduces cerebral thrombosis in TgNotch3R90C mice. Using the approaches of bone marrow transplantation to track bone marrow-derived cells and confocal imaging, we observed bone marrow-derived blood cell occlusion in cerebral small vessels and capillaries (thrombosis). Most thrombosis occurred in the cerebral capillaries (93% of total occluded vessels), and the thrombosis showed an increased frequency in the regions of capillary bifurcation. Degenerated capillary ECs were seen inside and surrounding the thrombosis, and the bone marrow-derived ECs were also found next to the thrombosis. IgG extravasation was seen in and next to the areas of thrombosis. SCF+G-CSF treatment significantly reduced cerebral capillary thrombosis and IgG extravasation. These data suggest that the EC damage is associated with thrombosis and blood–brain barrier leakage in the cerebral capillaries under the CADASIL-like condition, whereas SCF+G-CSF treatment diminishes these pathological alterations. This study provides new insight into the involvement of cerebral capillary thrombosis in the development of CADASIL and potential approaches to reduce the thrombosis, which may restrict the pathological progression of CADASIL.

The First Report of CADASIL in Peru: Olfactory Dysfunction on Initial Presentation.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare, heritable, small vessel vascular disease caused by mutations in the Notch3 gene that is characterized by migraines, subcortical vascular events, cognitive decline, and mood disturbances. However, many CADASIL cases present with unusual symptoms such as status epilepticus, a movement disorder, or sensory dysfunction. This study describes the clinical, genetic, and radiologic characteristics of a Peruvian family with CADASIL in which multiple family members presented with severe olfactory deficits. Seven members of the family have symptoms suggestive of CADASIL, with genetic testing revealing R133C mutations in the two patients who underwent genetic testing. Cognitive testing and olfactory identification testing (Smell Identification Test) were performed in three CADASIL patients revealing total anosmia in two tested patients and severe hyposmia in the other. Olfactory dysfunction has been associated with various neurologic and psychiatric conditions, though few studies have linked it with neurovascular disorders such as CADASIL. This first reported case of CADASIL in Peru emphasizes that symptomatic olfactory dysfunction may be an unusual presentation of CADASIL and that olfactory dysfunction is important to evaluate in CADASIL patients.

Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is an autosomal dominant vascular disorder. Diagnosis and follow-up in patients with CADASIL are based mainly on magnetic resonance imaging (MRI). MRI shows white matter hyperintensities (WMHs), lacunar infarcts and cerebral microbleeds (CMBs). WMHs lesions tend to be symmetrical and bilateral, distributed in the periventricular and deep white matter. The anterior temporal lobe and external capsules are predilection sites for WMHs, with higher specificity and sensitivity of anterior temporal lobe involvement compared to an external capsule involvement. Lacunar infarcts are presented by an imaging signal that has intensity of cerebrospinal fluid in all MRI sequences. They are localized within the semioval center, thalamus, basal ganglia and pons. CMBs are depicted as focal areas of signal loss on T2 images which increases in size on the T2*-weighted gradient echo planar images ("blooming effect").

New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cerebrovascular small-vessel disease caused by stereotyped mutations in the Notch3 gene altering the number of cysteine residues. MethodsWe directly sequenced exons 2–23 of the Notch3 gene in 30 unrelated Russian patients with clinical/neuroimaging picture suggestive of CADASIL. To confirm the pathogenicity of new nucleotide variants, we used the standard bioinformatics tools and screened 200 ethnically matched individuals as controls. ResultsWe identified 16 different point mutations in the Notch3 gene in 18 unrelated patients, including 4 new missense mutations (C194G, V252M, C338F, and C484G). All but two mutations affected the cysteine residue. The non-cysteine change V322M was shown to be associated with CADASIL-specific deposits of granular osmiophilic material in the vascular smooth-muscle cells, which confirmed the pathogenicity of this Notch3 variant. Two patients were shown to be compound-heterozygotes carrying two pathogenic Notch3 mutations. The disease was characterized by marked clinical variability, without evident phenotype-genotype correlations. ConclusionsIn our sample, 60% of Russian patients with ‘clinically suspected’ CADASIL received the definitive molecularly proven diagnosis. Careful assessment of genealogical, clinical, and neuroimaging data in patients with lacunar stroke can help selecting patients with a high probability of finding mutations on genetic screening.

