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OBJECTIVE: To investigate the feasibility of using noninvasive neuroimaging methods in visualizing and evaluating the clearance of the glymphatic-meningeal lymphatic system (GMLS) in patients with arteriosclerotic cerebral small-vessel disease (CSVD) and controls. METHODS: This observational study recruited patients with high-burden CSVD and controls (age 50-80 years). At multiple time points before and after intravenous administration of a contrast agent, three-dimensional (3D) brain volume T1-weighted imaging and 3D Cube T2-fluid attenuated inversion recovery imaging were performed to visualize and assess the clearance of the glymphatics and meningeal lymphatic vessels (mLVs). We measured the signal intensity ratio (SIR) of four regions of interest representing the glymphatics and mLVs at each time point. The clearance rate at 24 h (CR24h) and changes in the SIR from baseline to 24 h (∆SIR) were defined as the clearance function. The analysis of variance was used to evaluate the group differences after adjusting for hypertension. RESULTS: A total of 20 CSVD patients and 15 controls were included. Cortical periarterial enhancement and the enhancement of enlarged perivascular spaces in the basal ganglia were respectively observed in 11 (55.00%) and 16 (80.00%) CSVD patients, but in none of controls. All CSVD patients and most of controls (80.00%) showed cortical perivenous enhancement. Para-sinus enhancement was observed in all participants. CSVD patients showed lower CR24h and higher ∆SIR of the glymphatics and mLVs (all p < 0.05). CONCLUSION: The impaired drainage of the GMLS in patients with high-burden CSVD could be visually evaluated using noninvasive neuroimaging methods with intravenous gadolinium-based contrast-enhancement. CLINICAL RELEVANCE STATEMENT: Dynamic intravenous contrast-enhanced MRI could visually evaluate the impaired drainage of the glymphatic-meningeal lymphatic system in patients with high-burden cerebral small-vessel disease and could help to explore a new therapeutic target. KEY POINTS: ⢠Signal intensity changes in regions representing the glymphatic-meningeal lymphatic system (GMLS) can reflect the drainage function based on contrast-enhanced 3D-FLAIR and 3D T1-weighted MRI. ⢠Impaired drainage of the GMLS in patients with high-burden CSVD can be visually evaluated using dynamic intravenous contrast-enhanced MRI. ⢠This direct, noninvasive technique could serve as a basis for further GMLS studies and could help to explore a new therapeutic target in CSVD patients.
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Enfermedades de los Pequeños Vasos Cerebrales , Sistema Glinfático , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Sistema Glinfático/diagnóstico por imagen , Gadolinio , Imagen por Resonancia Magnética/métodos , Meninges , Administración IntravenosaRESUMEN
BACKGROUND: There is uncertainty regarding the predictors of early neurological deterioration (END) after endovascular thrombectomy in patients with acute ischemic stroke (AIS). Limited studies have focused on the effect of END on functional outcome. Our aim was to determine the predictors of END after endovascular thrombectomy in AIS and its effect on functional outcome at 90 days. METHODS: This is a secondary analysis of the DIRECT-MT trial. Patients who failed to complete endovascular thrombectomy were additionally excluded. END was defined as ≥4-point increase in National Institutes of Health Stroke Scale score between admission and 24 hours after endovascular thrombectomy. Multivariable logistic regression was used to identify predictors for END and its effect on the modified Rankin Scale (mRS) score at 90 days. RESULTS: Of 591 patients enrolled, 111 (18.8%) had postoperative END, which was associated with higher ordinal mRS score at 90 days (adjusted common OR (aOR) 6.968, 95% CI 4.444 to 10.926). Non-modifiable factors included baseline Alberta Stroke Program Early CT Score (aOR 0.883, 95% CI 0.790 to 0.987), systolic blood pressure (aOR 1.017, 95% CI 1.006 to 1.028), glucose level (aOR 1.178, 95% CI 1.090 to 1.273), collateral status (aOR 0.238, 95% CI 0.093 to 0.608), occlusion site (aOR 0.496, 95% CI 0.290 to 0.851) and the presence of an anterior communicating artery (aOR 0.323, 95% CI 0.148 to 0.707). Admission-to-groin puncture time (aOR 1.010, 95% CI 1.003 to 1.017), general anesthesia (aOR 2.299, 95% CI 1.193 to 4.444), number of passes (aOR 1.561, 95% CI 1.243 to 1.961) and contrast extravasation (aOR 6.096, 95% CI 1.543 to 24.088) were modifiable predictors for END. CONCLUSIONS: Postoperative END is associated with adverse functional outcome. Several non-modifiable and modifiable factors can predict END and support future treatment decision-making to improve the potential utility of endovascular thrombectomy. TRIAL REGISTRATION NUMBER: DIRECT-MT ClinicalTrials.gov NCT03469206.
