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OBJECTIVE: To investigate which cardiometabolic factors underlie clustering of osteoarthritis (OA) with cardiovascular disease, and the extent to which these mediate an effect of education. DESIGN: Genome-wide association study (GWAS) of OA was performed in UK Biobank (60,800 cases and 328,251 controls) to obtain genetic association estimates for OA risk. Genetic instruments and association estimates for body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP), smoking and education were obtained from existing GWAS summary data (sample sizes 188,577-866,834 individuals). Two-sample Mendelian randomization (MR) analyses were performed to investigate the effects of exposure traits on OA risk. MR mediation analyses were undertaken to investigate whether the cardiometabolic traits mediate any effect of education on OA risk. RESULTS: MR analyses identified protective effects of higher genetically predicted education (main MR analysis odds ratio (OR) per standard deviation increase 0.59, 95% confidence interval (CI) 0.54-0.64) and LDL-C levels (OR 0.94, 95%CI 0.91-0.98) on OA risk, and unfavourable effects of higher genetically predicted BMI (OR 1.82, 95%CI 1.73-1.92) and smoking (OR 2.23, 95%CI 1.85-2.68). There was no strong evidence of an effect of genetically predicted SBP on OA risk (OR 0.98, 95% CI 0.90-1.06). The proportion of the effect of genetically predicted education mediated through genetically predicted BMI and smoking was 35% (95%CI 13-57%). CONCLUSIONS: These findings highlight education, obesity and smoking as common mechanisms underlying OA and cardiovascular disease. These risk factors represent clinical and public health targets for reducing multi-morbidity related to the burden these common conditions.
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Pressão Sanguínea/genética , Fatores de Risco Cardiometabólico , LDL-Colesterol/genética , Escolaridade , Obesidade/epidemiologia , Osteoartrite/epidemiologia , Fumar/epidemiologia , Idoso , Índice de Massa Corporal , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise de Mediação , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Obesidade/genética , Razão de Chances , Osteoartrite/genética , Fumar/genéticaRESUMO
OBJECTIVES: To compare the use of an unenhanced high-resolution time-of-flight MR angiography sequence (Hr-TOF MRA) with fat-suppressed axial/coronal T1-weighted images and contrast-enhanced angiography (standard MRI) for the diagnosis of cervical artery dissection (cDISS). METHODS: Twenty consecutive patients (9 women, 11 men, aged 24-66 years) with proven cDISS on standard MRI underwent Hr-TOF MRA at 3.0 T using dedicated surface coils. Sensitivity (SE), specificity (SP), positive and negative predictive values (PPV, NPV), Cohen's kappa (к) and accuracy of Hr-TOF MRA were calculated using the standard protocol as the gold standard. Image quality and diagnostic confidence were assessed on a four-point scale. RESULTS: Image quality was rated better for standard MRI (P = 0.02), whereas diagnostic confidence did not differ significantly (P = 0.27). There was good agreement between Hr-TOF images and the standard protocol for the presence/absence of cDISS, with к = 0.95 for reader 1 and к = 0.89 for reader 2 (P < 0.001). This resulted in SE, SP, PPV, NPV and accuracy of 97 %, 98 %, 97 %, 98 % and 97 % for reader 1 and 93 %, 96 %, 93 %, 96 % and 95 % for reader 2. CONCLUSIONS: Hr-TOF MRA can be used to diagnose cDISS with excellent agreement compared with the standard protocol. This might be useful in patients with renal insufficiency or if contrast-enhanced MR angiography is of insufficient image quality. KEY POINTS: ⢠New magnetic resonance angiography sequences are increasingly used for vertebral artery assessment. ⢠A high-resolution time-of-flight sequence allows the diagnosis of cervical artery dissection. ⢠This technique allows the diagnosis without intravenous contrast medium. ⢠It could help in renal insufficiency or when contrast-enhanced MRA fails.
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Tecido Adiposo/patologia , Dissecação da Artéria Carótida Interna/patologia , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Armazenamento e Recuperação da Informação/métodos , Imageamento por Ressonância Magnética/métodos , Técnica de Subtração , Adulto , Idoso , Algoritmos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Stroke is one of the most widespread causes of mortality und disability worldwide. Around 80 % of strokes are ischemic and different forms of intracranial bleeding account for the remaining cases. Monogenic stroke disorders are rare but the diagnosis may lead to specific therapeutic consequences for the affected patients who are predominantly young. In common sporadic stroke, genetic factors play a role in the form of susceptibility genes. Their discovery may give rise to new therapeutic options in the future.
