RESUMEN
BACKGROUND: Oily fish is a major dietary source of omega-3 polyunsaturated fatty acids and other nutrients that may reduce the expression of cerebral small vessel disease (cSVD) biomarkers, including white matter hyperintensities (WMH) of presumed vascular origin. However, information on this relationship is limited. We aimed to assess the association between oily fish intake and WMH severity in a population of frequent fish consumers. METHODS: The study included 572 individuals aged ≥60 years living in three neighboring rural villages of coastal Ecuador. Dietary oily fish intake was calculated and all participants received a brain MRI. Logistic regression models, adjusted for demographics, level of education, cardiovascular risk factors and other cSVD biomarkers, were fitted to assess the independent association between amounts of oily fish intake and WMH severity. RESULTS: Overall, the mean intake of oily fish was 8.5 ± 4.7 servings per week, and 164 individuals (29%) had moderate-to-severe WMH (according to the modified Fazekas scale). A multivariate logistic regression model disclosed a significant inverse association between the amount of oily fish intake and the presence of moderate-to-severe WMH (OR: 0.89; 95% C.I.: 0.85-0.94; p < 0.001). Predictive margins revealed an almost linear inverse relationship between quartiles of oily fish intake and probabilities of WMH severity, which became significant when the 1st quartile was compared with the 3rd and 4th quartiles. CONCLUSIONS: Increased amounts of oily fish intake are inversely associated with WMH severity. Further studies are warranted to determine whether oily fish intake reduces the risk of cSVD-related cerebrovascular complications.
Asunto(s)
Dieta Saludable/etnología , Aceites de Pescado/administración & dosificación , Indígenas Sudamericanos , Leucoencefalopatías/prevención & control , Valor Nutritivo , Alimentos Marinos , Anciano , Anciano de 80 o más Años , Estudios Transversales , Ecuador/epidemiología , Femenino , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/etnología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Factores Protectores , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
[Figure: see text].
Asunto(s)
Arterias Cerebrales/fisiopatología , Trastornos Cerebrovasculares/fisiopatología , Leucoencefalopatías/fisiopatología , Remodelación Vascular , Rigidez Vascular , Anciano , Anciano de 80 o más Años , Velocidad de la Onda del Pulso Carotídeo-Femoral , Arterias Cerebrales/patología , Trastornos Cerebrovasculares/diagnóstico , Trastornos Cerebrovasculares/etnología , Estudios Transversales , Dilatación Patológica , Femenino , Humanos , Leucoencefalopatías/diagnóstico , Leucoencefalopatías/etnología , Imagen por Resonancia Magnética , Masculino , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: The aim of this study was screening for single nucleotide polymorphisms (SNPs) associated with white matter hyperintensities (WMHs) in symptomatic intracranial atherosclerotic stenosis (sICAS) patients and exploring a possible connection in the genetic background between macrovascular disease and small vessel disease. METHODS: There were 400 sICAS patients enrolled in the study. Fazekas scores were applied to WMH classification. Healthy controls were referred to 1,000 Genome Project and GeneSky company who provided 1,007 Chinese healthy controls. Fast target sequencing technology was used to select the SNPs of 102 genes related to the pathogenesis of sICAS in the sICAS patients. RESULTS: The allele frequencies of 88 SNPs were significantly different between the sICAS group and the healthy controls (p < 0.05). The allele frequencies of 53 SNPs were significantly different between the sICAS patients with and without WMHs (p < 0.05). Further analysis found that matrix metalloproteinase 9 (MMP9) rs17576 was simultaneously related to sICAS and WMHs. The frequency of the rs17576 A allele was significantly lower in sICAS patients when compared to the normal controls (p = 0.03, OR [95% CI] = 0.75 [0.625-0.91]). Also, the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.009), dominant (p = 0.014), and recessive (p= 0.023) models. The frequency of the rs17576 A allele was significantly higher in sICAS with WMH patients, compared to those without WMHs (p = 0.022, OR [95% CI] = 1.54 [1.06-2.22]); the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.019) and recessive (p = 0.032) models. Logistic regression analysis showed that age, hypertension, and MMP9 rs17576 AA genotype were independent risk factors for sICAS with WMHs. CONCLUSION: MMP9 rs17576 may be simultaneously associated with the risk of sICAS and WMHs.
