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Hereditary multi infarct dementia
... Besides their importance for the ongoing positional cloning of the CADASIL gene, these data help to refine the genetic mapping of CADASIL relative to familial hemiplegic migraine and hereditary paroxysmal cerebellar ataxia, conditions that we both mapped within the same chromosome 19 region. Introduction Since 1977, several families suffering from an autosomal dominant stroke condition of unknown etiology have been reported under various names such as hereditary multi-infarct dementia or familial sclerosing vasculopathy (Sourander and Walinder 1977; Stevens et al. 1977; Colmant 1980; Sonninen and Savontaus 1987). In 1991, the clinical, neuroimaging, and genetic parameters of this hereditary condition were precisely defined, on the basis of the analysis of a very large pedigree originating from France (Tournier-Lasserve et al. 1991 ). ...
... Neurological symptoms included transient ischemic attacks or completed strokes (51 patients), migraine with aura (26 patients, including 15 patients suffering from both strokes and migraine with aura and 11 patients suffering only from migraine with aura), dementia (22 patients with preceding strokes and 6 patients with an isolated progressive dementia), and mood disorders (8 patients with associated strokes and 3 patients with isolated mood disorders). One hundred fourteen individuals had an MRI showing neither WMA nor subcortical infarcts: Pathological data were available in six of these families (Fl-11, F10-PM, F12-PM, F16-PM, F18-1, and F21- 3) and showed in all cases a nonatherosclerotic, nonamyloid angiopathy affecting the small arteries of the cerebral white matter and the basal ganglia strikingly similar to previously reported lesions (Sourander and Walinder 1977; Baudrimont et al. 1993; Gray et al. 1994; Jung et al. 1995). Karyotype analysis performed in one index case from eight families (Fl, F2, F5, F8, F10, F11, F13, and F14) was unremarkable. ...
... Since 1977, several families suffering from an autosomal dominant stroke condition of unknown etiology have been reported under various names such as hereditary multi-infarct dementia or familial sclerosing vasculopathy (Sourander and Walinder 1977;Stevens et al. 1977;Colmant 1980; Sonninen and Savontaus 1987). In 1991, the clinical, neuroimaging, and genetic parameters of this hereditary condition were precisely defined, on the basis of the analysis of a very large pedigree originating from France ( Tournier-Lasserve et al. 1991). ...
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently identified autosomal dominant cerebral arteriopathy characterized by the recurrence of subcortical infarcts leading to dementia. A genetic linkage analysis conducted in two large families recently allowed us to map the affected gene on chromosome 19 in a 12-cM interval bracketed by D19S221 and D19S215. In the present study, these first 2 families and 13 additional ones, including a total of 199 potentially informative meiosis, have been genotyped with eight polymorphic markers located between D19S221 and D19S215. All families were linked to chromosome 19. The highest combined lod score (Zmax = 37.24 at theta = .01) was obtained with marker D19S841, a new CAn microsatellite marker that we isolated from chromosome 19 cosmids. The recombinant events observed within these families were used to refine the genetic mapping of CADASIL within a 2-cM interval that is now bracketed by D19S226 and D19S199 on 19p13.1. These data strongly suggest the genetic homogeneity of this recently identified condition and establish the value of its clinical and neuroimaging diagnostic criteria. Besides their importance for the ongoing positional cloning of the CADASIL gene, these data help to refine the genetic mapping of CADASIL relative to familial hemiplegic migraine and hereditary paroxysmal cerebellar ataxia, conditions that we both mapped within the same chromosome 19 region.
... CADASIL was diagnosed on the basis of a NOTCH3 mutation in 123 (95.3%), a known family mutation with clinical features in the absence of genetic confirmation in 2 (1.6%) [13,40], GOM in the absence of genetic testing in 3 (2.3%) [16,17,30], and GOM in 1 patient with negative testing in exon 2-24 [19], Of those with a diagnosed NOTCH3 mutation, 119 (96.7%) were typical cysteine altering, 3 (2.4%) were cysteine sparing, and 1 with genetically confirmed CADASIL but NOTCH3 mutation detail wasn't mentioned [33]. ...
Background
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is characterised by early onset stroke and dementia. Most strokes are lacunar ischaemic strokes, but intracerebral haemorrhage (ICH) has also been reported, although there are limited published data on its frequency and characteristics.
Methods
A retrospective review of a prospectively recruited CADASIL register from the British National Referral clinic was performed to identify acute ICH cases and their characteristics. In addition, a systematic review of ICH in CADASIL was performed. MEDLINE (Pubmed), Embase, and Web of Science were searched for articles published from inception until 31/05/2023.
Results
Ten cases of ICH were identified from the National clinic register of 516 symptomatic patients, giving an estimated point prevalence of 1.9%. An additional 119 cases were identified from the systematic review, comprising 129 cases and 142 ICH events in total. Including all identified cases, the mean age at onset of ICH was 56.6 ± 15.7 (SD) years, and 74 (57.4%) were male. ICH was the first manifestation of the disease in 32 patients (38.1%), and ICH recurrence occurred in 16 (12.4%). Most ICHs were subcortical, with the thalamus, 58 (40.8%), and basal ganglia, 34 (23.9%), being the commonest sites. Anticoagulation, but not antiplatelet agents, was associated with an increased risk of ICH (20.0% vs. 1.9%, p = 0.006).
Conclusions
ICH is a relatively rare manifestation of CADASIL, occurring in about 2% of symptomatic cases. Most of the haemorrhages occurred in the subcortical regions.
... 3 In 1977, Sourander and Walinder, described in eight members of the same family, the clinical, genetic and morphological characteristics of a previously unrecognized type of multiple heart attack dementia that affected young adults of both sexes. 4,5 Te n years later, Sonninen and Savontaus, reported a family in which 16 members had multipart dementia beginning in adulthood associated with cerebrovascular infarctions in white matter. 6 The disorder was characterized by recurrent strokes with neuropsychiatric symptoms, affecting young adults of both sexes and transmitted in an autosomal dominant pattern. ...
