Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts And Leukoencephalopathy Patient Research Articles

The imaging findings of migraine with visual aura in a CADASIL patient.

Head MRI images of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)patients during migraine attacks are rare.

Management of Coronary Artery Disease in CADASIL Patients: Review of Current Literature.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable form of vascular dementia in adults. It is well-established that CADASIL results in neurocognitive dysfunction and mood disturbance. There is also cumulative evidence that CADASIL patients are more susceptible to ischemic heart disease. The aim of this study is to review the current literature regarding the incidence of coronary artery disease in CADASIL patients with a focus on the various management options and the clinical challenges associated with each of these treatment strategies. We conducted a literature search using Cochrane, MEDLINE, and EMBASE for papers that reported the occurrence of coronary artery disease in patients with CADASIL. We supplemented the search with a manual search in Google Scholar. Only case reports, case series, and original articles were included. The search resulted in six reports indicating the association between coronary artery disease and CADASIL and its management. Evidence suggests that extracranial manifestations of CADASIL may include coronary artery disease, presenting as a more extensive burden of disease in younger patients. Surgical and percutaneous revascularization strategies are feasible, but the incidence of peri-procedural stroke remains significant and should be weighed against the potential benefit derived from either of these strategies. A multidisciplinary approach to therapy, with perspectives from neurologists, cardiologists, and cardiac surgeons, is needed to provide the appropriate treatment to the CADASIL patient with severe coronary artery disease. Future studies should be directed toward the development of targeted therapies that may help with the early detection and prevention of disease progress in these patients.

A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan.

ObjectivesClinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed.MethodsSubjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire.ResultsBased on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of NOTCH3 were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 (n = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan.ConclusionThis questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.

The potential danger of blocking CGRP for treating migraine in CADASIL patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease characterised by recurrent ischemic stroke, cognitive decline progressing to dementia, psychiatric disturbances and apathy. More than half of mutation carriers suffer from migraine, most often migraine with aura. Recently, a CADASIL patient was treated with a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor. Monoclonal antibodies targeting the CGRP system have been demonstrated to be safe, well tolerated, and effective in reducing migraine attacks. There is, however, abundant evidence that CGRP is important in maintaining cardiovascular homeostasis under (patho)physiological conditions. CGRP may act as a vasodilatory safeguard during cerebral and cardiac ischemia and blockage of the system could, therefore, potentially worsen ischemic events. Therefore, we caution against treating patients with small vessel diseases, such as the monogenic disorder CADASIL, with these drugs until relevant safety data and long term follow up results are available. Alternative preventive migraine treatments in CADASIL may be acetazolamide, sodium valproate, lamotrigine, topiramate, verapamil, or flunarizine.

CADASIL with clinical manifestations of lumbago, hunchback and Parkinson's syndrome

To report a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) manifesting as lumbago, hunchback and Parkinson's syndrome. A 49-years-old male CADASIL patient was reported. Results of clinical examination, neuroimaging and genetic testing were analyzed. His family members were also subjected to genetic testing. Related literature was reviewed. The patient had no typical symptoms of CADASIL such as headache, repeated stroke, dementia and emotional disorders, but progressive Parkinson's syndrome, late onset lumbago, hunchback, dysphagia, and diplopia. Brain MRI showed left basal ganglia and external capsule lacunar infarction. Genetic testing revealed a point mutation c.1630C>T (p.R544C) in exon 11 of the NOTCH3 gene. A heterozygous mutation was detected in the same gene in his mother, elder sister and younger brother, all of whom showed different clinical phenotypes. The clinical features of CADASIL are heterogeneous. Lumbago, humpback, and Parkinson's syndrome may be a rare clinical phenotype of CADASIL.

Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation. However, the underlying cellular and molecular mechanisms remain unidentified. Here, we generated non-integrative induced pluripotent stem cells (iPSCs) from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation (c.3226C>T, p.R1076C). Vascular smooth muscle cells (VSMCs) differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes, including activation of the NOTCH and NF-κB signaling pathway, cytoskeleton disorganization, and excessive cell proliferation. In comparison, these abnormalities were not observed in vascular endothelial cells (VECs) derived from the patient’s iPSCs. Importantly, the abnormal upregulation of NF-κB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this iPSC-based disease model, our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.