Asunto(s)
Arteriosclerosis Intracraneal/genética , Ataque Isquémico Transitorio/genética , Accidente Cerebrovascular Isquémico/genética , Leucoencefalopatías/genética , Metaloproteinasa 9 de la Matriz/genética , Polimorfismo de Nucleótido Simple , Anciano , Pueblo Asiatico/genética , Estudios de Casos y Controles , China/epidemiología , Estudios Transversales , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Arteriosclerosis Intracraneal/diagnóstico , Arteriosclerosis Intracraneal/etnología , Ataque Isquémico Transitorio/diagnóstico , Ataque Isquémico Transitorio/etnología , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/etnología , Leucoencefalopatías/diagnóstico , Leucoencefalopatías/etnología , Masculino , Persona de Mediana Edad , Fenotipo , Medición de Riesgo , Factores de RiesgoRESUMEN
BACKGROUND: Intraventricular hemorrhage (IVH) and white matter lesion (WML) severity are associated with higher rates of death and disability in intracerebral hemorrhage (ICH). A prior report identified an increased risk of IVH with greater WML burden but did not control for location of ICH. We sought to determine whether a higher degree of WML is associated with a higher risk of IVH after controlling for ICH location. METHODS: Utilizing the patient population from 2 large ICH studies; the Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS III) Study and the Ethnic/Racial Variations of Intracerebral Hemorrhage study, we graded WML using the Van Swieten Scale (0-1 for mild, 2 for moderate, and 3-4 for severe WML) and presence or absence of IVH in baseline CT scans. We used multivariable regression models to adjust for relevant covariates. RESULTS: Among 3023 ICH patients, 1260 (41.7%) had presence of IVH. In patients with IVH, the proportion of severe WML (28.6%) was higher compared with patients without IVH (21.8%) (P < .0001). Multivariable analysis demonstrated that moderate-severe WML, deep ICH, and increasing ICH volume were independently associated with presence of IVH. We found an increased risk of IVH with moderate-severe WML (ORâ¯=â¯1.38; 95%Cl 1.03-1.86, Pâ¯=â¯.0328) in the subset of lobar hemorrhages. CONCLUSIONS: Moderate to severe WML is a risk for IVH. Even in lobar ICH hemorrhages, severe WML leads to an independent increased risk for ventricular rupture.
Asunto(s)
Hemorragia Cerebral/complicaciones , Hemorragia Cerebral Intraventricular/etiología , Leucoencefalopatías/complicaciones , Anciano , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/etnología , Hemorragia Cerebral Intraventricular/diagnóstico por imagen , Hemorragia Cerebral Intraventricular/etnología , Femenino , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/etnología , Masculino , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Neuronal ceroid lipofuscinosis (NCLs) are lysosomal storage disorders characterized by seizures, motor impairment, and loss of vision. Ceroid lipofuscinosis (CLN) gene mutations are the cause, but NCL cases arising from CLN6 mutations have not been described in China to date. The CLN6 protein, which plays a role in lysosomal function, is an endoplasmic reticulum (ER) membrane protein with seven transmembrane (TM) domains. It has a cytosolic-facing amino terminal domain and a luminal-facing carboxyl terminal domain, with six loops between the TM domains. CASE PRESENTATION: Here we report a case involving a Chinese boy whose suspected diagnosis was a hereditary leukoencephalopathy, based on brain MRI imaging and epilepsy symptoms, language articulation disorders, ataxia, and unstable gait. The electroencephalogram showed epileptic discharges, and the brain MRI scan showed high signal intensity adjacent to the bilateral posterior horns of the lateral ventricles on T2-weighted images, along with cerebellar atrophy. Using next-generation sequencing for the genes in a panel for hereditary leukoencephalopathies, we detected a homozygous missense point mutation c.892G > A(p.Glu298Lys) in CLN6, and the variant was interpreted as pathogenic on in silico analysis. Absence of this mutation was confirmed in 259 controls. Late infantile NCL and secondary epilepsy were diagnosed, and oral sodium valproate was prescribed. The epilepsy was not well controlled, however, and the other signs had not improved at the 6-month follow-up. We also analyzed the loci of 31 CLN6 missense mutations, including those previously reported and the current one. We found that 22.6% (7/31) of the mutations are in the cytoplasmic domains, about 32.2% (10/31) are in the TM domains, and about 45.2% (14/31) are in the luminal domains. These mutations were mostly located in the TM3-TM4 loop (6/31), TM1-TM2 loop (4/31), and C-terminus (4/31), with none found in the TM4-TM5 loop, TM5-TM6 loop, or TM7. CONCLUSIONS: We report the first case in China of NCL caused by a CLN6 mutation, expanding the genotype options for NCLs. In practice, NCLs generally are not the initial suspected diagnosis for such cases. Use of a gene sequencing panel for investigating unexplained seizures or leukoencephalopathies can help confirm the diagnosis.
