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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: Study of two American families with predominant dementia
Abstract
Few European families have been reported with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We describe four patients from two independent American families. All four cases underwent comprehensive clinical, neuropsychological and pathological examination. Pathological data were correlated with clinical features. Dementia was a prominent and constant feature in all subjects. The families differed in phenotypical presentation and we analyzed possible pathological substrates that may account for the differences. Autopsy showed multiple ischemic infarcts in the white matter, abnormal vasculature with thickening and degeneration of the vessel wall. The clinical course in the first family was characterized by early dementia without stroke-like episodes; however, autopsy demonstrated strokes in the basal ganglia and thalamus. The members of the second family developed dementia later and had history of several clinically evident strokes. Pathological examination showed only widespread degeneration of the white matter. Our study of two American families with CADASIL suggests that involvement of the basal ganglia and thalamus is important for early development of dementia and clinically can present as a gradual dementia, resembling a neurodegenerative process. Selective damage of the white matter and central gray matter provides further insight to the pathogenesis of vascular dementia.
... C erebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic arteriopathy caused by mutations of the Notch3 gene on chromosome 19. 1 The main clinical manifestations of the disease include attacks of migraine with aura, mood disturbances, recurrent subcortical ischemic strokes, and stepwise or progressive dementia. [2][3][4] One of the hallmarks of CADASIL is the presence of white matter (WM) hyperintensities on MR T2weighted images (T2-WI). ...
... 18 In CADASIL, only lacunar lesions within the basal ganglia or thalamus have been reported in vivo or postmortem. 5,19 In addition, dementia has been observed in 2 affected subjects in the absence of small infarcts within the thalamus or basal ganglia, 19 raising the question of whether additional tissue changes are present in these structures at distance from the typical infarcts in CADA-SIL. In this study we used DTI to investigate the tissue microstructure in the putamen and the thalamus in the absence of typical small infarcts, or at distance from these lesions, in 20 patients with Notch3 gene mutations and 12 controls. ...
... 18 In CADASIL, only lacunar lesions within the basal ganglia or thalamus have been reported in vivo or postmortem. 5,19 In addition, dementia has been observed in 2 affected subjects in the absence of small infarcts within the thalamus or basal ganglia, 19 raising the question of whether additional tissue changes are present in these structures at distance from the typical infarcts in CADA-SIL. In this study we used DTI to investigate the tissue microstructure in the putamen and the thalamus in the absence of typical small infarcts, or at distance from these lesions, in 20 patients with Notch3 gene mutations and 12 controls. ...
In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), water diffusion changes suggestive of microstructural tissue alterations have been recently reported in abnormal- and normal-appearing white matter as seen on T2-weighted images. In the subcortical gray matter, typical lacunar infarcts are repeatedly observed. Whether microstructural tissue changes are also present outside these lesions within the putamen or thalamus remains unknown.
We used diffusion tensor imaging, an MRI method highly sensitive to cerebral microstructure, in 20 CADASIL patients and 12 controls. Both the trace of the diffusion tensor [Tr(D)] and an anisotropic diffusion index (volume ratio) of diffusion were measured within the putamen and thalamus outside typical lacunar infarcts as detected on both T1- and T2-weighted images.
A significant increase in Tr(D) and a decrease in anisotropy were observed in the putamen and thalamus in patients. The right/left indices of Tr(D) in the thalamus, but not in the putamen, were strongly correlated with the corresponding indices calculated in the white matter of the centrum semiovale. In addition, the diffusion increase in the thalamus was positively correlated with Tr(D) and with the load of small deep infarcts within the white matter and negatively correlated with the Mini-Mental State Examination score.
Our results suggest that microstructural tissue alterations are present in the putamen and thalamus, outside the typical lacunar infarcts in CADASIL. In the thalamus, these microstructural changes appear constant and are even observed in asymptomatic subjects. Some of these thalamic changes appear to result from degeneration of thalamocortical pathways secondary to ischemic white matter damage. The importance of this degenerative phenomenon in the pathophysiology of CADASIL requires further investigation.
... Asymptomatic cerebral microbleeds are also frequent, while spontaneous lobar hemorrhages are very rare [2]. Vascular dementia generally follows recurrent strokes, while progressive subcortical dementia without strokes is rare [3,4]. Cognitive decline generally starts with alterations in attention and executive functions and is the result of dysfunction within the subcortical/frontal network. ...
... Cognitive impairment in CADASIL is similar to that reported for sporadic subcortical ischemic vascular dementia and is thought to the result of dysfunction within the subcortical/frontal network due to the leukoaraiosis, although a multi-infarction origin based on the accumulation of cerebral infarcts was also proposed [5,13,14]. Cognitive decline preceding strokes is unusual in CADASIL, but several cases were reported [1,3,4]. In these cases, it is not clear whether the cognitive impairment is due to the accumulation of focal asymptomatic ischemic lesions rather than the disconnection mechanism due to the diffuse white matter damage. ...
Key Clinical Message
Despite transient global amnesia is considered unusual in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and causal relation is still unclear, this report suggests to consider CADASIL in those patients with recurrent transient global amnesia, especially when MRI shows multifocal hyperintensities affecting the cerebral white matter or when it is followed by cognitive decline.
... According to the literature, the geographically most widespread form of hereditary SAE (HSAE) is a vasculopathy designated with the acronym CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy) extensively investigated by Tournier-Lasserve et al. [20,42]. CADASIL cases have been observed in families living in Europe [43, 21, 36, 23, 28], in the USA [17] and Japan [45] . The disease is characterised by PAS-positive deposits in the tunica media which are present in all arteries and appear as electrondense granules upon electron microscopic investigation. ...
... Neuropathologically the disorder is characterised by lacunar infarcts and diffuse demyelination of the subcortical white matter with sparing of U-fibres. Upon light microscopic investigation small arteries show concentric intimal thickening, degeneration of the tunica muscularis, splitting of the lamina elastica interna and deposition of faintly PAS-positive granular material [17, 21, 23, 35] . The granular material is osmiophilic and upon electron microscopy appears as electrondense granules measuring 10–15 nm in diameter [2, 11]. ...
A cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is described with a pedigree suggestive for an autosomal dominant condition. In contrast to the vasculopathy designated with the acronym CADASIL, no deposits of granular osmiophilic material were detected in the vasculature and no point mutations in the NOTCH 3 gene were found. The disease occurred in a family living near Hamburg, Germany, and affected 11 women and 11 men over the last six generations. Onset of the disease was between the age of 12 and 50. Clinical symptoms included gait disturbances, dysarthria, sensomotoric deficits and a progressive dementia. Migraine-like complaints and epileptic seizures were observed in one case each. Cranial computer tomography and magnetic resonance imaging scans showed large confluent areas with decreased density in the white matter and small necroses in the brain stem, the basal ganglia and the white matter. A correlation with factors predisposing for vascular diseases could not be demonstrated. In five cases an autopsy was performed which disclosed an angiopathy affecting predominantly the penetrating arteries with consecutive lacunar infarcts, diffuse demyelination and rarefication of the subcortical white matter and degeneration of the pyramidal tracts. Histologically, the vessels showed concentric and excentric intimal proliferation, an elastosis and hyalinosis, splitting of the lamina elastica interna and a degeneration of the tunica muscularis. Electron microscopy revealed fragmentation and thickening of the basal lamina but electron-dense granules characteristic for CADASIL were not detected.
... In 1993, the acronym CADASIL, an abbreviation for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, was adopted to designate a form of this disorder as specified by genetic homogeneity . This disease has now been reported from many regions worldwide, including Europe (Jung et al., 1995;Bergmann et al., 1996), North America (Hedera and Friedland, 1997;Desmond et al., 1998) and the Far East (Nishio et al., 1997). ...
Ischaemic stroke can be caused by a number of monogenic disorders, and in such cases stroke is frequently part of a multisystem disorder. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the NOTCH: 3 gene, is increasingly appreciated as a cause of familial subcortical stroke. The genetics and phenotypes of monogenic stroke are covered in this review. However, the majority of cases of ischaemic stroke are multifactorial in aetiology. Strong evidence from epidemiological and animal studies has implicated genetic influences in the pathogenesis of multifactorial ischaemic stroke, but the identification of individual causative mutations remains problematic; this is in part limited by the number of approaches currently available. In addition, genetic influences are likely to be polygenic, and ischaemic stroke itself consists of a number of different phenotypes which may each have different genetic profiles. Almost all human studies to date have employed a candidate gene approach. Associations with polymorphisms in a variety of candidate genes have been investigated, including haemostatic genes, genes controlling homocysteine metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The results of these studies, and the advantages and limitations of the candidate gene approach, are presented. The recent biological revolution, spurred by the human genome project, promises the advent of novel technologies supported by bioinformatics resources that will transform the study of polygenic disorders such as stroke. Their potential application to polygenic ischaemic stroke is discussed.
