Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts And Leukoencephalopathy Research Articles

Changes in the Morphology, Number, and Protein Levels of Plasma Exosomes in CADASIL Patients.

Exosomes are nano-sized extracellular vesicles which are secreted by cells and usually found in body fluids. Previous research has shown that exosomal secretion and autophagy-lysosomal pathway synergistically participates in intracellular abnormal protein elimination. The main pathological manifestations of Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is abnormal accumulation of mutant NOTCH3, and CADASIL vascular smooth muscle cells have been found with autophagy-lysosomal dysfunction. However, whether plasma exosomes change in CADASIL patients is still unclear. We are aimed to investigate the differences of plasma exosomes between CADASIL patients and healthy controls. The subjects included 30 CADASIL patients and 30 healthy controls without NOTCH3 mutation. The severity of white matter lesions (WMLs) of CADASIL patients was quantified by Fazekas score. Transmission electron microscopy and nanoparticle tracking analysis were performed to characterize plasma exosomes. In addition, NOTCH3, Neurofilament light and Aβ42 levels in plasma exosomes were quantified by enzyme-linked immunosorbent assays. We found that exosomes from CADASIL patients were lower in quantity. In addition, CADASIL plasma exosomes had significantly lower levels of NOTCH3 and significantly increased levels of NFL than those of matched healthy subjects. Interestingly, plasma exosome NOTCH3 levels of CADASIL patients significantly correlated with severity of WMLs. The exosome NOTCH3 may be related to the pathological changes of CADASIL, which provides a basis for the pathogenesis research of CADASIL. In addition, plasma exosome NOTCH3 and NFL levels may act as biomarkers to monitor and predict disease progression and measure therapeutic effectiveness in the future clinical trials.

NOTCH3 variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants

BackgroundCysteine-altering NOTCH3 variants identical to those causing the rare monogenic form of stroke, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), have been reported more common than expected...

Skin biopsy as an aid to diagnosis of disorders of the nervous system without cutaneous manifestations.

There are several neurological diseases wherein skin biopsy is useful for diagnosis, even in the absence of skin involvement. Skin biopsy is especially relevant in diseases in which the metabolic error is unknown or has no available diagnostic biochemical test. Skin biopsy, being relatively noninvasive, obviates the need for an invasive procedure such as a brain biopsy. These disorders wherein skin biopsies are particularly useful include the progressive myoclonic epilepsies, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), neuroaxonal dystrophy, and small fiber neuropathies (SFN). We review the role of skin biopsy in such conditions with notes on preferred sites and techniques.

Diffuse Tract Damage Correlates With Global Cognitive Impairment in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: A Tract-Based Spatial Statistics Study.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial arteriopathy characterized by recurrent lacunar stroke, migraine, and depression. The mechanism of cognitive dysfunction in CADASIL is still uncertain. The aim of this study was to use tract-based spatial statistics (TBSS) to map voxelwise the spatial distribution of brain microstructural change revealed by DTI-derived indices in patients with CADASIL to further study the underlying neuropsychopathological mechanism of CADASIL. Twelve patients with CADASIL and 11 age-, sex-matched healthy controls underwent magnetic resonance imaging at 3 T. Then we evaluated DTI-derived indices (fractional anisotropy [FA], mode of anisotropy [MO], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]) of brain white matter (WM) between CADASIL patients and healthy subjects through TBSS. Compared with healthy controls, patients with CADASIL showed extensive decreased FA, MO and increased RD, AD, and MD throughout the entire brain (mainly the WM of the temporal poles, inferior and superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corpus callosum, uncinate fasciculus, internal capsule, external capsule, corona radiata, thalamic radiation, and cingulum). Furthermore, these WM microstructural alterations were significantly correlated with cognitive scores and Scheltens scores. Decreased FA values and MO values were positively correlated with Montreal Cognitive Assessment scores in CADASIL patients. Increased AD, RD, and MD values were significantly negatively correlated with Montreal Cognitive Assessment scores. Widespread WM abnormalities were clearly shown in CADASIL by using TBSS. Severity of microstructural changes correlates significantly with extension of T2 hyperintensity. Moreover, WM microstructural damage and cognitive impairment were significantly correlated. This study indicated that WM tract damage plays an important role in cognitive impairment in CADASIL.