... 1955). In den folgenden Jahren wurden unter verschiedenen Bezeichnungen ähnliche Fälle einer erblichen zerebralen Gefäßerkrankung veröffentlicht (Colmant, 1980;Davous and Fallet-Bianco, 1991;Mas et al., 1992;Salvi et al., 1992;Sonninen and Savontaus, 1987;Sourander and Walinder, 1977;Stevens et al., 1977) ...
Strukturelle und funktionelle Beeinträchtigungen von Blutgefäßen sind an der Entstehung zahlreicher Erkrankungen beteiligt. Glatte Gefäßmuskelzellen stellen den häufigsten Zelltyp in Gefäßwänden dar und sind essentieller Bestandteil zahlreicher pathomechanistischer Überlegungen. Hierbei spielt die außergewöhnliche Plastizität dieser Zellen eine entscheidende Rolle. Diese erlaubt es ihnen, auf bestimmte Reize mit einer Änderung ihres Phänotyps zu antworten und dabei ihre Kontraktilität zugunsten einer erhöhten Migrations- und Proliferationsfähigkeit sowie einer vermehrten Syntheseleistung zu vermindern. Die Protease HTRA1 wird sowohl in Endothel- als auch in glatten Gefäßmuskelzellen exprimiert und größtenteils nach extrazellulär sezerniert. Ihre physiologischen Aufgaben sind weithin unbekannt, Mutationen im HTRA1-Gen stellen allerdings die Ursache der zerebralen Mikroangiopathie CARASIL dar. Bislang unbekannte Mechanismen führen hierbei zu einer insbesondere zerebral veränderten Gefäßarchitektur mit Verlust von glatten Gefäßmuskelzellen und daraus resultierenden, vorwiegend neurologischen, Beeinträchtigungen. Unser Labor konnte kürzlich eine Interaktion zwischen HTRA1 und dem Notch-Liganden Jagged1 mit darauffolgender Degradation des Liganden nachweisen. Der Notch-Signalweg ist ein bekannter Regulator der Phänotyp-Modulation glatter Gefäßmuskelzellen, spielte aber in bisherigen Modellen der CARASIL-Pathogenese keine Rolle. Diese Arbeit zeigt, dass HTRA1 in glatten Gefäßmuskelzellen für eine kontraktile Differenzierung notwendig ist und ein Mangel der Protease zur Phänotyp-Modulation mit Etablierung eines synthetischen Phänotyps führt. Eine HTRA1-Überexpression reduzierte die Migrations- und Proliferationsrate, während ein Verlust eine Steigerung dieser Parameter sowie eine verminderte Kontraktilität der Muskelzellen zur Folge hatte. HTRA1-Knockoutmäuse wiesen dementsprechend eine beeinträchtigte arterielle Vasokonstriktion und einen verminderten Blutdruckanstieg nach Hypertonie-Induktion mittels DOCA-Salz auf. Expressionsanalysen zeigten eine Abhängigkeit der Expression einiger Notch-Zielgene vom Expressionslevel der HTRA1-Protease. Gemeinsam mit weiteren Ergebnissen unseres Labors führte dies zu der Schlussfolgerung, dass die Phänotyp-Modulation nach HTRA1-Verlust auf eine Jagged1-mediierte simultane Überaktivierung des TGFβ- und Notch-Signalwegs zurückzuführen ist. Zusammenfassend verdeutlichen die beschriebenen Ergebnisse, dass HTRA1 eine wesentliche Rolle in der Homöostase glatter Gefäßmuskelzellen spielt. Zudem zeigt die in Muskelzellen erstmals beschriebene Interaktion zwischen HTRA1 und dem Notch-Signalweg mögliche pathogenetische Parallelen der zerebralen Mikroangiopathien CARASIL und CADASIL auf.
... It presents with autosomal dominant arteriopathy, subcortical infarctions, and leukoencephalopathy (Tournier-Lasserve et al. 1993;Bousser and Tournier-Lasserve 1994). Cases associated with multiple hereditary infarctions and dementia were reported by Sourander and Walinder (1977) and Robinson et al. (2001). Tournier-Lasserve was first to use the term BCADASIL syndrome^ (Tournier-Lasserve et al. 1993;Chabriat and Bousser 2003). ...
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy with adult onset caused by a missense mutation in the NOTCH3 gene in chromosome 19p13. It presents with autosomal dominant arteriopathy, subcortical infarctions, and leukoencephalopathy. Its common clinical presentations are seen as recurrent strokes, migraine or migraine-like headaches, progressive dementia, pseudobulbar paralysis, and psychiatric conditions. Two patients with CADASIL syndrome, whose diagnosis was made based on clinical course, age of onset, imaging findings, and genetic assays in the patients and family members, are presented here because of new familial polymorphisms. The first patient, with cerebellar and psychotic findings, had widespread non-confluent hyperintense lesions as well as moderate cerebellar atrophy in cranial magnetic resonance scanning. The other patient, with headache, dizziness, and forgetfulness, had gliotic lesions in both cerebral hemispheres. CADASIL gene studies revealed a new polymorphism in exon 33 in the first patient. In the other patient, the NOTCH3 gene was identified as a new variant of p.H243P (c.728A > C heterozygous). By reporting a family presenting with various clinical symptoms in the presence of new polymorphisms, we emphasize that CADASIL syndrome may present with various clinical courses and should be considered in differential diagnoses.
... In 1977, Sourander and Walinder reported a hereditary multi-infarct dementia with autosomal-dominant mode of inheritance in multiple members of a three-generation family [189,190]. About 20 years earlier, van Bogaert had described a progressive subcortical encephalopathy in two sisters [191], which was verified much later by genetic analysis of old tissue specimens as the first family reported with this condition. ...
