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PubMed2001

Correlations between clinical findings and magnetization transfer imaging metrics of tissue damage in individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND AND PURPOSE: We obtained magnetization transfer imaging (MTI) scans from individuals with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (1) to investigate the presence, extent, and nature of pathology in white and gray matter outside proton density (PD)-visible lesions; (2) to quantify the degree of tissue damage occurring in lesions seen on PD-weighted scans; and (3) to correlate MTI-derived measures of disease burden with age, physical disability, and cognitive performance. METHODS: Dual-echo, T1-weighted, and MTI scans of the brain were obtained from 33 individuals with CADASIL and 12 control subjects. Magnetization transfer ratio (MTR) values from PD-visible lesions, normal-appearing white matter (NAWM), and normal-appearing gray matter (NAGM) were measured. Histograms of MTR from the whole brain and normal-appearing brain tissue were also produced. RESULTS: All MTR values from NAWM and NAGM regions studied were significantly lower for individuals with CADASIL than for control subjects, with the exception of those obtained from the NAWM of the infratentorial structures and the NAGM of the occipital cortex. The average MTR from PD lesions in individuals with CADASIL was significantly lower than that from all the NAWM regions. Average MTR and peak location from whole-brain and normal-appearing brain tissue histograms were significantly lower for individuals with CADASIL than for control subjects. MTR values from NAWM were strongly correlated with the extent of macroscopic lesions and their average MTR. Apart from NAGM, average MTR from all other tissues studied significantly decreased with increasing age, physical disability, and cognitive impairment. CONCLUSIONS: PD lesions of individuals with CADASIL have variable degrees of tissue damage. Brain tissue outside PD abnormalities is also damaged. This study suggests that the extent and the severity of the brain tissue damage are critical factors in determining clinical status in CADASIL.

Age Factors↗
PubMed1994

[Familial hemiplegic migraine. Localization of a responsible gene on chromosome 19].

Familial hemiplegic migraine is an autosomal dominant disorder of unknown pathogenesis in which the migrainous attacks are marked by the occurrence of a transient hemiplegia during the aura. The aim of our study was the identification of the affected gene. The first step was the chromosomal mapping of the affected gene, for which we used a "candidate gene" strategy. The first candidate gene was the gene responsible for CADASIL. While investigating CADASIL, mapped previously to chromosome 19, we observed that some patients had recurrent attacks of migraine with aura. Although the clinical and neuroimaging features of familial hemiplegic migraine differ markedly from CADASIL, we hypothesized that the same gene could be involved in the pathogenesis of both conditions. We chose two large pedigrees for linkage analysis of familial hemiplegic migraine. A maximum lodsore > 8 was found with two markers that are strongly linked to CADASIL. Multilocus linkage analysis located the affected gene within an interval of about 30 cM on chromosome 19, containing the gene responsible for CADASIL. At this step it's not possible to conclude that CADASIL and familial hemiplegic migraine are due to the same mutated gene. It will be necessary to analyse other familial hemiplegic migraine and CADASIL families in order to reduce the size of their respective interval and ultimately identify the mutated gene(s).

Chromosomes, Human, Pair 19↗
PubMed2006

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: two novel mutations in the NOTCH3 gene in Chinese.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disorder caused by NOTCH3 mutations, usually localized to exons 3 and 4, and characterized by recurrent subcortical infarctions, dementia and leukoencephalopathy. So far, there has been only limited information about CADASIL in Chinese population. OBJECTIVES: To analyze the NOTCH3 mutations in ethnic Chinese in Taiwan with clinically suspected CADASIL and to characterize their clinical and molecular features. METHODS: Mutation analysis of NOTCH3 by direct nucleotide sequencing was performed in eight unrelated Chinese patients with clinically suspected CADASIL. Skin biopsy with ultrastructural studies by electronic microscopy was performed in four patients. RESULTS: Five NOTCH3 mutations, S118C, R141C, R332C, R544C and C977S, respectively, were identified from five patients, of which S118C and C977S are novel. None of these nucleotide sequence variations could be found among 50 healthy controls. Among the five mutations, two were in exon 4, and the other three were in exons 6, 11 and 18, respectively. Skin biopsy showed the presence of characteristic granular osmiophilic material only in the patient with the NOTCH3 mutation of R332C. CONCLUSION: Our study demonstrated the clinical and molecular features of CADASIL in Chinese patients and broadened the spectrum of NOTCH3 mutations. Lack of evidence of a strong clustering of mutations in a particular exon tentatively suggests that a comprehensive screening of NOTCH3 mutation is still necessary for molecular diagnosis of CADASIL in Chinese population.

