RESUMO
A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1-2 µm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity.
Assuntos
CADASIL , Artéria Retiniana , Humanos , CADASIL/fisiopatologia , CADASIL/diagnóstico por imagem , CADASIL/patologia , Pessoa de Meia-Idade , Masculino , Feminino , Adulto , Artéria Retiniana/diagnóstico por imagem , Artéria Retiniana/fisiopatologia , Artéria Retiniana/patologia , Idoso , Luz , Vasodilatação/fisiologia , Remodelação Vascular/fisiologiaRESUMO
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a typical neurodegenerative disease associated with mitochondrial dysfunction. Methylation of the D-loop region and mitochondrial DNA copy number (mtDNAcn) play a critical role in the maintenance of mitochondrial function. However, the association between D-loop region methylation, mtDNAcn and CADASIL remains unclear. METHODS: Overall, 162 individuals were recruited, including 66 CADASIL patients and 96 age- and sex-matched controls. After extracting genomic DNA from the peripheral white blood cells, levels of D-loop methylation and mtDNAcn were assessed using MethylTarget sequencing and real-time PCR, respectively. RESULTS: We observed increased mtDNAcn and decreased D-loop methylation levels in CADASIL patients compared to the control group, regardless of gender stratification. Besides, we found a negative correlation between D-loop methylation levels and mtDNAcn. Mediation effect analysis shows that the proportion of the association between mtDNAcn and CADASIL that is mediated by D-loop methylation is 11.6% (95% CI 5.6, 22.6). After gender stratification, the proportions of such associations that are mediated by D-loop methylation in males and females were 7.2% (95% CI 2.4, 19.8) and 22.0% (95% CI 7.4, 50.1), respectively. CONCLUSION: Decreased methylation of the D-loop region mediates increased mtDNAcn in CADASIL, which may be caused by a compensatory mechanism of mitochondrial dysfunction in patients with CADASIL.
Assuntos
CADASIL/genética , CADASIL/fisiopatologia , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , DNA Mitocondrial/sangue , DNA Mitocondrial/genética , Adulto , Idoso , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: To identify the underlying genetic defect for a consanguineous family with an unusually high number of members affected by cerebral small vessel disease. MATERIALS AND METHODS: A total of 6 individuals, of whom 3 are severely affected, from the family were clinically and radiologically evaluated. SNP genotyping was performed in multiple members to demonstrate genome-wide runs-of-homozygosity. Coding variants in the most likely candidate gene, HTRA1 were explored by Sanger sequencing. Published HTRA1-related phenotypes were extensively reviewed to explore the effect of number of affected alleles on phenotypic expression. RESULTS: Genome-wide homozygosity mapping identified a 3.2 Mbp stretch on chromosome 10q26.3 where HTRA1 gene is located. HTRA1 sequencing revealed an evolutionarily conserved novel homozygous c.824C>T (p.Pro275Leu) mutation, affecting the serine protease domain of HtrA1. Early-onset of cognitive and motor deterioration in homozygotes are in consensus with CARASIL. However, there was a clear phenotypic variability between homozygotes which includes alopecia, a suggested hallmark of CARASIL. All heterozygotes, presenting as CADASIL type 2, had spinal disk degeneration and several neuroimaging findings, including leukoencephalopathy and microhemorrhage despite a lack of severe clinical presentation. CONCLUSION: Here, we clearly demonstrate that CARASIL and CADASIL type 2 are two clinical consequences of the same disorder with different severities thorough the evaluation of the largest collection of homozygotes and heterozygotes segregating in a family. Considering the semi-dominant inheritance of HTRA1-related phenotypes, genetic testing and clinical follow-up must be offered for all members of a family with HTRA1 mutations regardless of symptoms.
Assuntos
Alopecia/genética , CADASIL/genética , Infarto Cerebral/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Leucoencefalopatias/genética , Mutação , Doenças da Coluna Vertebral/genética , Adulto , Idade de Início , Alopecia/diagnóstico , Alopecia/fisiopatologia , CADASIL/diagnóstico , CADASIL/fisiopatologia , Infarto Cerebral/diagnóstico , Infarto Cerebral/fisiopatologia , Consanguinidade , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Índice de Gravidade de Doença , Doenças da Coluna Vertebral/diagnóstico , Doenças da Coluna Vertebral/fisiopatologiaRESUMO
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor ß (TGFß) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.
