Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy in acromegalic patient with severe headache.

A 68-year-old female patient was admitted in our clinic with severe frontal bilateral headache, dizziness, depression and cognitive decline in the context of a previously diagnosed acromegaly. She also had high blood pressure, dyslipidemia, secondary diabetes mellitus. Acromegaly was caused by a growth hormone (GH) secreting-pituitary macroadenoma, so a transsphenoidal surgery was performed. The postoperative magnetic resonance imaging (MRI) scan revealed a 20÷22÷25 mm pituitary mass remnant and medical therapy with somatostatin analogues (SSAs) was started. After nine months of treatment with SSAs, she continued having severe headache, the blood pressure was well controlled, but GH secretion was only partially controlled with insulin-like growth factor-1 (IGF-1) level still above the normal value. The MRI scan showed the same pituitary tumor remnant with supra- and parasellar right extension and also multiple fronto-temporo-parietal subcortical lesions that could suggest in the clinical context cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). According to a pregenetic screening tool, the Pescini Scale, the patient had a 19 points score, which is highly suggestive for CADASIL, an inherited cerebrovascular disease due to mutations of the Notch3 gene at the chromosome locus 19p13. In the absence of genetic testing, an alternate way to prove small vessels disease, the skin biopsy, was performed. Electron microscopy showed granular osmiophilic material (GOM) surrounding the vascular smooth muscle cells on that are pathognomonic for the disease. Our report underscores the importance of repeated investigations even in patients with apparently obvious explanations of their condition since they may have multiple diseases with the same presenting clinical signs.

Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

OBJECTIVE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited small-vessel disease, is associated with vascular aggregation of mutant Notch3 protein, dysfunction of cerebral vessels, and dementia. Pericytes, perivascular cells involved in microvascular function, express Notch3. Therefore, we hypothesize that these cells may play a role in the pathogenesis of CADASIL. METHODS: Two-, 7-, and 12-month-old CADASIL mutant mice (TgNotch3(R169C) ) and wild-type controls were examined regarding Notch3 aggregation in pericytes, the coverage of cerebral vessels by pericytes, pericyte numbers, capillary density, blood-brain barrier (BBB) integrity, astrocytic end-feet, and the expression of astrocytic gap junction and endothelial adherens junction protein using immunostaining and Western blot analysis. In addition, we examined cerebrovascular CO2 reactivity using laser Doppler fluxmetry and in vivo microscopy. RESULTS: With increasing age, mutated Notch3 aggregated around pericytes and smooth muscle cells. Notch3 aggregation caused significant reduction of pericyte number and coverage of capillaries by pericyte processes (p < 0.01). These changes were associated with detachment of astrocytic end-feet from cerebral microvessels, leakage of plasma proteins, reduction in expression of endothelial adherens junction protein, and reduced microvascular reactivity to CO2 . Smooth muscle cells were not affected by Notch3 accumulation. INTERPRETATION: Our results show that pericytes are the first cells affected by Notch3 aggregation in CADASIL mice. Pericyte pathology causes opening of the BBB and microvascular dysfunction. Therefore, protecting pericytes may represent a novel therapeutic strategy for vascular dementia.

[Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)].

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small vessel diseases caused by a mutation in the NOTCH3 gene. The clinical manifestations of CADASIL range from single or multiple lacunar infarcts, transient ischemic attacks, dementia, migraine with aura to psychiatric disorders. The features of brain MRI of CADASIL include multiple lacunar infarcts and diffuse leukoencephalopathy, which frequently involves external capsules and anterior temporal regions. Almost all patients with CADASIL harbor cysteine-involving mutations in NOTCH3. In Taiwan, two thirds of CADASIL patients carry NOTCH3 p.R544C mutations, and only approximately 56% of patients with CADASIL have leukoencephalopathy with anterior temporal regions involvement.

Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy.

Failure of elimination of proteins from the brain is a major feature in many neurodegenerative diseases. Insoluble proteins accumulate in brain parenchyma and in walls of cerebral capillaries and arteries. Cerebral amyloid angiopathy (CAA) is a descriptive term for amyloid in vessel walls. Here, we adopt the term protein elimination failure angiopathy (PEFA) to focus on mechanisms involved in the pathogenesis of a spectrum of disorders that exhibit both unique and common features of protein accumulation in blood vessel walls. We review (a) normal pathways and mechanisms by which proteins and other soluble metabolites are eliminated from the brain along 100- to 150-nm-thick basement membranes in walls of cerebral capillaries and arteries that serve as routes for lymphatic drainage of the brain; (b) a spectrum of proteins involved in PEFA; and (c) changes that occur in artery walls and contribute to failure of protein elimination. We use accumulation of amyloid beta (Aß), prion protein and granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as examples of different factors involved in the aetiology and pathogenesis of PEFA. Finally, we discuss how knowledge of factors involved in PEFA may help to focus on new therapies for neurodegenerative diseases. When Aß (following immunotherapy) and prion protein are released from brain parenchyma they deposit in walls of cerebral capillaries and arteries; GOM in CADASIL accumulates primarily in artery walls. Therefore, the focus of therapy for protein clearance in neurodegenerative disease should perhaps be on facilitating perivascular elimination of proteins and reducing PEFA.