Hypomorphic NOTCH3 mutation in an Italian family with CADASIL features

The cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is because of NOTCH3 mutations affecting the number of cysteine residues. In this view, the role of atypical NOTCH3 mutations is still debated. Therefore, we investigated a family carrying a NOTCH3 nonsense mutation, with dominantly inherited recurrent cerebrovascular disorders. Among 7 family members, 4 received a clinical diagnosis of CADASIL. A heterozygous truncating mutation in exon 3 (c.307C>T, p.Arg103X) was found in the 4 clinically affected subjects and in one 27-year old lady, only complaining of migraine with aura. Magnetic resonance imaging scans found typical signs of small-vessel disease in the 4 affected subjects, supporting the clinical diagnosis. Skin biopsies did not show the typical granular osmiophilic material, but only nonspecific signs of vascular damage, resembling those previously described in Notch3 knockout mice. Interestingly, messenger RNA (mRNA) analysis supports the hypothesis of an atypical NOTCH3 mutation, suggesting a nonsense-mediated mRNA decay. In conclusion, the present study broadens the spectrum of CADASIL mutations, and, therefore, opens new insights about Notch3 signaling.

De novo mutation in the NOTCH3 gene causing CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is one of the most common hereditary forms of stroke, and migraine with aura, mood disorders and dementia. CADASIL is caused by mutations of the NOTCH3 gene. This mutation is inherited as an autosomal dominant trait. Most individuals with CADASIL have a parent with the disorder. In extremely rare cases, CADASIL may occur due to a spontaneous genetic mutation that occurs for unknown reasons (de novo mutation). We report a new case of patient with de novo mutation of the NOTCH3 gene and 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.

A novel Notch3 deletion mutation in a Chinese patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare autosomal dominant hereditary cerebrovascular disease characterised by migraine attacks, recurrent subcortical transient ischemic attacks or strokes, cognitive decline, and dementia. It is caused by mutations in the Notch3 gene on chromosome 19p13.1, which is the only gene currently known to be closely associated with CADASIL. We describe a novel 100 base pair base fragment deletion mutation (ENST 00000263388, c.512-611del) in the Notch3 gene from a Chinese patient with CADASIL. The present patient has the characteristic clinical and family history for CADASIL, which suggests that C.512del611 may be a cause of CADASIL as well as most of the previously reported Notch3 mutations.

Longitudinal changes of cortical morphology in CADASIL

In CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy), a genetic model of subcortical ischemic vascular dementia (SIVD), clinical status was previously found related to cortex morphology. In the present report, alterations of cortex morphology and their links to clinical worsening were investigated in 190 CADASIL patients followed during 24.4 months. Linear models were used to test relationships between: (1) clinical worsening and changes of depth of cortical sulci and of cortical thickness; (2) alterations of cortical morphology and changes of volume of white matter hyperintensities (WMHv) and of lacunar lesions (LLv). Reduction of sulcal depth was independently associated with increased time to complete trail making test A and B (p < 0.0001 and p = 0.004) and that of cortical thickness to increased disability (modified Rankin's scale, p = 0.008), while brain atrophy was only related to global cognitive worsening (Mattis dementia rating scale, p = 0.002). The impact of volume of lacunar lesions on cortical alterations was larger than that of volume of white matter hyperintensities. Cortical alterations, mainly related to lacunar lesions, evolve parallel to clinical worsening. These results further support the eventual role of cortical alterations in subcortical ischemic vascular dementia.

Focal epilepsy as first symptom in CADASIL

Recurrent transient ischemic attacks, migraine and dementia represent the principal symptoms of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). During the course of the disease, about 10% of patients may experience epileptic seizures, mainly related to the presence of an ischemic stroke. We present a 30-year-old woman with new-onset focal epilepsy leading to the diagnosis of CADASIL. The neuropsychological testing revealed no cognitive impairment. Interictal EEG demonstrated spikes and polyspikes with low amplitude over the right occipital region during NREM sleep. MRI showed white-matter hyperintensities on both hemispheres with confluent lesions at the right parieto-occipital junction, with juxtacortical components. Like in multiple sclerosis, we can suppose that this type of white matter lesions, close to the cortex, may be causative of seizures.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL): a familial cause of depression and headache.