Assuntos
CADASIL/fisiopatologia , Genômica/métodos , Proteômica/métodos , Receptor Notch3/genética , CADASIL/epidemiologia , CADASIL/genética , CADASIL/metabolismo , Cisteína/química , Microbioma Gastrointestinal , Frequência do Gene , Ontologia Genética , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Moleculares , Mutação , Proteínas do Tecido Nervoso/análise , Prevalência , Prognóstico , Agregação Patológica de Proteínas/etiologia , Conformação Proteica , Domínios Proteicos , Receptor Notch3/química , Receptor Notch3/fisiologia , Análise de Sequência de DNA , TranscriptomaRESUMO
BACKGROUND AND PURPOSE: The cognitive decline in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is assumed to be due to a cortical-subcortical disconnection secondary to damage to the cerebral white matter (WM). Using resting state functional MRI (rsfMRI) and analysis of the regional homogeneity (ReHo), we examined a group of CADASIL patients and a group of healthy subjects in order to: (1) explore possible differences between the two groups; and (2) to assess, in CADASIL patients, whether any ReHo abnormalities correlate with individual burdens of WM T2 -weighted hyperintensity and diffusion tensor imaging (DTI)-derived index of mean diffusivity (MD) of the cerebral WM, an index reflecting microstructural damage in CADASIL. METHODS: Twenty-three paucisymptomatic CADASIL patients (13 females; age mean ± standard deviation = 43.6 ± 11.1 years; three symptomatic and 20 with no or few symptoms) and 16 healthy controls (nine females; age 46.6 ± 11.0 years) were examined with T1 -weighted, T2 -weighted fluid attenuated inversion recovery images, DTI, and rsfMRI. RESULTS: When compared to controls, CADASIL patients showed four clusters of significantly lower ReHo values in cortical areas belonging to networks involved in inhibition and attention, including the right insula, the left superior frontal gyrus, and the bilateral anterior cingulated cortex. ReHo changes did not correlate with an individual patient's lesion burden or MD. CONCLUSIONS: This study reveals decreased ReHo of rsfMRI signals in cortical areas involved in inhibition and attention processes, suggesting a potential role for these functional cortical changes in CADASIL.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , CADASIL/diagnóstico por imagem , CADASIL/patologia , Imagem de Tensor de Difusão , Descanso , Adulto , Encéfalo/fisiopatologia , CADASIL/fisiopatologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: To test the hypothesis that multi-shell diffusion models improve the characterization of microstructural alterations in cerebral small vessel disease (SVD), we assessed associations with processing speed performance, longitudinal change, and reproducibility of diffusion metrics. METHODS: We included 50 patients with sporadic and 59 patients with genetically defined SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) with cognitive testing and standardized 3T MRI, including multi-shell diffusion imaging. We applied the simple diffusion tensor imaging (DTI) model and 2 advanced models: diffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI). Linear regression and multivariable random forest regression (including conventional SVD markers) were used to determine associations between diffusion metrics and processing speed performance. The detection of short-term disease progression was assessed by linear mixed models in 49 patients with sporadic SVD with longitudinal high-frequency imaging (in total 459 MRIs). Intersite reproducibility was determined in 10 patients with CADASIL scanned back-to-back on 2 different 3T MRI scanners. RESULTS: Metrics from DKI showed the strongest associations with processing speed performance (R 2 up to 21%) and the largest added benefit on top of conventional SVD imaging markers in patients with sporadic SVD and patients with CADASIL with lower SVD burden. Several metrics from DTI and DKI performed similarly in detecting disease progression. Reproducibility was excellent (intraclass correlation coefficient >0.93) for DTI and DKI metrics. NODDI metrics were less reproducible. CONCLUSION: Multi-shell diffusion imaging and DKI improve the detection and characterization of cognitively relevant microstructural white matter alterations in SVD. Excellent reproducibility of diffusion metrics endorses their use as SVD markers in research and clinical care. Our publicly available intersite dataset facilitates future studies. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with SVD, diffusion MRI metrics are associated with processing speed performance.