Asunto(s)
Leucoencefalopatías/genética , Proteínas de la Membrana/genética , Mutación Missense , Lipofuscinosis Ceroideas Neuronales/genética , Convulsiones/genética , Adulto , Pueblo Asiatico , Secuencia de Bases , Preescolar , Diagnóstico Diferencial , Electroencefalografía , Femenino , Expresión Génica , Heterocigoto , Homocigoto , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/etnología , Leucoencefalopatías/fisiopatología , Imagen por Resonancia Magnética , Masculino , Lipofuscinosis Ceroideas Neuronales/diagnóstico por imagen , Lipofuscinosis Ceroideas Neuronales/etnología , Lipofuscinosis Ceroideas Neuronales/fisiopatología , Linaje , Dominios Proteicos , Convulsiones/diagnóstico por imagen , Convulsiones/etnología , Convulsiones/fisiopatologíaRESUMEN
Our objective is to reported a Chinese CARASIL patient caused by novel compound heterozygous mutations in HTRA1. Detailed clinical and neuroimaging examination were conducted in proband and her available family members. Sanger sequencing of NOTCH3 and HTRA1 was used to investigate causative mutations. The patient was born in an outbred family. She experienced recurrent transient ischemic attacks, hair loss, and low back pain. Brain magnetic resonance imaging showed multiple lacunar infarctions, diffuse leukoencephalopathy, and multiple microbleeds of white matter. A compound heterozygous mutation, c.958G > A (p.D320N) and c.1021G > A (p.G341J), were identified in the proband. This report highlights that screening of HTRA1 should be considered in young SVD patient despite from outbred families.
Asunto(s)
Alopecia/genética , Pueblo Asiatico/genética , Infarto Cerebral/genética , Serina Peptidasa A1 que Requiere Temperaturas Altas/genética , Leucoencefalopatías/genética , Mutación , Enfermedades de la Columna Vertebral/genética , Adulto , Alopecia/diagnóstico por imagen , Alopecia/etnología , Infarto Cerebral/diagnóstico por imagen , Infarto Cerebral/etnología , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Herencia , Heterocigoto , Humanos , Hemorragias Intracraneales/diagnóstico por imagen , Hemorragias Intracraneales/genética , Ataque Isquémico Transitorio/diagnóstico por imagen , Ataque Isquémico Transitorio/genética , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/etnología , Imagen por Resonancia Magnética , Linaje , Fenotipo , Enfermedades de la Columna Vertebral/diagnóstico por imagen , Enfermedades de la Columna Vertebral/etnología , Accidente Vascular Cerebral Lacunar/diagnóstico por imagen , Accidente Vascular Cerebral Lacunar/genéticaRESUMEN
BACKGROUND: African Americans (AAs) are at high risk for hypertension (HTN) and poor blood pressure (BP) control. Persistently elevated BP contributes to cardiovascular morbidity. White matter hyperintensities (WMHs) are a definable magnetic resonance imaging (MRI) marker of cerebrovascular injury linked to impairments in higher level thinking (i.e., executive functions), memory formation, and speed of perceptual-motor processing. METHODS: This subinvestigation evaluated neuropsychological functioning in association with WMH on brain MRIs in 23 otherwise-healthy hypertensive AAs participating in an NIH-funded study of the effects of vitamin D on BP and cardiac remodeling in AA patients 30-74 years of age with HTN and left ventricular hypertrophy. Neuropsychological assessment included psychomotor processing speed [(Symbol Digit Modality Test (SDMT) and Trail Making Test], executive functioning (Controlled Oral Word Association Test and Trail Making Test Part B), memory (Rey Auditory