Abstract P332: Cerebral Small Vessel Disease Score in CADASIL: Relationships to Cognitive Dysfunctions

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease (cSVD) linked to NOTCH3 mutations and leading to the early onset of stroke and vascular cognitive impairment. Neuroimaging features of CADASIL include extensive white matter hyperintensity, lacunes, cerebral microbleeds and enlarged perivascular spaces. Researchers from the Rotterdam study recently proposed a MRI-based cSVD Score reflecting the overall burden of cerebrovascular injury (Yilmaz et al., 2018). Here, we explored the relevance of this cSVD Score in distinguishing CADASIL subjects from non-carriers and its relationships to cognition. We evaluated 26 NOTCH3 mutation carriers and 25 non-carriers from large Colombian families. Of the CADASIL subjects, 4 had previous strokes (symptomatic) and 22 had no history of strokes (asymptomatic). All subjects underwent a 3T MRI and a neuropsychological evaluation. Structural MRI markers of cSVD, as well as the cSVD Score, were quantified in each subject following established protocols. Demographic, cognitive and neuroimaging features across groups are presented in Table 1. The cSVD Score significantly differed between groups, after adjusting for age (Figure 1-A). In CADASIL subjects, the cSVD Score was negatively related to performance in Memory, Processing Speed, Executive Function, after accounting for age and education (Figure 1-B). These results suggest that the cSVD Score could be a useful marker of disease severity in CADASIL. Longitudinal studies are now needed to determine if this score allows predicting clinical outcomes in CADASIL, such as stroke or dementia.

Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis.

Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis.

Intracerebral Hemorrhage in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Prevalence, Clinical and Neuroimaging Features and Risk Factors.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic cerebral small vessel disease. The role of intracerebral hemorrhage (ICH) in CADASIL remains elusive. The present study aims to investigate the prevalence, characteristics, and risk factors for ICH in CADASIL. This retrospective cross-sectional study investigated ICH and cerebral microbleeds (CMBs) in brain susceptibility-weighted imaging or T2*-weighted gradient-recalled echo images of 127 Taiwanese patients with genetically confirmed CADASIL. We analyzed CMBs, lacunes, white matter hyperintensity, and perivascular space. The total small vessel disease score (range, 0-4) was calculated to estimate the overall magnetic resonance imaging burden of small vessel disease. Multivariate regression analysis was performed to identify factors related to ICH lesions in CADASIL. Thirty-seven ICH lesions, including 15 symptomatic and 22 asymptomatic lesions, were found in 27 (21.3% [95% CI, 14.0%-30.9%]) of the 127 patients with CADASIL. The thalamus and lobar regions were the most common ICH locations, and 72.7% of the lobar hemorrhages occurred silently. Patients with CADASIL with ICH lesions more often had hypertension and a higher total small vessel disease score than those without ICH (odds ratio [95% CI]: 3.22 [1.25-8.30] and 3.79 [1.51-9.51]). The presence of CMBs in the brain stem and a total CMB count >10 were independently associated with ICH lesions in patients with CADASIL, with odds ratio (95% CI) of 5.82 (1.80-18.80) and 3.83 (1.08-13.67), respectively. ICH is an underestimated but important manifestation of CADASIL. The location and number of CMBs are associated with the presence of ICH lesions in patients with CADASIL.

Intracerebral hemorrhage in CADASIL.