Cerebrovascular disorders are underlain by perturbations in cerebral blood flow and abnormalities in blood vessel structure. Here, we provide an overview of the current knowledge of select cerebrovascular disorders that are associated with genetic lesions and connect genomic findings with analyses aiming to elucidate the cellular and molecular mechanisms of disease pathogenesis. We argue that a mechanistic understanding of genetic (familial) forms of cerebrovascular disease is a prerequisite for the development of rational therapeutic approaches, and has wider implications for treatment of sporadic (non-familial) forms, which are usually more common.
... In 1955, Ludo van Bogaert [82] reported two sisters with a familial form of Binswanger disease and provided the first neuropathological description of the clinical condition that eventually became known as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), the first monogenic form of pure SSVD [83]. Other variants of SSVD with a genetic basis were later reported [84,85]. However, the mechanisms of contribution of risk genes to the development of sporadic SSVD are not fully known, due to the complexity of the pathogenesis caused by the interaction of genetic and environmental factors. ...
Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer's disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.
... 6 In other ones, such as conditions associated with glycin missense mutations within the triple helical domain of COL4A1/COL4A2 collagen genes, cerebral hemorrhage is the main cerebrovascular manifestation. 7 Additional familial cSVD pedigrees have been reported, including a pedigree with an autosomal dominant vascular leukoencephalopathy linked to chromosome 20q, 8 a pedigree with familial multi-infarct "Swedish-type" dementia, 9,10 and a pedigree with PAD-MAL. 11,12 Causative mutations in these pedigrees have not yet been reported. ...
Objective:
Cerebral small vessel disease (cSVD) is a heterogeneous group of disorders. Screening of known cSVD genes identifies the causative mutation in <15% of familial cSVD cases. We sought to identify novel causes of cSVD.
Methods:
We used linkage analysis and exome sequencing to identify the causal mutation in a French cSVD family. The identified candidate gene was then screened in 202 cSVD unrelated probands, including 1 proband from the first reported pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) family. Sanger sequencing was used to confirm variants in all mutated probands and analyze their segregation in probands' relatives. Mutation consequences were assessed with luciferase reporter assays and real-time quantitative polymerase chain reaction (RT-qPCR).
Results:
A candidate heterozygous variant located in a predicted miR-29 microRNA binding site, within the 3' untranslated region of COL4A1, was identified in the large French cSVD family. Five additional unrelated probands, including the PADMAL proband, harbored heterozygous variants in this microRNA binding site. Variants cosegregated with the affected phenotype, and cumulative logarithm of odds score reached 6.03, establishing linkage to this locus. A highly significant difference was observed when comparing the number of variants within this binding site in cases and controls (p = 1.77 × 10E-12). RT-qPCR analyses of patients' primary fibroblasts and luciferase reporter assays strongly favor an upregulation of COL4A1 mediated by disruption of miR-29 binding to its target site. Magnetic resonance imaging features were characterized by the presence of multiple pontine infarcts in all symptomatic mutation carriers.
Interpretation:
Mutations upregulating COL4A1 expression lead to PADMAL, a severe early onset ischemic cSVD, distinct from the various phenotypes associated with COL4A1 missense glycine mutations. Ann Neurol 2016;80:741-753.
... L'examen pathologique révéla une raréfaction myélinique associée à des foyers de nécrose au sein de la substance blanche et des noyaux gris [4]. En 1977, Sourander et Walinder [5,6] ont rapporté l'histoire d'une famille suédoise dont de nombreux membres sur trois générations avaient eu des signes pyramidaux, bulbaires et cérébelleux évoluant vers une démence sévère. L'examen post mortem révélait de nombreux infarctus lacunaires au sein la substance blanche, des noyaux gris centraux et du pont. ...
CADASIL is an inherited small vessel disease of the brain caused by mutations of the NOTCH3 gene encoding a receptor of smooth muscle cells and pericytes within the wall of arterioles and capillaries. The mutated gene is responsible for accumulation of NOTCH3 protein and aggregation of various proteins in the vascular wall. The disease occurs during mid-adulthood and is responsible for attacks of migraine with aura, ischemic stroke, mood disorders and cognitive impairment ranging from mild alterations of attentional performances and executive functions to severe dementia. The disease develops in adults with aging and is responsible at the latest stage of gait and balance troubles associated with cognitive impairment that may lead to severe disability and dependence. MRI shows widespread white matter lesions that may involve the anterior part of temporal lobes often associated with small cerebral infarcts and with microbleeds. The clinical severity is related to accumulation of small infarcts and the development of cerebral atrophy over time. The diagnosis of the disease is confirmed by genetic testing or skin biopsy.
... These clinical characteristics also distinguish this phenotype from the other familial arteriopathies reported, consistent with an autosomal dominant pattern of inheritance but not yet linked to the CADASIL locus. 4 New phenotype of the cerebral autosomal dominant arteriopathy mapped to chromosome 19: migraine as prominent clinicalfeature the 31 living members) or from medical files or history given by the family (for the 12 deceased members). The 31 living subjects were genetically and radiologically studied after giving their informed consent. ...
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.
Die Darstellung der normalen Anatomie der zentralnervösen GefäBe und ihrer Versorgung kann nicht Aufgabe dieses Kapitels sein. Ihre Kenntnis ist allerdings die Voraussetzung für die Deutung eines Nekrose- oder Blutungsbezirks. Bestimmte topographische Verteilungen erlauben vielfach auf den ersten Blick eine Aussage dartiber, ob eine venöse AbfluBstörung oder der VerschluB eines bestimmten Arterienastes vorlag, ob das Grenzgebiet von Arterien betroffen ist oder ob angesichts einer unsystematischen Verteilung eher an embolische Vorgänge zu denken ist. Beispiel für charakteristische Verteilungsmuster werden auf den anschlieBenden Schemata und Abbildungen geboten.
Die morphologischen Untersuchungen der Durchblutungsstörungen war — im deutschen Sprachraum — eng mit der Entwicklung der Neuropathologie überhaupt verbunden: In der beginnenden mikroskopischen Ära ist dieses Fach mit den Namen Flechsig, Meynert und von Gudden verknüpft [56], später wurde durch Kraepelin die Neuropathologie mit ihren neuro-histologischen Spezialmethoden auf die Entschlüsselung psychiatrischer Erkrankungen „angesetzt“ [60]. Die pathologische Bearbeitung wichtiger neurologischer Krankheitsbilder wie die der Durchblutungsstörungen oder auch der Tumoren war dann ein Nebenprodukt der Untersuchungen, die in der Deutschen Forschungsanstalt für Psychiatrie von Alzheimer, Nissl und Spielmeyer durchgeführt wurden [59].