Verbal Learning Test), and fine motor functioning (Finger Tapping). RESULTS: Significant correlations (P < 0.05) were found between volume of periventricular lesions and trails A (r = 0.51) and dominant hand finger tapping speed (r = -0.69) and between subcortical lesion volume and trails A (r = 0.60), both dominant (r = -0.62) and nondominant hand finger tapping speed (r = -0.76) and oral SDMT (r = -0.60); higher lesion volumes correlated to worse neuropsychological performance. CONCLUSIONS: Psychomotor tests including the Trail Making Test and finger tapping speed are sensitive indicators of subclinical deficits in mental processing speed and could serve as early markers of deep subcortical cerebrovascular injury in otherwise-healthy individuals with uncontrolled chronic HTN.
Asunto(s)
Negro o Afroamericano , Hipertensión/etnología , Hipertrofia Ventricular Izquierda/etnología , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/etnología , Imagen por Resonancia Magnética , Adulto , Negro o Afroamericano/psicología , Anciano , Presión Sanguínea , Función Ejecutiva , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/fisiopatología , Leucoencefalopatías/psicología , Masculino , Memoria , Michigan/epidemiología , Persona de Mediana Edad , Actividad Motora , Pruebas Neuropsicológicas , Valor Predictivo de las Pruebas , Factores de Riesgo , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
BACKGROUND: Cerebral white matter hyperintensities (WMHs) on MRI are common and associated with vascular and functional outcomes. However, the relationship between WMHs and longitudinal trajectories of functional status is not well characterized. We hypothesized that whole brain WMHs are associated with functional decline independently of intervening clinical vascular events and other vascular risk factors. METHODS AND FINDINGS: In the Northern Manhattan Study (NOMAS), a population-based racially/ethnically diverse prospective cohort study, 1,290 stroke-free individuals underwent brain MRI and were followed afterwards for a mean 7.3 years with annual functional assessments using the Barthel index (BI) (range 0-100) and vascular event surveillance. Whole brain white matter hyperintensity volume (WMHV) (as percentage of total cranial volume [TCV]) was standardized and treated continuously. Generalized estimating equation (GEE) models tested associations between whole brain WMHV and baseline BI and change in BI, adjusting for sociodemographic, vascular, and cognitive risk factors, as well as stroke and myocardial infarction (MI) occurring during follow-up. Mean age was 70.6 (standard deviation [SD] 9.0) years, 40% of participants were male, 66% Hispanic; mean whole brain WMHV was 0.68% (SD 0.84). In fully adjusted models, annual functional change was -1.04 BI points (-1.20, -0.88), with -0.74 additional points annually per SD whole brain WMHV increase from the mean (-0.99, -0.49). Whole brain WMHV was not associated with baseline BI, and results were similar for mobility and non-mobility BI domains and among those with baseline BI 95-100. A limitation of the study is the possibility of a healthy survivor bias, which would likely have underestimated the associations we found. CONCLUSIONS: In this large population-based study, greater whole brain WMHV was associated with steeper annual decline in functional status over the long term, independently of risk factors, vascular events, and baseline functional status. Subclinical brain ischemic changes may be an independent marker of long-term functional decline.