Adult↗
PubMed2006

Electrocardiogram in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients without any clinical evidence of coronary artery disease: a case-control study.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited systemic arteriopathy caused by highly stereotyped mutations in NOTCH3. The clinical expression of CADASIL is confined to the central nervous system with characteristic recurrent subcortical infarcts and vascular dementia. However, cases have been reported with associated circulatory small vessel abnormalities in the retina or the myocardium and with myocardial infarction. Classical cardiovascular risk factors may influence such circulatory abnormalities. Thus, we conducted a case control study to determine the frequency of electrical abnormalities on a 12-lead resting ECG in CADASIL patients without classical atherosclerotic risk factors. METHODS: Twenty-three CADASIL patients (mean age+/-SD; 55.1+/-11 years) free of any classical cardiovascular risk factors except for hypercholesterolemia were recruited from 1 neurology department and compared with 23 sex- and age-matched healthy controls (mean age+/-SD; 54.7+/-9.5 years). A resting supine 12-lead ECG was recorded at inclusion and analyzed later by 2 reviewers. Signs of myocardial infarction or ischemia, conduction, and rhythm disturbances were looked for. RESULTS: We found no ECG sign evoking myocardial infarction or myocardial ischemia. CADASIL patients had, compared with healthy controls, a significantly higher heart rate and a significantly lower Sokolow index, but these values remained in the normal ranges. CONCLUSIONS: In this case-control study, we found no ECG evidence for myocardial infarction or ischemia, conduction disturbances, or arrhythmias in CADASIL patients compared with healthy controls.

Adult↗
PubMed2002

Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

PURPOSE: To assess the prevalence and distribution of subcortical lacunar lesions (SLLs) in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), to determine whether SLLs are an abnormal finding by studying their prevalence in healthy subjects, and to assess whether SLLs occur in other conditions associated with small vessel disease and white matter areas of high signal intensity (WMH). MATERIALS AND METHODS: The presence of SLLs, their location, and their relation to other abnormalities were assessed on magnetic resonance (MR) images (T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery) obtained in 34 CADASIL patients and 20 healthy family members. Three additional control groups of healthy volunteers, elderly patients with vascular risk factors, and patients with another hereditary small vessel disease were also screened for the presence and location of SLLs. Sensitivity and specificity of the presence of SLLs for the diagnosis of CADASIL were assessed. RESULTS: SLLs were found in 20 (59%) of CADASIL patients. Incidence of SLLs increased with age (20%, <30 years; 50%, 30-50 years; 80%, >50 years). SLLs invariably occurred in the anterior temporal lobes and in areas where diffuse WMH expanded into arcuate fibers. From the anterior temporal lobe, the lesions could extend dorsally into the temporal lobes and rostrally into the frontal lobes. Lesions were not found in the parietal and occipital lobes. None of the control subjects had SLLs. Specificity and sensitivity of SLLs for CADASIL were 100% and 59%, respectively. CONCLUSION: SLLs are an abnormal finding at MR imaging that frequently occur in CADASIL patients.

Adult↗
PubMed2004

Arg332Cys mutation of NOTCH3 gene in the first known Taiwanese family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

The phenotype and genotype of cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL) in Caucasians have been well characterized, but CADASIL is less recognized in Asian populations. Here we investigated the first known Taiwanese family affected by CADASIL and identified an uncommon NOTCH3 mutation. The family had clinical manifestations in affected members including recurrent strokes, early dementia, and depression, but not migraine. A skin biopsy in the proband patient showed characteristic pathological findings of CADASIL on electron microscopy. Afterward, genetic analysis found an Arg332Cys mutation at exon 6 of NOTCH3. Neuropsychological evaluation showed vascular dementia in two of four affected people. Head MRI showed multiple infarcts in bilateral basal ganglia, thalami, periventricular white matter, external capsules, and brainstem, but involvement of the anterior temporal pole was found only in two people with milder symptoms. To our knowledge, the Arg332Cys NOTCH3 mutation at exon 6, which was identified in the studied family, has not been reported in Asian populations. Our findings emphasize the importance of genetic analysis of NOTCH3 for Asians with a phenotype typical of CADASIL.