[Diagnosis, pathomechanism and treatment of CADASIL].

During the past 10 years, our understanding of the pathomechanism and pathophysiology of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has improved through clinical examination, imaging studies, pathological studies, cell experiments and the development of transgenic mice. Although epidemiological studies of CADASIL in Japan have been limited, more than 100 cases of this condition have been diagnosed in Japan. In our laboratory, we diagnosed 37 CADASIL cases genetically and identified three features common to Japanese cases. One is the wide distribution of onset age for clinical symptoms other than migraine, with the onset of symptoms being later than age 60 in 22% of cases. Second, the majority (65%) of Japanese CADASIL cases have stroke risk factors, such as hypertension, hyperlipidemia, or smoking. Third, in 22% cases there was no definite family history of stroke. However, the previous diagnostic criteria proposed by Dabous excluded several definite cases in our cohort. Therefore, to avoid missing undiagnosed cases of CADASIL, we have generated new diagnostic criteria for Japanese CADASIL based on the knowledge accumulated during the past 10 years, and compared sensitivity of two criteria. In our diagnosed Japanese CADASIL cases, the sensitivity of the new criteria was 19% and 78% for probable and possible cases, respectively, and only one case was (Fig. 3) missed when using the new criteria. In comparison, the sensitivity of Dabous's was 11% and 51% for probable and possible cases, respectively, and 24% cases were excluded due to hypertension, elderly onset or no family history, although these cases showed recurrent strokes, white matter lesions and NOTCH3 mutations. Using our new criteria, diagnosis of CADASIL can be made even in cases with elderly onset, stroke risk factors, and obscure family history.

[Vascular dementia]. / Vaskuläre Demenz.

Vascular dementia (VaD) constitutes the second most frequent cause of dementia following Alzheimer's disease (AD). In contrast to AD, VaD encompasses a variety of conditions and dementia mechanisms including multiple and strategic infarcts, widespread white matter lesions and hemorrhages. The diagnosis of VaD is based on the patient history, the clinical evaluation and neuroimaging. Treatment of VaD should account for the underlying vascular condition and is directed towards the control of vascular risk factors and stroke prevention. The need for early diagnosis and preventive treatment has promoted the concept of vascular cognitive impairment (VCI). Harmonization standards for the description and study of VCI have recently been published. A common and distinct subtype of VaD is subcortical ischemic vascular dementia (SIVD) which is related to cerebral small vessel disease. SIVD is clinically characterized by impairment of executive functions and processing speed with relatively preserved memory. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of SIVD, represents an important differential diagnosis and may serve as a model of SIVD.

Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype: study in 200 consecutively recruited individuals.

BACKGROUND AND PURPOSE: Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited arteriopathy with clinical features that include recurrent lacunar stroke, migraine, and cognitive impairment. For reasons that remain unclear, there is great variability in the clinical expression of CADASIL, both between and within families. This study examined the clinical phenotype as well as any associations with risk factors and genotype in a large, prospective cohort. METHODS: Two hundred symptomatic individuals from 124 families were recruited as part of a UK prevalence study of CADASIL and were seen subsequently in a national referral clinic. All were assessed by a standardized questionnaire and examination. RESULTS: Mean age at assessment was 47.7 years and was 33.6 years at symptom onset. Migraine, usually with aura, was the most prevalent feature, affecting 75% of individuals. More than half had a history of stroke, with a mean age at onset of 46 years. Hypertension (odds ratio=2.57, P=0.007) and pack-years of smoking (odds ratio=1.07, P=0.001) were associated with an increased risk of stroke. A history of stroke was a significant risk factor for both dementia and disability. Mutations clustered in exon 4 of the NOTCH3 gene, which contained > or = 71.4% of familial mutations. Four previously unreported mutations were found (T697C, C1279T, G1370C, and C1774T). No associations were identified between genotype and clinical phenotype. CONCLUSIONS: Our data suggest that cardiovascular risk factors may modulate the clinical expression of CADASIL. The associations with hypertension and smoking suggest that risk factors should be treated aggressively in patients with CADASIL.

Notch signaling and CADASIL.