Assuntos
CADASIL/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Substância Branca/diagnóstico por imagem , Adulto , Idoso , CADASIL/fisiopatologia , CADASIL/psicologia , Hemorragia Cerebral/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Doenças de Pequenos Vasos Cerebrais/psicologia , Imagem de Tensor de Difusão , Progressão da Doença , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Leucoaraiose/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral Lacunar/diagnóstico por imagemRESUMO
Headache is a common accompanying symptom of cerebrovascular diseases. The most common patterns of headache for different cerebrovascular disorders, aetiology and pathogenesis and diagnostic workup are reviewed with emphasis on distinguishing characteristics. It will be a clinical guide for physicians who treat patients with headache or cerebral vascular disease.
Assuntos
Circulação Cerebrovascular , Transtornos Cerebrovasculares/complicações , Cefaleia/etiologia , Hemodinâmica , CADASIL/complicações , CADASIL/fisiopatologia , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/fisiopatologia , Transtornos Cerebrovasculares/terapia , Cefaleia/diagnóstico , Cefaleia/fisiopatologia , Cefaleia/terapia , Humanos , Trombose Intracraniana/complicações , Trombose Intracraniana/fisiopatologia , Síndrome MELAS/complicações , Síndrome MELAS/fisiopatologia , Prognóstico , Fatores de Risco , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/fisiopatologia , Vasculite do Sistema Nervoso Central/complicações , Vasculite do Sistema Nervoso Central/fisiopatologia , Vasoespasmo Intracraniano/complicações , Vasoespasmo Intracraniano/fisiopatologia , Dissecação da Artéria Vertebral/complicações , Dissecação da Artéria Vertebral/fisiopatologiaRESUMO
Autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), is a genetic disease caused by mutations in the Notch3 gene. More than 170 monogenic mutations leading to the development of CADASIL have been reported. We describe a case of a patient and her family with compatible symptoms of CADASIL disease, in which a variable not yet described in the Notch3 gene was detected, that generates a probably pathogenic change in the protein.
Assuntos
CADASIL/genética , Mutação , Receptor Notch3/genética , Adulto , CADASIL/diagnóstico por imagem , CADASIL/fisiopatologia , CADASIL/psicologia , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , FenótipoRESUMO
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL; OMIM #125310) is the most common cause of monogenic familial cerebral small vessel disease. It typically manifests at middle adulthood with highly variable clinical features including migraine with aura, recurrent transient ischemic attacks or ischemic strokes, mood disorders, and progressive cognitive decline. It is caused by mutations in the NOTCH3 gene, which maps to the short arm of chromosome 19 and encode for epidermal growth factor-like repeats. In this article, we report a 40-year-old male patient who presented with a two-year history of progressive cognitive decline including impaired attention, memory, executive functions, and processing speed whose family history was strongly positive for young-onset ischemic stroke and memory impairment. His father, uncle, and grandfather died due to ischemic strokes and cognitive impairment (similar condition). A whole exome sequencing to the patient (proband II-1) revealed a novel heterozygous missense variant c.3009G>T, p.(Trp1003Cys) (chr19;15291625; hg19) in exon 19 of the NOTCH3 gene. Sanger sequencing was used to confirm the variant in other family members. This variant has not been described in the literature so far. The novel mutation described in the present study widened the genetic spectrum of NOTCH3-associated diseases, which will benefit studies addressing this disease in the future. CADASIL remains a disabling disorder leading to medical retirement in our patient due to late clinical presentation, lack of family history taking prior to joining the military, and lack of curative therapy. Further research for therapeutic options is needed including stem cell therapy .