Intracerebral hemorrhage (ICH) has been reported in few cases of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), mostly in hypertensive patients. We aimed to assess the clinical and radiological characteristics of patients with CADASIL who presented with ICH. A retrospective analysis of all neuroimaging exams of CADASIL patients hospitalized in our academic neurology department for acute cerebrovascular events was performed to find ICH. A systematic review of the literature was performed on this topic. Including our five patients, a total number of 52 subjects with CADASIL and ICH (mean age: 56 years, SD 11, 36-69%- male) were reported. Intracerebral hemorrhages were mainly deep (34 subjects), followed by lobar (8 subjects), infratentorial (6 subjects) and mixed locations (4 subjects). Three ICHs were asymptomatic. Fourteen patients were taking antithrombotic medication, 18 had no regular antiplatelet or anticoagulant treatment while in 20 patients medical treatment was not detailed. Arterial hypertension was present in 37 out of 51 patients with available information. Neuroimaging showed extensive FLAIR hyperintensities in all CADASIL subjects with ICH, cerebral microbleeds in all but three patients, and lacunar infarction in 19 out of 25 subjects with available information. Intracerebral hemorrhage represents a possible yet uncommon manifestation of CADASIL and should be considered as a possibility in patients with ICH associated with leukoencephalopathy and microbleeds, even in the absence of other clinical symptoms.

Stem Cell Factor in Combination With Granulocyte Colony-Stimulating Factor Protects the Brain From Capillary Thrombosis-Induced Ischemic Neuron Loss in a Mouse Model of CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is a Notch3 mutation-induced cerebral small vessel disease, leading to recurrent ischemic stroke and vascular dementia. There is currently no treatment that can stop or delay CADASIL progression. We have demonstrated the efficacy of treatment with combined stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in reducing cerebral small vessel thrombosis in a TgNotch3R90C mouse model of CADASIL. However, it remains unknown whether SCF+G-CSF treatment protects neurons from microvascular thrombosis-induced ischemic damage. Using bone marrow transplantation to track thrombosis, we observed that capillary thrombosis was widely distributed in the cortex, striatum and hippocampus of 22-month-old TgNotch3R90C mice. However, the capillary thrombosis mainly occurred in the cortex. Neuron loss was seen in the area next to the thrombotic capillaries, and severe neuron loss was found in the areas adjacent to the thrombotic capillaries with bifurcations. SCF+G-CSF repeated treatment significantly attenuated neuron loss in the areas next to the thrombotic capillaries in the cortex of the 22-month-old TgNotch3R90C mice. Neuron loss caused by capillary thrombosis in the cerebral cortex may play a crucial role in the pathogenesis of CADASIL. SCF+G-CSF treatment ameliorates the capillary thrombosis-induced ischemic neuron loss in TgNotch3R90C mice. This study provides new insight into the understanding of CADASIL progression and therapeutic potential of SCF+G-CSF in neuroprotection under microvascular ischemia in CADASIL.

Coronavirus disease 2019 in a patient with CADASIL syndrome: a case report

We present a case report of a patient with a previously identified cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), who was admitted due to coronavirus disease 2019 (COVID-19), confirmed by polymerase chain reaction and computed tomography. Examination and treatment of these patients presents certain difficulties due to the large number of thromboembolic complications caused by a combination of congenital and infectious angiopathies. CADASIL syndrome and COVID-19 were manifested by the progression of neurological symptoms and increasing cognitive impairment. During therapy, there was a positive change with a gradual regression of these disorders.

Ex Vivo Models to Decipher the Molecular Mechanisms of Genetic Notch Cardiovascular Disorders.

Notch is an evolutionary, conserved, cell–cell signaling pathway that is central to several biological processes, from tissue morphogenesis to homeostasis. It is therefore not surprising that several genetic mutations of Notch components cause inherited human diseases, especially cardiovascular disorders. Despite numerous efforts, current in vivo models are still insufficient to unravel the underlying mechanisms of these pathologies, hindering the development of utmost needed medical therapies. In this perspective review, we discuss the limitations of current murine models and outline how the combination of microphysiological systems (MPSs) and targeted computational models can lead to breakthroughs in this field. In particular, while MPSs enable the experimentation on human cells in controlled and physiological environments, in silico models can provide a versatile tool to translate the in vitro findings to the more complex in vivo setting. As a showcase example, we focus on Notch-related cardiovascular diseases, such as Alagille syndrome, Adams–Oliver syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).Impact statementIn this review, a comprehensive overview of the limitations of current in vivo models of genetic Notch cardiovascular diseases is provided, followed by a discussion over the potential of microphysiological systems and computational models in overcoming these limitations and in potentiating drug testing and modeling of these pathologies.