Asunto(s)
Actividades Cotidianas , Encéfalo , Trastornos Cerebrovasculares , Leucoencefalopatías , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Trastornos Cerebrovasculares/diagnóstico , Trastornos Cerebrovasculares/epidemiología , Cognición , Estudios de Cohortes , Femenino , Neuroimagen Funcional/métodos , Evaluación Geriátrica/métodos , Humanos , Leucoencefalopatías/diagnóstico , Leucoencefalopatías/etnología , Leucoencefalopatías/fisiopatología , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The effects of white matter hyperintensity volume and subclinical brain infarcts on the risk of incident stroke, its ischemic subtypes, and mortality require further study in diverse samples. METHODS AND RESULTS: Stroke-free participants in the Northern Manhattan Study underwent magnetic resonance imaging (N=1287; mean age 71±9 years, 60% women, 15% non-Hispanic white, 17% non-Hispanic black, 68% Hispanic) and were followed for a median of 8 years (interquartile range: 6-9 years). Cox models estimated proportional hazards of incident stroke of all types, ischemic stroke (and its subtypes), and mortality and stratified by race/ethnicity. In total 72 participants (6%) had incident strokes and 244 died (19%). In fully adjusted models, those with larger white matter hyperintensity volume had greater risk of all stroke types (hazard ratio [HR]: 1.4; 95% CI, 1.1-1.9), ischemic stroke (HR: 1.3; 95% CI, 1.0-1.8), and cryptogenic stroke (HR: 2.2; 95% CI, 1.1-4.4). White and black but not Hispanic participants had increased stroke risk (P<0.05 for heterogeneity for all and ischemic stroke). Those with subclinical brain infarct had greater risk for all stroke types (HR: 1.9; 95% CI, 1.1-3.3), ischemic stroke (HR: 2.2; 95% CI, 1.3-3.8), lacunar (HR: 4.0; 95% CI, 1.3-12.3), and cryptogenic stroke (HR: 3.6; 95% CI, 1.0-12.7), without significant heterogeneity across race/ethnic groups. Greater white matter hyperintensity volume increased both vascular (HR: 1.3; 95% CI, 1.1-1.7) and nonvascular (HR: 1.2; 95% CI, 1.0-1.5) mortality among Hispanic and white but not black participants (P=0.040 for heterogeneity). Subclinical brain infarct was associated with increased vascular mortality among Hispanic participants only (HR: 2.9; 95% CI, 1.4-5.8). CONCLUSIONS: In this urban US sample, subclinical cerebrovascular lesions increased the risk of clinical stroke and vascular mortality and varied by race/ethnicity and lesion type.
Asunto(s)
Infarto Encefálico/mortalidad , Leucoencefalopatías/mortalidad , Accidente Cerebrovascular/mortalidad , Anciano , Anciano de 80 o más Años , Enfermedades Asintomáticas , Infarto Encefálico/diagnóstico por imagen , Infarto Encefálico/etnología , Supervivencia sin Enfermedad , Femenino , Humanos , Incidencia , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/etnología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/epidemiología , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etnología , Factores de TiempoRESUMEN
BACKGROUND: Cerebral microbleeds (CMBs) are associated with focal hemosiderin deposits and represent a form of cerebral small vessel disease. To date, indefinite and inconsistent reports are available regarding the association between serum lipid fractions and CMBs. In addition, these previous studies did not include Asian populations, who may have a higher risk of cerebral hemorrhage. The purpose of this study was to examine the associations between serum lipid fractions and CMBs in healthy Japanese subjects. METHODS: We performed a cross-sectional study involving 4,024 neurologically normal Japanese subjects (mean age 61.6 years). All the participants underwent 1.5-Tesla magnetic resonance imaging scan, and CMBs were classified into 3 groups based on their locations. The concentrations of lipid fractions were categorized into quartiles and the association between the lipid fractions and CMBs were investigated using logistic regression analysis. RESULTS: CMBs were observed in 164 (4.1%) of participants. Of these participants with CMBs, 33 (20.1%) had lobar CMBs and 91 (55.5%) had deep CMBs. Subjects with deep CMBs had lower total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels. After adjusting for confounding factors, lower TC and HDL-C levels were still associated with the presence of deep CMBs (OR for the highest vs. the lowest quartiles of TC and HDL-C was 2.28 [95% CI 1.05-4.94], and 1.93 [95% CI 1.02-3.65], respectively). The presence of subcortical infarcts and periventricular hyperintensities was more frequently observed in deep CMBs, whereas white matter hyperintensities were more frequently observed in lobar CMBs. CONCLUSIONS: Our results suggest that low serum TC and HDL-C levels are closely associated with deep CMBs.