A 31 year-old man with a history of a depressive episode presented with acute severe 'thunderclap' headache. Magnetic resonance imaging (MRI) revealed abnormalities typical of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), which was subsequently confirmed by genetic analysis. The psychiatric features of this genetic cause of depression and headache are discussed.

Association of a Notch 3 gene polymorphism with migraine susceptibility

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) shares common symptoms with migraine. Most CADASIL causative mutations occur in exons 3 and 4 of the Notch 3 gene. This study investigated the role of C381T (rs 3815188) and G684A (rs 1043994) single nucleotide polymorphisms (SNP) in exons 3 and 4, respectively, of the Notch 3 gene in migraine. The first part of the study, in a population of 275 migraineurs and 275 control individuals, found a significant association between the C381T variant and migraine, specifically in migraine without aura (MO) sufferers. The G684A variant was also found to be significantly associated with migraine, specifically in migraine with aura (MA) sufferers. A follow-up study in 300 migraineurs and 300 control individuals did not show replicated association of the C381T variant with migraineurs. However, the G684A variant was again shown to be significantly associated with migraine, specifically with MA. Further investigation of the G684A variant and the Notch 3 gene is warranted to understand their role in migraine.

CADASIL and ALS: A link?

We report the case of a 66-year-old female who presented with dysarthria and dysphonia. Brain MRI abnormalities showed confluent white matter lesions and subcortical lacunar infarcts, suggesting cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), confirmed by the presence of a heterozygous mutation in the Notch3 gene. Clinical signs and course were consistent with amyotrophic lateral sclerosis (ALS) as was the electromyo-graphic pattern. The possible pathogenic role for a mutation in the Notch3 gene is discussed considering recent data on hypoxia in the pathophysiology of ALS.

Migraine and Genetic and Acquired Vasculopathies

It is remarkable that migraine is a prominent part of the phenotype of several genetic vasculopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and hereditary infantile hemiparessis, retinal arteriolar tortuosity and leukoencephalopahty (HIHRATL). The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear. Common genetic susceptibility, increased susceptibility to cortical spreading depression (CSD) and vascular endothelial dysfunction are among the possible explanations. The relation between migraine and acquired vasculopathies such as ischaemic stroke and coronary heart disease has long been established, further supporting a role of the (cerebral) blood vessels in migraine. This review focuses on genetic and acquired vasculopathies associated with migraine. We speculate how genetic and acquired vascular mechanisms might be involved in migraine.

CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. Clinical and neuroimaging features resemble those of sporadic small-artery disease, although patients with CADASIL have an earlier age at onset of stroke events, an increased frequency of migraine with aura, and a slightly variable pattern of ischaemic white-matter lesions on brain MRI. NOTCH3 (Notch homolog 3), the gene involved in CADASIL, encodes a transmembrane receptor primarily expressed in systemic arterial smooth-muscle cells. Pathogenetic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, which accumulates in small arteries of affected individuals. Functional and imaging studies in cultured cells, genetically engineered mice, and patients with CADASIL have all provided insights into the molecular and vascular mechanisms underlying this disease. A recent multicentre trial in patients with cognitive impairment emphasises the feasibility of randomised trials in patients with CADASIL. In this Review, we summarise the current understanding of CADASIL, a devastating disorder that also serves as a model for the more common forms of subcortical ischaemic strokes and pure vascular dementia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leuco-encephalopathy (CADASIL) is a hereditary autosomal dominant non-atherosclerotic non-amyloid cerebral arteriopathy. The disease was identified in 1993. We are not aware of reports in the literature of its occurrence in South Africa, and we present the clinical and laboratory features of 5 patients with CADASIL. Patients with the characteristic radiological white matter disease and typical features (family history, ischaemic events, migraine or dementia) were evaluated for possible CADASIL by means of clinical examination, routine investigations for strokes, magnetic resonance imaging, skin biopsy electron microscopy, evoked potentials and electroencephalography. The clinical and laboratory features of our study largely correlate with reported studies. However, all of the skin biopsies were positive, and the onset of migraine in our patients was considerably earlier. A new finding, to our knowledge, was the normality of visual, somatosensory and auditory evoked potentials. Our study confirms the existence of CADASIL in South Africa, and also suggests that skin electron microscopy is useful, despite recent reports of its low sensitivity, and that evoked potentials in CADASIL are likely to be normal.