... A T 2 -weighted MRI scan showing both confluent regions of periventricular and deep white matter high signal, referred to as leucoaraiosis, in addition to small punctate regions of high signal consistent with lacunar infarction. This patient had an exon 4 mutation in the North America (Hedera and Friedland, 1997; Desmond et al., 1998) and the Far East (Nishio et al., 1997). The clinical phenotype is characterized by subcortical stroke-like episodes, which occur usually in mid-adulthood in the absence of normal vascular risk factors, and a stepwise subcortical dementia with pseudobulbar palsy (Chabriat et al., 1995b; Dichgans et al., 1998). ...
Matarin M, Singleton A, Hardy J, Meschia J (Laboratory of Neurogenetics, Bethesda, MD, USA; UCL Institute of Neurology, London, UK; Mayo Clinic, Jacksonville, FL, USA). The genetics of ischaemic stroke (Review). J Intern Med 2010; 267: 139–155.
In this review, we discuss the genetic factors in both the aetiology and treatment of ischaemic stroke. We discuss candidate gene association studies, family linkage studies and the more recent whole genome association studies and whole genome expression studies. We also briefly discuss genetic testing for stroke risk and genetic analysis of treatment complications.
... 30,31 This expansion might be caused by the major loss of white-matter structural components (astrocytes, oligodendrocytes, axons, and myelin), a nonspecific feature of the disease. [32][33][34][35][36] This is consistent with postmortem findings in CADASIL. Histological studies in patients deceased after a long course of the disease showed a marked white-matter rarefaction with increase of the extracellular space. ...
CADASIL is a newly recognized cause of subcortical ischemic strokes that progressively leads to dementia associated with pseudobulbar palsy and severe motor disability. This deleterious progression and the severity of clinical presentation are widely variable among affected subjects. The exact role played by MRI white-matter abnormalities, a hallmark of the disease, in the severity of the clinical phenotype remains poorly understood.
To address this issue, we used diffusion tensor imaging (DTI), a new MRI technique highly sensitive to white-matter microstructural changes, in 16 symptomatic patients and 10 age-matched controls. Mean diffusivity and anisotropy of diffusion were measured within hyperintensities identified on T2-weighted images (T2WI) and outside these lesions on 4 slices at the level of centrum semiovale.
We found a 60% increase of water mean diffusivity and a parallel loss of diffusion anisotropy in hyperintensities identified on T2WI. The same pattern of diffusion changes, but of lesser intensity, was found in the normal-appearing white matter on T2WI. Mean diffusivity in regions with increased signal on T2WI was higher in patients with severe clinical disability compared with those with no or mild deficit (1.33+/-0.11 versus 1.13+/-0.11 10(-3) mm(2)/s, P<0.01). Furthermore, diffusion measured within T2 hyperintensities correlated with both the Mini-Mental State Examination and Rankin scale scores. In patients with a severe clinical status, the increase of water diffusion in these regions exceeded 70% in comparison with values obtained in the normal white matter in control subjects.
These results indicate that DTI is able to detect important ultrastructural changes in regions with increased signal on T2WI and within the normal-appearing white matter in CADASIL. The diffusion changes might be related to both neuronal loss and demyelination. The degree of the underlying ultrastructural alterations is related to the severity of the clinical status with a possible threshold level of white-matter damage above which severe neurological impairment may occur in this disease. DTI appears to be a promising technique for monitoring disease progression in CADASIL.
... CADASIL was originally described by Sourander and Walinder (1977) as an inherited, autosomally-dominant dementia with multiple infarcts. Epidemiologically, CADASIL is limited to sporadic identification in Europe (Chabriat et al., 1995; Dichgans et al., 1998) and North America (Hedera and Friedland, 1997; Desmond et al., 1998 ). The principal symptoms of CADASIL are migraine with aura, ischemic stroke, and psychiatric symptoms including dementia (Viitanen and Kalimo, 2000). ...
Sequencing of the human genome is nearing completion and biologists, molecular biologists, and bioinformatics specialists have teamed up to develop global genomic technologies to help decipher the complex nature of pathophysiologic gene function. This review will focus on differential gene expression in ischemic stroke. It will discuss inheritance in the broader stroke population, how experimental models of spontaneous stroke might be applied to humans to identify chromosomal loci of increased risk and ischemic sensitivity, and also how the gene expression induced by stroke is related to the poststroke processes of brain injury, repair, and recovery. In addition, we discuss and summarise the literature of experimental stroke genomics and compare several approaches of differential gene expression analyzes. These include a comparison of representational difference analysis we have provided using an experimental stroke model that is representative of stroke evolution observed most often in man, and a summary of available data on stroke differential gene expression. Issues regarding validation of potential genes as stroke targets, the verification of message translation to protein products, the relevance of the expression of neuroprotective and neurodestructive genes and their specific timings, and the emerging problems of handling novel genes that may be discovered during differential gene expression analyses will also be addressed.
... Typically, cognitive deficit occurs in a step-wise fashion, reflecting new ischemic events. However, many patients may present with a progressive deterioration of cognitive function without any obvious strokes or TIAs, resembling a neurodegenerative dementing process [40]. The prevalence of dementia in CADASIL is estimated between 30% to 50% in symptomatic patients, even though more patients have signs of mild cognitive deficit without meeting formal criteria for dementia [19,21,112]. ...
Dementia, defined as progressive cognitive decline, is a feature of a wide variety of genetic disorders. For example, a search of "dementia" in the Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/Omim) reveals 162 entries. Therefore this article cannot be encyclopedic and will be necessarily restricted to more prevalent or illustrative etiologies of familial dementia in adults. These disorders also have in common an initial and primarily dementing clinical presentation. Thus, this article is limited to: familial Alzheimer's disease (AD) and related amyloid angiopathies, frontotemporal dementias (FTD) and related tauopathies, familial prion diseases, British and Danish familial dementias, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
... Les études récentes avec l'imagerie de diffusion ont montré que les lésions microstructurales de la substance blanche pouvaient aussi être à l'origine du déficit cognitif dans CADASIL (cf infra) [15] . L'étude de Hédéra et al suggère qu'une démence progressive et tardive peut apparaître au cours de la maladie en raison de la destruction progressive de la substance blanche, et que des lésions ischémiques au sein des noyaux gris pourraient accélérer le déclin cognitif chez certains individus [30] . ...
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.
... The cognitive deficit most often progresses in the total absence of ischemic events, mimicking in some cases a degenerative dementia.5, 57, 58 The temporal progression of cognitive symptoms varies among subjects from rapid and marked deterioration to stable or even slightly improving performances.59 ...
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL) is an inherited small-artery disease of mid-adulthood caused by mutations of the NOTCH3 gene. The disease is responsible for widespread white-matter Iesions associated with lacunar infarctions in varinus subcortical areas. The disease is responsible for migraine with aura and ischemic strokes, and is associated with various degrees of cognitive impairment and with mood disturbances. CADASIL is considered as a unique model to investigate what is known as "subcortical ischemic vascular dementia. "Recent data suggest
that the number of lacunar infarctions and severity of cerebral atrophy are the main magnetic resonance imaging markers associated with cognitive and motor disabilities in this disorder. Mood disturbances are reported in 10% to 20% of patients, most often in association with cognitive alterations. Their exact origin remains unknown; the presence of ischemic lesions within the basal ganglia or the frontal white matter may promote the occurrence of these symptoms. Further studies are needed to better understand the relationships between cerebral lesions and both cognitive and psychiatric symptoms in this small-vessel disease of the brain.
Translation of the explosion in knowledge of acute ischemic stroke into satisfactory treatment regimens has yet to happen. At present tPA, intra-arterial prourokinase and low-molecular-weight heparin form the vanguard for therapeutic intervention, yet these treatments have a limited therapeutic window. Part of this expansion in understanding has been driven by the contribution of stroke genetics and genomics. However, despite the enormous preclinical and clinical information of receptors, enzymes, second messenger systems, and so forth, that are implicated in stroke pathophysiology, delivery of novel drug treatment has been slow. This introductory chapter discusses the multiple sources of clinical and preclinical genetic information. It will describe the importance of integrating expression information into multiple preclinical models with temporal and spatial roles in lesion pathology and, furthermore developing an understanding of function in the clinic before claiming a role in ischemic stroke. The goal of such a holistic integration of information is to increase the yield from current datasets of gene expression and ultimately to help expand the choice of treatment available to the physician and patient.
