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1.  Case report: bipolar disorder as the first manifestation of CADASIL 
BMC Psychiatry  2014;14:175.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease, clinically characterized by variable manifestations of migraine, recurrent transient ischemic attack or lacunar strokes, cognitive decline, and mood disturbances. However, manic episodes have rarely been documented as an initial symptom of CADASIL and bipolar disorder presenting as the first manifestation in CADASIL has not been reported previously from evaluations by psychiatrists or psychological testing by psychologists.
Case presentation
A 53 year old woman developed symptoms of mania in her 50s leading to a personality change involving a continuously labile mood and irritability over a number of years. Neuropsychological testing revealed an intact memory, but impairment in attention and executive function. In the Rorschach test, she showed a high level of cognitive rigidity. Magnetic resonance imaging findings were very consistent with a diagnosis of CADASIL, which was confirmed by genetic testing for NOTCH3 mutations. Atypical antipsychotics proved to be helpful in treating her manic symptoms and for behavior control.
We present a novel case of CADASIL that first presented as bipolar disorder. We contend that when patients show a late onset personality change or chronically irritable mood that deteriorates over many years, an organic cause such as CADASIL must be considered. Further studies are needed to better understand the exact impacts of cerebral tissue lesions and psychiatric symptoms in CADASIL patients.
PMCID: PMC4080756  PMID: 24929957
CADASIL; Bipolar disorder; Mood disorder; NOTCH3
2.  A Novel Cysteine-Sparing NOTCH3 Mutation in a Chinese Family with CADASIL 
PLoS ONE  2014;9(8):e104533.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult onset cerebral small vessel disorder caused by the mutations of the neurogenic locus notch homolog protein 3 (NOTCH3) gene. The extracellular part of NOTCH3 is composed of 34 epidermal growth factor-like (EGF-like) repeat domains. Each EGF-like domain is rich of cysteine and glycine to produce three loops that are essential for high-affinity binding to its ligand. Nearly all reported CADASIL-associated mutations result in gain or loss of a cysteine residue within the EGF-like domains. Only a few cysteine-sparing NOTCH3 mutations have been documented in the patients with CADASIL to date. Here, we reported a Chinese CADASIL family with a cysteine-sparing NOTCH3 mutation. In this family, affected patients had dizziness, memory loss, gait instability, or hemiplegia. Brain magnetic resonance imaging (MRI) showed diffuse leukoencephalopathy with confluent signal abnormalities in the periventricular white matter, basal ganglia, and centrum semiovale bilaterally. By screening the entire coding region of NOTCH3, a novel missense mutation p.G149V (c.446G>T) was found. This mutation was not detected in 400 normal controls. Considering the critical position of glycine within the C-loop of EGF-like domain and its high conservation through evolution, p.G149V mutation could be a potential pathogenic cause for CADASIL.
PMCID: PMC4123979  PMID: 25098330
3.  Fractal Analysis Reveals Reduced Complexity of Retinal Vessels in CADASIL 
PLoS ONE  2011;6(4):e19150.
The Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) affects mainly small cerebral arteries and leads to disability and dementia. The relationship between clinical expression of the disease and progression of the microvessel pathology is, however, uncertain as we lack tools for imaging brain vessels in vivo. Ophthalmoscopy is regarded as a window into the cerebral microcirculation. In this study we carried out an ophthalmoscopic examination in subjects with CADASIL. Specifically, we performed fractal analysis of digital retinal photographs. Data are expressed as mean fractal dimension (mean-D), a parameter that reflects complexity of the retinal vessel branching. Ten subjects with genetically confirmed diagnosis of CADASIL and 10 sex and age-matched control subjects were enrolled. Fractal analysis of retinal digital images was performed by means of a computer-based program, and the data expressed as mean-D. Brain MRI lesion volume in FLAIR and T1-weighted images was assessed using MIPAV software. Paired t-test was used to disclose differences in mean-D between CADASIL and control groups. Spearman rank analysis was performed to evaluate potential associations between mean-D values and both disease duration and disease severity, the latter expressed as brain MRI lesion volumes, in the subjects with CADASIL. The results showed that mean-D value of patients (1.42±0.05; mean±SD) was lower than control (1.50±0.04; p = 0.002). Mean-D did not correlate with disease duration nor with MRI lesion volumes of the subjects with CADASIL. The findings suggest that fractal analysis is a sensitive tool to assess changes of retinal vessel branching, likely reflecting early brain microvessel alterations, in CADASIL patients.