Fibrinogen is an Independent Risk Factor for White Matter Hyperintensities in CADASIL but not in Sporadic Cerebral Small Vessel Disease Patients.

The relationship between fibrinogen and white matter hyperintensities (WMHs) are inconsistent. Whether there are different relationships between WMHs and fibrinogen in disparate subtypes of cerebral small vessel disease (CSVD) remains unknown. Here, we investigated the roles of plasma fibrinogen in sporadic CSVD (sCSVD) and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients. We performed a cross-sectional study that included 74 CSVD patients (19 CADASIL and 55 sporadic) and 74 age- and gender-matched healthy controls (HCs). Plasma fibrinogen was determined, and the severity of WMHs in CSVD patients was rated according to Fazekas scales. Univariate analysis and ordinal logistic regression were performed to evaluate the relationship between fibrinogen and the severity of WMHs in CSVD. Both CADASIL and sCSVD patients showed significantly higher plasma fibrinogen levels than HCs. No significant difference in the plasma fibrinogen level was observed between CADASIL and sCSVD. Univariate analysis and ordinal logistic regression indicated that fibrinogen is an independent risk factor for the severity of WMHs in CADASIL patients (odds ratio [OR] =1.064; 95% Confidence interval (CI, 1.004-1.127); p =0.037). However, age (odds ratio [OR] =1.093; 95% CI (1.033-1.156); P = 0.002), but not fibrinogen (odds ratio [OR] =1.004; 95% CI (0.997-1.011); P=0.262), is an independent risk factor for the severity of WMHs in sCSVD patients. Our results suggest that high levels of plasma fibrinogen are associated with the severity of WMHs in CADASIL but not in sCSVD patients, indicating that the role of fibrinogen may be different in disparate subtypes of CSVD. A better understanding of fibrinogen may yield insights into the pathogenesis of CSVD.

Imaging neurovascular, endothelial and structural integrity in preparation to treat small vessel diseases. The INVESTIGATE-SVDs study protocol. Part of the SVDs@Target project.

Sporadic cerebral small vessel disease (SVD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) share clinical and neuroimaging features and possibly vascular dysfunction(s). However few studies have included both conditions, assessed more than one vascular dysfunction simultaneously, or included more than one centre. The INVESTIGATE-SVDs study will assess several cerebrovascular dysfunctions with MRI in participants with sporadic SVD or CADASIL at three European centres. We will recruit participants with sporadic SVDs (ischaemic stroke or vascular cognitive impairment) and CADASIL in Edinburgh, Maastricht and Munich. We will perform detailed clinical and neuropsychological phenotyping of the participants, and neuroimaging including structural MRI, cerebrovascular reactivity MRI (CVR: using carbon dioxide challenge), phase contrast MRI (arterial, venous and CSF flow and pulsatility), dynamic contrast-enhanced MRI (blood brain barrier (BBB) leakage) and multishell diffusion imaging. Participants will measure their blood pressure (BP) and its variability over seven days using a telemetric device. INVESTIGATE-SVDs will assess the relationships of BBB integrity, CVR, pulsatility and CSF flow in sporadic SVD and CADASIL using a multisite, multimodal MRI protocol. We aim to establish associations between these measures of vascular function, risk factors particularly BP and its variability, and brain parenchymal lesions in these two SVD phenotypes. Additionally we will test feasibility of complex multisite MRI, provide reliable intermediary outcome measures and sample size estimates for future trials.

The pericyte: A critical cell in the pathogenesis of CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease presenting with migraine, mood and cognitive disorders, focal neurological deficits, recurrent ischemic attacks, lacunar infarcts and brain white matter changes. As they age, CADASIL patients invariably develop cognitive impairment and subcortical dementia. CADASIL is caused by missense mutations in the NOTCH3 gene resulting in a profound cerebral vasculopathy affecting primarily arterial vascular smooth muscle cells, which target the microcirculation and perfusion. Based on a thorough review of morphological lesions in arteries, veins, and capillaries in CADASIL, we surmise that arteriolar and capillary pericyte damage or deficiency appears a key feature in the pathogenesis of the disease. This may affect critical pericyte-endothelial interactions causing stroke injury and vasomotor disturbances. Changes in microvascular permeability due to perhaps localized blood-brain barrier alterations and pericyte secretory dysfunction likely contribute to delayed neuronal as well as glial cell death. Moreover, pericyte-mediated cerebral venous insufficiency may explain white matter lesions and the dilatation of Virchow-Robin perivascular spaces typical of CADASIL. The postulated central role of the pericyte offers some novel approaches to the study and treatment of CADASIL and enable elucidation of other forms of cerebral small vessel diseases and subcortical vascular dementia.