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Infarto Cerebral/genética , Acidente Vascular Cerebral/genética , Adulto , Encéfalo/patologia , CADASIL/genética , CADASIL/mortalidade , CADASIL/terapia , Causas de Morte , Infarto Cerebral/mortalidade , Criança , Estudos Transversais , Análise Mutacional de DNA , Avaliação da Deficiência , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/terapia , Análise de SobrevidaRESUMO
Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the α subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory.
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Estudo de Associação Genômica Ampla , Memória de Curto Prazo/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/irrigação sanguínea , Coleta de Dados , Europa (Continente) , Feminino , Perfilação da Expressão Gênica , Genótipo , Humanos , Processamento de Imagem Assistida por Computador/métodos , Cooperação Internacional , Imageamento por Ressonância Magnética/métodos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1 , Proteínas do Tecido Nervoso/genética , Testes Neuropsicológicos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Oxigênio/sangue , Polimorfismo de Nucleotídeo Único , Canais de Sódio/genética , Adulto JovemRESUMO
INTRODUCTION: Differential diagnoses of the reversible cerebral vasoconstriction syndrome (RCVS) include all forms of intracranial stenotic disease, such as primary or secondary vasculitis of the central nervous system. Here, we tested the hypothesis that angiographic response to intra-arterial nimodipine application may be helpful in differentiating between RCVS and other entities. METHODS: A digital subtraction angiographic (DSA) series of nine consecutive patients with suspected RCVS that were treated by intra-arterial nimodipine due to clinical worsening were retrospectively analyzed. Pre- and post-therapeutic DSA findings of patients with later-confirmed RCVS were compared to those in which another diagnosis was finally made. RESULTS: Intra-arterial nimodipine resulted in a normalization of both the diameter of the main trunks of the cerebral vessels and the caliber of the peripheral vessels in all RCVS patients. This was not the case in the non-RCVS patients, in whom only a slight general vasodilatation was observed. DISCUSSION: Our preliminary results indicate that angiographic response to intra-arterial application might be a helpful differential diagnostic tool in select patients with suspected RCVS.
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Nimodipina , Vasodilatadores , Vasoespasmo Intracraniano/diagnóstico , Adulto , Angiografia Digital , Diagnóstico Diferencial , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Infusões Intra-Arteriais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Nimodipina/administração & dosagem , Estudos Retrospectivos , Vasodilatadores/administração & dosagem , Vasoespasmo Intracraniano/tratamento farmacológicoRESUMO
In numerous situations stroke physicians face a lack of evidence during their daily practice. In this report the authors address some of the difficult treatment decisions encountered in acute therapy and secondary prevention. Examples include off-label thrombolysis and prevention in high-risk situations. The available data from trials and registries are discussed, and personal views and recommendations are expressed.
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Acidente Vascular Cerebral/terapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/mortalidade , Glicemia/metabolismo , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/mortalidade , Ensaios Clínicos como Assunto , Diagnóstico Diferencial , Endarterectomia das Carótidas , Epilepsia/diagnóstico , Medicina Baseada em Evidências , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/mortalidade , Coeficiente Internacional Normatizado , Uso Off-Label , Femprocumona/efeitos adversos , Femprocumona/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Sistema de Registros , Fatores de Risco , Prevenção Secundária , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Análise de Sobrevida , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Resultado do TratamentoRESUMO
The first European Stroke Organization (ESO) standard operating procedure (SOP) published in 2015 aimed at the implementation the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to provide evidence-based guidelines for stroke management. This second ESO-SOP is aiming at further increase of the practicability of ESO guidelines and its technical implications. Authors comprised of the members of the ESO guideline Board and ESO Executive Committee. The final document was agreed on by several internal reviews. The second SOP comprises of the following aspects: rational for the SOP, the introduction of expert consensus statements, types of guideline documents, structures involved and detailed description of the guideline preparation process, handling of financial and intellectual conflicts of interest (CoI), involvement of ESO members in the guideline process, review process, authorship and publication policy, updating of guidelines, cooperation with other societies, and dealing with falsified data. This second SOP supersedes the first SOP published in 2015.