Assuntos
CADASIL/genética , Mutação de Sentido Incorreto , Receptor Notch3/genética , Adulto , CADASIL/diagnóstico por imagem , CADASIL/fisiopatologia , CADASIL/terapia , Análise Mutacional de DNA , Éxons , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Arábia Saudita , Sequenciamento do ExomaRESUMO
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3, and characterized by recurrent cerebral ischemic events without vascular risk factors, mood disturbance, and dementia. MRI testing shows cerebral white matter hyperintensities, especially in the external capsule and temporal pole. Typical mutations are cysteine-related missense ones located in one of 34 EGF-like repeats (EGFr) in the NOTCH3 receptor. To identify genotype-phenotype correlations, 179 Japanese CADASIL probands were recruited. Of the 68 mutations identified, p.Cys388Arg, p.Cys435Phe, p.Gly481Cys, p.Cys743Tyr, and p.Cys1009Phe were novel ones. The genotype-phenotype correlation was analyzed based on the three most common mutations: p.Arg75Pro, p.Arg141Cys, and p.Arg182Cys. p.Arg141Cys showed typical CADASIL phenotypes, whereas p.Arg75Pro showed mild and atypical phenotypes, a low frequency of stroke/TIA, high frequency of hypertension, and low frequency of temporal pole lesions. p.Arg182Cys showed various initial symptoms other than stroke/TIA. Subsequently, we analyzed the effect of the mutation location on the age at onset of stroke/TIA. We found that mutations in EGFr 1-6 excluding the cysteine-sparing mutation p.Arg75Pro were significantly correlated with a younger age at onset of stroke/TIA compared with those in EGFr 7-34. This was in agreement with a recent European report, suggesting that the effect of the mutation location is a consensus finding in CADASIL worldwide.
Assuntos
CADASIL/genética , Receptor Notch3/genética , Idoso , CADASIL/diagnóstico por imagem , CADASIL/fisiopatologia , Éxons/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Japão , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Acidente Vascular Cerebral/genéticaRESUMO
While structural network analysis consolidated the hypothesis of cerebral small vessel disease (SVD) being a disconnection syndrome, little is known about functional changes on the level of brain networks. In patients with genetically defined SVD (CADASIL, n = 41) and sporadic SVD (n = 46), we independently tested the hypothesis that functional networks change with SVD burden and mediate the effect of disease burden on cognitive performance, in particular slowing of processing speed. We further determined test-retest reliability of functional network measures in sporadic SVD patients participating in a high-frequency (monthly) serial imaging study (RUN DMC-InTENse, median: 8 MRIs per participant). Functional networks for the whole brain and major subsystems (i.e., default mode network, DMN; fronto-parietal task control network, FPCN; visual network, VN; hand somatosensory-motor network, HSMN) were constructed based on resting-state multi-band functional MRI. In CADASIL, global efficiency (a graph metric capturing network integration) of the DMN was lower in patients with high disease burden (standardized beta = -.44; p [corrected] = .035) and mediated the negative effect of disease burden on processing speed (indirect path: std. beta = -.20, p = .047; direct path: std. beta = -.19, p = .25; total effect: std. beta = -.39, p = .02). The corresponding analyses in sporadic SVD showed no effect. Intraclass correlations in the high-frequency serial MRI dataset of the sporadic SVD patients revealed poor test-retest reliability and analysis of individual variability suggested an influence of age, but not disease burden, on global efficiency. In conclusion, our results suggest that changes in functional connectivity networks mediate the effect of SVD-related brain damage on cognitive deficits. However, limited reliability of functional network measures, possibly due to age-related comorbidities, impedes the analysis in elderly SVD patients.