The spectrum of microvascular ultrastructural changes in the subpopulation of patients with migraine and cerebral white matter hyperintensities on MRI.

Migraine is considered not only as aseparate clinical entity but also as asymptom of various brain disorders, including cerebral small vessel diseases. Since cerebral small vessel diseases are usually general angiopathies, evaluation of biopsy material other than brain tissue may help in their diagnosis in vivo. In patients with migraine, brain magnetic resonance imaging (MRI) often shows hyperintense changes in the cerebral white matter. Such changes may indicate the symptomatic nature of migraine and coexisting structural or biochemical vascular abnormalities. To verify the hypothesis of the symptomatic nature of migraine in patients with abnormal brain neuroimaging, we performed an ultrastructural examination of skin and skeletal muscle vessels in biopsy material from 40 patients with clinically diagnosed migraine and hyperintense white matter lesions on MRI. In 80% of the examined patients, ultrastructural examination showed various pathological changes in the microvessels including abnormalities characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and elastin disorders, as well as less specific changes such as thickening of the basal lamina, narrowing of the vessel lumen, degeneration of the vessel wall cells, endothelial activation, oncosis-like changes, and the presence of various types of deposits in the vessel wall. In 20% of the examined cases, ultrastructural examination of the vessels was normal. Patients with migraine and hyperintense cerebral white matter changes on MRI have an increased risk of concomitant microangiopathy. In this group of patients, skin-muscle biopsy allows the identification of cases with coexisting vessel abnormalities.

Coronary microvascular function is impaired in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited disease caused by NOTCH3 gene mutations. Although the main clinical features reflect brain injury, CADASIL is a systemic microangiopathy, and cardiac involvement has been observed but not systematically assessed. We aimed to study the prevalence and severity of coronary microvascular dysfunction (CMD) in CADASIL patients. Seventeen patients with genetically confirmed CADASIL, aged <60years (mean age 40±9years), with ≤1 cardiovascular risk factor underwent neurological and neuropsychological evaluation, 3T brain magnetic resonance imaging (MRI), 12-lead electrocardiography (ECG), standard echocardiography, and measurement of myocardial blood flow at rest (resting MBF) and of maximal myocardial blood flow following Regadenoson infusion (Reg-MBF) by 13 NH3 positron emission tomography (PET). Coronary flow reserve (CFR) was defined as Reg-MBF/resting MBF. PET results were compared to those of 15 healthy controls who were age and sex matched. Twelve patients (71%) presented migraine, none (53%) had psychiatric disturbances, and one (6%) had a previous stroke. None had cognitive impairment or ECG or echocardiography abnormalities. Both Reg-MBF and CFR were blunted in CADASIL patients compared with controls (Reg-MBF 2.46±0.54 vs. 3.09±0.44ml/g/min, respectively; p<0.01; CFR 2.74±0.36 vs. 3.28±0.66, respectively, p<0.01). No correlations were found between Reg-MBF values and neuropsychological performance or cerebral lesion burden on MRI. CADASIL patients exhibit blunted CFR due to CMD, which can be severe and is independent of the severity of brain lesion load and cognitive performances. CADASIL is a systemic microcirculation disease, and active surveillance of cardiac symptoms should be considered in these patients.