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Despite intensive investigations, about 30% of stroke cases remains of undetermined origin. After exclusion of common causes of stroke, there is a number of rare heritable and non-heritable conditions, which often remain misdiagnosed, that should be additionally considered in the diagnosis of cryptogenic stroke. The identification of these diseases requires a complex work up including detailed clinical evaluation for the detection of systemic symptoms and signs, an adequate neuroimaging assessment and a careful family history collection. The task becomes more complicated by phenotype heterogeneity since stroke could be the primary or unique manifestation of a syndrome or represent just a manifestation (sometimes minor) of a multisystem disorder. The aim of this review paper is to provide clinicians with an update on clinical and neuroradiological features and a set of practical suggestions for the diagnostic work up and management of these uncommon causes of stroke. The identification of these stroke causes is important to avoid inappropriate and expensive diagnostic tests, to establish appropriate management measures, including presymptomatic testing, genetic counseling, and, if available, therapy. Therefore, physicians should become familiar with these diseases to provide future risk assessment and family counseling.
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Acidente Vascular Cerebral , Causalidade , Testes Genéticos , Humanos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/genéticaRESUMO
Vascular dementia (VaD) constitutes the second most frequent cause of dementia following Alzheimer's disease (AD). In contrast to AD, VaD encompasses a variety of conditions and dementia mechanisms including multiple and strategic infarcts, widespread white matter lesions and hemorrhages. The diagnosis of VaD is based on the patient history, the clinical evaluation and neuroimaging. Treatment of VaD should account for the underlying vascular condition and is directed towards the control of vascular risk factors and stroke prevention. The need for early diagnosis and preventive treatment has promoted the concept of vascular cognitive impairment (VCI). Harmonization standards for the description and study of VCI have recently been published. A common and distinct subtype of VaD is subcortical ischemic vascular dementia (SIVD) which is related to cerebral small vessel disease. SIVD is clinically characterized by impairment of executive functions and processing speed with relatively preserved memory. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of SIVD, represents an important differential diagnosis and may serve as a model of SIVD.
Assuntos
Demência Vascular/diagnóstico , Idoso , Encéfalo/patologia , CADASIL/diagnóstico , CADASIL/epidemiologia , CADASIL/etiologia , CADASIL/terapia , Inibidores da Colinesterase/uso terapêutico , Estudos Transversais , Demência por Múltiplos Infartos/diagnóstico , Demência por Múltiplos Infartos/epidemiologia , Demência por Múltiplos Infartos/etiologia , Demência por Múltiplos Infartos/terapia , Demência Vascular/epidemiologia , Demência Vascular/etiologia , Demência Vascular/terapia , Diagnóstico Diferencial , Humanos , Comunicação Interdisciplinar , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Memantina/uso terapêutico , Testes Neuropsicológicos , Equipe de Assistência ao Paciente , Dinâmica Populacional , Guias de Prática Clínica como Assunto , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/terapiaRESUMO
Mitochondrial dysfunction is a hypothesized component in the multifactorial pathogenesis of migraine without aura (MoA, 'common migraine') and the related condition of cyclic vomiting syndrome (CVS). In this study, the entire mitochondrial genome was sequenced in 20 haplogroup-H CVS patients, a subject group studied because of greater genotypic and phenotypic homogeneity. Sequences were compared against haplogroup-H controls. Polymorphisms of interest were tested in 10 additional CVS subjects and in 112 haplogroup-H adults with MoA. The 16519C-->T polymorphism was found to be highly disease associated: 21/30 CVS subjects [70%, odds ratio (OR) 6.2] and 58/112 migraineurs (52%, OR 3.6) vs. 63/231 controls (27%). A second polymorphism, 3010G-->A, was found to be highly disease associated in those subjects with 16519T: 6/21 CVS subjects (29%, OR 17) and 15/58 migraineurs (26%, OR 15) vs. 1/63 controls (1.6%). Our data suggest that these polymorphisms constitute a substantial proportion of the genetic factor in migraine pathogenesis, and strengthen the hypothesis that there is a component of mitochondrial dysfunction in migraine.