Notch signaling plays an essential role in vascular development and human vascular diseases. In adults, mutations of the Notch3 gene cause a hereditary vascular degenerative disease known as cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL). CADASIL is characterized by recurrent strokes and cognitive impairment. Over the past decade, the number of CADASIL patients increased significantly with improvements in genetic testing and other diagnostic tools, but the true prevalence of CADASIL is still underestimated, especially in Asia. Basic studies suggest that Notch3 is essential for the development and survival of the vascular smooth muscle cells, but the mechanisms by which Notch3 mutations become pathogenic are still unclear. This article reviews the clinical features and possible pathogenesis of CADASIL. Efforts to improve the diagnostic accuracy and define the role of Notch3 mutation in brain damage and clinical presentations of CADASIL should be continued.

Autosomal dominant leukoencephalopathy with mild clinical symptoms due to cerebrovascular dysfunctions: a new disease entity?

A family with cerebrovascular dysfunctions and extensive white matter lesions was presented. The proband had suffered migraine. His brother showed syncopal episodes and migraine. His mother also suffered severe migraine with aura, and had transient hemiparesis during pregnancy. Their brain MRIs, being quite similar to each other, revealed diffuse bilateral deep white matter lesions, with no changes in serial follow-up. His grandmother showed similar white matter changes on CT, consistent with autosomal dominant inheritance. Lesions were considered to be due to chronic vasogenic edema based upon increased apparent diffusion coefficient (ADC) values on diffusion-weighted imaging, normal spectrum ratio of metabolites on (1)H MR spectroscopy, and decreased regional cerebral blood flows on single-photon emission CT (SPECT). A deficiency of genetically determined factors contributing to the autoregulation of small blood vessels might possibly lead to both clinical symptoms and white matter lesions through the breakdown of the blood-brain barrier and resultant vasogenic edema. Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was suspected, neither NOTCH3 mutation nor granular osmiphilic material (GOM) in the arteriole walls were detected. Further accumulation of similar cases is necessary to establish the possibility of a new familial leukoencephalopathy.

Notch signaling in vascular development and physiology.

Notch signaling is an ancient intercellular signaling mechanism that plays myriad roles during vascular development and physiology in vertebrates. These roles include regulation of artery/vein differentiation in endothelial and vascular smooth muscle cells, regulation of blood vessel sprouting and branching during both normal development and tumor angiogenesis, and the differentiation and physiological responses of vascular smooth muscle cells. Defects in Notch signaling also cause inherited vascular and cardiovascular diseases. In this review, I summarize recent findings and discuss the growing relevance of Notch pathway modulation for therapeutic applications in disease.

[A case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), diagnosed in the age of puberty].

We report a 13-year-old boy with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) at an early stage. He showed migraine, cognitive deficits, depressive episodes and areas of white matter hyperintensity on MRI. There were no first-degree relatives accompanied with similar symptoms. T2-and fluid-attenuated inversion recovery (FLAIR)--weighted brain MRI revealed areas of apparently symmetric high intensity in the deep white matter and periventicular caps. On ultrastructural studies of the biopsied skin, there were free granular osmiophilic materials (GOM) between vascular smooth muscle cells in the cutaneous vessels. But there were no excavations in the cell membranes that contained GOM. On immunostaining with Notch3 monoclonal antibodies, granular staining was not observed in vessels of the skin. No mutation was detected on DNA analysis of the Notch3 gene (exon 4 and part of exon 5) in peripheral leukocytes. Although the frequencies of migraine episodes and depressive episodes decreased with amitriptyline and ibuprofen, the cognitive deficits (delayed-recall impairment) and areas of white matter hyperintensity on MRI have been unchanged for the past four

[Results of control MRI examinations performed due to radiological indication--preliminary report]. / Wyniki powtórnych badan MR mózgu u dzieci wykonywanych ze wskazan radiologicznych--doniesienie wstepne.