Asunto(s)
Hemorragia Cerebral/etiología , Enfermedades de los Pequeños Vasos Cerebrales/etiología , HDL-Colesterol/sangre , Leucoencefalopatías/etiología , Triglicéridos/sangre , Anciano , Pueblo Asiatico , Biomarcadores/sangre , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/etnología , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/etnología , Estudios Transversales , Femenino , Estado de Salud , Humanos , Japón , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/etnología , Modelos Logísticos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de RiesgoRESUMEN
Cerebral small vessel disease (CSVD) is a very common neurological disease in older people. It causes stroke and dementia, mood disturbance and gait problems. Since it is difficult to visualise CSVD pathologies in vivo, the diagnosis of CSVD has relied on imaging findings including white matter hyperintensities, lacunar ischaemic stroke, lacunes, microbleeds, visible perivascular spaces and many haemorrhagic strokes. However, variations in the use of definition and terms of these features have probably caused confusion and difficulties in interpreting results of previous studies. A standardised use of terms should be encouraged in CSVD research. These CSVD features have long been regarded as different lesions, but emerging evidence has indicated that they might share some common intrinsic microvascular pathologies and therefore, owing to its diffuse nature, CSVD should be regarded as a 'whole-brain disease'. Single antiplatelet (for acute lacunar ischaemic stroke) and management of traditional risk factors still remain the most important therapeutic and preventive approach, due to limited understanding of pathophysiology in CSVD. Increasing evidence suggests that new studies should consider drugs that target endothelium and blood-brain barrier to prevent and treat CSVD. Epidemiology of CSVD might differ in Asian compared with Western populations (where most results and guidelines about CSVD and stroke originate), but more community-based data and clear stratification of stroke types are required to address this.
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Encéfalo/irrigación sanguínea , Enfermedades de los Pequeños Vasos Cerebrales , Leucoencefalopatías , Accidente Vascular Cerebral Lacunar , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/etnología , Enfermedades de los Pequeños Vasos Cerebrales/fisiopatología , Enfermedades de los Pequeños Vasos Cerebrales/terapia , Progresión de la Enfermedad , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/etnología , Leucoencefalopatías/fisiopatología , Leucoencefalopatías/terapia , Pronóstico , Medición de Riesgo , Factores de Riesgo , Accidente Vascular Cerebral Lacunar/diagnóstico por imagen , Accidente Vascular Cerebral Lacunar/etnología , Accidente Vascular Cerebral Lacunar/fisiopatología , Accidente Vascular Cerebral Lacunar/terapia , Terminología como AsuntoAsunto(s)
Asiático , Anciano Frágil , Leucoencefalopatías/diagnóstico , Leucoencefalopatías/etnología , Microvasos/patología , Vasos Retinianos/patología , Actividades Cotidianas/clasificación , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Femenino , Evaluación Geriátrica , Humanos , Leucoencefalopatías/patología , Imagen por Resonancia Magnética , Masculino , Oftalmoscopios , Factores de Riesgo , Estadística como AsuntoRESUMEN
OBJECTIVE: Mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene were studied in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). METHODS: Exons 1-9 of the HTRA1 gene were amplified and bidirectionally sequenced in a Chinese family with CARASIL. Mutation effects were analysed by three-dimensional modelling of the serine protease HTRA1 protein. RESULTS: The proband was found to be homozygous for a novel missense mutation (c.854 C > T) identified in exon 4 of the HTRA1 gene; the parents of the proband were heterozygous for the same missense mutation. This c.854 C > T mutation resulted in a change from proline to leucine (p.P285L) in serine protease HTRA1, and was absent in 260 control chromosomes. Three-dimensional models showed that the change from proline to leucine (p.P285L) could attenuate the hydrogen bond between S284 and S287 residues, which might affect function of serine protease HTRA1. CONCLUSION: Discovery of a novel missense mutation (c.854C>T) associated with CARASIL expands the known CARASIL-related mutations in HTRA1.