PMCID: PMC3083432  PMID: 21556373
4.  Abnormal recruitment of extracellular matrix proteins by excess Notch3ECD: a new pathomechanism in CADASIL 
Brain  2013;136(6):1830-1845.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL, one of the most common inherited small vessel diseases of the brain, is characterized by a progressive loss of vascular smooth muscle cells and extracellular matrix accumulation. The disease is caused by highly stereotyped mutations within the extracellular domain of the NOTCH3 receptor (Notch3ECD) that result in an odd number of cysteine residues. While CADASIL-associated NOTCH3 mutations differentially affect NOTCH3 receptor function and activity, they all are associated with early accumulation of Notch3ECD-containing aggregates in small vessels. We still lack mechanistic explanation to link NOTCH3 mutations with small vessel pathology. Herein, we hypothesized that excess Notch3ECD could recruit and sequester functionally important proteins within small vessels of the brain. We performed biochemical, nano-liquid chromatography-tandem mass spectrometry and immunohistochemical analyses, using cerebral and arterial tissue derived from patients with CADASIL and mouse models of CADASIL that exhibit vascular lesions in the end- and early-stage of the disease, respectively. Biochemical fractionation of brain and artery samples demonstrated that mutant Notch3ECD accumulates in disulphide cross-linked detergent-insoluble aggregates in mice and patients with CADASIL. Further proteomic and immunohistochemical analyses identified two functionally important extracellular matrix proteins, tissue inhibitor of metalloproteinases 3 (TIMP3) and vitronectin (VTN) that are sequestered into Notch3ECD-containing aggregates. Using cultured cells, we show that increased levels or aggregation of Notch3 enhances the formation of Notch3ECD–TIMP3 complex, promoting TIMP3 recruitment and accumulation. In turn, TIMP3 promotes complex formation including NOTCH3 and VTN. In vivo, brain vessels from mice and patients with CADASIL exhibit elevated levels of both insoluble cross-linked and soluble TIMP3 species. Moreover, reverse zymography assays show a significant elevation of TIMP3 activity in the brain vessels from mice and patients with CADASIL. Collectively, our findings lend support to a Notch3ECD cascade hypothesis in CADASIL disease pathology, which posits that aggregation/accumulation of Notch3ECD in the brain vessels is a central event, promoting the abnormal recruitment of functionally important extracellular matrix proteins that may ultimately cause multifactorial toxicity. Specifically, our results suggest a dysregulation of TIMP3 activity, which could contribute to mutant Notch3ECD toxicity by impairing extracellular matrix homeostasis in small vessels.
PMCID: PMC3673461  PMID: 23649698
CADASIL; Notch3; protein aggregation; extracellular matrix proteins; cerebrovasculature
5.  Description of a simple test for CADASIL disease and determination of mutation frequencies in sporadic ischaemic stroke and dementia patients 
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited adult onset disease characterised most commonly by cerebral ischaemic events and dementia. It is caused by mutations in the Notch3 gene with most clustering in exons 3 and 4. Whether these mutations have any influence on common sporadic ischaemic stroke or dementia cases has not been investigated, partly hampered by the lack of a readily usable genetic test.
An easy to use diagnostic array for CADASIL was designed using various restriction endonucleases for the known mutations in exons 3 and 4 and novel mismatch primers were designed where no such enzymes existed. This array was used to identify the allele frequencies of CADASIL mutations and polymorphisms in selected disease cohorts. Seventy patients with radiologically established sporadic ischaemic stroke and 77 patients from a specialist young dementia clinic were recruited. One hundred and seventeen age and sex matched asymptomatic controls were also identified.
The diagnostic array was found to work well. None of the 14 known mutations and three previously identified polymorphisms (C474A, A587G, and C594A) in exons 3 and 4 were present in 140stroke, 110 dementia, or 234 control chromosomes. Molecular variant C381T occurred with a higher frequency of 0.13, whereas G684A occurred with a lower frequency (0.09) than previously reported, although there were no statistical differences between selected cohorts.
In conclusion, a readily usable genetic test for CADASIL has been devised that was used to determine allele frequencies in well characterised cohorts of sporadic stroke and dementia patients. The data suggest that despite the clinical resemblance, CADASIL is not a common masquerading cause of stroke or dementia. The test will enable units locally to rapidly screen patients with suspected CADASIL.

PMCID: PMC1763386  PMID: 11032621
6.  CADASIL in Arabs: clinical and genetic findings 
BMC Medical Genetics  2007;8:67.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is increasingly recognized as an inherited arterial disease leading to a step-wise decline and eventually to dementia. CADASIL is caused by mutations in NOTCH3 epidermal growth factor-like repeat that maps to chromosome 19. CADASIL cases have been identified in most countries of Western and Central Europe, the Americas, Japan, Australia, the Caribbean, South America, Tanzania, Turkey, South Africa and Southeast Asia, but not in Arabs.
We studied three families from Saudi Arabia (Family A), Kuwait (Family B) and Yemen (Family C) with 19 individuals affected by CADASIL.
The mean age of onset was 31 ± 6 and the clinical presentation included stroke in 68%, subcortical dementia in 17% and asymptomatic leukoariosis detected by MRI in 15%. Migraine and depression were frequently associated, 38% and 68% respectively. The mean age of death was 56 ± 11. All NOTCH3 exons were screened for mutations, which revealed the presence of previously reported mutations c.406C>T (p.Arg110>Cys) in two families (family A&B) and c.475C>T (p.Arg133>Cys) mutation in family C.
CADASIL occurs in Arabs, with clinical phenotype and genotype similar to that in other ethnic groups.