Introduction It will be clear from Chs. 1 to 4 that the term cerebral microbleed (CMB) was introduced by radiologists to describe hypointensities (small signal voids) thought to reflect small hemorrhages. Naturally, it has been hoped that the correlation of these MRI lesions with histopathological analysis will definitively establish the causes of CMBs. Indeed, MRI-pathology correlations have shown that the majority of radiologically detected CMBs result from the accumulation of blood or blood products in the vicinity of pathologically altered vessels, in the context of a widespread cerebral small vessel vasculopathy, typically cerebral amyloid angiopathy (CAA) or hypertensive vasculopathy. However, although MRI-pathology studies, as discussed in this chapter, are critical in fully understanding the causes of CMBs, such studies are limited by technical factors. The CMBs are small lesions (radiological generally <5 mm, and pathologically often considerably smaller than this) that may be present almost anywhere in the brain. They may, therefore, be easily missed by visual inspection of postmortem material but can be detected by conventional histology when specimens are carefully and systematically examined. Notwithstanding these challenges, this chapter will describe the vascular pathologies that underlie CMBs, concentrating on the two commonest disorders: hypertensive small vessel disease (SVD) and CAA. It will also describe the process of blood degradation, and the correlation of imaging with histological findings. Vascular pathology underlying cerebral microbleeds The most common pathological processes underlying CMBs are (1) arteriosclerosis in the context of chronic hypertension; and (2) amyloid angiopathies with intramural accumulation of beta-amyloid (Aβ).
BACKGROUND- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain. The affected gene was mapped in 1993 to chromosome 19. This mapping was essential in defining the natural history of the disease. REVIEW SUMMARY- CADASIL can start with attacks of migraine with aura occurring at a mean age of 30 years. The most frequent clinical manifestations are subcortical transient ischemic attacks or completed strokes usually observed between 40 and 50 years of age. The stroke events are sometimes associated with severe mood disturbances. The disease leads progressively to a subcortical dementia associated with pseudobulbar palsy and urinary incontinence. Mean age at death is 65 years. The severity of the clinical presentation is greatly variable between and within families. Magnetic resonance imaging (MRI) is always abnormal in symptomatic subjects. On T2-weighted images areas of increased signals in white matter and basal ganglia and on T1-weighted images, it shows a decreased signal in the same regions. Signal abnormalities can be observed a long time before the onset of clinical manifestations, as they are present in asymptomatic young family members. The severity of the MRI findings dramatically increases with age. Pathologic studies show a widespread pallor of white matter and multiple small infarcts in both the white matter and basal ganglia, associated with a small artery disease of the brain. Electron microscopy studies show that the medium of the small arteries is thickened by a granular, eosinophilic, and nonamyloid material of undetermined origin that surrounds the smooth muscle cells. These ultrastructural abnormalities have been observed in other arteries, particularly in muscular and skin arteries. The gene of CADASIL is mapped to chromosome 19 in close vicinity to the locus of familial hemiplegic migraine and to that of acetazolamide-responsive cerebellar paroxysmal ataxia. CONCLUSION- CADASIL should be suspected in subjects with a history of unexplained subcortical ischemic strokes, attacks of migraine with aura, mood disorders, or subcortical dementia whenever they are associated with MRI signal abnormalities in white matter and basal ganglia. These findings should prompt a genealogical study including all first-and second-degree relatives. CADASIL is an underdiagnosed cause of subcortical strokes.
A new hereditary syndrome characterized by a frontoparietal lobe pseudotumor and retinal capillary abnormalities is described. A pedigree is presented in which characteristic ophthalmic findings have been found in ten family members and are suspected in eight additional family members spanning a total of four generations. Typical retinal findings include perifoveal capillary obliteration, peripheral focal capillary occlusion, and microvascular abnormalities, particularly involving the posterior pole. Eight patients spanning three generations had a central nervous system pseudotumor with identical histopathology. Histopathologic analysis of brain tissue shows a characteristic pattern of an unusual vasculopathy without vasculitis characterized by fibrinoid necrosis and resulting in necrosis of white matter with sparing of cortical brain tissue. The pedigree shows an apparent autosomal dominant pattern of inheritance with delayed expression of abnormalities. Of note, two patients unrelated to the pedigree having similar neuropathologic and retinal findings also have been seen at the authors' institution.
Die Kenntnis der normalen Anatomie der zentralnervösen Gefäße und ihrer Versorgung ist die Voraussetzung für die Deutung eines Nekrose- oder Blutungsbezirks. Bestimmte topographische Verteilungen erlauben vielfach auf den ersten Blick eine Aussage darüber, ob eine venöse Abflussstörung oder der Verschluss eines bestimmten Arterienastes vorlag, ob das Grenzgebiet von Arterien betroffen ist oder ob angesichts einer unsystematischen Verteilung eher an embolische Vorgänge zu denken ist. Beispiele für charakteristische Verteilungsmuster werden auf den anschließenden Schemata und Abbildungen geboten (Übersicht der normalen Anatomie bei Cervós-Navarro 1980 und Lang 1979.)
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by a cerebral non-atherosclerotic, non-amyloid angiopathy mainly affecting the small arteries penetrating the white matter. In the brain vessels of two patients with CADASIL, abnormal patches of granular osmiophilic material have recently been described. Here we report the observation of similar granular osmiophilic material within the vessel walls of muscle and skin biopsies from a 54-year-old woman belonging to a CADASIL family, who suffered from subcortical dementia with leukoencephalopathy demonstrated on neuroimaging. Postmortem examination disclosed changes of the vessel walls in all the organs chiefly leading to cerebral lesions. Ultrastructural study showed destruction of the vascular smooth muscle cells (VSMC) and the granular osmiophilic material already found in muscle and skin biopsies in this patient. Both changes were found all along the arterial tree. The findings of this study indicate that CADASIL is a systemic vascular disease involving arterial VSMC and that the lesions are different in each organ and vessel wall, depending on their fine structure. Moreover, it emphasizes that skin and muscle biopsies might be useful for diagnosis of and research into CADASIL.