CADASIL in a patient with bilateral internal carotid artery agenesis

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a well-recognised cause of stroke in the young. Bilateral internal carotid artery (ICA) agenesis is a rare congenital malformation, with few previous reported cases in the literature. CADASIL is not reported to be associated with ICA agenesis. We report the case of a 41 year old man who presented with recurrent orthostatic symptoms associated with increasingly frequent falls. Initial investigation with CT angiography revealed absent bilateral ICAs with an ectatic vertebrobasilar arterial tree supplying the intracranial circulation. Skull base CT revealed simultaneous absence of ICAs and bilateral carotid canals, confirming agenesis of bilateral ICAs. MRI of the brain revealed extensive areas of confluent high T2 signal intensity in the subcortical and periventricular zones of both hemispheres. The patient subsequently developed episodic and progressive headache, dysarthria, ataxia, cognitive impairment and personality changes. Radiological progression of cerebral subcortical and periventricular abnormalities was demonstrated with established lacunar infarcts and generalised atrophic changes. Genetic testing confirmed the diagnosis of CADASIL with the presence of a heterozygous c.994C > T (p.Arg332Cys) mutation in exon 6 of the NOTCH 3 gene.We report the first case of coexistent bilateral ICA agenesis and CADASIL. This case highlights the need to consider CADASIL in patients with cerebral subcortical and periventricular imaging abnormalities, even with coexistent large vessel pathology.

Altered Regional Brain Homogeneity of BOLD Signal in CADASIL: A Resting State fMRI Study.

The cognitive decline in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is assumed to be due to a cortical-subcortical disconnection secondary to damage to the cerebral white matter (WM). Using resting state functional MRI (rsfMRI) and analysis of the regional homogeneity (ReHo), we examined a group of CADASIL patients and a group of healthy subjects in order to: (1) explore possible differences between the two groups; and (2) to assess, in CADASIL patients, whether any ReHo abnormalities correlate with individual burdens of WM T2 -weighted hyperintensity and diffusion tensor imaging (DTI)-derived index of mean diffusivity (MD) of the cerebral WM, an index reflecting microstructural damage in CADASIL. Twenty-three paucisymptomatic CADASIL patients (13 females; age mean ± standard deviation = 43.6 ± 11.1 years; three symptomatic and 20 with no or few symptoms) and 16 healthy controls (nine females; age 46.6 ± 11.0 years) were examined with T1 -weighted, T2 -weighted fluid attenuated inversion recovery images, DTI, and rsfMRI. When compared to controls, CADASIL patients showed four clusters of significantly lower ReHo values in cortical areas belonging to networks involved in inhibition and attention, including the right insula, the left superior frontal gyrus, and the bilateral anterior cingulated cortex. ReHo changes did not correlate with an individual patient's lesion burden or MD. This study reveals decreased ReHo of rsfMRI signals in cortical areas involved in inhibition and attention processes, suggesting a potential role for these functional cortical changes in CADASIL.

18756 Skin biopsy for the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: A report of two cases

Skin biopsy has become a useful tool for the diagnosis of extracutaneous diseases as a relatively benign procedure with a good performance. The evaluation of dermal and epidermal innervation and vasculature show distinct changes that support the diagnosis of specific neurologic diseases. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited angiopathy caused by mutations in the NOTCH3 gene on chromosome 19. It is characterized by stroke and vascular cognitive impairment in the young and other neurological manifestations. Diagnosis is based upon the demonstration of the particular mutations in genetic analysis or the skin biopsy findings on electron microscopy or NOTCH3 immunostaining. We present 2 patients with multiple lacunar infarctions and family history of ischemic strokes without a specific cause. Both patients had a normal skin examination. Electron microscopy demonstrated granular, electron dense and osmiophilic material in the basal lamina of skin vessels. Diagnosis of CADASIL was confirmed upon the ultrastructural findings in the skin biopsy. Patients and their families were enrolled in a specific monitoring and control program. Dermatologists should know about the useful of biopsy in this type of disorder, because, genetic analysis and specific immunostaining are not accessible in all countries, including Chilean health centers. Skin biopsy with electron microscopy analysis provides a powerful tool for the diagnosis of this neurological disease and gives the clinician valuable information to initiate appropriate treatment for these patients.

CADASIL Syndrome Presenting as Adjustment Disorder

CADASIL Syndrome Presenting as Adjustment Disorder