Assuntos
Doenças de Pequenos Vasos Cerebrais , Disfunção Cognitiva , Conectoma/normas , Rede de Modo Padrão , Imagem de Tensor de Difusão/normas , Rede Nervosa , Adulto , Idoso , Idoso de 80 Anos ou mais , CADASIL/diagnóstico por imagem , CADASIL/patologia , CADASIL/fisiopatologia , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/patologia , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Conectoma/métodos , Estudos Transversais , Rede de Modo Padrão/diagnóstico por imagem , Rede de Modo Padrão/patologia , Rede de Modo Padrão/fisiopatologia , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Reprodutibilidade dos TestesRESUMO
CADASIL is a vascular protein aggregation disorder caused by cysteine-altering NOTCH3 variants, leading to mid-adult-onset stroke and dementia. Here, we report individuals with a cysteine-altering NOTCH3 variant that induces exon 9 skipping, mimicking therapeutic NOTCH3 cysteine correction. The index came to our attention after a coincidental finding on a commercial screening MRI, revealing white matter hyperintensities. A heterozygous NOTCH3 c.1492G>T, p.Gly498Cys variant, was identified using a gene panel, which was also present in four first- and second-degree relatives. Although some degree of white matter hyperintensities was present on MRI in all family members with the NOTCH3 variant, the CADASIL phenotype was mild, as none had lacunes on MRI and there was no disability or cognitive impairment above the age of 60 years. RT-PCR and Sanger sequencing analysis on patient fibroblast RNA revealed that exon 9 was absent from the majority of NOTCH3 transcripts of the mutant allele, effectively excluding the mutation. NOTCH3 aggregation was assessed in skin biopsies using electron microscopy and immunohistochemistry and did not show granular osmiophilic material and only very mild NOTCH3 staining. For purposes of therapeutic translatability, we show that, in cell models, exon 9 exclusion can be obtained using antisense-mediated exon skipping and CRISPR/Cas9-mediated genome editing. In conclusion, this study provides the first in-human evidence that cysteine corrective NOTCH3 exon skipping is associated with less NOTCH3 aggregation and an attenuated phenotype, justifying further therapeutic development of NOTCH3 cysteine correction for CADASIL.
Assuntos
CADASIL/genética , Cisteína/genética , Agregação Patológica de Proteínas/genética , Receptor Notch3/genética , Substância Branca/metabolismo , Adulto , Idoso , Biópsia , CADASIL/diagnóstico por imagem , CADASIL/metabolismo , CADASIL/fisiopatologia , Sistemas CRISPR-Cas/genética , Éxons/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Agregação Patológica de Proteínas/diagnóstico por imagem , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Índice de Gravidade de Doença , Pele/química , Pele/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
Small-vessel diseases (SVDs) of the brain are involved in about one-fourth of ischemic strokes and a vast majority of intracerebral hemorrhages and are responsible for nearly half of dementia cases in the elderly. SVDs are a heavy burden for society, a burden that is expected to increase further in the absence of significant therapeutic advances, given the aging population. Here, we provide a critical appraisal of currently available therapeutic approaches for nonamyloid sporadic SVDs that are largely based on targeting modifiable risk factors. We review what is known about the pathogenic mechanisms of vascular risk factor-related SVDs and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most frequent hereditary SVD, and elaborate on two mechanism-based therapeutic approaches worth exploring in sporadic SVD and CADASIL. We conclude by discussing opportunities and challenges that need to be tackled if efforts to achieve significant therapeutic advances for these diseases are to be successful.
Assuntos
Encefalopatias/prevenção & controle , Encéfalo/fisiopatologia , Idoso , Animais , Encéfalo/irrigação sanguínea , Encefalopatias/fisiopatologia , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/prevenção & controle , CADASIL/fisiopatologia , CADASIL/prevenção & controle , Hemorragia Cerebral/fisiopatologia , Hemorragia Cerebral/prevenção & controle , Demência/fisiopatologia , Demência/prevenção & controle , Humanos , Fatores de Risco , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/prevenção & controleRESUMO
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) manifests principally as a suite of cognitive impairments, particularly in the executive domain. Executive functioning requires the dynamic coordination of neural activity over large-scale networks. It remains unclear whether changes in resting-state brain functional network connectivity and regional homogeneities (ReHos) underly the mechanisms of executive dysfunction evident in CADASIL patients. METHODS: In this study, 22 CADASIL patients and 44 matched healthy controls underwent resting-state functional magnetic resonance imaging (fMRI). Independent component analysis (ICA) was used to measure functional brain network connectivity, and ReHos were calculated to evaluate local brain activities. We used seed-based functional connectivity (FC) analyses to determine whether dysfunctional areas (as defined by ReHos) exhibited abnormal FC with other brain areas. Relationships among the mean intra-network connectivity z-scores of dysfunctional areas within functional networks, and cognitive scores were evaluated using Pearson correlation analyses. RESULTS: Compared