PMCID: PMC2190758  PMID: 17996090
7.  Neuropathological Correlates of Temporal Pole White Matter Hyperintensities in CADASIL 
Background and Purpose
White matter (WM) hyperintensities upon magnetic resonance imaging (MRI) or leukoaraiosis is characteristic of stroke syndromes. Increased MRI signals in the anterior temporal pole are suggested to be diagnostic for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with 90% sensitivity and 100% specificity. The structural correlates of these specific WM hyperintensities seen on T2-weighted and FLAIR sequences in the temporal pole of CADASIL are unclear. We assessed pathological changes in post-mortem tissue from the temporal pole to reveal the cause of CADASIL specific WM hyperintensities.
Materials & Methods
A combination of tinctorial and immunostaining approaches and in vitro imaging methods were used to quantify the extent of perivascular space (PVS), arteriosclerosis determined as the sclerotic index (SI), WM myelination as the myelin index (MI) and damage within the WM as accumulated degraded myelin basic protein (dMBP) in samples of the anterior temporal pole from 9 CADASIL and 8 sporadic subcortical ischaemic vascular dementia (SIVD) cases, and 5 similar age (young) and 5 older controls. Luxol fast blue (LFB) stained serial sections from a CADASIL case were also used to reconstruct the temporal pole, which was then compared to the MR images.
LFB sections used to reconstruct the temporal pole revealed an abundance of enlarged PVS in the WM that topographically appeared as indistinct opaque regions. The mean and total areas of the PVS per WM area (%PVS) were significantly greater in CADASIL compared to the controls. The MI was severely reduced in CADASIL in relation to the SIVD and control sample that was consistent with increased immunoreactivity of dMBP, indicating myelin degeneration. Cerebral microvessels associated with the PVS exhibited a 4.5 fold greater number of basophilic (hyalinised) vessels and a 57% increase in the SI values in CADASIL subjects compared to young controls. A significant correlation between the quantity of hyalinised vessels and SI values was also apparent (P<0.05).
Our findings suggest that MRI hyperintensities in the temporal pole of CADASIL patients are explained by enlarged PVS and degeneration of myelin accompanied by lack of drainage of the interstitial fluid rather than lacunar infarcts. Consistent with the lack of MR hypersignals in the temporal pole of older SIVD subjects, our observations imply greater progression of pathological changes in CADASIL patients.
PMCID: PMC2724668  PMID: 19359623
CADASIL; dementia; cognitive impairment; stroke; subcortical ischaemic vascular dementia; vascular dementia
8.  A novel mutation (C67Y)in the NOTCH3 gene in a Korean CADASIL patient. 
Journal of Korean Medical Science  2003;18(1):141-144.
We report a 52-yr-old Korean woman with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) whose diagnosis was confirmed by skin biopsy and the presence of a novel mutation in the NOTCH3 gene. The patient's clinical features were rather unusual in that 1) clinical presentations were only two episodes of stroke and mild dementia unaccompanied by mood disturbances or migraine, and 2) there was no family history. Brain MRI showed T2 hyperintensities in both temporal pole areas in line with the recent suggestion by O'Sullivan et al. that the abnormality could be a radiologic marker of CADASIL. FDG-PET also showed a hypometabolism in the temporal pole areas with an abnormal finding on MRI in addition to the hypometabolism in cortical and subcortical regions. We could learn from this case that CADASIL may be included in the differential diagnoses in patients with vascular dementia associated with a small vessel disease, even in the absence of a family history, especially when there are no known stroke risk factors and when the MRI shows T2 hyperintensity in the temporal pole regions.
PMCID: PMC3055005  PMID: 12589106
9.  Bidirectional encroachment of collagen into the tunica media in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy 
Brain Research  2012;1456:64-71.
Arteries in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are susceptible to smooth muscle loss and fibrosis, but the molecular components underlying these dramatic vascular changes are not well characterized. The purpose of this study was to investigate the distribution of collagen isoforms in the cerebral vessels of North American CADASIL patients with classical NOTCH3 mutations. Expression of type I-VI collagen in brains obtained at autopsy from six CADASIL patients with cysteine-altering mutations in NOTCH3 was compared to control brain expression. We identified a consistent increase of type I, III, IV, and VI collagen in CADASIL brains. Strong accumulation of type I, III, IV and VI collagen was noted in all calibers of vessels, including small and medium-sized leptomeningeal arteries, small penetrating white matter arteries, and capillaries. Within leptomeningeal arteries, where we could define the three tunicae of each vessel, we found distinct collagen subtype distribution patterns in CADASIL. Type I and III collagen were largely found in either adventitial/medial or transmural locations. Type IV collagen was strictly intimal/medial. Type VI collagen was adventitial or adventitial/medial. Within the thickened penetrating arteries of CADASIL patients, all four collagens extended through most of the arterial wall. We observed increased staining of capillaries in CADASIL for type I, IV, and VI collagen. In conclusion, brain vascular collagen subtypes are increased in CADASIL in multiple layers of all sizes of arteries, with disease-specific changes most prominent in the tunica media and thickened small penetrating vessels. In diseased arteries, type I, III, and VI collagen spreads from an external location (adventitia) into the vascular media, while type IV collagen accumulates in an internal pattern (intima and media). These observations are consistent with a pathological role for collagen accumulation in the vascular media in CADASIL.