Recent reports suggest the existence of several forms of hereditary cerebrovascular disease leading to multiinfarct dementia or vascular dementia. The most common form of familial vascular dementia appears to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which has also been called a familial form of Binswanger’s disease. CADASIL is a disease of the arteries that has been linked to single missense mutations in the NOTCH 3 gene on chromosome 19. The pathogenesis of the disorder or how the mutations lead to brain infarcts and dementia is not known. Elucidation of the microvascular pathology associated with such genetic disorders not necessarily involving physiological risk factors for cardiovascular disease or stroke can bear much light on the primary vascular mechanisms that lead to ischemic blood flow and neuronal vulnerability. The investigation of vascular changes found in CADASIL may be one way of delineating direct gene effects in brain vascular and neuronal cells from peripheral influences.
CADASIL is an inherited small artery disease caused by mutations of the NOTCH3 gene. The disease is responsible for migraine with aura at onset, for transient ischemic attacks and stroke during mid-adulthood, and can lead progressively to dementia. The neuropsychiatric manifestations of CADASIL include mood and behavior disturbances and various degrees of cognitive impairment. They are observed at all stages of the disorder. Episodes of mood disturbances (depression, manic episodes) are reported in 10–20 % of patients during the course of the disease; they are usually observed after the first ischemic events. Apathy is detected in more than one-third of patients several years after onset and alters the quality of life of patients. A marked decline of cognitive performances is detected in the vast majority of subjects with aging, particularly after age 50 years. However, executive dysfunction can be detected earlier, even after the third decade using dedicated cognitive tests. Dementia occurs after 60 years, usually after repeated ischemic event, and is nearly constant at the end stage of the disorder.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy is an autosomal dominant disease affecting small vessels and often resulting in subcortical infarcts. A skin biopsy may facilitate its diagnosis as the cutaneous surface is much easier to sample than the central nervous system's tissue. Unfortunately, there is no effective treatment available today.
Seborrheic dermatitis is a multifactorial skin disease characterized by a chronic course with periods of exacerbation and remission. Although topical corticosteroids have been the mainstay of treatment, alternative therapies are often needed to avoid protracted use of topical corticosteroid therapy in order to avert side effects and to sustain control of the disorder. Topical pimecrolimus, a calcinuerin inhibitor, is a safe alternative for seborrheic dermatitis and is more ideal for long-term use. More specifically, topical pimecrolimus not only has an attractive safety profile with no risk of many of the potential side effects seen with topical corticosteroids, but also has favorable efficacy data, including more data on long-term use. This is a review of literature evaluating the efficacy and safety profile of topical pimecrolimus 1% cream for the treatment of seborrheic dermatitis.
IntroductionCADASIL is a hereditary cerebral arteriopathy leading to progressive disability and dementia usually observed at 60 years.ObservationWe report four patients aged >60 years with typical Notch3 mutations leading to CADASIL who did not have dementia or disability. Three of them presented with only transient neurological manifestations. MRI results showed extensive hyperintense signals in the white-matter on T2-weighted images contrasting with very few lacunar infarcts.Conclusion
These observations suggest that silent or symptomatic infarcts, which were rare in the present cases may be responsible for the clinical severity in this disorder.
This chapter describes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as an inherited small artery disease of mid-adulthood caused by mutations of the NOTCH3 gene on chromosome 19. The exact frequency of CADASIL remains unknown. The disease is not limited to Caucasian families although the disorder was initially recognized in European pedigrees. It has now been diagnosed in Asian, African, and American as well as in Australian and European families. The chapter emphasizes that for patients with a first lacunar stroke before the age of 65 and with leukoaraiosis, the prevalence was estimated at 2%. The screening of mutations in exons 3 and 4 was negative in limited samples of subjects with stroke or dementia in the absence of selective criteria. The acronym CADASIL was proposed to designate this disease and highlight its main characteristics when the gene responsible for the disorder was located on chromosome 19. The chapter concludes that no treatment has been evaluated for CADASIL. Because of the variability in the natural history of the disease, a large number of subjects would have to be included in a randomized trial for a preventive treatment. Some drugs are useful in relieving specific symptoms during the course of CADASIL.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease that is characterized by recurrent stroke episodes and focal neurologic deficits progressing to pseudobulbar palsy and dementia. The causative gene is the Notch3 gene on chromosome 19, and 22 missense mutations have been identified in Caucasian patients to date. To perform mutational analysis of the Notch3 gene, we identified its exon intron boundaries and prepared sets of primers for amplification of each exon. Using these primers, we determined the Notch3 gene in a Japanese family with CADASIL symptoms and found a missense mutation (Arg133Cys) in exon 4. The mutation was heterozygous and cosegregated with the disease. Thus, the Notch3 gene is responsible for CADASIL in patients across different ethnic groups.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a dominantly inherited small artery disease that leads to dementia and disability in mid-life. The clinical presentation of CADASIL is variable between and within affected families and is characterized by symptoms including migraine with aura, subcortical ischemic events, mood disturbances, apathy, and cognitive impairment. The mean age at onset of symptoms is 45 years, with variable duration of the disease ranging from 10 to 40 years. In 1996, linkage studies mapped and identified mutations in the NOTCH3 gene on chromosome 19 as causative in CADASIL. Head magnetic resonance imaging (MRI) is always abnormal in participants with NOTCH3 mutations after age 35. Magnetic resonance imaging shows on T2-weighted images or fluid attenuation inversion recovery (FLAIR) sequence, widespread areas of increased signal in the white matter associated with focal hyperintensities in basal ganglia, thalamus, and brainstem. The pathologic hallmark of CADASIL is the presence of electron-dense granules in the media of arterioles that can be identified by electron microscopic evaluation of skin biopsies.
We describe the clinical, molecular, genetic, MRI, and SPECT features of a German family with autosomal dominant migraine and dementia, mapping to the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) locus. We studied the correlation of cerebral blood flow, MRI, and cognitive function.
CADASIL is a small-vessel disease of the brain mapped to chromosome 19p13.1. Mutations of the Notch3 gene cause this disorder. Most phenotypes are characterized by transient ischemic attacks (TIAs) and lacunar strokes leading to dementia. Migraine is frequent. A single photon emission computed tomographic (SPECT) study of this disorder has not yet been published.
We studied 13 individuals clinically and performed neuroimaging studies with MRI and SPECT.
Genetic analysis strongly supported linkage to the CADASIL locus, and the disease haplotype was found in six individuals. Analysis by single-strand confirmation polymorphism did not identify Notch3 mutations. All affected individuals had MRI white matter hyperintensities and four individuals had additional basal ganglial signal abnormalities. Four affected individuals had migraine, two of whom had slowly progressive dementia. TIAs, stroke, and focal neurologic signs were absent. Cerebral blood flow reduction in SPECT studies of affected individuals matched with MRI signal abnormalities. Cognitive impairment was linked to signal abnormalities and hypoperfusion in the basal ganglia. Demented patients had a pattern of frontal, temporal, and basal ganglial hypoperfusion.
We describe a CADASIL phenotype that is characterized by the absence of focal neurologic symptoms and present the first SPECT study of this disorder.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized autosomal dominant disorder that leads to cerebrovascular manifestations in early adulthood. This study delineates the phenotypic spectrum and the natural history of the disease in 102 affected individuals from 29 families with biopsy-proven CADASIL. Recurrent ischemic episodes (transient ischemic attack [TIA] or stroke) were the most frequent presentation found in 71% of the cases (mean age at onset, 46.1 years; range, 30-66 years; SD, 9.0 years). Forty-eight percent of the cases had developed cognitive deficits. Dementia (28%) was frequently accompanied by gait disturbance (90%), urinary incontinence (86%), and pseudobulbar palsy (52%). Thirty-nine patients (38%) had a history of migraine (mean age at onset, 26.0 years; SD, 8.2 years), which was classified as migraine with aura in 87% of the cases. Psychiatric disturbances were present in 30% of the cases, with adjustment disorder (24%) being the most frequent diagnosis. Ten patients (10%) had a history of epileptic seizures. To delineate the functional consequences of ischemic deficits, we studied the extent of disability in different age groups. The full spectrum of disability was seen in all groups older than age 45. Fifty-five percent of the patients older than age 60 were unable to walk without assistance. However, 14% in this age group exhibited no disability at all. Kaplan-Meier analysis disclosed median survival times of 64 years (males) and 69 years (females). An investigation of the 18 multiplex families revealed marked intrafamilial variations.