INTRODUCTION: MR is very important examination of central nervous system in children in the evaluation of differences dependent of sex and age as well as in the diagnostics. Radiological indications are important in many cases to perform a control study, to evaluate a dynamic changes or to establish the diagnosis. THE AIM: The aim of this study was to examine the results of control MRI examination in children with neurologic syndromes. MATERIAL AND METHODS: In the year 2006 control MRI was performed in 22 cases since it was advised after previous MRI examinations in children hospitalized in the Department of Pediatric Neurology UJ CM in Kraków. The group of children aged 4-18 years (mean 12 years) consisted of 14 boys and 8 girls. The commonest clinical diagnoses were epilepsy, encephalopathies, hemiparesis, cranial neuropathies, headache, anizocoria, vertigo, paraparesis and NF I. RESULTS: Repeated MRI in 14 children did not revealed significant changes, independently from clinical changes. In 3 patients positive changes or regres of pathological foci were observed within the subarachnoid hemorrhage. In 3 children MRI revealed progressive changes, within in the child with NFI, and in patient with pyramidolextrapyramidal syndrome which progressed from hemiparesis to quadriplegia and also in a child with disseminated symptoms, such as ataxia, piramidal syndrome and cranial nerve palsies. In 2 other children the repeated MRI helped to establish the final diagnosis. The evolution of neuroradiological changes in the first child with the history of hemiparesis indicated ischemia as a cause of neurological syndrome. The other patient with cranial neuropathies of VII, VIII and XII nerves associated with intellectual impairment was diagnosed with CADASIL only with the help of control MRI examination. CONCLUSIONS: In 9% children the second MRI which helped to analyze evolution of changes was important to establish the final diagnosis. The control MRI examination in 64% children did not revealed significant changes independently of clinical changes, such as recovery or aggravation of symptoms, what explains the decision to repeat MR examination in unclear cases.

Co-existing spinal canal tumours and CADASIL - a diagnostic challenge.

We would like to present a case of a 51-year-old patient with two rare co-existing diseases. The patient was suffering from two tumours in the lumbar region of the spinal canal, which caused development of hydrocephalus. Diffuse white matter hyperintensities (WMH) were observed in our patient's brain imaging. She was also suffering from headaches and she had two mild strokes. We performed some further diagnostic procedures and found out that the patient was suffering from CADASIL. CADASIL was confirmed by both ultrastructural analysis and genetic testing.

Common versus uncommon causes of dementia.

When patients present with a dementia syndrome at a young age, the experienced clinician will automatically include uncommon dementias in the diagnostic considerations, as familial uncommon dementias due to genetic mutations frequently present as early-onset dementias. This paper highlights why uncommon dementias due to genetic mutations, although marginal in terms of prevalence numbers in the total population, are of significance in the quest to unravel the underlying cause of common dementias such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementias (FTD) and vascular dementia (VaD).

Impaired vascular mechanotransduction in a transgenic mouse model of CADASIL arteriopathy.

BACKGROUND AND PURPOSE: CADASIL is an inherited small-vessel disease responsible for lacunar strokes and cognitive impairment. The disease is caused by highly stereotyped mutations in Notch3, the expression of which is highly restricted to vascular smooth muscle cells (VSMCs). The underlying vasculopathy is characterized by degeneration of VSMCs and the accumulation of granular osmiophilic material (GOM) and Notch3 protein within the cell surface of these cells. In this study, we assessed early functional changes related to the expression of mutant Notch3 in resistance arteries. METHODS: Vasomotor function was examined in vitro in arteries from transgenic mice that express a mutant Notch3 in VSMC. Tail artery segments from transgenic and normal wild-type male mice were mounted on small-vessel arteriographs, and reactivity to mechanical (flow and pressure) forces and pharmacological stimuli were determined. Mice were studied at 10 to 11 months of age when VSMC degeneration, GOM deposits, and Notch3 accumulation were not yet present. RESULTS: Passive arterial diameter, contraction to phenylephrine, and endothelium-dependent relaxation to acetylcholine were unaffected in transgenic mice. By contrast, flow-induced dilation was significantly decreased and pressure-induced myogenic tone significantly increased in arteries from transgenic mice compared with wild-type mice. CONCLUSIONS: This is the first study to our knowledge providing evidence that mutant Notch3 impairs selectively the response of resistance arteries to flow and pressure. The data suggest an early role of vascular dysfunction in the pathogenic process of the disease.

The pathogenesis of CADASIL: an update.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) appears to be the most common form of hereditary stroke disorder. CADASIL is associated with arterial smooth muscle degeneration linked to mutations in the Notch3 gene, whose product is a transmembrane receptor that functions in cell-cell communication. The pathogenesis of CADASIL remains unclear. Current research efforts are directed towards the elucidation of various features of the disorder including investigations on CADASIL-like disorders, early cognitive changes, specificity of neuroimaging for diagnosis, discovery of de novo mutations, the development of Notch3 transgenic mouse models and molecular cellular studies in Notch3 signaling. The genetics of cerebrovascular disorders (CVD) was virtually unknown until recently. Genetic associations may have been evaded because of widely variable phenotypes, even within monogenic disorders such as CADASIL. Several investigators have attempted genotype-phenotype correlation in CADASIL cases but the relationship between genetic alterations and overt manifestation of phenotype remains elusive. However, the elucidation of the genetics and pathogenesis of CADASIL have been important in further understanding of the primary vascular mechanisms that lead to ischemic blood flow and its consequences on neuronal survival. This report summarizes some of the highlights of the satellite symposium on CADASIL at Vas-Cog 2003.