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DNA Mitocondrial/genética , Predisposição Genética para Doença , Transtornos de Enxaqueca/genética , Vômito/genética , Adulto , Criança , Feminino , Humanos , Masculino , Transtornos de Enxaqueca/complicações , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Síndrome , Vômito/etiologiaRESUMO
In younger patients with stroke, cerebral vasculitis and hereditary small vessel diseases should be considered as important differential diagnoses. Since the clinical course of cerebral vasculitis is highly variable, diagnostic workup, which includes laboratory tests, CSF analysis, cranial magnetic resonance imaging and biopsy, is often challenging. Therapy should be initiated on an interdisciplinary basis and includes immunosuppressive induction and maintenance regimes. Hereditary small vessel diseases, e.g. CADASIL or Fabry's disease, can mimic clinical features of cerebral vasculitis. Their diagnosis which is based on family history, typical clinical features and genetic analysis often has implications for treatment and genetic counselling.
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Doenças Vasculares Periféricas/diagnóstico , Doenças Vasculares Periféricas/genética , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico , Vasculite do Sistema Nervoso Central/complicações , Vasculite do Sistema Nervoso Central/diagnóstico , Humanos , Doenças Vasculares Periféricas/complicações , Doenças Vasculares Periféricas/terapia , Acidente Vascular Cerebral/terapia , Vasculite do Sistema Nervoso Central/terapiaRESUMO
Lake Eibsee, Garmisch-Partenkirchen, 16 to 18 November, 2017: The European Stroke Organisation convened >120 stroke experts from 21 countries to discuss latest results and hot topics in clinical, translational and basic stroke research. Since its inception in 2011, the European Stroke Science Workshop has become a cornerstone of European Stroke Organisation's academic activities and a major highlight for researchers in the field. Participants include stroke researchers at all career stages and with different backgrounds, who convene for plenary lectures and discussions. The workshop was organised in seven scientific sessions focusing on the following topics: (1) acute stroke treatment and endovascular therapy; (2) small vessel disease; (3) opportunities for stroke research in the omics era; (4) vascular cognitive impairment; (5) intracerebral and subarachnoid haemorrhage; (6) alternative treatment concepts and (7) neural circuits, recovery and rehabilitation. All sessions started with a keynote lecture providing an overview on current developments, followed by focused talks on a timely topic with the most recent findings, including unpublished data. In the following, we summarise the key contents of the meeting. The program is provided in the online only Data Supplement. The workshop started with a key note lecture on how to improve the efficiency of clinical trial endpoints in stroke, which was delivered by Craig Anderson (Sydney, Australia) and set the scene for the following discussions.
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Mutations in the parkin gene encoding an E3 ligase are responsible for autosomal recessive Parkinson's disease. Putative parkin substrates and interacting partners have been identified, but the molecular mechanism underlying parkin-related neurodegeneration is still unclear. We have identified the 20S proteasomal subunit alpha4 (synonyms: PSMA7, XAPC7, subunit alpha type 7) as a new interacting partner of parkin. The C-terminal IBR-RING domain of parkin and the C-terminal part of alpha4 were essential for the interaction. Biochemical studies revealed that alpha4 was not a substrate for parkin-dependent ubiquitylation. Putative functions of the interaction might therefore be substrate presentation to the proteasome or regulation of proteasomal activity. Full-length parkin and parkin lacking the N-terminal ubiquitin-like domain slightly increased the proteasomal activity in HEK 293T cells, in line with the latter hypothesis.