Although numerous families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been reported, our understanding of the disease remains incomplete. Thus, we performed this study to investigate the phenotypic range and natural history of CADASIL.
We performed a pooled analysis of previously published cases.
We identified 105 symptomatic patients in 33 families. Vascular risk factors were uncommon, with hypertension reported in only 8 patients. The mean age of symptom onset was 36. 7+/-12.9 years. Stroke or transient ischemic attack was an initial symptom in 45 patients, with a mean age of onset of 41.2+/-9.2 years. Migraine was also a common initial symptom, reported by 42 patients at a younger mean age of 28.3+/-11.7 years. Other initial symptoms included depression in 9 patients, cognitive impairment in 6 patients, and seizures in 3 patients. Regarding clinical course, 71 patients experienced a stroke or transient ischemic attack, and 52 of those patients had 1 or more recurrent ischemic events. Dementia was reported in 44 patients. Only 3 additional patients experienced migraine at a later time, while 13 additional patients developed depression. Six patients had seizures. Twenty-two of the 105 patients had died, with a mean age of death of 54.8+/-10.6 years. Nineteen of those 22 patients had experienced a stroke or transient ischemic attack and 19 patients were demented.
CADASIL typically becomes evident in early or middle adulthood with migraine or an ischemic event, later manifests itself through recurrent subcortical ischemic strokes leading to a stepwise decline and dementia, and results in reduced survival.
Cerebral white matter disorders may be associated with profound neurobehavioral dysfunction. We report a 62-year-old man who had a slowly progressive 25-year history of personality change, psychosis, mood disorder, and dementia. Neurologic examination disclosed abulia, impaired memory retrieval, and preserved language, with only minimal motor impairment. Neuropsychological testing found a sustained attention deficit, cognitive slowing, impaired learning with intact recognition, and perseveration. Magnetic resonance imaging of the brain revealed extensive leukoencephalopathy. Right frontal brain biopsy showed ill-defined white matter pallor with hyaline narrowing of white matter arterioles. Granular osmiophilic material adjacent to vascular smooth muscle cells on electron microscopy of a skin biopsy, and an arginine for cysteine replacement at position 169 in the 4 EGF motif of the notch 3 region on chromosome 19q12 established the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This case illustrates that CADASIL can manifest as an isolated neurobehavioral disorder over an extended time period. The dementia associated with CADASIL closely resembles that which may occur with other white matter disorders, and represents an example of white matter dementia.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a microangiopathic syndrome. Although the defective gene has been identified, genetic analysis may be effort some due to its large size and various mutations. Providing a reliable diagnostic marker would therefore be helpful. Electron microscopy has revealed characteristic electron-dense granular deposits in the basal lamina of vessels of patients with CADASIL. We investigated the sensitivity of skin and muscle biopsies for diagnosing CADASIL. We examined 30 family members of three unrelated German families affected by CADASIL. In 14 of the 21 affected individuals we performed skin and muscle biopsies; two patients were clinically asymptomatic. Under electron microscopy all muscle and skin biopsy specimens showed patches of granular and electron-dense material in the basal layer of both arterioles and capillaries. These findings confirm that general microangiopathy is a typical feature of this syndrome and is present in the early phase of the disease with or without clinical manifestation. Thus, as electron microscopy of skin biopsy specimens can establish the diagnosis of CADASIL with high certainty, it may be considered the method of first choice.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral vasculopathy progressing to subcortical dementia, caused by multiple lacunar infarcts and ischemic white matter degeneration. Migraine with aura, epileptic seizures and affective disorders are frequent additional symptoms of CADASIL. The causative mutations of the Notch3 gene are located on chromosome 19p13.1. There is complete penetrance of this disorder, although individual expression of symptoms may vary. Manifestation of CADASIL is usually in the 3rd decade, but some individuals remain asymptomatic close to the age of 60. MRI displays a marked leukoencephalopathy in affected individuals as early as in the age of 20. Frontal and subcortical hypoperfusion in demented individuals was demonstrated by SPECT-studies. The prevalence of CADASIL is still not known. To date there is no causative therapy.
The most common form of familial vascular dementia is considered to be CADASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is now also increasingly manifest in the United Kingdom. CADASIL has been previously dubbed as a familial form of Binswanger disease. However, unlike in Binswanger disease CADASIL does not involve hypertension or other risk factors associated with cardiovascular disease. CADASIL appears to be essentially a disorder of the arteries that is linked to single missense mutations in the NOTCH 3 gene locus on chromosome 19. The pathogenesis of the disorder or the genetic mechanism leading to brain infarcts and dementia is not known. The elucidation of the microvascular pathology evident in CADASIL may be an interesting way to delineate effects of defective genes on brain cells from systemic vascular influences.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described neurovascular disease affecting young to middle age individuals. The disease is caused by mutations in the Notch3 gene located in the short arm of chromosome 19. Clinically, the disease is characterized by migrainous headaches (with or without aura), mood disturbances, focal neurologic deficits, transient ischemic attacks, strokes, and dementia. Pathologically, the disease is characterized by a stereotypic degeneration of the arterial walls (especially in the intracranial compartments) with deposition in the media of a nonatheromatous, nonamyloidotic substance that under the electron microscope (EM) appears as a granular osmiophilic material (GOM), pathognomonic for the disease. The nature of the GOM is undetermined and the pathogenesis remains to be elucidated. A review of current literature in English language is presented on the clinical, radiologic, pathologic, and genetic features of CADASIL.
Atypical phenotypes of CADASIL and corresponding anatomical data in two cases are described in 6 members of 2 new French families. In the first family, 4 cases in the same kindred were probably affected, two of them with a predominant psychiatric presentation, two others with dementia and a pseudo-bulbar syndrome of progressive evolution. No history of migraine or ischemic event were documented in any. In the propositus, the diagnosis was documented by skin biopsy, Notch 3 gene mutation and autopsy after the patient had died when 67 years old, 8 years after onset. Brain examination showed a widespread leukoencephalopathy with subcortical infarcts. Characteristic granular lesions of the small arteries of the brain and other organs were observed. In the second family, two cases are reported. One patient died when 63 years old after a subacute evolution mimicking intracranial hypertension. The anatomical diagnosis was retrospectively proven typical of CADASIL with Notch 3 immunostaining of arterial smooth muscle cells. The other case had a progressive evolution over 20 years of limb paresthesia with a mild spasticity diagnosed as a progressive form of multiple sclerosis. It was followed by a pseudo-bulbar syndrome and a mild subcortical dementia without acute ischemic attack. The diagnosis was confirmed by skin biopsy and mutation of the Notch 3 gene. This report illustrates
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (CADASIL) is a recently described cause of stroke or stroke-like episodes. It is caused by mutations in the Notch3 gene on chromosome 19p. We sought to demonstrate mutations of the Notch3 gene in Australian patients suspected of having CADASIL. Patients from several families were referred to the study. A diagnosis was determined clinically and by neuroimaging. Those suspected of having CADASIL had sequencing of exons 3 and 4 of the Notch3 gene. Eight patients, two of whom were siblings, were suspected of having CADASIL. Five patients (including the siblings) had mutations. Because of strong clustering of Notch3 mutations in CADASIL, this has potential as a reliable test for the disease in Australian patients.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary brain disease with a variety of neurologic and psychiatric manifestations. We studied 3 members of a family who each had leukoencephalopathy on neuroimaging studies and a characteristic mutation for CADASIL in the notch 3 region of chromosome 19q12. In all 3 cases, neurobehavioral impairment dominated the clinical picture, and a pattern of psychiatric dysfunction heralding cognitive decline emerged. Neuropsychological evaluation revealed diverse deficits, but a profile of frontal lobe dysfunction, declarative memory impairment suggestive of a retrieval deficit, and relatively preserved language was evident. These cases provide a cross-sectional study of the evolution of CADASIL, and suggest that, as in other diseases characterized by white matter dementia, psychiatric dysfunction may occur initially, followed by pervasive cognitive dysfunction later in the course of the disease. CADASIL should be considered in young adults with unexplained leukoencephalopathy on neuroimaging studies, and in those with neurobehavioral dysfunction and a suggestive family history.