Asunto(s)
Alopecia/genética , Infarto Cerebral/genética , Leucoencefalopatías/genética , Modelos Moleculares , Mutación Missense , Serina Endopeptidasas/genética , Enfermedades de la Columna Vertebral/genética , Adulto , Alopecia/enzimología , Alopecia/etnología , Alopecia/patología , Sustitución de Aminoácidos , Pueblo Asiatico , Secuencia de Bases , Estudios de Casos y Controles , Infarto Cerebral/enzimología , Infarto Cerebral/etnología , Infarto Cerebral/patología , Análisis Mutacional de ADN , Exones , Familia , Femenino , Heterocigoto , Serina Peptidasa A1 que Requiere Temperaturas Altas , Homocigoto , Humanos , Enlace de Hidrógeno , Leucoencefalopatías/enzimología , Leucoencefalopatías/etnología , Leucoencefalopatías/patología , Masculino , Datos de Secuencia Molecular , Linaje , Serina Endopeptidasas/química , Serina Endopeptidasas/metabolismo , Enfermedades de la Columna Vertebral/enzimología , Enfermedades de la Columna Vertebral/etnología , Enfermedades de la Columna Vertebral/patologíaRESUMEN
White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.
Asunto(s)
Envejecimiento Prematuro/genética , Secuencia de Bases , Predisposición Genética a la Enfermedad , Trastornos del Desarrollo del Lenguaje/genética , Leucoencefalopatías/genética , Eliminación de Secuencia , Tetraspaninas/genética , Edad de Inicio , Envejecimiento Prematuro/complicaciones , Envejecimiento Prematuro/etnología , Envejecimiento Prematuro/patología , Pueblo Asiatico , Encéfalo/metabolismo , Encéfalo/patología , Niño , Preescolar , Cromosomas Humanos Par 2 , Exones , Femenino , Humanos , Trastornos del Desarrollo del Lenguaje/complicaciones , Trastornos del Desarrollo del Lenguaje/etnología , Trastornos del Desarrollo del Lenguaje/patología , Leucoencefalopatías/complicaciones , Leucoencefalopatías/etnología , Leucoencefalopatías/patología , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Linaje , Análisis de Secuencia de ADNRESUMEN
OBJECTIVES: To study white matter lesions (WMLs) and 5-year cognitive decline in elderly Japanese-American men. DESIGN: Longitudinal cohort study. SETTING: Population-based study in Honolulu, Hawaii. PARTICIPANTS: Japanese-American men aged 74 to 95 from the Honolulu-Asia Aging Study (HAAS) who were free of prevalent dementia, underwent a protocol brain MRI scan at the fifth HAAS examination (1994-1996), and returned for cognitive testing 5 years later (N=267). MEASUREMENTS: WMLs were dichotomized as present (grade 3-9, 38.2%) or absent (grade 1-2, 61.8%). Cognitive function was measured using the Cognitive Abilities Screening Instrument (CASI), and 5-year cognitive decline was defined as a drop in CASI score of 12 points or more (1 standard deviation). RESULTS: Men with WMLs on MRI at baseline were significantly more likely to experience cognitive decline at 5 years than those without (22.4% vs 34.4%, P=.03). Using multiple logistic regression, adjusting for age, education, apolipoprotein (Apo)E4 allele, large or small infarcts on MRI, baseline CASI score, and hypertension, those with WMLs were significantly more likely to develop 5-year cognitive decline (odds ratio=2.00, 95% confidence interval=1.10-3.65, P=.02). This association was stronger in men who were cognitively intact and free of the ApoE4 genotype and clinical stroke at baseline. CONCLUSION: Presence of WMLs on MRI was significantly associated with higher odds of 5-year cognitive decline in older Japanese-American men. Presence of WMLs may help identify people at risk for developing dementia, who may benefit from early intervention.