Amino Acid Substitution↗
PubMed2005

Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease causing stroke and dementia. The disease is caused by highly stereotyped mutations in NOTCH3, which is restrictively expressed in vascular smooth muscle cells (VSMCs). The mechanisms of compromised cerebral hemodynamics in CADASIL remain to be elucidated. We tested the hypothesis that mutant NOTCH3 impairs the vasomotor function of cerebral vessels. METHODS: Vasomotor function was examined in vivo in transgenic mice expressing a mutant NOTCH3 in VSMCs (TgNotch3R90C). Mice develop an age-dependent arteriopathy similar to that seen in CADASIL, without brain parenchyma lesions. Using laser-Doppler flowmetry, we assessed in awake TgNotch3R90C mice and wild-type littermates the cerebrovascular reactivity to 2 potent vasodilator stimuli (acetazolamide and hypercapnia) and cerebral blood flow (CBF) autoregulation during stepwise blood pressure elevations and reductions. Mice were studied at 18 months of age, when the CADASIL features are apparent, and at 10 months of age, before their appearance. RESULTS: Eighteen-month-old TgNotch3R90C mice showed reduced responses to hypercapnia and acetazolamide, higher cerebrovascular resistance during hypertension, and their lower limit of CBF autoregulation was shifted to higher blood pressures. Cerebrovascular responses were similarly impaired in 10-month-old TgNotch3R90C mice. CONCLUSIONS: Cerebrovascular reactivity is compromised early in TgNotch3R90C mice. The data show an impaired autoregulation and are suggestive of a decreased relaxation or increased resistance of cerebral vessels. Our findings indicate that vascular dysfunction is an early pathogenic event that may promote the subsequent development of brain ischemia in CADASIL.

Acetazolamide↗
PubMed2001

A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: genetic and magnetic resonance spectroscopic findings.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary syndrome caused by mutations of the Notch3 gene, usually localized to exons 3 and 4. OBJECTIVES: To report a novel pathogenetic mutation occurring in exon 6 of the Notch3 gene, a location not previously recognized in patients with CADASIL, and to report the results of magnetic resonance spectroscopy in CADASIL. METHODS: Mutation analysis of the Notch3 gene was performed in 2 patients belonging to a large kindred manifesting CADASIL, as well as in 7 clinically unaffected members of the family and 200 control chromosomes. Proton magnetic resonance spectroscopy was used to estimate metabolite resonance intensities in the 2 affected subjects. RESULTS: Sequence analysis of the Notch3 gene showed a new missense mutation CGC-->TGC in codon 332 of exon 6, resulting in the replacement of an arginine residue with a cysteine. This mutation was never observed in the 7 unaffected members of the family and the 200 control chromosomes examined. Proton magnetic resonance spectroscopy showed a diffuse decrease in cerebral N-acetylaspartate, indicating the presence of widespread axonal damage. CONCLUSIONS: Our findings emphasize the role of direct DNA sequence analysis for the diagnosis of CADASIL. Moreover, the results of proton magnetic resonance spectroscopy suggest that widespread axonal damage may be an early finding of the disease.