Recent advances suggest the existence of several autosomal dominantly inherited forms of cerebrovascular disorders. Mutations in diverse genes may induce direct pathological changes in intracranial vessels to cause cerebral ischaemic or haemorrhagic strokes leading to cognitive impairment and dementia. Similar pathology may also be caused by systemic vascular disease resulting from mutations and polymorphisms in genes that regulate cardiovascular physiology, blood coagulation and metabolic functions. The most common form of familial stroke appears to be CADASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is an arterial disease that has been linked to nucleotide substitutions and deletions in the Notch 3 gene. The pathogenesis of the disorder or how the mutations lead to cerebral infarcts and dementia is not known. However, elucidation of the microvascular pathology associated with such genetic disorders not associated with physiological risk factors for cardiovascular disease or stroke can bear much light on primary vascular mechanisms that lead to ischaemic blood flow and neuronal vulnerability.
CADASIL is a small artery disease of the brain responsible for migraine with aura, subcortical ischemic strokes, mood disturbances and dementia. The disease is transmitted with an autosomal dominant pattern and usually starts during midadulthood. On MRI, the presence of more or less diffuse signal abnormalities within the white-matter associated with typical lacunar infarcts are suggestive of the disorder. The definite diagnosis is obtained using genetic testing which is currently used to detect the most frequent mutations of the Notch3 gene on chromosome 19. Skin biopsy with electron microscopy or immunostaining of the Notch3 protein are also useful as complementary diagnostic tool. The frequency of CADASIL remains largely underestimated.
CADASIL is a hereditary cerebral arteriopathy leading to progressive disability and dementia usually observed at 60 years.
We report four patients aged>60 years with typical Notch3 mutations leading to CADASIL who did not have dementia or disability. Three of them presented with only transient neurological manifestations. MRI results showed extensive hyperintense signals in the white-matter on T2-weighted images contrasting with very few lacunar infarcts.
These observations suggest that silent or symptomatic infarcts, which were rare in the present cases may be responsible for the clinical severity in this disorder.
Psychiatric manifestations are an integral part of Huntington's disease. They may be divided into those syndromes which resemble idiopathic disorders, but for which HD patients may be particularly at risk, those constellations which are peculiar to HD and related conditions, such as the executive dysfunction syndrome, and those symptoms that can truly be regarded as nonspecific, such as delirium. Most of these problems are believed to arise from subcortical neuropathologic changes. Major depression is a common psychiatric diagnosis, but the executive dysfunction syndrome, a difficult-to-define condition characterized by often simultaneous apathy and disinhibition, may be even more widespread. There are no large controlled studies of psychiatric treatments in HD, but case series, anecdotal reports, and clinical experience indicate that many of these syndromes respond readily to treatment. Further study of the neuropsychiatry of HD may help to reveal the underpinnings of psychiatric conditions found in the general population.
Tourette's syndrome (TS) is a disorder characterized by simple and complex motor tics, vocal tics, and frequently obsessive-compulsive symptoms. Its onset occurs before the age of 21. Typically, TS shows a waxing and waning course, but a chronification of the tics, even during later life, is often observed. TS mainly occurs in boys, and shows genetic heritability with differing penetrance. The pathological mechanism is still unclear Neuroanatomical and neuroimaging studies, as well as effective treatment using antipsychotics, suggest that a disturbance of the dopaminergic system in the basal ganglia plays an important role in the pathogenesis of TS. Several possibly causative mechanisms of the disturbed dopaminergic neurotransmission are discussed, with the main emphasis on the-infection-triggered-inflammatory immune process. Extrapyramidal movement disorders are known to occur as a symptom of poststreptococcal disease, such as in Sydenham's chorea. Cases of childhood TS are proposed to be caused by such a poststreptococcal mechanism, being part of a spectrum of childhood neurobehavioral disorders termed pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS). The overlap between TS and PANDAS is discussed, and a critical view of the PANDAS concept is presented. The therapeutic implications of the different pathological mechanisms are described, taking into consideration not only the acute or chronic natures of different infections, but also an autoimmune process. Moreover, therapeutic strategies using typical and atypical antipsychotics, and also experimental therapies such as repetitive transcranial magnetic stimulation and deep brain stimulation, are critically discussed.
Behavioral manifestations may dominate the clinical picture of the frontal variant of frontotemporal dementia (fv-FTD) for a long time before the appearance of true cognitive deficits. On the other hand, a deficit in the episodic memory domain represents the main manifestation of Alzheimer's disease (AD). Many behavioral disorders have been described in the clinical course of both FTD and AD; however, apathy and personality changes characterize frontal dementias, while depression dominates in AD, at least in the earlier stages. Depending on the distribution of neural damage, different patterns of noncognitive manifestations may be expected in different subtypes of FTD. Recent research on the social cognition deficit in FTD has offered new insights into the relationship between cognition and behavior, suggesting that some aspects of the behavioral changes in dementia may be generated by impairment in this domain.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disease characterized by ischemic stroke with early onset, migraine, seizures, and vascular dementia. CADASIL is associated with mutations within NOCT3 gene, mainly clustered in exons 3 and 4. We report a case of CADASIL presenting progressive subcortical dementia in the sixth decade. Neither family history, nor acute ischemic events were present. MRI findings were typical for CADASIL. NOTCH3 analysis disclosed a new missense mutation within exon 7, leading to the substitution of cysteine 366 with a tryptophan (Cys366Trp). Our finding suggests CADASIL diagnosis must be considered in patients with vascular dementia also in absence of stroke-like events and of family history.
We studied 23 patients with clinically defined mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), 25 oligosymptomatic or asymptomatic maternal relatives, and 50 mitochondrial disease control subjects for the presence of a previously reported heteroplasmic point mutation at nt 3,243 in the transfer RNALeu(UUR) gene of mitochondrial DNA. We found a high concordance between clinical diagnosis of MELAS and transfer RNALeu(UUR) mutation, which was present in 21 of the 23 patients with MELAS, all 11 oligosymptomatic and 12 of 14 asymptomatic relatives, but in only five of 50 patients without MELAS. The proportion of mutant genomes in muscle ranged from 56 to 95% and was significantly higher in the patients with MELAS than in their oligosymptomatic or asymptomatic relatives. In subjects in whom both muscle and blood were studied, the percentage of mutations was significantly lower in blood and was not detected in three of 12 asymptomatic relatives. The activities of complexes I + III, II + III, and IV were decreased in muscle biopsies harboring the mutation, but there was no clear correlation between percentage of mutant mitochondrial DNAs and severity of the biochemical defect.
A 49-year-old normotensive man died after a series of strokes, slowly evolving dementia and personality change occurring over a period of 23 years. CT scan showed large infarcts involving the cortex and white matter of the temporo-occipital areas, small subcortical infarcts and low attenuation in the white matter of the frontal and parietal lobes. Neuropathological examination revealed large cortical and small subcortical infarcts corresponding to the radiological findings as well as degeneration/demyelination of central white matter corresponding to the areas of low attenuation seen on CT. The basic underlying pathological process was hyaline arteriosclerosis and atheroma which diffusely affected the small intracerebral arteries and to a lesser extent the arteries of the circle of Willis. Though usual because of the absence of hypertension, the very early age at onset of the syndrome and the presence of large cortical infarcts this case illustrates the clinical, radiological and neuropathological features of subcortical arteriosclerotic encephalopathy (Binswanger's type).
A survey was carried out on a large family presenting the symptoms of familial arteriopathy (CADASIL) recently mapped to chromosome 19. This is characterised clinically by recurrent subcortical infarcts developing into pseudobulbar palsy and subcortical dementia, and radiologically by early MRI abnormalities. To characterise this familial condition, 43 members older than 20 years and spreading over four generations were studied clinically (31 living, 12 deceased), genetically, and radiologically by MRI (n = 31). Twenty out of 43 were found to be clinically symptomatic and of these 13 out of 31 had MRI abnormalities. Genetic studies mapped this condition to the locus of CADASIL (lod score > 3). The natural history suggests a chronological clinicoradiological staging of this phenotype of CADASIL: stage I between 20 and 40 years with frequent migraine-like episodes and well delineated lesions of the white matter; stage II between 40 and 60 years with stroke-like episodes, bipolar or monopolar-like psychotic disorders, coalescent lesions of the white matter, and well delineated lesions of the basal ganglia; and stage III over 60 years with subcortical dementia, pseudobulbar palsy, diffuse leukoencephalopathy, and multiple well delineated lesions of the basal ganglia. This phenotype differs from the other two previously described by high frequency of migraine, frequency of psychotic disorders, and early neurological manifestations. The new acronym "cerebral autosomal dominant arteriopathy with subcortical infarcts, leukoencephalopathy, and migraine" (CADASILM) is proposed to better describe this particular subvariety of CADASIL.