CADASIL brain vessels show a HTRA1 loss-of-function profile.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and a phenotypically similar recessive condition (CARASIL) have emerged as important genetic model diseases for studying the molecular pathomechanisms of cerebral small vessel disease (SVD). CADASIL, the most frequent and intensely explored monogenic SVD, is characterized by a severe pathology in the cerebral vasculature including the mutation-induced aggregation of the Notch3 extracellular domain (Notch3ECD) and the formation of protein deposits of insufficiently determined composition in vessel walls. To identify key molecules and pathways involved in this process, we quantitatively determined the brain vessel proteome from CADASIL patient and control autopsy samples (n = 6 for each group), obtaining 95 proteins with significantly increased abundance. Intriguingly, high-temperature requirement protein A1 (HTRA1), the extracellular protease mutated in CARASIL, was found to be strongly enriched (4.9-fold, p = 1.6 × 10-3) and to colocalize with Notch3ECD deposits in patient vessels suggesting a sequestration process. Furthermore, the presence of increased levels of several HTRA1 substrates in the CADASIL proteome was compatible with their reduced degradation as consequence of a loss of HTRA1 activity. Indeed, a comparison with the brain vessel proteome of HTRA1 knockout mice (n = 5) revealed a highly significant overlap of 18 enriched proteins (p = 2.2 × 10-16), primarily representing secreted and extracellular matrix factors. Several of them were shown to be processed by HTRA1 in an invitro proteolysis assay identifying them as novel substrates. Our study provides evidence for a loss of HTRA1 function as a critical step in the development of CADASIL pathology linking the molecular mechanisms of two distinct SVD forms.

Generation and characterization of the human iPSC line IDISi001-A isolated from blood cells of a CADASIL patient carrying a NOTCH3 mutation

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary stroke disorder. It is caused by mutations in NOTCH3 that lead to progressive degeneration of the smooth muscle cells in blood vessels. There is currently no treatment for this disorder. We reprogrammed to pluripotency blood mononuclear cells isolated from a patient carrying a NOTCH3 mutation by using a commercially available non-integrating system. The success in the generation of this iPSC line (IDISi001-A) suggests that the NOTCH3 mutation did not limit cell reprogramming and offers an unprecedented opportunity for studying and modeling CADASIL pathology.

Targeted next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients.

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic, hereditary, small vessel disease of the brain causing stroke and vascular dementia in adults. CADASIL has previously been shown to be caused by varying mutations in the NOTCH3 gene. The disorder is often misdiagnosed due to its significant clinical heterogeneic manifestation with familial hemiplegic migraine and several ataxia disorders as well as the location of the currently identified causative mutations. The aim of this study was to develop a new, comprehensive and efficient single assay strategy for complete molecular diagnosis of NOTCH3 mutations through the use of a custom next-generation sequencing (NGS) panel for improved routine clinical molecular diagnostic testing.ResultsOur custom NGS panel identified nine genetic variants in NOTCH3 (p.D139V, p.C183R, p.R332C, p.Y465C, p.C597W, p.R607H, p.E813E, p.C977G and p.Y1106C). Six mutations were stereotypical CADASIL mutations leading to an odd number of cysteine residues in one of the 34 NOTCH3 gene epidermal growth factor (EGF)-like repeats, including three new typical cysteine mutations identified in exon 11 (p.C597W; c.1791C>G); exon 18 (p.C977G; c.2929T>G) and exon 20 (p.Y1106C; c.3317A>G). Interestingly, a novel missense mutation in the CACNA1A gene was also identified in one CADASIL patient. All variants identified (novel and known) were further investigated using in silico bioinformatic analyses and confirmed through Sanger sequencing.ConclusionsNGS provides an improved and effective methodology for the diagnosis of CADASIL. The NGS approach reduced time and cost for comprehensive genetic diagnosis, placing genetic diagnostic testing within reach of more patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-016-0093-z) contains supplementary material, which is available to authorized users.

Hypomorphic NOTCH3 Alleles Do Not Cause CADASIL in Humans

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by stereotyped missense mutations in NOTCH3. Whether these mutations lead to the CADASIL phenotype via a neomorphic effect, or rather by a hypomorphic effect, is subject of debate. Here, we report two novel NOTCH3 mutations, both leading to a premature stop codon with predicted loss of NOTCH3 function. The first mutation, c.307C>T, p.Arg103*, was detected in two brothers aged 50 and 55 years, with a brain MRI and skin biopsy incompatible with CADASIL. The other mutation was found in a 40-year-old CADASIL patient compound heterozygous for a pathogenic NOTCH3 mutation (c.2129A>G, p.Tyr710Cys) and an intragenic frameshift deletion. The deletion was inherited from his father, who did not have the skin biopsy abnormalities seen in CADASIL patients. These individuals with rare NOTCH3 mutations indicate that hypomorphic NOTCH3 alleles do not cause CADASIL.