PMCID: PMC3370335  PMID: 22503071
10.  Is the Oxidant/Antioxidant Status Altered in CADASIL Patients? 
PLoS ONE  2013;8(6):e67077.
The altered aggregation of proteins in non-native conformation is associated with endoplasmic reticulum derangements, mitochondrial dysfunction and excessive production of reactive oxygen species. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary systemic vasculopathy, caused by NOTCH3 mutations within the receptor extracellular domain, that lead to abnormal accumulation of the mutated protein in the vascular wall. NOTCH3 misfolding could cause free radicals increase also in CADASIL. Aim of the study was to verify whether CADASIL patients have increased oxidative stress compared to unrelated healthy controls. We enrolled 15 CADASIL patients and 16 gender- and age-matched healthy controls with comparable cardiovascular risk factor. Blood and plasma reduced and total aminothiols (homocysteine, cysteine, glutathione, cysteinylglycine) were measured by HPLC and plasma 3-nitrotyrosine by ELISA. Only plasma reduced cysteine (Pr-Cys) and blood reduced glutathione (Br-GSH) concentrations differed between groups: in CADASIL patients Br-GSH levels were higher (p = 0.019) and Pr-Cys lower (p = 0.010) than in controls. No correlation was found between Br-GSH and Pr-Cys either in CADASIL patients (rho 0.25, P=0.36) or in controls (rho -0.15, P=0.44). Conversely, 3-nitrotyrosine values were similar in CADASIL and healthy subjects (p = 0.82). The high levels of antioxidant molecules and low levels of oxidant mediators found in our CADASIL population might either be expression of an effective protective action against free radical formation at an early stage of clinical symptoms or they could suggest that oxidative stress is not directly involved in the pathogenesis of CADASIL.
PMCID: PMC3682996  PMID: 23799141
11.  Von Willebrand Factor permeates small vessels in CADASIL and inhibits smooth muscle gene expression 
Translational stroke research  2011;3(1):138-145.
Background and Purpose
CADASIL (cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy) is a genetic disorder hallmarked by ischemic stroke and vascular dementia. Characteristic pathological changes in the vasculature include thickening of small arteries and accumulation of heterogeneous material within the vessel wall. We tested whether endothelial von Willebrand factor (vWF) accumulates in CADASIL vessels and whether exposure of smooth muscle cells to vWF alters the expression of smooth muscle gene expression.
Brain sections obtained at autopsy from six North American CADASIL patients were examined using immunohistochemistry for vWF and IgG. Rat aortic smooth muscle cells (A7R5 cells) were tested for binding to infrared-tag labeled vWF. Finally, A7R5 cells were exposed to vWF, and expression of mature smooth muscle marker genes was analyzed by quantitative reverse transcriptase PCR.
vWF is expressed in the penetrating arterial walls in all CADASIL samples. IgG, a marker of serum extravasation, was present only in a minority of arterial walls. vWF binds to smooth muscle cells in vitro, and low concentrations of vWF rapidly activate c-fos, EGR, TSP1, and c-myc while specifically inhibiting RNA encoding smooth muscle actin, calponin, and SM22.
These data demonstrate that vWF, likely produced by the endothelium, permeates the vessel wall of CADASIL brains. Exposure of smooth muscle cells to vWF results in reduction of specific RNAs required for normal vascular homeostasis. This is the first report of accumulation of a protein within CADASIL vessels that inhibits vascular gene expression and implicates a role for vWF beyond hemostasis.
PMCID: PMC3358806  PMID: 22639698
CADASIL; von Willebrand Factor (vWF); smooth muscle; small vessel disease; vascular permeability; immunoglobulin
12.  Functional analysis of a recurrent missense mutation in Notch3 in CADASIL 
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vascular dementia characterised by recurrent ischemic strokes in the deep white matter. Mutations in the gene encoding the cell surface receptor, Notch3, have been identified in CADASIL patients, and accumulation of the extracellular domain of Notch3 has been demonstrated in affected vessels. Almost all CADASIL mutations alter the number of cysteine residues in the epidermal growth factor (EGF)-like repeats in the extracellular domain of the protein.
Objectives: To understand the functional consequences of a recurrent CADASIL mutation on furin processing, cell surface expression, ligand binding, and activation of a downstream effector CBF1 by the Notch3 receptor.
Methods: We expressed wild type and mutant Notch3 receptors in cultured cells and examined cell surface expression of the proteins. We also applied a new flow cytometry based approach to semi-quantitatively measure binding to three Notch ligands. Additionally, we used a well characterised co-culture system to examine ligand dependent activation of transcription from a CBF1-luciferase reporter construct.
Results: These studies revealed subtle abnormalities in furin processing of the mutant receptor, although both heterodimeric and full length receptors are present on the cell surface, are capable of interacting with soluble forms of three ligands, Delta1, Delta4, and Jagged1, and retain the ability to activate CBF1 in a ligand dependent manner.