to the controls, CADASIL patients exhibited decreased intra-network connectivity within the bilateral lingual gyrus (LG) and the right cuneus (CU) (thus within the visual network [VIN)], and within the right precuneus (Pcu), inferior frontal gyrus (IFG), and precentral gyrus (thus within the frontal network [FRN]). Compared to the controls, patients also exhibited significantly lower ReHos in the right precuneus and cuneus (Pcu/CU), visual association cortex, calcarine gyri, posterior cingulate, limbic lobe, and weaker FC between the right Pcu/CU and the bilateral parahippocampal gyrus (PHG), and between the right Pcu/CU and the right postcentral gyrus. Notably, the mean connectivity z-scores of the bilateral LG and the right CU within the VIN were positively associated with compromised attention, calculation and delayed recall as revealed by tests of the various cognitive domains explored by the Mini-Mental State Examination. CONCLUSIONS: The decreases in intra-network connectivity within the VIN and FRN and reduced local brain activity in the posterior parietal area suggest that patients with CADASIL may exhibit dysfunctional visuomotor behaviors (a hallmark of executive function), and that all visual information processing, visuomotor planning, and movement execution may be affected.
Assuntos
Encéfalo/diagnóstico por imagem , CADASIL/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Função Executiva , Adulto , Encéfalo/fisiopatologia , CADASIL/fisiopatologia , CADASIL/psicologia , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Cognição , Disfunção Cognitiva/psicologia , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Neuroimagem Funcional , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiopatologia , Descanso , Córtex Visual/diagnóstico por imagem , Córtex Visual/fisiopatologiaRESUMO
OBJECTIVE: Gait impairment is common in patients with cerebral small vessel disease (SVD). However, gait studies in elderly SVD patients might be confounded by age-related comorbidities, such as polyneuropathy or sarcopenia. We therefore studied young patients with the genetically defined SVD CADASIL. Our aim was to examine the effects of pure SVD on single and dual task gait, and to investigate associations of gait performance with cognitive deficits and white matter alterations. METHODS: We investigated single task walking and calculatory, semantic, or motoric dual task costs in 39 CADASIL patients (mean age 50 ± 8) using a computerized walkway. We obtained 3.0T MRI and neuropsychological data on processing speed, the main cognitive deficit in CADASIL. Spatiotemporal gait parameters were standardized based on data from 192 healthy controls. Associations between white matter integrity, assessed by diffusion tensor imaging, and gait were analyzed using both a global marker and voxel-wise analysis. RESULTS: Compared to controls, CADASIL patients showed only mild single task gait impairment, and only in the rhythm domain. The semantic dual task additionally uncovered mild deficits in the pace domain. Processing speed was not associated with gait. White matter alterations were related to single task stride length but not to dual task performance. INTERPRETATION: Despite severe disease burden, gait performance in patients with pure small vessel disease was relatively preserved in single and dual tasks. Results suggest that age-related pathologies other than small vessel disease might play a role for gait impairment in elderly SVD patients.
Assuntos
CADASIL/patologia , CADASIL/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Função Executiva/fisiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Desempenho Psicomotor/fisiologia , Substância Branca/patologia , Adulto , CADASIL/complicações , CADASIL/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Imagem de Tensor de Difusão , Feminino , Transtornos Neurológicos da Marcha/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Substância Branca/diagnóstico por imagemRESUMO
BACKGROUND This study aimed to identify NOTCH3 mutations and describe the genetic and clinical features and magnetic resonance imaging results in 11 unrelated patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) from Henan province in China. MATERIAL AND METHODS NOTCH3 was directly sequenced in 11 unrelated patients of Chinese descent. The clinical presentations and magnetic resonance imaging features were retrospectively analyzed in the 11 index patients with a definite diagnosis. RESULTS Seven different mutations were identified in 11 unrelated patients, including 4 novel mutations (p.P167S, p.P652S, p.C709R, and p.R1100H) in China and 3 reported mutations (p.C117R, p.R578C, and p.R607C). Four novel mutations (p.P167S, p.P652S, p.C709R, and p.R1100H) were predicted to be probably pathogenic using an online pathogenicity prediction program through comprehensive analysis. Clinical presentations in symptomatic patients included stroke, cognitive decline, psychiatric disturbances, and migraine. Multiple lacunars infarcts and leukoaraiosis were detected on MRI in most symptomatic patients, while white-matter lesions were identified in the temporal pole or the external capsule in all affected patients. CONCLUSIONS The mutation spectrum of CADASIL patients from Henan province in China displayed some differences from that of those reported previously. DNA sequencing was used to diagnose all 11 patients as having CADASIL, and we found 4 novel mutations. The present results further contribute to the enrichment of NOTCH3 mutation databases.