“CADASIL coma” in an Italian homozygous CADASIL patient: comparison with clinical and MRI findings in age-matched heterozygous patients with the same G528C NOTCH3 mutation

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder caused by mutations in the NOTCH3 gene, with a striking variability in phenotypic expression. To date, only two homozygous patients have been reported, with divergent phenotypic features. We describe an Italian CADASIL patient, homozygous for G528C mutation, in whom early manifestation of the disease was migraine, but whose clinical evolution was characterized by a reversible acute encephalopathy followed by full recovery ("CADASIL coma"). Clinical evaluation, MR scan, neuropsychological and neurophysiological investigation did not reveal substantial differences between our homozygous patient and her heterozygous relatives sharing the same mutation, or between our patient and a group of heterozygous individuals with the same mutation but from different families. Skin biopsy identified peculiar features in the homozygous patient, with cytoplasmic pseudoinclusions likely containing granular osmiophilic material (GOM) in the vascular smooth muscle cells, but further studies are necessary to substantiate their possible relationships with CADASIL homozygosis. "CADASIL coma" did not seem to be specific of patient's homozygosis, since it was observed in one of her heterozygous relatives, whereas its pathogenesis seems to be related to peculiar constellations of unknown predisposing factors. The present study demonstrated that CADASIL conforms to the classical definition of dominant diseases, according to which homozygotes and heterozygotes for a defect are phenotypically indistinguishable.

Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): report of a case with a six-year follow-up.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a disorder of the cerebral small blood vessels caused by a mutation in the NOTCH3 gene, which encodes a large transmembrane receptor NOTCH3. It is associated with systemic arteriopathy involving small arteries, besides the brain, in skin, spleen, liver, muscle, aorta and in the kidney. The key pathological finding is the accumulation of granular osmiophilic material (GOM) on degenerating vascular smooth muscle cells. In the kidney GOMs have been described only in a very limited number of CADASIL patients. We describe a genetically confirmed CADASIL patient with mild renal dysfunction and GOMs in the interlobular and juxtaglomerular arteries and, for the first time, also within the glomerulus, whose nephrology conditions remained stable, whereas the neurological manifestations markedly worsened over a six-year follow-up period. The reasons for this discrepancy are probably related to differences in the structure and function of brain and kidney blood vessels.

Assessment of Cerebral Hemodynamics to Acetazolamide Using Brain Perfusion SPECT in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy caused by mutations in the Notch3 gene located on chromosome 19, leading to 4 cardinal features with aura, cerebrovascular ischemic events, mood disturbances, and dementia. Acetazolamide (ACZ) has been promoted as a drug to determine cerebral hemodynamics, including cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) in patients with cerebrovascular disease. In CADASIL patients with small-vessel disease, ACZ may be possible to increase CBF. We present that reduced CBF was dramatically improved after administration of ACZ on Tc-99m ECD brain perfusion SPECT in a CADASIL patient.

Stroke recurrence in an elderly CADASIL patient on aspirin discontinuation due to severe auto-immune thrombocytopenia

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a rare inherited cerebrovascular disease caused by mutations of the Notch3 gene and resulting in diffuse microangiopathy (1). The clinical picture of CADASIL is characterized by a variable association of recurrent strokes, cognitive decline, mood disturbances, migraine, often with aura, and epilepsy, usually occurring in mid-adult age (2, 3). No specific treatment currently exists for CADASIL. Counseling and support are the major part of CADASIL patient management and the main target of therapy is control of symptoms (4). Although not yet based on evidence, the strict control of conventional vascular risk factors may have a beneficial effect (5). Current secondary prevention of cerebrovascular events in CADASIL is extrapolated from studies on sporadic stroke; therefore, although there is no specific evidence about its efficacy in CADASIL, aspirin is commonly prescribed for its patients (4). Here we describe an elderly CADASIL patient who underwent stroke recurrence when aspirin treatment was stopped due to severe auto-immune thrombocytopenia.