Conclusions: By comparison with other mutant forms of Notch3, these data indicate that individual CADASIL mutations can have disparate effects on Notch3 expression and function.
PMCID: PMC1739793  PMID: 16107360
13.  Spontaneous intracerebral hemorrhage in CADASIL 
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary small vascular disease and its mainly clinical manifestations are ischemic events. Spontaneous intracerebral hemorrhage (ICH) involvement in patients with CADASIL is extremely uncommon.
Case report
A 46-year-old normotensive Chinese man developed a large hematoma in the left basal ganglia after he was diagnosed with CADASIL 2 months ago, the patient did not take any antithrombotics. Susceptibility weighted imaging at pre-ICH showed multiple cerebral microbleeds (CMBs) in the bilateral basal ganglia. He experienced migraine at about 10 months post-ICH. To our knowledge, this is the first report of ICH in CADASIL patients with Arg90Cys mutation in exon 3.
Discussion and conclusions
ICH should be considered when evaluating new attacks in CADASIL patients. Thus, MRI screening for CMBs might be helpful in predicting the risk of ICH and guiding antithrombotic therapy. In addition, strict control of hypertension and cautious use of antithrombotics may be important in this context.
PMCID: PMC3878525  PMID: 24344756
Migraine; CADASIL; Intracerebral hemorrhage; NOTCH3; Microbleeds
14.  Advanced intimal hyperplasia without luminal narrowing of leptomeningeal arteries in CADASIL 
Leptomeningeal artery abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have not been extensively characterized. We quantified substructure and diameter of leptomeningeal arteries in CADASIL in comparison to age matched controls and the very old; in addition, we characterized intimal thickening in CADASIL using immunohistochemistry.
Frontal and temporal cortex of six genetically proven CADASIL brains (average age 66), six controls without symptoms of cerebrovascular disease, and six very old brains (average age 89) were examined for leptomeningeal artery intimal, medial, and adventitial thickness, inner diameter, and sclerotic index (SI) and for smooth muscle markers.
The intima of CADASIL arteries was thickened five-fold compared to controls and the very aged (p<0.0001). Medial thickness was lower in CADASIL compared to controls and the very old (p<0.01). The adventitia was not significantly increased in CADASIL compared to age-matched controls. Arterial diameters were not smaller in CADASIL compared to controls. SI was significantly increased in CADASIL compared to other groups (p<0.00001). Intimal cells in CADASIL expressed smooth muscle actin, S100A4, and vimentin but not desmin.
Principle changes of leptomeningeal arteries in CADASIL include intimal thickening and medial thinning, but not luminal narrowing. Smooth muscle-like cells participate in neointimal thickening of CADASIL arteries.
PMCID: PMC3641653  PMID: 23482599
neointimal hyperplasia; CADASIL; leptomeningeal; cortex; S100A4; vimentin; smooth muscle actin
15.  Non-convulsive status epilepticus causing focal neurological deficits in CADASIL 
BMJ Case Reports  2009;2009:bcr07.2008.0529.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations of the Notch3 gene. Clinical manifestations include migraine with or without aura, psychiatric disorders, recurrent ischaemic strokes and cognitive decline. Brain MRI shows confluent hyperintense signal alterations involving characteristically the anterior part of the temporal lobes and widespread areas of the deep and periventricular white matter. Focal or generalised seizures represent a rare neurological manifestation in CADASIL with a frequency of 6–10% in two large series.1,2 Status epilepticus, however, has not been reported so far. Herein we describe a patient with CADASIL with an acute focal neurological deficit following a prolonged migraine attack. The symptoms were first interpreted as an ischaemic stroke but subsequently diagnosed to be due to a non-convulsive status epilepticus.
PMCID: PMC3028380  PMID: 21686761
16.  Non-convulsive status epilepticus causing focal neurological deficits in CADASIL 
BMJ Case Reports  2009;2009:bcr08.2008.0713.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations of the Notch3 gene. Clinical manifestations include migraine with or without aura, psychiatric disorders, recurrent ischaemic strokes and cognitive decline. Brain MRI shows confluent hyperintense signal alterations involving characteristically the anterior part of the temporal lobes and widespread areas of the deep and periventricular white matter. Focal or generalised seizures represent a rare neurological manifestation in CADASIL with a frequency of 6–10% in two large series. Status epilepticus, however, has not been reported so far. Herein we describe a patient with CADASIL with an acute focal neurological deficit following a prolonged migraine attack. The symptoms were first interpreted as an ischaemic stroke but subsequently diagnosed to be due to a non-convulsive status epilepticus.
PMCID: PMC3029129  PMID: 21686667
17.  Sequestration of latent TGF-β binding protein 1 into CADASIL-related Notch3-ECD deposits 
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) represents the most common hereditary form of cerebral small vessel disease characterized by early-onset stroke and premature dementia. It is caused by mutations in the transmembrane receptor Notch3, which promote the aggregation and accumulation of the Notch3 extracellular domain (Notch3-ECD) within blood vessel walls. This process is believed to mediate the abnormal recruitment and dysregulation of additional factors including extracellular matrix (ECM) proteins resulting in brain vessel dysfunction. Based on recent evidence indicating a role for the transforming growth factor-β (TGF-β) pathway in sporadic and familial small vessel disease we studied fibronectin, fibrillin-1 and latent TGF-β binding protein 1 (LTBP-1), three ECM constituents involved in the regulation of TGF-β bioavailability, in post-mortem brain tissue from CADASIL patients and control subjects.