This paper reports a Swiss family affected by a cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) linked to chromosome 19q12. In three generations several members of this family had recurrent stroke-like episodes and, some developed subcortical dementia, migraine-like headaches, and depression. The clinically affected family members had multiple subcortical infarcts and diffuse leukoencephalopathy on MRI. Necropsy of one patient showed a distinctive non-amyloid and non-atherosclerotic angiopathy of small cerebral and leptomeningeal arteries with concentric depositions of a basophilic granular material replacing the smooth muscle cells of the media. Linkage analysis with five chromosome 19 markers spanning the estimated CADASIL interval showed the absence of any recombinant and positive Lod scores, highly suggestive of linkage of this condition to the CADASIL locus. CADASIL might be an underestimated cause of familial stroke and should be considered in the differential diagnosis of hereditary stroke.
Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-epsilon 4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50 +/- 0.06; the allele frequency of APOE-epsilon 4 in 91 age-matched unrelated controls was 0.16 +/- 0.03 (Z = 2.44, P = 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary CNS disease with autosomal dominant inheritance caused by NOTCH3 gene mutations. Typically, CADASIL manifests with headaches, recurrent strokes, and progressive cognitive decline. Neuroimaging plays an important diagnostic role as it reveals multiple lacunar infarcts in the basal ganglia, brainstem, and cerebellum, as well as focal white matter lesions and diffuse leukoaraiosis-type changes. CADASIL can sometimes have other symptoms and mimic different phenotypes atypical of the disease. We hereby present two genetically confirmed CADASIL cases that manifested with predominantly cerebellar or essential tremor combined with cognitive and affective disturbances. The main principles of diagnosis of this disease characterized by clinical polymorphism are discussed.
Eight patients are reported who shared the combination of bilateral basal ganglia lesions and a frontal lobe-like syndrome. The main features were inertia and loss of drive, with preservation of intellectual function. Some patients showed stereotyped activities with compulsive and obsessive behaviour which were sometimes highly elaborate in pattern. Extrapyramidal clinical signs were absent or mild. Brain damage, related to anoxic or toxic encephalopathy, was demonstrated by CT scans and MRI. The lesions appeared to be confined to the lentiform nuclei, particularly affecting the pallidum, although there was generalized brain atrophy in 2 cases. Positron emission tomography (PET) in 7 patients revealed hypometabolism of the prefrontal cortex relative to other parts of the brain. The PET studies suggest dysfunction of the prefrontal cortex as a result of damage to the lentiform nuclei These clinical, anatomical and functional observations emphasize the role of the circuits linking the prefrontal associative cortex and some specific areas of the neostriatum, including the pallidum. The existence of distinct nonoverlapping circuits in the motor field or in the associative field can explain the fact that basal ganglia lesions may give rise to a clinical picture that is either purely motor, purely behavioural (as in some of our patients), or both. Similarities existed between some symptoms found in our patients and certain features of major psychiatric illnesses such as severe depression, catatonic schizophrenia, and obsessive-compulsive disorder. This raises the hypothesis that some aspects of these psychiatric disorders could be related to structural and physiological disturbances in the systems linking the frontal associative cortex and the basal ganglia.
CADASIL is the acronym (Cerebral Autosomal Dominant Arteriopathy with Subcortical Ischemic Strokes and Leukoencephalopathy) designating a recently identified mendelian cerebral arteriopathy characterized by the recurrence of ischemic sensory and motor deficits leading to a progressive subcortical dementia. Magnetic resonance imaging of the brain shows extensive areas of increased signal in the hemispheric white matter. We recently mapped the CADASIL locus in 2 large families on chromosome 19 in a 14 cM interval bracketed by D19S221 and D19S215{sup *}. Forty additional families have been collected. Twelve of them including more than 200 members have already been genotyped with a set of 10 highly polymorphic markers located between D19S221 and D19S215. All families are significantly linked to chromosome 19 demonstrating genetic homogeneity. Combined lod scores for several of these markers are above 30. The size of the mapping interval has been reduced to 2 cM. Genetic testing for presymptomatic individuals is now possible with respect to all ethical rules in this severe condition. Lastly, physical mapping of the affected gene has been started and data will be presented at the meeting.
A family is described in which for three subsequent generations numerous individuals were affected with a progressive neuropsychiatric disease with pyramidal, bulbar and cerebellar symptoms, relapsing course and gradually evolving severe dementia.
Post-mortem studies performed on three siblings afflicted with the disease suggest that the remarkably uniform macroscopic picture of the cerebral changes consisting in multiple small cystic infarctions, particularly localized to the central grey and white matter and pons as well as the cortical and central brain atrophy, is caused by an occlusive disease of small intracerebral and leptomeningeal arteries and arterioles. Collected pertinent information concerning the affected family members shows that the illness begins in early adulthood (at 29–38 years of age), affects both sexes and generally lasts for 10–15 years. The only exception so far noticed was a second generation descendant of one of the siblings. This patient died about 5 months after clinical onset of the disease in masslve cerebral haemorrhage and showed similar vascular changes as the older members of the family. The disease is considered to be genetically caused and transmitted as a dominant autosomal character. For this apparently new nosological entity the eponym “hereditary multi-infarct dementia” is suggested.
SummaryCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain recently mapped to chromosome 19. We studied 148 subjects belonging to seven families by magnetic resonance imaging and genetic linkage analysis. 45 family members (23 males and 22 females) were clinically affected. Frequent signs were recurrent subcortical ischaemic events (84%), progressive or stepwise subcortical dementia with pseudobulbar palsy (31%), migraine with aura (22%), and mood disorders with severe depressive episodes (20%). All symptomatic subjects had prominent signal abnormalities on MRI with hyperintense lesions on T2-weighted images in the subcortical white-matter and basal ganglia which were also present in 19 asymptomatic subjects. The age at onset of symptoms was mean 45 (SD [10·6]) years, with attacks of migraine with aura occurring earlier in life (38·1 [8·03] years) than ischaemic events (49·3 [10·7] years). The mean age at death was 64·5 (10·6) years. On the basis of MRI data, the penetrance of the disease appears complete between 30 and 40 years of age. Genetic analysis showed strong linkage to the CADASIL locus for all seven families, suggesting genetic homogeneity.CADASIL is a hereditary cause of stroke, migraine with aura, mood disorders and dementia. The diagnosis should be considered not only in patients with recurrent small subcortical infarcts leading to dementia, but also in patients with transient ischaemic attacks, migraine with aura or severe mood disturbances, whenever MRI reveals prominent signal abnormalities in the subcortical white-matter and basal ganglia. Clinical and MRI investigations of family members are then crucial for the diagnosis which can be confirmed by genetic linkage analysis. The disease is probably largely undiagnosed.
A family is described in which for three subsequent generations numerous individuals were affected with a progressive neuropsychiatric disease with pyramidal, bulbar and cerebellar symptoms, relapsing course and gradually evolving severe dementia. Post-mortem studies performed on three siblings afflicted with the disease suggest that the remarkably uniform macroscopic picture of the cerebral changes consisting in multiple small cystic infarctions, particularly localized to the central grey and white matter and pons as well as the cortical and central brain atrophy, is caused by an occlusive disease of small intracerebral and leptomeningeal arteries and arterioles. Collected pertinent information concerning the affected family members shows that the illness begins in early adulthood (at 29--38 years of age), affects both sexes and generally lasts for 10--15 years. The only exception so far noticed was a second generation descendant of one of the siblings. This patient died about 5 months after clinical onset of the disease in massive cerebral haemorrhage and showed similar vascular changes as the older members of the family. The disease is considered to be genetically caused and transmitted as a dominant autosomal character. For this apparently new nosological entity the eponym "hereditary multi-infarct dementia" is suggested.
Clinical and pathological studies have been conducted on two brothers with unusual encephalopathy of Binswanger's type. The disease started in the third decade with steady progressive course leading to death in eight or nine years. The clinical picture was summarized as a combination of organic dementia, extrapyramidal disorders associated with pseudobulbar symptoms and marked pyramidal tract signs. The blood pressure remained always normal during the course. Pathologically, there were diffuse and focal demyelination with sparing of U-fibers, multiple small foci of perivascular softening in the cerebral white matter and in the basal ganglia and severe arterio-sclerotic changes of meningeal small arteries and long arteries with 100 to 400 micron caliber in the cerebral white matter. Vessel changes consisted of fibrous intimal proliferation, severe hyalinosis and splitting of intima and/or internal elastic membrane.