Cognitive Impairment and Cerebral Hypoperfusion in a CADASIL Patient Improved During Administration of Lomerizine

A 64-year-old woman was admitted to our hospital for recurrent stroke and cognitive impairment and was diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Iodine-123 iodoamphetamine single photon emission computed tomography showed hypoperfusion in the whole brain, but cerebral blood flow increased dramatically after the administration of acetazolamide in the cerebral cortex. Lomerizine, a diphenylmethylpiperazine Ca2+ channel blocker, can selectively increase cerebral blood flow. Cognitive decline and cerebral hypoperfusion improved during 2-year administration of lomerizine in this CADASIL patient, and thus, lomerizine is a potential candidate for treating cognitive impairment in CADASIL patients.

A Novel Mechanism of Vascular Smooth Muscle Cell Regulation by Notch

See related article, pages 1483–1491 The Notch family of receptors, Notch1 to -4, are heterodimer transmembrane proteins, consisting of an extracellular domain and a noncovalently linked intracellular domain (ICD). Upon interaction with the DSL family of proteins (Jagged, Delta-like) on neighboring cells, Notch undergoes proteolytic cleavage, which frees the ICD from the plasma membrane. This results in translocation of the ICD into the nucleus, where it forms a complex with the CSL family of transcriptional repressors (CBF1/RBP-Jk), removing the repression and allowing for target gene (Hes, Hey) transcription.1,2 Tissue distribution of the Notch proteins varies widely. Notch1 and -4 are predominantly endothelial, prominent in both arteries and veins, and present in all stages of development (embryonic to adult); the expression of Notch2 is typically confined to pulmonary endothelium, but Notch3 is primarily expressed in adult arterial vascular smooth muscle cells (VSMCs) in large conduit, pulmonary, and systemic resistance arteries.3 This specific pattern of temporal and spatial distribution correlate to diverse functions of the Notch family in vascular development and physiology in vertebrates reported to date.4 In the cardiovascular system, Notch signaling plays a role in several aspects of vascular development, including vasculogenesis, angiogenesis, differentiation, vascular remodeling, and VSMC maturation. Notch1 and -4 signaling appears critical in vasculogenesis and angiogenesis during early development, when it interacts with vascular endothelial growth factor signaling to specify artery–vein differentiation of endothelial cells (ECs). Transgenic mice deficient for Notch1 fail to undergo embryonic angiogenic remodeling, and vascular development is arrested at the primitive undifferentiated plexus, resulting in an embryonic lethal phenotype. Notch2-null mutations likewise result in embryonic lethality characterized by multiple large and small vessel aneurysms. Notch4 deletion results in no obvious phenotypic alteration. Notch3−/− mice are viable; however, they fail to develop proper arterial VSMC phenotype, resulting in vein-like …

Proteome analysis of cultivated vascular smooth muscle cells from a CADASIL patient.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a vascular dementing disease caused by mutations in the NOTCH3 gene, most which are missense mutations leading to an uneven number of cysteine residues in epidermal growth factor-like repeats in the extracellular domain of Notch3 receptor (N3ECD). CADASIL is characterized by degeneration of vascular smooth muscle cells (VSMC) and accumulation of N3ECD on the VSMCs of small and middle-sized arteries. Recent studies have demonstrated that impairment of Notch3 signaling is not the primary cause of the disease. In the present study we used proteomic analysis to characterize the protein expression pattern of a unique material of genetically genuine cultured human CADASIL VSMCs. We identified 11 differentially expressed proteins, which are involved in protein degradation and folding, contraction of VSMCs, and cellular stress. Our findings indicate that misfolding of Notch3 may cause endoplasmic reticulum stress and activation of unfolded protein response, leading to increased reactive oxygen species and inhibition of cell proliferation. In addition, upregulation of contractile proteins suggests an alteration in the signaling system of VSMC contraction. The accumulation of N3ECD on the cell surface possibly upregulates the angiotensin II regulatory feedback loop and thereby enhances the readiness of the cells to respond to angiotensin II stimulation.

Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary systemic arteriopathy presenting with migraines, mood disorders, focal neurologic deficits, recurrent ischemic attacks and dementia in young adults. The genesis of this disease relates to missense mutation of the Notch3 gene. We report here a newly identified CADASIL patient and discuss unique vascular lesions observed in the kidney. A 64-year-old female was admitted to our hospital for the investigation of proteinuria, hematuria and progressive neurological abnormalities. Her mother and brother died of cerebral infarction at a relatively young age despite a lack of apparent risk factors for arteriosclerosis. Over the past 4 months before admission, she had suffered from frequent transient ischemic attacks despite appropriate antiplatelet therapy. Blood examination revealed mild renal insufficiency and urinalysis revealed moderate protein excretion and dysmorphic hematuria. Magnetic resonance imaging of the brain revealed multiple infarcts and leukoencephalopathy. Histopathological analysis of the kidney revealed focal segmental mesangial proliferation, the loss and degeneration of arterial medial smooth muscle cells and arterial intimal thickening. Immunofluorescence analysis of glomeruli revealed IgA deposition in the mesangial area. Electron microscope analysis revealed electron-dense deposition also in the mesangial area. In addition, granular osmophilic material (GOM) was observed in the extraglomerular mesangial area and around the vascular smooth muscle cells. Genetic analysis of Notch3 revealed an R141C missense mutation and she was diagnosed with CADASIL complicated with IgA nephropathy. In immunohistological analysis, Notch3 stains were positive in vascular smooth muscle cells of the interlobular arteries and both afferent and efferent arterioles, and weak in the glomerular mesangial area. Antihypertensive treatment using angiotensin II receptor blocker and a low protein diet were initiated, and her urinary protein excretion decreased to 0.2 g/day. However, due to the progression of her neurological abnormalities, she became socially withdrawn. In CADASIL, GOM, abnormal accumulation of Notch3 ectodomain, is thought to induce the degeneration and loss of vascular smooth muscle cells and subsequent intimal thickening. Analysis of our cases provided that these morphological abnormalities were also observed in the CADASIL patient kidney.

Cerebellar arteriovenous malformation and vertebral artery aneurysm in a CADASIL patient

The presence of large vessels malformations has not been reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We describe a CADASIL patient in whom a brain cerebellar arteriovenous malformation was revealed by magnetic resonance (MR) imaging. An MR angiogram documented also an aneurysm along the right intracranial vertebral artery at the junction with the posterior-inferior cerebellar artery. The aneurysm was successfully treated by means of endovascular coil embolization. No neurological complication occurred in our patient during the angiographic procedure. In this case, in addition to an incidental coexistence of CADASIL and large vessels abnormalities, a causal role of the Notch pathway alteration could be hypothesized. Dysregulation of the Notch pathway is linked to several human diseases besides CADASIL. In one of these (the Alagille syndrome) intracranial aneurysms are reported. This hypothesis contrasts however with the absence of similar reports in other CADASIL cases and needs corroboration in large series.

Systemic Blood Pressure Profile in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic form of subcortical ischemic vascular dementia (SIVD). The most common vascular risk factors are unremarkable in CADASIL; however, studies on systemic blood pressure (BP) changes over time are substantially lacking. Because BP instability is a relevant risk factor for developing or worsening white matter changes in sporadic SIVD, we aimed to study the BP profile of CADASIL to investigate its relationship with cognitive decline and white matter injury. Twenty-four-hour ambulatory BP monitoring was performed in a group of 14 CADASIL patients (12 males and 2 females) and in a group of 15 healthy age-matched control subjects. The following BP variables were compared between the 2 groups: mean daytime and nighttime systolic, diastolic, and mean arterial BP (SABPday, DABPday, and MABPday, and SABPnight, DABPnight, and MABPnight) and nocturnal percentage decline in arterial BP (%MABP reduction). Cognitive performances were tested by mini mental status examination (MMSE), and brain MRI was performed to extrapolate the T2-weighted lesion volume (LV) in each CADASIL patient. The 24-hour arterial BP variables were compared between CADASIL and controls. In addition, for CADASIL patients only, MMSE, LV, and age were compared with each pressure variable. Patients with CADASIL showed a significant reduction (P<0.05) of SABPday, DABPday, MABPday and %MABP decline with respect to controls. In addition, MMSE of CADASIL subjects correlated significantly (P<0.0001) with daytime MABP. The low systemic BP profile observed in CADASIL patients was specifically attributable to reduced diurnal BP values. This may further affect cerebral hemodynamics and increase the risk of cognitive impairment in these patients. The pathogenesis of abnormal BP profile in CADASIL remains to be clarified. It is likely that central and peripheral mechanisms controlling BP variations are involved.