Fibronectin and fibrillin-1 were found to be enriched in CADASIL vessels without co-localizing with Notch3-ECD deposits, likely as a result of fibrotic processes secondary to aggregate formation. In contrast, LTBP-1 showed both an accumulation and a striking co-localization with Notch3-ECD deposits suggesting specific recruitment into aggregates. We also detected increased levels of the TGF-β prodomain (also known as latency-associated peptide, LAP) indicating dysregulation of the TGF-β pathway in CADASIL development. In vitro analyses revealed a direct interaction between LTBP-1 and Notch3-ECD and demonstrated a specific co-aggregation of LTBP-1 with mutant Notch3.
We propose LTBP-1 as a novel component of Notch3-ECD deposits and suggest its involvement in pathological processes triggered by Notch3-ECD aggregation.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-014-0096-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4243959  PMID: 25190493
Latent TGF-β binding protein 1 (LTBP-1); Small vessel disease; CADASIL; TGF-β signaling; Granular osmiophilic material (GOM); Extracellular matrix (ECM)
18.  Three-Dimensional MRI Analysis of Individual Volume of Lacunes in CADASIL 
Background and Purpose
Three-dimensional MRI segmentation may be useful to better understand the physiopathology of lacunar infarctions. Using this technique, the distribution of lacunar infarctions volumes has been recently reported in patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Whether the volume of each lacune (individual lacunar volume [ILV]) is associated with the patients’ other MRI lesions or vascular risk factors has never been investigated. The purpose of this study was to study the impact of age, vascular risk factors, and MRI markers on the ILV in a large cohort of patients with CADASIL.
Of 113 patients with CADASIL, 1568 lacunes were detected and ILV was estimated after automatic segmentation on 3-dimensional T1-weighted imaging. Relationships between ILV and age, blood pressure, cholesterol, diabetes, white matter hyperintensities load, number of cerebral microbleeds, apparent diffusion coefficient, brain parenchymal fraction, and mean and median of distribution of lacunes volumes at the patient level were investigated. We used random effect models to take into account intraindividual correlations.
The ILV varied from 4.28 to 1619 mm3. ILV was not significantly correlated with age, vascular risk factors, or different MRI markers (white matter hyperintensity volume, cerebral microbleed number, mean apparent diffusion coefficient or brain parenchymal fraction). In contrast, ILV was positively correlated with the patients’ mean and median of lacunar volume distribution (P=0.0001).
These results suggest that the ILV is not related to the associated cerebral lesions or to vascular risk factors in CADASIL, but that an individual predisposition may explain predominating small or predominating large lacunes among patients. Local anatomic factors or genetic factors may be involved in these variations.
PMCID: PMC3085999  PMID: 18948610
CADASIL; cerebral lacunes; MRI
19.  Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain 
Brain  2009;132(6):1601-1612.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant small-vessel disease of the brain caused by mutations in the NOTCH3 receptor. The highly stereotyped nature of the mutations, which alter the number of cysteine residues within the epidermal growth factor-like repeats (EGFR), predicts that all mutations share common mechanisms. Prior in vitro assays and genetic studies in the mouse support the hypothesis that common mutations do not compromise canonical Notch3 function but instead convey a non-physiological and deleterious activity to the receptor through the unpaired cysteine residue. Intriguingly, in vitro studies predict that mutations located in the Delta/Serrate/LAG-2 ligand binding domain-(EGFR10-11) may result in a loss of Notch3 receptor function. However, the in vivo relevance and functional significance of this with respect to the pathogenic mechanisms and clinical expression of the disease remain largely unexplored. To ascertain, in vivo, the functional significance of EGFR10-11 mutations, we generated transgenic mice with one representative mutation (C428S) in EGFR10 of Notch3. These mice, like those with a common R90C mutation, developed characteristic arterial accumulation of Notch3 protein and granular osmiophilic material upon aging. By introducing the mutant C428S transgene into a Notch3 null background, we found that, unlike the R90C mutant protein, the C428S mutant protein has lost wild-type Notch3 activity and exhibited mild dominant-negative activity in three different biological settings. From a large prospectively recruited cohort of 176 CADASIL patients, we identified 10 patients, from five distinct pedigrees carrying a mutation in EGFR10 or 11. These mutations were associated with significantly higher Mini-Mental State Examination and Mattis Dementia Rating Scale scores (P < 0.05), when compared with common mutations. Additionally, we found a strong effect of this genotype on the burden of white matter hyperintensities (P < 0.01). Collectively, these results highlight distinctive functional and phenotypic features of EGFR10-11 mutations relative to the common CADASIL mutations. Our findings are compatible with the hypothesis that EGFR10-11 mutations cause the disease through the same gain of novel function as the common mutations, and lead us to propose that reduced Notch3 signalling acts as a modifier of the CADASIL phenotype.