Relations between brain damage and memory disturbance are outlined with emphasis on the so-called amnesic syndrome. Following a brief introduction into forms of memory and memory failures, the basic causes of brain damage (with relevance to mnestic failures) are described. Thereafter, the two best-known forms of brain damage-amnesia relations are reviewed: the consequences of damage to medial temporal lobe structures and to diencephalic regions. For the cases with medial temporal lobe damage, evidence is reported in greater detail for H.M., who has been examined more than any other amnesic patient for more than 30 years now, as a considerable amount of literature has accumulated on his behavior in diverse situations.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease of small vessel caused by mutations in the NOTCH3 gene (NCBI Gene ID: 4854) located on chromosome 19p13.1. NOTCH3 consists of 33 exons which encode a protein of 2321 amino acids. Exons 3 and 4 were found to be mutation hotspots, containing more than 65% of all CADASIL mutations. We performed direct sequencing on an ABI 3130 Genetic Analyser to screen for mutations and polymorphisms on 300 patients who were clinically suspected to have CADASIL. First, exons 3 and 4 were screened in NOTCH3 and if there were no variations found, then extended CADASIL testing (exons 2, 11, 18 and 19) was offered to patients. Here we report two novel non-synonymous mutations identified in the NOTCH3 gene. The first mutation, located in exon 4 was found in a 49-year-old female and causes an alanine to valine amino acid change at position 202 (605C>T). The second mutation, located in exon 11, was found in a 66-year-old female and causes a cysteine to arginine amino acid change at position 579 (1735T>C). We also report a 46-year-old male with a known polymorphism Thr101Thr (rs3815188) and an unreported polymorphism NM_000435.2:c.679+60G>A observed in intron 4 of the NOTCH3 gene. Although Ala202Ala (rs1043994) is a common polymorphism in the NOTCH3 gene, our reported novel mutation (Ala202Val) causes an amino acid change at the same locus. Our other reported mutation (Cys579Arg) correlates well with other known mutations in NOTCH3, as the majority of the CADASIL-associated mutations in NOTCH3 generally occur in the EGF-like (epidermal growth factor-like) repeat domain, causing a change in the number of cysteine residues. The intronic polymorphism NM_000435.2:c.679+60G>A lies close to the intron-exon boundary and may affect the splicing mechanism in the NOTCH3 gene.
The understanding of the genetic basis of late-onset leukoencephalopathies has continued to increase in recent years. The most commonly presenting leukoencephalopathies in adulthood can be late-onset manifestations of metabolic pathways. The understanding of these diagnoses is crucial to the evaluation of adult patients presenting with leukoencephalopathies. The authors provide an overview of the common leukoencephalopathies in adulthood, the current understanding of the pathology, and genetics of these disorders with typical imaging findings. When available, treatment options will be discussed.
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.
A 17-year-old girl presented with migraine with prolonged aura and aura without headache. Neurologic examination was normal. Her mother, who did not have a history of migraine, developed right-face and -arm numbness at the age of 45. Evaluation revealed white matter changes consistent with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and genetic testing showed a Notch3 gene mutation consistent with CADASIL. Our patient's MRI revealed white matter changes and the same Notch3 gene mutation. Low-dose aspirin was started in an attempt to prevent stroke. CADASIL is considered a degenerative disease of adult onset that leads to progressive neurologic deterioration. Onset of symptoms is in the third decade. Migraine, one of its most common manifestations, can develop in childhood. Evaluation for secondary causes is warranted in select pediatric patients who present with atypical migraine, when there is a family history of CADASIL or atypical patterns such as aura without headache, or in the presence of white matter abnormalities. The pathophysiology of CADASIL is poorly understood, and there is no proven effective therapy. Patients require genetic counseling and close follow-up. It is not known if interventions such as antiplatelet therapy are beneficial if instituted early in the course of the disease. Screening of family members at risk for CADASIL, even in the pediatric population, should be considered and offered to patients with CADASIL and their families. CADASIL has rarely been described in the pediatric population. This case report expands our current understanding of the disorder in children.
In recent years, a considerable number of new sporadic or hereditary small artery diseases of the brain have been detected which preferably occur in younger age, below 45 years. Cerebral microangiopathies constitute an appreciable portion of all strokes. In middle aged patients, hereditary cerebral small vessel diseases have to be separated from sporadic degenerative cerebral microangiopathy which is mainly due to a high vascular risk load. Features of the following disorders and details how to differentiate them, are reviewed here, namely CADASIL, MELAS, AD-RVLC, HEMID, CARASIL, PADMAL, FABRY, COL4A1-related cerebral small vessel diseases and a Portuguese type of autosomal dominant cerebral small vessel disease (SVDB). The symptomatic overlap of the cerebral microangiopathies include also other distinctive non-hereditary diseases like posterior (reversible) encephalopathy and Susac's syndrome which are also described. Some of the microangiopathies described here are not only seen in the young but also in the elderly. The precise diagnosis has direct therapeutic implications in several of these entities. Cerebral microangiopathies cause recurring strokes and diffuse white matter lesions leading to a broad spectrum of gait disturbances and in most of these disorders cognitive impairment or even vascular dementia in the long term. Often, they also involve the eye, the inner ear or the kidney. Several typical imaging findings from illustrative cases are presented. The order in which these diseases are presented here is not dictated by an inner logic principle, because a genetically or pathophysiologically based classification system of all these entities does not exist yet. Some entities are well established and not unusual, whereas others have only been described in a few cases in total.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease caused by mutations in the NOTCH3 gene on chromosome 19. Magnetic resonance (MR) imaging plays an important role in the diagnostic work-up of CADASIL patients. In this thesis we describe the presence of microbleeds and a new, highly characteristic radiological finding in CADASIL patients, the so called subcortical lacunar lesions (SLL). We describe the natural history of the various brain lesions that can be observed in CADASIL patients, the microbleeds, SLL, lacunar infarcts, and white matter hyperintensities (WMHs). Also included are the results of a study on the differences of the lesions seen in CADASIL as compared to the lesions that occur in multiple sclerosis, a disease with radiological and clinical similarities to CADASIL. We found that MR lesions develop in a predictable way during the course of the disease and that SLL and WMHs in the anterior temporal lobe are helpful radiological hallmarks for the of detection CADASIL. The WMHs in the anterior lobe especially in combination with one of the other CADASIL MR hallmarks should distinguish CADASIL patients from patients with multiple sclerosis.