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Cisteína Endopeptidases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Linhagem Celular , Cisteína Endopeptidases/química , DNA Complementar/metabolismo , Humanos , Imunoprecipitação , Modelos Genéticos , Complexos Multienzimáticos/química , Mutação , Células PC12 , Plasmídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Transdução de Sinais , Técnicas do Sistema de Duplo-Híbrido , Ubiquitina/química , Ubiquitina-Proteína Ligases/químicaAssuntos
Isquemia Encefálica/etiologia , Doenças Cardiovasculares/diagnóstico , Embolia/diagnóstico , Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Clopidogrel , Quimioterapia Combinada , Ecocardiografia , Eletrocardiografia Ambulatorial , Embolia/complicações , Embolia/tratamento farmacológico , Teste de Esforço , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Fatores de Risco , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêutico , Varfarina/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) is a hereditary angiopathy caused by mutations in Notch3. Cerebral microvessels show an accumulation of granular osmiophilic material in the vicinity of degenerating vascular smooth muscle cells. To study cerebrovascular function in CADASIL, we performed measurements on cerebral hemodynamics by using transcranial Doppler sonography. METHODS: Middle cerebral artery (MCA) mean blood flow velocity (MFV), cerebrovascular CO(2) reactivity, and the resistance index were measured by bilateral transcranial Doppler sonography in 29 CADASIL individuals (mean age, 49.0+/-2.4 years) and an equal number of age- and sex-matched control subjects. RESULTS: Compared with control subjects, CO(2) reactivity was reduced in CADASIL (33.4+/-2.7% versus 45.3+/-3.0%; P:<0.01). This difference remained significant when only nondisabled CADASIL individuals (Rankin=0, n=21) were included in the analysis (P:<0.05). CO(2) reactivity was significantly lower in disabled than in nondisabled CADASIL individuals (24.5+/-2.7% versus 36.8+/-3.4%; P:<0.05). MCA MFV was reduced in CADASIL (45.6+/-2.2 cm/s versus 54.2+/-2.4 cm/s; P:<0.05) and correlated negatively with age both in affected individuals (r=-0.314; P:<0.05) and control subjects (r=-0.339; P:<0.05). Resistance index was not significantly altered (59.0+/-1.0% versus 57.7+/-1.2%; P:=0.42). CONCLUSIONS: In CADASIL, there is a reduction of both CO(2) reactivity and basal MCA MFV. The reduced CO(2) reactivity suggests functional impairment of cerebral vasoreactivity probably related to vascular smooth muscle cell dysfunction. The reduction of CO(2) reactivity in nondisabled CADASIL individuals suggests an early role of impaired cerebral vasoreactivity in the evolution of the disease.
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Dióxido de Carbono/metabolismo , Circulação Cerebrovascular , Demência por Múltiplos Infartos/diagnóstico por imagem , Demência por Múltiplos Infartos/metabolismo , Receptores de Superfície Celular , Ultrassonografia Doppler Transcraniana , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Velocidade do Fluxo Sanguíneo , Demência por Múltiplos Infartos/genética , Demência por Múltiplos Infartos/fisiopatologia , Feminino , Humanos , Hipercapnia/metabolismo , Hipocapnia/metabolismo , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Músculo Liso Vascular/fisiopatologia , Proteínas Proto-Oncogênicas/genética , Receptor Notch3 , Receptores Notch , Resistência VascularRESUMO
BACKGROUND AND PURPOSE: We obtained magnetization transfer imaging (MTI) scans from individuals with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (1) to investigate the presence, extent, and nature of pathology in white and gray matter outside proton density (PD)-visible lesions; (2) to quantify the degree of tissue damage occurring in lesions seen on PD-weighted scans; and (3) to correlate MTI-derived measures of disease burden with age, physical disability, and cognitive performance. METHODS: Dual-echo, T1-weighted, and MTI scans of the brain were obtained from 33 individuals with CADASIL and 12 control subjects. Magnetization transfer ratio (MTR) values from PD-visible lesions, normal-appearing white matter (NAWM), and normal-appearing gray matter (NAGM) were measured. Histograms of MTR from the whole brain and normal-appearing brain tissue were also produced. RESULTS: All MTR values from NAWM and NAGM regions studied were significantly lower for individuals with CADASIL than for control subjects, with the exception of those obtained from the NAWM of the infratentorial structures and the NAGM of the occipital cortex. The average MTR from PD lesions in individuals with CADASIL was significantly lower than that from all the NAWM regions. Average MTR and peak location from whole-brain and normal-appearing brain tissue histograms were significantly lower for individuals with CADASIL than for control subjects. MTR values from NAWM were strongly correlated with the extent of macroscopic lesions and their average MTR. Apart from NAGM, average MTR from all other tissues studied significantly decreased with increasing age, physical disability, and cognitive impairment. CONCLUSIONS: PD lesions of individuals with CADASIL have variable degrees of tissue damage. Brain tissue outside PD abnormalities is also damaged. This study suggests that the extent and the severity of the brain tissue damage are critical factors in determining clinical status in CADASIL.