PMCID: PMC2685919  PMID: 19293235
CADASIL; Notch3; transgenic; genotype-phenotype correlations
20.  New phenotype of the cerebral autosomal dominant arteriopathy mapped to chromosome 19: migraine as the prominent clinical feature. 
A survey was carried out on a large family presenting the symptoms of familial arteriopathy (CADASIL) recently mapped to chromosome 19. This is characterised clinically by recurrent subcortical infarcts developing into pseudobulbar palsy and subcortical dementia, and radiologically by early MRI abnormalities. To characterise this familial condition, 43 members older than 20 years and spreading over four generations were studied clinically (31 living, 12 deceased), genetically, and radiologically by MRI (n = 31). Twenty out of 43 were found to be clinically symptomatic and of these 13 out of 31 had MRI abnormalities. Genetic studies mapped this condition to the locus of CADASIL (lod score > 3). The natural history suggests a chronological clinicoradiological staging of this phenotype of CADASIL: stage I between 20 and 40 years with frequent migraine-like episodes and well delineated lesions of the white matter; stage II between 40 and 60 years with stroke-like episodes, bipolar or monopolar-like psychotic disorders, coalescent lesions of the white matter, and well delineated lesions of the basal ganglia; and stage III over 60 years with subcortical dementia, pseudobulbar palsy, diffuse leukoencephalopathy, and multiple well delineated lesions of the basal ganglia. This phenotype differs from the other two previously described by high frequency of migraine, frequency of psychotic disorders, and early neurological manifestations. The new acronym "cerebral autosomal dominant arteriopathy with subcortical infarcts, leukoencephalopathy, and migraine" (CADASILM) is proposed to better describe this particular subvariety of CADASIL.
PMCID: PMC1073751  PMID: 7500094
21.  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in an Israeli family 
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of hereditary cerebral microangiopathy, and is caused by over 170 different mutations in the NOTCH3 gene at locus 19p13.1–13.26. We report the first study of familial CADASIL in a 39-year-old Jewish woman and her mother who had died previously. The patient’s investigations revealed a normal hemogram with no vascular risk factors or chronic disease. Lumbar puncture was normal. Cranial computed tomography scan revealed bilateral diffuse hypodensities in the subcortical white matter. Cranial magnetic resonance imaging showed hyperintense lesions in the cerebral white matter on T2-weighted images. On electron microscopy, a characteristic granular osmiophilic material was seen in the basement membrane surrounding the pericytes and smooth muscle cells in small-sized and medium-sized vessels. Molecular analysis of the NOTCH3 gene was performed with automatic sequencing of exon 3 and 4 (and intron-exon boundaries) showing a nucleotide c.268C > T substitution, leading to a pathogenic amino acid substitution of p.Arg90Cys, confirming a diagnosis of CADASIL. This mutation was also found in the patient’s mother. Although the exact prevalence of CADASIL is not known, this disorder has been reported worldwide, and now including Jews, with a genotype and clinical phenotype similar to that in other ethnic groups.
PMCID: PMC3148930  PMID: 21822390
CADASIL; autosomal-dominant inheritance; genetic diagnostics; NOTCH3; arteriopathy
22.  In Vivo High-Resolution 7 Tesla MRI Shows Early and Diffuse Cortical Alterations in CADASIL 
PLoS ONE  2014;9(8):e106311.
Background and Purpose
Recent data suggest that early symptoms may be related to cortex alterations in CADASIL (Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a monogenic model of cerebral small vessel disease (SVD). The aim of this study was to investigate cortical alterations using both high-resolution T2* acquisitions obtained with 7 Tesla MRI and structural T1 images with 3 Tesla MRI in CADASIL patients with no or only mild symptomatology (modified Rankin’s scale ≤1 and Mini Mental State Examination (MMSE) ≥24).
Complete reconstructions of the cortex using 7 Tesla T2* acquisitions with 0.7 mm isotropic resolution were obtained in 11 patients (52.1±13.2 years, 36% male) and 24 controls (54.8±11.0 years, 42% male). Seven Tesla T2* within the cortex and cortical thickness and morphology obtained from 3 Tesla images were compared between CADASIL and control subjects using general linear models.
MMSE, brain volume, cortical thickness and global sulcal morphology did not differ between groups. By contrast, T2* measured by 7 Tesla MRI was significantly increased in frontal, parietal, occipital and cingulate cortices in patients after correction for multiple testing. These changes were not related to white matter lesions, lacunes or microhemorrhages in patients having no brain atrophy compared to controls.
Seven Tesla MRI, by contrast to state of the art post-processing of 3 Tesla acquisitions, shows diffuse T2* alterations within the cortical mantle in CADASIL whose origin remains to be determined.