The histopathological process belonged to the category of subcortical arteriosclero-tic encephalopathy of Binswanger's type. There has been some discussion as to differential diagnosis among various forms of vasculitis such as cerebral endangiitis obli-terans, periarteritis nodosa, systemic lupus erythematosus, rheumatic vascular disease and giant cell arteritis.
The distribution of occlusive atherosclerotic lesions in the aortocranial circulation as determined by arteriography was correlated with results of plasma lipid and lipoprotein determinations of patients with symptoms and signs of cerebrovascular disease. The incidence of hyperlipoproteinemia in the total study population was 31.8%. The frequency of hyperlipoproteinemia was signigicantly higher in patients with atherosclerotic lesions limited to extracranial (51%) and intracranial major vessels (44.2%) when compared to the total number of patients and patients with only intracranial small-vessel disease (P less than .05). Type IV hyperlipoproteinemia was the most common abnormality (extracranial group, 42% type IV, 9% type II; intracranial major-vessel group, 35.8% type IV, 8.4% type II). Patients with intracranial small-vessel disease had the lowest frequency of hyperlipoproteinemia (14.2%). The frequency of hypertension with or without hyperlipoproteinemia was higher in patients with intracranial small-vessel disease (P less than .01).
A family had a disorder characterized by (1) a pattern suggestive of autosomal dominant inheritance, (2) recurrent attacks of focal brain deficits starting in mid adulthood and often leading to severe motor disability with pseudobulbar palsy and dementia of the subcortical type, and (3) neuroimaging evidence of leukoencephalopathy and well-circumscribed lesions consistent with small deep infarcts. Some affected members were clinically asymptomatic but had MRI signs of leukoencephalopathy. Extensive investigations failed to uncover a previously described recognizable genetic disorder.
We describe 2 normotensive sisters presenting slowly progressive dementia associated with acute or subacute focal neurological symptoms, unilateral or bilateral motor signs, and dysarthria. Their father, who died in the seventh decade, had a similar clinical picture. Computerized axial tomography (CT) scan of the head showed symmetrical hypodensities in the periventricular white matter and mild to moderate hydrocephalus. In these patients a diagnosis of Binswanger's disease was based on the clinical features supported by white matter changes on CT scan. Our study suggests that genetic factors may play a role in the etiology of Binswanger's disease.
We conducted a prospective survey of a family presenting a new syndrome characterized mainly by recurrent strokelike episodes and neuroimaging evidence of leukoencephalopathy.
Forty-five members of a single family were studied clinically and with magnetic resonance imaging. Nine had strokelike episodes, including transient ischemic attacks, and minor or major strokes starting between the fourth and sixth decades, with neuroimaging evidence of small, deep infarcts and a widespread white matter disorder. Other symptoms included migraine (three), dementia (two), epilepsy (one), and hearing loss (one). In some patients, we found various immunologic anomalies and muscular lipidosis without ragged-red fibers. Eight other family members were clinically normal, but had identical neuroimaging signs of leukoencephalopathy. No abnormality was detected in the 28 other members of the family examined. Extensive investigations failed to reveal any known cause of cerebral ischemia.
There appears to be a new syndrome in this family that is characterized by recurrent subcortical strokelike episodes, leukoencephalopathy, immunologic anomalies, muscular lipidosis, and an autosomal dominant pattern of transmission.
The issues described above are important for understanding genetic diseases in populations. The techniques described below are used for studying the molecular genetic abnormalities responsible for these complex diseases
A genetic component in the etiology of Alzheimer disease (AD) has been supported by indirect evidence for several years, with autosomal dominant inheritance with age-dependent pcnctrancc being suggested to explain the familial aggregation of affecteds. St. George Hyslop et al. reported linkage of familial AD (FAD) in four early-onset families (mean age at onset [M] < 50 years). Subsequent studies have been inconsistent in their results; Goate et al. also reported positive lod scores. However, both Pericak-Vance et al.'s study of a series of mainly late-onset FAD families (M > 60 years) and Schellenberg et al.'s study failed to confirm linkage to chromosome 21 (CH21). These various studies suggest the possibility of genetic heterogeneity, with some families linked to CH21 and others unlocalized. Recently, St. George Hyslop et al. extended their analysis to include additional families. The extended analyses supported their earlier finding of linkage to CH21, while showing strong evidence of heterogeneity between early-onset (M < 65 years) and late-onset (M > 60 years) FAD families. Because our families did not show linkage to CH21, we undertook a genomic search for an additional locus for FAD. Because of both the confounding factor of late age at onset of FAD and the lack of clear evidence of Mendelian transmission in some of our families, we employed the affected-pedigree-member (APM) method of linkage analysis as an initial screen for possible linkage. Using this method, we identified two regions suggesting linkage: the proximal long arm of chromosome 19 (CH19) and the CH21 region of FAD linkage reported by St. George Hyslop et al. Application of standard likelihood (LOD score) analysis to these data support the possibility of an FAD gene located on CH19, particularly in the late-onset FAD families. These data further suggest genetic heterogeneity and delineate this region of CH19 as an area needing additional investigation in FAD.
Eight patients are reported who shared the combination of bilateral basal ganglia lesions and a frontal lobe-like syndrome. The main features were inertia and loss of drive, with preservation of intellectual function. Some patients showed stereotyped activities with compulsive and obsessive behaviour which were sometimes highly elaborate in pattern. Extrapyramidal clinical signs were absent or mild. Brain damage, related to anoxic or toxic encephalopathy, was demonstrated by CT scans and MRI. The lesions appeared to be confined to the lentiform nuclei, particularly affecting the pallidum, although there was generalized brain atrophy in 2 cases. Positron emission tomography (PET) in 7 patients revealed hypometabolism of the prefrontal cortex relative to other parts of the brain. The PET studies suggest dysfunction of the prefrontal cortex as a result of damage to the lentiform nuclei. These clinical, anatomical and functional observations emphasize the role of the circuits linking the prefrontal associative cortex and some specific areas of the neostriatum, including the pallidum. The existence of distinct nonoverlapping circuits in the motor field or in the associative field can explain the fact that basal ganglia lesions may give rise to a clinical picture that is either purely motor, purely behavioural (as in some of our patients), or both. Similarities existed between some symptoms found in our patients and certain features of major psychiatric illnesses such as severe depression, catatonic schizophrenia, and obsessive-compulsive disorder. This raises the hypothesis that some aspects of these psychiatric disorders could be related to structural and physiological disturbances in the systems linking the frontal associative cortex and the basal ganglia.
We report behavioral and cognitive characteristics of 12 patients with caudate nuclei lesions, 11 unilateral and one bilateral. These patients developed an acute behavioral change characterized by apathy, disinhibition, or a major affective disturbance. The pattern of personality change correlated with size and location of lesion within the caudate but not the laterality. Seven patients were further compared with matched controls on a series of neuropsychological tests. Their performance was impaired on tasks requiring planning and sequencing. They had short attention spans and decreased free recall of episodic and semantic items with good recognition memory scores. Similar behavioral and cognitive changes also occur in early Huntington's disease, frontal-lesioned patients, and caudate-lesioned animals, and correspond to disturbances of specific frontal-caudate circuits. These results implicate the caudate nuclei in mediating prefrontal behaviors and possibly in the conceptual integration of memories.
There are many genetic disorders associated with an increased risk for stroke that may easily be overlooked in the evaluation of both adult and pediatric acute stroke victims. The recognition of a genetic disorder as the cause of a stroke has important implications not only for the immediate care of the stroke victim, but often also for others in the patient's family who may be at risk for the same disease and for whom preventive measures sometimes can be taken. We present here a comprehensive review of genetic disorders associated with stroke in the nongeriatric age groups for which a causative role in the evolution of stroke has been recognized or is likely. For each disorder, the major clinical and biochemical characteristics as well as the probable pathogenetic mechanisms of stroke are discussed, together with the appropriate testing required to screen for and confirm the diagnosis. The great variety of genetic disorders and mechanisms causing stroke underscores the increasing importance of understanding genetic disease for appropriate diagnosis and treatment of a common clinical problem affecting both children and adults.
We studied forty patients with CT-proven thalamic infarcts without involvement of the superficial territory of the posterior cerebral artery. The delineation into four arterial thalamic territories (inferolateral, tuberothalamic, posterior choroidal, paramedian) corresponded clinically to four different syndromes. The most common etiologies were lacunar infarction, large artery atherosclerosis with presumed artery-to-artery embolism, cardioembolism, and migrainous stroke. We found no risk factor other than age or oral contraceptive use in six patients. One patient died in the acute phase. During follow-up (45.6 months), the stroke or death rate was 7.4% per year. Delayed pain developed in three patients and abnormal movements in three. Late disability was mainly secondary to persisting neuropsychological dysfunction (thalamic dementia).