Assuntos
CADASIL/genética , Receptor Notch3/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Sequência de Bases , CADASIL/fisiopatologia , Infarto Cerebral/genética , China , Feminino , Humanos , Leucoencefalopatias/genética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Receptor Notch3/metabolismo , Estudos Retrospectivos , Análise de Sequência de DNARESUMO
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare monogenic disorder caused by mutations in the NOTCH3 gene. The clinical features are primarily neurological, which include recurrent transient ischaemic attacks, strokes, and migraines. However, psychiatric manifestations which mainly include mood disturbances have also been reported in CADASIL. Manic symptoms and bipolar disorders are rarely documented in CADASIL and existing reports generally lack detailed descriptions of the psychiatric evaluation. We discuss a case of Bipolar Affective Disorder (BD) in a British woman with a family history of CADASIL. This case provides insight into the diagnosis and management of BD as well as the possible underlying aetiologies that should be considered. The similarities between BD and CADASIL in terms of imaging, genetic, and therapeutic aspects raise the possibility of common dysfunctional pathways. BD in CADASIL may warrant greater consideration by both psychiatrists as well as non-psychiatric specialists and further studies are required to understand the pathological significance.
Assuntos
Transtorno Bipolar/complicações , CADASIL/complicações , Transtorno Bipolar/genética , Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/psicologia , CADASIL/genética , CADASIL/fisiopatologia , CADASIL/psicologia , Feminino , Humanos , Transtornos de Enxaqueca/complicações , Transtornos do Humor/complicações , Mutação , Receptor Notch3/genética , Reino UnidoRESUMO
BACKGROUND: Population-based studies have highlighted a close relationship between migraine and stroke. Migraine, especially with aura, is a risk factor for both ischemic and hemorrhagic stroke. Interestingly, stroke risk is highest for migraineurs who are young and otherwise healthy. MAIN BODY: Preclinical models have provided us with possible mechanisms to explain the increased vulnerability of migraineurs' brains towards ischemia and suggest a key role for enhanced cerebral excitability and increased incidence of microembolic events. Spreading depolarization (SD), a slowly propagating wave of neuronal depolarization, is the electrophysiologic event underlying migraine aura and a known headache trigger. Increased SD susceptibility has been demonstrated in migraine animal models, including transgenic mice carrying human mutations for the migraine-associated syndrome CADASIL and familial hemiplegic migraine (type 1 and 2). Upon experimentally induced SD, these mice develop aura-like neurological symptoms, akin to patients with the respective mutations. Migraine mutant mice also exhibit an increased frequency of ischemia-triggered SDs upon experimental stroke, associated with accelerated infarct growth and worse outcomes. The severe stroke phenotype can be explained by SD-related downstream events that exacerbate the metabolic mismatch, including pericyte contraction and neuroglial inflammation. Pharmacological suppression of the genetically enhanced SD susceptibility normalizes the stroke phenotype in familial hemiplegic migraine mutant mice. Recent epidemiologic and imaging studies suggest that these preclinical findings can be extrapolated to migraine patients. Migraine patients are at risk for particularly cardioembolic stroke. At the same time, studies suggest an increased incidence of coagulopathy, atrial fibrillation and patent foramen ovale among migraineurs, providing a possible path for microembolic induction of SD and, in rare instances, stroke in hyperexcitable brains. Indeed, recent imaging studies document an accelerated infarct progression with only little potentially salvageable brain tissue in acute stroke patients with a migraine history, suggesting an increased vulnerability towards cerebral ischemia. CONCLUSION: Preclinical models suggest a key role for enhanced SD susceptibility and microembolization to explain both the occurrence of migraine attacks and the increased stroke risk in migraineurs. Therapeutic targeting of SD and microembolic events, or potential causes thereof, will be promising for treatment of aura and may also prevent ischemic infarction in vulnerable brains.