PMCID: PMC4148432  PMID: 25165824
23.  Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Genetic Cause of Cerebral Small Vessel Disease 
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder of the cerebral small blood vessels caused by mutations in the Notch3 gene. The exact prevalence of this disorder was unknown currently, and the number of reported CADASIL families is steadily increasing as the clinical picture and diagnostic examinations are becoming more widely known. The main clinical manifestations are recurrent stroke, migraine, psychiatric symptoms, and progressive cognitive impairment. The clinical course of CADASIL is highly variable, even within families. The involvement of the anterior temporal lobe and the external capsule on brain magnetic resonance imaging was found to have high sensitivity and specificity in differentiating CADASIL from the much more common sporadic cerebral small-vessel disease (SVD). The pathologic hallmark of the disease is the presence of granular osmiophilic material in the walls of affected vessels. CADASIL is a prototype single-gene disorder that has evolved as a unique model for studying the mechanisms underlying cerebral SVD. At present, the incidence and prevalence of CADASIL seem to be underestimated due to limitations in clinical, neuroradiological, and genetic diagnoses of this disorder.
PMCID: PMC2851292  PMID: 20386637
cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; ischemic stroke; migraine; small-vessel disease; Notch3
24.  Glial Vascular Degeneration in CADASIL 
Journal of Alzheimer's disease : JAD  2010;21(4):1393-1402.
CADASIL is a genetic vascular dementia caused by mutations in the Notch 3 gene on Chromosome 19. However, little is known about the mechanisms of vascular degeneration.
We characterized upstream components of Notch signaling pathways that may be disrupted in CADASIL, by measuring expression of insulin, IGF-1, and IGF-2 receptors, Notch 1, Notch 3, and aspartyl-(asparaginyl)-β-hydroxylase (AAH) in cortex and white matter from 3 CADASIL and 6 control brains. We assessed CADASIL-associated cell loss by measuring mRNA corresponding to neurons, oligodendroglia, and astrocytes, and indices of vascular degeneration by measuring smooth muscle actin (SMA) and endothelin-1 (ET-1) expression in isolated vessels. Immunohistochemical staining was used to assess SMA degeneration.
Significant abnormalities including reduced cerebral white matter mRNA levels of Notch 1, Notch 3, AAH, SMA, IGF receptors, myelin-associated glycoproteins, and glial fibrillary acidic protein, and reduced vascular expression of SMA, IGF receptors, Notch 1 and Notch 3 were detected in CADASIL-lesioned brains. In addition, we found CADASIL-associated reductions in SMA, and increases in ubiquitin immunoreactivity in the media of white matter and meningeal vessels. No abnormalities in gene expression or immunoreactivity were observed in CADASIL cerebral cortex.
Molecular abnormalities in CADASIL are largely restricted to white matter and white matter vessels, corresponding to the distribution of neuropathological lesions. These preliminary findings suggest that CADASIL is mediated by both glial and vascular degeneration with reduced expression of IGF receptors and AAH, which regulate Notch expression and function.
PMCID: PMC3019271  PMID: 21503135
vascular dementia; Notch; white matter degeneration; aspartyl-(asparaginyl)-β-hydroxylase; human
25.  Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients 
Brain  2009;132(4):933-939.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary subcortical vascular dementia. It is caused by mutations in NOTCH3 gene, which encodes a large transmembrane receptor Notch3. The key pathological finding is the accumulation of granular osmiophilic material (GOM), which contains extracellular domains of Notch3, on degenerating vascular smooth muscle cells (VSMCs). GOM has been considered specifically diagnostic for CADASIL, but the reports on the sensitivity of detecting GOM in patients’ skin biopsy have been contradictory. To solve this contradiction, we performed a retrospective investigation of 131 Finnish, Swedish and French CADASIL patients, who had been adequately examined for both NOTCH3 mutation and presence of GOM. The patients were examined according to the diagnostic practice in each country. NOTCH3 mutations were assessed by restriction enzyme analysis of specific mutations or by sequence analysis. Presence of GOM was examined by electron microscopy (EM) in skin biopsies. Biopsies of 26 mutation-negative relatives from CADASIL families served as the controls. GOM was detected in all 131 mutation positive patients. Altogether our patients had 34 different pathogenic mutations which included three novel point mutations (p.Cys67Ser, p.Cys251Tyr and p.Tyr1069Cys) and a novel duplication (p.Glu434_Leu436dup). The detection of GOM by EM in skin biopsies was a highly reliable diagnostic method: in this cohort the congruence between NOTCH3 mutations and presence of GOM was 100%. However, due to the retrospective nature of this study, exact figure for sensitivity cannot be determined, but it would require a prospective study to exclude possible selection bias. The identification of a pathogenic NOTCH3 mutation is an indisputable evidence for CADASIL, but demonstration of GOM provides a cost-effective guide for estimating how far one should proceed with the extensive search for a new or an uncommon mutations among the presently known over 170 different NOTCH3 gene defects. The diagnostic skin biopsy should include the border zone between deep dermis and upper subcutis, where small arterial vessels of correct size are located. Detection of GOM requires technically adequate biopsies and distinction of true GOM from fallacious deposits. If GOM is not found in the first vessel or biopsy, other vessels or additional biopsies should be examined.
PMCID: PMC2668941  PMID: 19174371
CADASIL; GOM; skin biopsy; NOTCH3; genetic testing

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