The cerebral changes are described in a woman of 54 who suffered from Binswanger's encephalopathy: there were no signs or symptoms of chronic arterial hypertension. The disease presented as dementia of about 3 years duration. Computed tomography of the brain 2.5 years before her death showed bilateral widespread hypodense lesions in the cerebral white matter. She died of an asthmatic attack. Autopsy disclosed extensive bilateral degeneration of the central white matter, lacunes and gliosis. Severe obliterative arteriolosclerosis occurred in the meningeal vessels and those supplying the affected parts of the brain. Light microscopy showed that the most severe lesions occurred in the arterioles. Immunohistochemistry demonstrated profound extravasation of plasma proteins chiefly albumin, indicating dysfunction of the blood-brain barrier. Thus, the lesions characteristic of Binswanger's encephalopathy may develop in the absence of chronic arterial hypertension. Additional pathogenic factors, possibly genetic predisposition to vascular injury may play a role in the development of this condition.
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.
A new hereditary syndrome characterized by a frontoparietal lobe pseudotumor and retinal capillary abnormalities is described. A pedigree is presented in which characteristic ophthalmic findings have been found in ten family members and are suspected in eight additional family members spanning a total of four generations. Typical retinal findings include perifoveal capillary obliteration, peripheral focal capillary occlusion, and microvascular abnormalities, particularly involving the posterior pole. Eight patients spanning three generations had a central nervous system pseudotumor with identical histopathology. Histopathologic analysis of brain tissue shows a characteristic pattern of an unusual vasculopathy without vasculitis characterized by fibrinoid necrosis and resulting in necrosis of white matter with sparing of cortical brain tissue. The pedigree shows an apparent autosomal dominant pattern of inheritance with delayed expression of abnormalities. Of note, two patients unrelated to the pedigree having similar neuropathologic and retinal findings also have been seen at the authors' institution.
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.
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.
Hereditary multi-infarct dementia is a rare autosomal dominant disorder that predominantly affects the cerebral white matter. A locus was recently mapped in French pedigrees to chromosome 19q12. We have examined a large Scottish pedigree with neuropathologically confirmed hereditary multi-infarct dementia using polymorphic DNA markers spanning the 19q12 region and found no evidence of linkage. This suggests that, as in familial Alzheimer's disease, there is more than one locus.
A report on a cerebro-vascular disease with autosomal dominant inheritance, characterised by stroke-like episodes beginning in early adulthood and progressive dementia, afflicting one family living in Sweden was presented in 1977. Another afflicted member showing gait and coordination disturbances and impaired cognitive functions is now introduced. Magnetic resonance imaging revealed multiple brain lesions indicating ischaemic injuries. Previous autopsy studies of other cases revealed white matter atrophy, multiple infarcts and lacunes. In one patient who had died from a cerebral haemorrhage, obliteration of intracerebral arteries, occasionally with organised thrombi was present. Autopsy material has now been reinvestigated with special attention to changes of intracerebral arterioles. Cases with long duration of the disease presented pronounced fibrous thickening of the wall of numerous intracerebral arterioles, degeneration of smooth muscle cells of the media and obliteration of the lumen. Immunohistochemistry showed marked expression of fibrillary collagen types I, III and V and of the basal lamina components collagen type IV and laminin. These depositions are probably induced by some primary dysfunction of smooth muscle cells or endothelial cells. Perivascular reactive astrocytes with endothelin-1-like immunoreactivity were present in some brain regions. Endothelin-1 is the most powerful vasoconstrictor peptide known to date. Structural remodelling of intracerebral arterial vessels, actions of different vasoactive factors and rheological disturbances may all interfere with local blood flow in this disease and cause the parenchymal changes of the brain.
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.
Today, multiple, thromboembolically generated cerebral infarcts are regarded as the main pathogenetic pathway of vascular dementia (VAD), with multi-infarct dementia (MID) as its clinical counterpart. However, taking into account other vascular mechanisms that may influence the brain, such as vessel-wall damage (atherosclerosis, hyalinosis, amyloid angiopathy, or blood-brain barrier dysfunction), cerebrovascular insufficiency (disturbance of systemic circulation, perfusion vulnerability related to the vascular anatomy of the brain, or disturbance of autoregulation), and hyperviscosity, it is evident that MID is not the only VAD category. The diagnosis of MID ought to be reserved for the combination of progressive dementia associated with cerebral ischemic events and evidence of infarction that is mainly associated with the large cerebral arteries. Subcortical white-matter dementia characterized by frontosubcortical symptomatology, white-matter lesions, and small-vessel involvement with or without lacunes/infarcts--a combination of lacunar dementia and Binswanger's disease--appears to be another important VAD disease.
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.
We describe a four-generation Dutch family suffering from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Of twenty affected family members, ten are still alive. Age at onset of the strokes was between 29 and 52 years, with a mean of 41.8 years. This family has the typical clinical and radiological features of CADASIL (except for the occurrence of ischemic heart disease at a relatively young age in some subjects), and is linked to chromosome 19p13. This disease has so far been described in families from Finland, France, Germany, Italy, Japan, Spain and the United Kingdom, and there is a remarkable clinical and genetical homogeneity among all families reported, including this Dutch family.