Adult↗
PubMed2004

Hemodynamic evaluation of the optic nerve head in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND: Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is considered a cerebrovascular disorder with almost exclusively neurological symptoms, arteriopathy is generalized and also involves the choroid and retina. OBJECTIVE: To study optic nerve head microvascular function in CADASIL by assessing blood flow, volume, and velocity with a retina flowmeter. PATIENTS AND METHODS: Scanning laser Doppler flowmetry permits the noninvasive assessment of relative blood velocity, volume, and flow in a sample volume of either retina or anterior optic nerve head. Measurements were performed in a first group of 9 eyes of 5 patients with CADASIL and a second group of 8 eyes of 4 healthy subjects. Hemodynamic parameters were computed in 4 quadrants of the optic disc (superior nasal, superior temporal, inferior nasal, and inferior temporal). The Wilcoxon rank sum test was used to assess differences in relative flow, volume, and velocity in each quadrant and between the 2 groups and differences in overall optic nerve head blood flow, volume, and velocity. RESULTS: Patients with CADASIL had a significant decrease in overall blood flow and volume compared with healthy subjects (P<.05). The reduction in blood flow and volume was particularly significant in the superior and inferior temporal quadrants. No significant differences were found nasally between the patients and the control groups. CONCLUSION: Our results suggest that hemodynamic parameters are abnormal in the superficial nerve fiber layer of the optic nerve head of patients with CADASIL, especially in the temporal quadrants of the neuroretinal rim.

Adult↗
PubMed1995

Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by a cerebral non-atherosclerotic, nonamyloid angiopathy mainly affecting the small arteries penetrating the white matter. In the brain vessels of two patients with CADASIL, abnormal patches of granular osmiophilic material have recently been described. Here we report the observation of similar granular osmiophilic material within the vessel walls of muscle and skin biopsies from a 54-year-old woman belonging to a CADASIL family, who suffered from subcortical dementia with leukoencephalopathy demonstrated on neuroimaging. Postmortem examination disclosed changes of the vessel walls in all the organs chiefly leading to cerebral lesions. Ultrastructural study showed destruction of the vascular smooth muscle cells (VSMC) and the granular osmiophilic material already found in muscle and skin biopsies in this patient. Both changes were found all along the arterial tree. The findings of this study indicate that CADASIL is a systemic vascular disease involving arterial VSMC and that the lesions are different in each organ and vessel wall, depending on their fine structure. Moreover, it emphasizes that skin and muscle biopsies might be useful for diagnosis of and research into CADASIL.

Brain↗
PubMed2003

Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized adult-onset autosomal dominant vascular dementia, caused by highly stereotyped mutations in the Notch3 receptor. CADASIL is a widespread angiopathy characterized by a degeneration of vascular smooth muscle cells (VSMCs) and the abnormal accumulation of electron-dense granular material called GOM and Notch3 protein, because of an impaired clearance. Evidence that VSMCs are the primary target of the pathogenic process is supported by the restricted expression of Notch3 in these cells but mechanisms of their degeneration remain essentially unknown. We generated transgenic mice in which the SM22alpha promoter drove, in VSMCs, the expression of a full-length human Notch3 carrying the Arg90Cys mutation, a CADASIL archetypal mutation. Transgenic mice showed no evidence of prominent brain parenchyma damage but demonstrated the two hallmarks of the CADASIL angiopathy, GOM deposits and Notch3 accumulation, within both the cerebral and peripheral arteries. Of interest, arteries of the tail were more severely affected with prominent signs of VSMC degeneration. Time-course analysis of vessel changes revealed that disruption of normal VSMC anchorage to adjacent extracellular matrix and cells, VSMC cytoskeleton changes as well as starting signs of VSMC degeneration, which were detected around 10 months of age, preceded Notch3 and GOM accumulation appearance, which were observed only by 14 to 16 months of age. In conclusion, we have generated transgenic mice that recapitulate the characteristic vascular lesions observed in CADASIL. Our results indicate that Notch3 or GOM accumulation are unlikely to be the prerequisites for the induction of VSMC degeneration and suggest that degeneration of VSMCs may rather be triggered by the disruption of their normal anchorage, based on the important role of adhesion for cell survival.

Age Factors↗
PubMed1999

[Young-adult-onset hereditary subcortical vascular dementia: cerebral autosomal recessive arteriosclerosis with subcortical infarcts and leukoencephalopathy (CARASIL)].