CADASIL and ALS: A link?

We report the case of a 66-year-old female who presented with dysarthria and dysphonia. Brain MRI abnormalities showed confluent white matter lesions and subcortical lacunar infarcts, suggesting cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), confirmed by the presence of a heterozygous mutation in the Notch3 gene. Clinical signs and course were consistent with amyotrophic lateral sclerosis (ALS) as was the electromyographic pattern. The possible pathogenic role for a mutation in the Notch3 gene is discussed considering recent data on hypoxia in the pathophysiology of ALS.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy and Right-to-Left Shunt: Lack of Evidence for an Association in a Prevalence Study

Background /Aims: Up to more than 50% of cryptogenetic stroke patients and patients with migraine with aura (MA) are found to have a right-to-left shunt (RLS), which is usually due to a patent foramen ovale. Moreover, both MA and stroke are cardinal features of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Notch3 mutations have been suggested to induce an abnormally high incidence of atrial septal defects in a family harbouring an Arg141Cys pathogenetic mutation. We sought to determine the prevalence of RLS in CADASIL patients with different Notch3 mutations, both with and without migraine as a clinical feature. Methods: Subjects with a molecular diagnosis of CADASIL were tested for the presence of an RLS by means of contrast-enhanced transcranial Doppler (TCD). The diagnosis of migraine was made according to the 2004 International Headache Classification. Results: Sixteen CADASIL patients were tested; 6 had MA. Four patients displayed an RLS on contrast-enhanced TCD examination. Three of these patients had MA. Both patients with Arg141Cys displayed a large RLS. Conclusion: We conclude that RLS is not necessarily linked to CADASIL as a comorbidity factor. Nevertheless, there could be a relation between RLS and specific Notch3 mutations, such as Arg141Cys.

Structural and metabolic brain abnormalities in preclinical cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy

Objective: To assess, by using quantitative MRI metrics, structural and metabolic brain abnormalities in subjects with preclinical cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Background: Brain MRI...

CADASIL: a guide to a comparatively unrecognised condition in psychiatry

This guide to the neurological disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leuco encephalopathy (CADASIL) is specifically targeted at psychiatrists. The aims are to enhance awareness, provide educational clinical information and offer practical guidance on management of the disorder. An overview of diagnostic algorithms and recent research is also provided.

Measurement of meaningful treatment effects in CADASIL

I read with interest Martin Dichgans and colleagues' study of donepezil in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy), in the April issue of The Lancet Neurology. 1 Dichgans M Markus HS Salloway S et al. Donepezil in patients with subcortical vascular cognitive impairment: a randomized double-blind trial in CADASIL. Lancet Neurol. 2008; 7: 310-318 Summary Full Text Full Text PDF PubMed Scopus (191) Google Scholar The researchers found significant effects on two measures of executive control function, including the executive interview (EXIT25). 2 Royall DR Mahurin RK Gray K Bedside assessment of executive cognitive impairment: the executive interview (EXIT). J Am Geriatr Soc. 1992; 40: 1221-1226 PubMed Google Scholar The EXIT25 effect of −1·5 points out of 50 was comparable to that in an earlier study by Auchus and co-workers 3 Auchus AP, Brashear HR, Salloway S, et al. Results of a trial of galantamine in subjects with vascular dementia confirmed by central MRI reading. American Academy of Neurology Meeting, San Francisco, CA, USA. April 27, 2004. Google Scholar of galantamine in patients with vascular dementia as defined by the National Institute of Neurological Disorders and Stroke (NINDS). Measurement of meaningful treatment effects in CADASIL – Authors' replyWe appreciate Dr Royall's comments on the EXIT25. We agree that the beneficial effect of donepezil on the EXIT25 scores, albeit statistically significant, might not be clinically meaningful. In fact, the lack of treatment effects on instrumental activities of daily living and global dementia rating, as assessed by the disability assessment for dementia and the sum of boxes of the clinical dementia rating scale seems to support this view. We also agree that, on average, patients in the current trial were mildly affected and that this might have limited our ability to detect clinically meaningful improvements in both executive function and instrumental activities of daily living. Full-Text PDF