To examine quantitatively white-matter changes at different sites in patients with definite vascular dementia and Alzheimer's disease.
Prospective clinical and neuropathological series.
University Hospital clinics (Helsinki, Finland and London, Ontario).
Twenty-two patients with a clinical and neuropathological diagnosis of vascular dementia and 20 patients with Alzheimer's disease.
The frequencies of focal white-matter lesions, arteriolosclerosis, and cerebral amyloid angiopathy were assessed. Validated ratings and cell counts were done in the subcortical U-fiber, centrum semiovale, and periventricular areas of the frontal white matter. Degrees of abnormality (none, mild, moderate, severe) were rated for spongiosis (vacuolization of white matter), état criblé (widening of perivascular spaces), myelin loss, oligodendrocyte density, axonal loss, and overall. Densities of oligodendrocytes and astrocytes (cells per square millimeter) were determined.
Patients with vascular dementia showed focal white-matter lesions and arteriolosclerosis more often than patients with Alzheimer's disease. The patients with vascular dementia also had significantly greater spongiosis (P<.001), état criblé (P=.004), myelin loss (P<.005) and overall white-matter abnormality (P<.001). Arteriolosclerosis was found in association with spongiosis but not with état criblé. Cerebral amyloid angiopathy did not appear to be related to any of the white-matter changes in patients with either vascular dementia or Alzheimer's disease. The U-fiber area showed fewer changes, and the periventricular area tended to be most affected.
In addition to focal infarcts, patients with vascular dementia showed widespread diffuse changes, including spongiosis and arteriolosclerosis, along with état criblé and myelin loss. White-matter changes in patients with Alzheimer's disease could not be related to infarction. Pathologic changes in small blood vessels are associated with diffuse white-matter changes and may have a distinct role in the genesis of vascular dementia.
This review concerns the fundamental cerebral lesions in cases of vascular dementia. Extracerebral vascular alterations are dominated by atherosclerosis with or without thrombosis. In addition, occlusion of extracerebral arteries can be induced by thrombo-embolism and in rare cases by other vascular diseases, chiefly arteritis. Intracerebral microangiopathies are usually of arteriolosclerotic or hyalinotic types in which there is degeneration of smooth muscle cells of the media and deposition of components of extracellular matrix, chiefly collagens. Ageing, chronic hypertension, hyperlipidemias and diabetes are important factors inducing vascular lesions. The vascular lesions, often combined with systemic factors, may produce various ischemic and edematous alterations of the brain parenchyma. Occlusion and obliteration of arteries (macroangiopathy) are associated with large infarcts, whereas microangiopathy may cause lacunar infarcts and some forms of white matter degeneration. Cases of vascular dementia usually present many types of lesions in the brain parenchyma and its arterial supply. The extent and location of the injuries differ considerably from case to case. Location of the lesions, volume of destroyed tissue, multiplicity and bilateral occurrence are most important parameters underlying the clinical manifestations in vascular dementia. A strategic location of a small injury is in some cases of particular importance.
Recently identified, CADASIL is a diffuse disease of small arteries, predominating in the brain. It starts during mid-adulthood and is characterized by recurrent ischemic events (transient or permanent), attacks of migraine with aura, severe mood disorders, subcortical dementia and, at MRI, a white spread leukoencephalopathy. There is so far no specific treatment and death occurs after a mean of twenty years. CADASIL is an autosomal dominant condition and the gene Notch 3 is located on chromosome 19, in the same region as another neurological disorder, familial hemiplegic migraine.
A pronounced obliterative microangiopathy of the deep cerebral white matter is one of the cardinal features in classical cases of Binswanger's encephalopathy. We have characterised the alterations taking place in the intima, media and adventitia of obliterated arterial vessels in seven autopsy cases of this encephalopathy. The adventitia of fibrosed vessels showed immunoreactive material indicating a marked deposition of normally occurring collagen types, i.e. I, III and V. Similar deposits occurred in degenerated parts of the media. Two of the cases had, in addition, signs of collagen type VI-immunoreactive material in the adventitia and media. The elastica of arteries was often split and formed multiple layers. The inner part of the blood vessel walls contained immunoreactivity to collagen type IV and laminin, indicating increased amounts of basal lamina components. Using actin immunostaining the fibrosed arterial vessels showed a severe reduction of smooth muscle cells of the media. However, many terminal arterioles presented a marked actin immunostaining, possibly indicating hypertrophy of smooth muscle cells. The endothelial cell layer did not show any changes with regard to expression of glucose transporter 1, factor VIII, Ulex europaeus agglutinin I and CD34. Degeneration of the media associated with depositions of collagens type I, III, IV, V and possibly type VI, as well as other components of extracellular matrix, will jeopardize the regulatory functions of the afflicted vessels. The maintenance of the endothelial lining of the obliterated vessels probably counteracts thrombosis in the vessels.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently identified cause of stroke and vascular dementia. It is a condition of mid-adulthood due to mutations of Notch 3 gene on chromosome 19. Whereas the disease was first reported in European families, since 1993 CADASIL has been observed in American, African and Asiatic pedigrees, suggesting that today, the disease probably still remains largely underdiagnosed. The pathological data first dealt with the white matter and the basal ganglia showing the features observed in Binswanger's subcortical arteriopathic encephalopathy; over the past few years, CADASIL has become appreciated as a systemic vascular disease with specific features. Here we have reviewed the literature from 1977 to the present for pathologically and genetically verified cases accompanied by relatively complete clinical descriptions so as to give the pathological features associated with this condition a clearer definition. The review will focus mainly on pathological studies and the pathophysiological mechanisms most likely to be involved in CADASIL.