The clinical features of a probably autosomal recessive syndrome ("CARASIL"), yet to be confined in Japan and characterized by prematurity of vascular dementia, alopecia and spondylosis deformans are reviewed through comparison with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which has been reported in Europe and North America, and recently in Japan. These two syndromes have many common features, such as familiality, encephalopathy of Binswanger type, and absence of vascular risk factors. There exists, however, a number of differences as follows: (1) Onset of encephalopathy is 32 years of age in "CARASIL" vs. 45 in CADASIL. (2) Male to female ratio is 3.2: 1 vs. 2:1.(3) Two thirds of "CARASIL" patients show stroke and/or stepwise deterioration, while almost all CADASIL patients have stroke. (4) Associated psychiatric features are euphoria, emotional lability and loss of spontaneity vs. severe mood disorders. (5) Migraine is a cardinal feature of CADASIL and vasospasm may occur during cerebral angiography. (6) White matter lesions on MRI are diffuse and homogeneous vs. punctuated and nodular. The latter four differences may mirror the difference in the pathology of arteriopathies. "CARASIL" is clearly different from CADASIL and reflect a second genetic condition with a seemingly direct effect upon the cerebral vasculature.

Age of Onset↗
PubMed2003

Frequency of subclinical lacunar infarcts in ischemic leukoaraiosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND AND PURPOSE: Small vessel cerebrovascular disease is an important cause of vascular cognitive impairment. It is usually sporadic but also occurs secondary to the genetic disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Recurrent lacunar stroke is a characteristic feature, although symptomatic events are relatively rare, making large numbers necessary for evaluation of potential therapies. Diffusion-weighted imaging is sensitive to acute ischemic lesions and differentiates them from chronic infarcts. Detection of asymptomatic lacunar infarcts with diffusion-weighted imaging is a potential surrogate marker for treatment trials. In this study, the frequency of asymptomatic new lesions in ischemic leukoaraiosis and CADASIL was determined as a step toward assessing the potential of this technique as a surrogate marker of disease activity. METHODS: Fifty patients with sporadic small vessel disease and 19 patients with CADASIL underwent diffusion-weighted imaging. All had been asymptomatic for 3 months before imaging. Diffusion-weighted images were screened by two raters for new lesions; lesions were confirmed as recent by a visible reduction of diffusivity on the corresponding apparent diffusion coefficient maps. RESULTS: Recent ischemic lesions were identified in four patients with sporadic small vessel disease (8.0%) and two patients with CADASIL (10.5%). CONCLUSION: Asymptomatic new lesions are found in cases of sporadic small vessel disease and CADASIL. The frequency of new lesions suggests that this approach has a potential role as a surrogate marker in therapeutic trials that warrants further investigation.

Adult↗
PubMed2006

Ophthalmologic findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a cross-sectional study.

OBJECTIVE: To determine the ophthalmologic findings, especially the nature of retinal vascular changes, and their clinical significance in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a disease that causes migraine, recurrent strokes, and finally subcortical vascular dementia. DESIGN: Cross-sectional study. PARTICIPANTS: Thirty-eight CADASIL patients (19 to 61 years old; 20 in a prestroke group, 15 in a stroke group, and 3 in a dementia group), all with the R133C NOTCH3 mutation and including one homozygous patient, underwent a detailed ophthalmologic examination. METHODS: Common cardiovascular risk factors were evaluated. Ophthalmologic examination included best-corrected visual acuity, anterior- and posterior-segment biomicroscopy, and measurement of intraocular pressure. In 33 patients and 16 healthy controls (20-64 years old), retinal fundus photographs were taken. Diameters of all arterioles and venules located in the area from 0.5 to 1.0 disc diameters from the optic disc margin were measured with a computer-based program and arteriole-to-venule (A/V) ratios were calculated from digitized photographs. RESULTS: General arterial narrowing and arteriovenous nickings were common. Straightening of the retinal arterioles and a marked wall reflex (n = 6) occurred. The A/V ratio of CADASIL patients was significantly (P< 0.001) lower than that of controls. One patient had one retinal microinfarct and hemorrhages. The homozygous patient had a chorioretinal scar as a sign of circulatory deficiency. Anterior-segment changes included mild iris atrophy (n = 5) and various degrees of lens opacities. Visual acuity was normal in all but 2 patients, who had cataract and amblyopia. CONCLUSIONS: The generalized arteriopathy of CADASIL causes a wide variety of changes in retinal arterioles but only minimal functional disturbances. These findings are consistent with alterations in arterioles in the cerebral cortex with which the retina and its arterioles are analogous, but contrast with the severe damage of cerebral white matter arterioles.