This paper summarizes the clinical and genetic features of a disease occurring in 16 patients from the same extended family, which resembles the multi-infarct dementia described by Sourander and Wålinder [Acta neuropath. 39: 247-254, 1977]. This family has relapsing strokes with neuropsychiatric symptoms, and they affect relatively young adult individuals of both sexes. The entity of the disease is characterized by autosomal dominant transmission with late onset and by association with occlusive cerebrovascular infarcts in the white matter, which was also generally reduced. Both of these features can be seen in the CT scan. In 13 members of this family the diagnosis can be regarded as certain and in a further 3 cases as more or less probable.
Vascular dementia is usually sporadic and associated with definite risk factors. Several cases also occur in a familial fashion, and may affect middle-aged or even younger subjects. Recently, an autosomal dominant inheritance was demonstrated in two unrelated French families, the members of which were affected by stroke-like episodes culminating in progressive dementia. Genetic linkage analysis assigned the disease locus to chromosome 19q12. We report an additional kindred of Italian origin in which at least 16 subjects presented leukoencephalopathic alterations. Recurrent strokes, psychiatric disturbances, dementia, and in 2 members, tetraplegia and pseudobulbar palsy were the hallmarks of this syndrome. Notably, 5 asymptomatic individuals had neuroradiological signs of leukoencephalopathy. Pathological examination of 1 subject revealed a widespread vasculopathy of the perforating arterioles, characterized by deposition of eosinophilic-congophilic material that did not immunostain with antibodies against prion protein, beta-amyloid, cystatin C, transthyretin, or heat-shock protein 70 and was similar to that described in the French families. Based on the maximum lod score, the most likely location for the disease locus was also mapped to chromosome 19q12, and found to coincide with the CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) locus. The present results confirm the existence of a nosologically distinct, autosomal dominant cerebrovascular disease, presenting with recurrent subcortical ischemic strokes independent of vascular risk factors.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy' (CADASIL) has recently been identified as a hereditary disorder with characteristic fine structural changes of small intracerebral arteries and arterioles. Electron microscopically there are characteristic perivascular deposits of granular electron-dense material resembling immunoglobulin deposits. The present case from a family with four affected members in three successive generations shows that similar vascular changes as described in the central nervous system are present in blood vessels of the sural nerve, although less pronounced and, therefore, affording electron microscopy for their unequivocal detection. Nevertheless it has been shown for the first time that the diagnosis of CADASIL can be verified by a sural nerve biopsy. Occasional focal accumulation of pinocytotic vesicles opposite the granular deposits suggests exocytosis as one of the possible pathomechanisms for their production.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare hereditary stroke disease. The gene has been recently mapped, in two French families, on chromosome 19q12 between two highly polymorphic genetic markers. We report on a new large Italian family affected with this disease, which is characterized by recurrent stroke episodes, focal neurological deficits progressing to pseudo-bulbar palsy, and dementia. Multiple deep infarcts and diffuse leucoencephalopathy were revealed by MRI and brain histopathology showed abnormalities of arterial media. A genetic study performed with microsatellite markers from region 19q12 showed that the disease locus lies in an interval largely overlapping that already described and is closely linked to two microsatellite markers, D19S212 and D19S222. A joint analysis of genotypic and phenotypic data shows that diffuse leucoencephalopathy is a reliable sign of the disease in otherwise normal 50%-risk subjects over the age 30 years and that penetrance of stroke episodes or dementia is most likely complete around age 60 years.
A 55-year-old mildly hypertensive woman died after having developed a subcortical dementia during the past 9 years, with focal neurological signs. She presented at the age of 46 years with short episodes of dizziness and diplopia, suggesting that transient ischemic attacks involved the posterior fossa structures. Over the next 8 years, she developed difficulty in walking, urinary incontinence and seizures. On examination in 1989, she was severely demented. There was tetraparesis, bilateral arm and leg spasticity with hyperreflexia and bilateral Babinski signs. She showed epilepsia partialis continua involving the eyes, left hemiface and limbs. CT showed hypodensity of the white matter and lacunes in the basal ganglia and centrum semiovale, moderate hydrocephalus with cerebellar and cortical atrophy. Clinical and radiological features were similar to those of Binswanger's disease. Similar cases had occurred in the family affecting the patient's grandfather, father and two brothers, suggesting an autosomal dominant hereditary disease. Postmortem examination disclosed a Binswanger type of leukoencephalopathy caused by a peculiar microangiopathy characterized by a slightly basophilic small arterial granular degeneration of the medial sheath associated with the presence of ballooned smooth muscle cells with clear cytoplasm. Electron microscopic study revealed degenerative changes in the parietal vessels with notable increase of basal-membrane-type material and electron-dense granular deposits. These lesions could correspond to a specific familial pathology of the small arteries of the brain. They are identical to those reported in some patients with autosomal dominant inheritance. For other patients with similar clinical features and the same familial pattern, reported as "hereditary multi-infarct dementia'' and "chronic familial vascular encephalopathy'', there are no sufficient objective pathological facts to consider that they have the same disease.(ABSTRACT TRUNCATED AT 250 WORDS)
A 49-year-old man suffered from progressive dementia and seizures leading to death after 2 years. CT scans showed severe cortical-subcortical atrophy and hypodensity of the white matter. His father had died at about the same age with similar clinical signs. Two sisters and one brother were also affected. Neuropathological study revealed predominant involvement of the cerebral white matter with myelin loss, gliosis and type I lacunes. The small arteries and arterioles of the white matter and basal ganglia, and, to a lesser extent those of the subarachnoidal space, displayed fibrosis and replacement of the media by an eosinophilic, PAS positive, Congo Red negative, granular substance. Electron microscopy showed swollen myocytes surrounded by collagen, elastin and a compact electron-dense material. Immunofluorescence using antibodies against IgA, IgG, IgM, C1q and C3 stained the abnormal media weakly. In the cortex, there were diffuse senile plaques and neurofibrillary tangles. Immunohistochemistry demonstrated beta/A4 positive material in cortical senile plaques but not in arterial walls. Adventitial macrophages were, however, immunoreactive for gamma-trace. Systemic arterioles were normal. The vascular changes and leukoencephalopathy are comparable to those described in 'Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy' (CADASIL). Similar vascular changes were also observed in nonfamilial cases. An association with Alzheimer changes in the cortex has not been described previously. The relationship between both diseases and the role of each in the causation of the dementia is unclear.
We recently described an autosomal dominant syndrome characterized mainly by recurrent strokes and neuroimaging evidence of leukoencephalopathy. We now report the pathological findings in one of the affected subjects.
A 40-year-old woman experienced her first grand mal seizure in 1971. From 1983 on she suffered recurrent strokes, seizures, and psychiatric disturbances with depressions, manic episodes, and dementia. In 1988, after her fourth stroke, she became tetraplegic with a severe pseudobulbar palsy, and she died in 1990. Pathological examination disclosed a recent capsulolenticular hematoma, multiple small deep infarcts, a diffuse myelin loss and pallor of the hemispheric white matter, and a widespread vasculopathy of the small arteries penetrating the white matter. The arterial wall was markedly thickened with an extensive nonamyloid eosinophilic deposit in the media and reduplication of the internal elastic lamella.
The underlying lesion of this hereditary disorder is located in the small arteries and is of unknown etiology. It differs from arteriosclerotic and amyloid angiopathies but is similar to that described in some cases of hereditary multi-infarct dementia.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has been recently reported as a cause of stroke. It is characterized, in the absence of hypertension, by recurrent subcortical ischaemic strokes, starting in early or midadulthood and leading in some patients to dementia. Magnetic resonance imaging and pathological examination show numerous small subcortical infarcts and a diffuse leukoencephalopathy underlaid by a non-arteriosclerotic, non-amyloid angiopathy. We performed genetic linkage analysis in two unrelated families and assigned the disease locus to chromosome 19q12. Multilocus analysis with the location scores method established the best estimate for the location of the affected gene within a 14 centimorgan interval bracketed by D19S221 and D19S222 loci.
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CADASIL in a North American family: linkage to chromosome 19
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An Italian kindred with cerebral autosomal dominant arteriopa-thy with subcortical infarcts and leukoencephalopatJry
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