CADASIL is an inherited arterial disease of the brain with an autosomal dominant pattern of transmission. The mapping of the affected gene in 1993 allowed us to describe the natural history of the disease. In some patients, the disease starts with attacks of migraine with aura at a mean age of 30 years. The most frequent clinical manifestations are subcortical transient ischemic attacks or completed strokes usually occurring between 40 and 50 years of age which are sometimes associated with severe mood disturbances. The disease leads about two decades later to death after a variable period of subcortical dementia associated with pseudobulbar palsy and urinary incontinence. In one given family, the severity of the clinical presentation varies among the affected subjects. MRI is always abnormal in symptomatic subjects. It shows more or less confluent hypersignals on T2-weighted images in white-matter and basal ganglia and hyposignals on T1-weighted images in the same regions corresponding to small infarcts. These signal abnormalities are even observed a long time before the onset of clinical manifestations as they are present in totally asymptomatic young family members. Histologic studies show a widespread palor of white-matter and multiple small infarcts in the white-matter and basal ganglia underlaid by a small artery disease of the brain. Electron microscopy studies show that the media of the white-matter and leptomeningeal small arteries is thickened by a granular, eosinophilic and non-amyloid material of undetermined origin close to the smooth muscle cells. These ultrastructural wall abnormalities have been observed in other arteries, particularly in muscular and skin arteries. Mutations of Notch3 gene located on chromosome 19 are responsible for the disease. The diagnosis should be discussed in subjects with a history of unexplained subcortical ischemic strokes, attacks of migraine with aura, mood disorders of subcortical dementia whenever associated with MRI signal abnormalities in white-matter and basal ganglia.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations of Notch3 gene on chromosome 19. Ultrastructural analysis of skin vessels discloses typical granular osmiophilic material (GOM) within the vascular smooth muscle basal lamina. We describe a CADASIL family in which two members suffering from a vascular leukoencephalopathy were shown to be CADASIL phenocopies: clinical and magnetic resonance imaging (MRI) findings in these two patients were similar to those observed in their affected relatives. However, the skin biopsy performed on one of them did not reveal any GOM in the vascular smooth muscle cells, and the Notch3 mutation present in this family was shown to be absent in these two individuals. We emphasize the role of a direct DNA test for gene mutation to make a differential diagnosis between CADASIL and other forms of vascular leukoencephalopathy.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be considered as a new disease predominantly affecting the small vessels of the brain with an autosomal dominant transmission linked to chromosome 19. This review includes an historical perspective showing how the disease was identified from the spectrum of vascular leukoencephalopathies. More than two hundred patients have now been described, belonging to at least 30 unrelated pedigrees in Europe, America and Asia. The clinical features include four major neurological presentations associated in variable degrees during the course of the disease: migraine with or without aura, strokes or stroke-like episodes, major psychiatric symptoms and dementia. The patients are free of the classical vascular risk factors. The disease has a progressive or stepwise course with age at onset in the forties and a mean duration of 13.6 +/- 10.7 years. Death occurs in the fifties in a characteristic condition associating a pseudo-bulbar syndrome and subcortical dementia. Cerebral magnetic resonance imaging (MRI) is highly contributive to the diagnosis, showing a diffuse leukoencephalopathy with subcortical infarcts in the basal ganglia and white matter. Pathological data show macroscopic lesions similar to Binswanger's disease but different lesions of the small vessels including thickening of the media, characteristic PAS+ granular material and narrowing of the lumen. Skin biopsy may be a valuable diagnostic tool, showing ultrastructural alterations of skin vessels similar to those of brain vessels. The disease is highly homogeneous on a genetic basis and the identification of the gene Notch 3 on chromosome 19 has opened new avenues for research and genetic counselling. The pathogenesis of the disease has still to be elucidated. A definite diagnosis relies on genetical or pathological data. Diagnostic criteria are proposed to recognize the disease on clinical and imaging parameters. So far, no treatment has been reported to be successful for CADASIL. Copyright Lippincott-Raven Publishers
The density and size of astrocyte-, oligodendrocyte- and neurone nuclei in corpus striatum were determined in rats with CCl4-induced liver encephalopathy by means of an electronic image analyzer. After 8 weeks of CCl4-administration, the astrocyte number had nearly doubled, and astrocytes with increased nuclear size appeared. After 20 weeks, a reduction (appr. 25%) was found in the number of nerve cells and oligodendrocytes. The total number of glial cells, however, was unchanged during the experiment; this demonstrates the need of performing differential counts when evaluating gliosis. Probably, a part of the increase in the number of astrocytes was due to a transformation from precursor cells, usually classified as oligodendrocytes. The increased number and size of astrocyte nuclei are probably connected with an enhanced astrocyte metabolic capacity due to alterations in the ammonia and amino acid metabolism.
The typical, insidious, slowly progressive dementia of old age (primary senile dementia) is not due to atherosclerosis. Most cases show Alzheimer-like degeneration of the brain at necropsy. There is no relationship between these parenchymal degenerative changes and arterial disease; hence the term "cerebral atherosclerosis" as applied to mental deterioration in the elderly is misleading and inaccurate. When vascular disease is responsible for dementia it is through the occurrence of multiple small or large cerebral infarcts (multi-infarct dementia). The investigation and precise diagnosis of all cases of dementia allow a more accurate prognosis and more rational management of the significant number of cases in which dementia is due to treatable conditions.
A new cephalosporin with a highly reactive β-lactam ring was found to give an immediate color change in the presence of β-lactamases
from many bacteria, including staphylococci, Bacillus species, Enterobacteriaceae, and Pseudomonas. The reaction is confined to organisms producing β-lactamases, but it is sufficiently sensitive to indicate the presence
of this enzyme is small amounts in strains previously considered not to produce it. The compound has an unusual ultraviolet
spectrum, and the color change can be followed quantitatively by measuring changes in absorption which occur in the 380- to
500-nm region, where cephalosporins normally have no absorption. The development of color is thought to be a consequence of
the β-lactam ring being unusually highly conjugated with the 3-substituent. Although in the bacteria only β-lactamases produce
this color change, it was found that serum and tissues from experimental animals also rapidly produced the colored breakdown
product, which was then excreted in the urine. The mechanism of the mammalian breakdown was considered to be different from
that found in bacteria.