Adult↗
PubMedDate not supplied

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited autosomal dominant condition characterized by migrane, recurrent stroke, subcortical dementia, and pseudobulbar palsy. It begins with migraine with aura in -33% of patients. CADASIL is commonly overlooked or misdiagnosed owing to its recent identification. The pathological hallmark of angiopathy is the presence of multiple, small, deep cerebral infarcts, leucoencephalopathy, and nonatherorosclerotic, nonamyloid angiopathy involving mainly small, deep perforating cerebral arteries. Changes also are present in vascular smooth muscle cells and consist in the presence of granular osmiophilic material (GOM). The defective gene in CADASIL is Notch 3, which encodes a large transmembrane receptor. Magnetic resonance imaging shows high intensity signal lesions, often confluent, and areas of cystic degeneration of subcortical white matter and basal ganglia. Diagnostic strategies in CADASIL are matter of discussions because the electron microscopic demonstration of GOM was reported in 100% of symptomatic patients of French authors, but only in 45% of a British study. GOMs are not present in presymptomatic patients.

CADASIL↗
PubMedDate not supplied

The spatial distribution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition causing recurrent subcortical strokes. MR imaging, which shows focal lacunar infarcts and leukoaraiosis, plays a central role in the diagnosis and evaluation. We studied MR imaging abnormalities in a large prospectively recruited cohort of CADASIL patients to describe the spatial distribution of abnormalities, determine how this distribution alters with age, and identify any correlations with the clinical features of the disease. METHODS: In this study, 112 CADASIL subjects from 64 families were prospectively recruited. MR imaging scans were graded by a single neuroradiologist, by using the modified Scheltens scale, to quantify the severity of high-signal-intensity changes in different brain regions. RESULTS: Lesion load increased progressively with age. Scores were maximal in the frontal, parietal, and anterior temporal cortex, and the external capsule; intermediate in the pons; and relatively low in the corpus callosum, caudate, globus pallidus, cerebellum, midbrain, and medulla. Anterior temporal pole involvement was common at all ages and, when present, usually confluent, but this was absent in 33% of patients 20-29 years of age. A history of stroke correlated with total Scheltens score and internal capsule and pontine scores. Dementia correlated with total Scheltens score and subcortical white matter score, whereas depression correlated with subcortical white matter score but not total Scheltens score. CONCLUSIONS: There is a characteristic pattern of MR imaging abnormalities in CADASIL that aids in differential diagnosis; however, some characteristic features, such as anterior temporal pole involvement, can be absent. MR imaging lesion load correlated with some clinical features including stroke and dementia, whereas depression is more common in individuals with deep white matter changes.

Adult↗
PubMed2006

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: structural MR imaging changes and apolipoprotein E genotype.

BACKGROUND AND PURPOSE: Apolipoprotein E (apoE) genotype plays an important role in the development, maintenance, and response to injury of the central nervous system. It has been suggested that apoE epsilon4 genotype is a risk factor for several neurologic disorders. We investigated the correlation between the apoE genotype and radiologic data in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: T1-weighted, dual fast spin-echo, T2*-weighted gradient echo, and fluid-attenuated inversion recovery MR imaging scans were obtained from 36 CADASIL patients (21-59 years of age). The number of lacunar infarcts and microbleeds and the presence of subcortical lacunar lesions were determined. The amount of white matter hyperintensities was assessed by using semiautomated segmentation software. The relation between the radiologic endophenotype of CADASIL and the apoE genotype was assessed by using a Student t test for unpaired data and Fisher exact test. RESULTS: White matter hyperintensities, lacunar infarcts, microbleeds, and subcortical lacunar lesions were not found to be associated with the presence of an epsilon4 allele. CONCLUSION: The variability of structural MR imaging lesions in CADASIL is independent of apoE genotype and other processes must underlie the variable natural history of the disease.

Adult↗