Assuntos
Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Modelos Animais de Doenças , Enxaqueca com Aura/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/fisiopatologia , CADASIL/diagnóstico , CADASIL/epidemiologia , CADASIL/fisiopatologia , Humanos , Camundongos , Enxaqueca com Aura/diagnóstico , Enxaqueca com Aura/epidemiologia , Neurônios/fisiologia , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologiaRESUMO
CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. CSVD can be asymptomatic; however, depending on location, lesions can cause mild cognitive dysfunction, dementia, mood disorders, motor and gait dysfunction, and urinary incontinence. CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity. Pathogenesis is thought to begin with an etiologically specific insult, with or without genetic predisposition, which results in dysfunction of the neurovascular unit. Uncertainties regarding pathogenesis have delayed development of effective treatment. The most widely accepted approach to treatment is to intensively control well-established vascular risk factors, of which hypertension is the most important. With better understanding of pathogenesis, specific therapies may emerge. Early identification of pathologic characteristics with advanced imaging provides an opportunity to forestall progression before emergence of symptoms.
Assuntos
Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Anti-Hipertensivos/uso terapêutico , CADASIL/complicações , CADASIL/diagnóstico por imagem , CADASIL/tratamento farmacológico , CADASIL/fisiopatologia , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/tratamento farmacológico , Angiopatia Amiloide Cerebral/fisiopatologia , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/tratamento farmacológico , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Demência/etiologia , Demência/fisiopatologia , Imagem de Difusão por Ressonância Magnética , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imageamento por Ressonância Magnética , Inibidores da Agregação Plaquetária/uso terapêutico , Acidente Vascular Cerebral Lacunar/diagnóstico por imagem , Acidente Vascular Cerebral Lacunar/etiologia , Acidente Vascular Cerebral Lacunar/fisiopatologiaRESUMO
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) mainly manifests with cognitive impairment. Cognitive deficits in patients with CADASIL are correlated with structural brain changes such as lacunar lesion burden, normalized brain volume, and anterior thalamic radiation lesions, but changes in resting-state functional brain activity in patients with CADASIL have not been reported. METHODS: This study used resting-state functional magnetic resonance imaging (fMRI) to measure the amplitude of low-frequency fluctuation (ALFF) in 22 patients with CADASIL and 44 healthy matched controls. A seed-based functional connectivity (FC) analysis was used to investigate whether the dysfunctional areas identified by ALFF analysis exhibited abnormal FC with other brain areas. Pearson's correlation analysis was used to detect correlations between the ALFF z-score of abnormal brain areas and clinical scores in patients with CADASIL. RESULTS: Patients with CADASIL exhibited significantly lower ALFF values in the right precuneus and cuneus (Pcu/CU) and higher ALFF values in the bilateral superior frontal gyrus (SFG) and left cerebellar anterior and posterior lobes compared with controls. Patients with CADASIL showed weaker FC between the areas with abnormal ALFF (using peaks in the left and right SFG and the right Pcu/CU) and other brain areas. Importantly, the ALFF z-scores for the left and right SFG were negatively associated with cognitive performance, including Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment scores (MoCA), respectively, whereas those of the right Pcu/CU were positively correlated with the MMSE score. CONCLUSIONS: This preliminary study provides evidence for changes in ALFF of the right Pcu/CU, bilateral SFG and left cerebellar anterior and posterior lobes, and associations between ALFF values for abnormal brain areas and cognitive performance in patients with CADASIL. Therefore, spontaneous brain activity may be a novel imaging biomarker of cognitive impairment in this population.