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Isquemia Encefálica , Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Isquemia Encefálica/cirugía , Accidente Cerebrovascular Isquémico/etiología , Resultado del Tratamiento , Procedimientos Endovasculares/efectos adversos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/cirugía , Trombectomía/efectos adversosRESUMEN
PURPOSE: We sought to analyze EEG spectral power during slow-wave sleep among patients with arteriosclerotic cerebral small vessel disease (CSVD) compared with community-dwelling individuals. We also sought to determine the relationship between EEG activity and the severity of enlarged perivascular spaces (EPVSs). METHODS: Consecutive subjects with arteriosclerotic CSVD ( n = 36) and community-dwelling individuals ( n = 26) between 50 and 80 years of age were included. Nocturnal polysomnography was performed, and EEG spectral analysis was conducted during slow-wave sleep using the F4/M1 and C4/M1 channel. Regionalized EPVSs in the basal ganglia and centrum semiovale were assessed on a validated 4-point visual rating scale (0 = none, 1 = 1-10, 2 = 11-20, 3 = 21-40, and 4 = >40) using MRI. RESULTS: CSVD group showed lower delta:beta ratios in the frontal ( P = 0.017) and central ( P = 0.038) regions after adjusting for age, sex, mini-mental state examination score, and arousal index. The significance still remained in the frontal region when including age, sex, mini-mental state examination, and apnea-hypopnea index as covariates ( P = 0.037). Among patients with arteriosclerotic CSVD, decreased delta power ( P = 0.031) and theta power ( P = 0.034) in the frontal region were associated with a higher degree of EPVSs in the centrum semiovale rather than in the basal ganglia. Delta power in the central region showed an extremely weak association with EPVSs in the centrum semiovale ( P = 0.047). CONCLUSIONS: Among patients with arteriosclerotic CSVD, the intrusion of high-frequency EEG activity into slow-wave sleep was identified, and slow-wave activity during slow-wave sleep might be negatively associated with the severity of EPVSs in the centrum semiovale. Further studies are required to corroborate the conclusions.
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Enfermedades de los Pequeños Vasos Cerebrales , Sueño de Onda Lenta , Humanos , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico , Imagen por Resonancia Magnética , PolisomnografíaRESUMEN
The mechanism of cognitive impairment in patients with cerebral small vessel disease (CSVD) remains unknown. The glymphatic system dysfunction, which has been demonstrated to influence cognitive impairment, can be evaluated by diffusion tensor image analysis along the perivascular space (ALPS index). We explored whether cognitive impairment in CSVD is associated with glymphatic clearance dysfunction. In this study, 133 patients with CSVD were enrolled and underwent neuropsychological test batteries as well as magnetic resonance imaging (MRI). They were then categorized into a CSVD with cognitive impairment (CSVD-CI) group and a cognitively normal CSVD (CSVD-CN) group. The ALPS index and four CSVD markers [white matter lesions (WMLs), cerebral microbleeds (CMBs), lacunes, and perivascular spaces (PVSs)] were also assessed. Univariate analysis showed that the ALPS index was significantly different between the CSVD-CN (n = 50) and CSVD-CI groups (n = 83) (p < 0.001). This difference remained significant (95% CI < 0.001-0.133) after adjusting for six common risk factors (age, education, hypertension, diabetes, smoking, and alcohol abuse) as well as CSVD markers. The ALPS index was independently linearly correlated with global cognitive function, executive function, attention function, and memory after adjusting for the aforementioned six risk factors or CSVD markers. Our results suggest that glymphatic system impairment is independently related to cognitive impairment in patients with CSVD.
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BACKGROUND: To assess heart rate variability (HRV) among patients with arteriosclerotic cerebral small vessel disease (CSVD) by comparing with control subjects, and to determine whether HRV parameters were related to structural alterations in brain regions involved in autonomic regulation among CSVD patients. METHODS: We consecutively recruited subjects aged between 50 and 80 years who visited the Stroke Prevention Clinic of our hospital and have completed brain magnetic resonance imaging examination from September 1, 2018 to August 31, 2019. Polysomnography and synchronous analyses of HRV were then performed in all participants. Multivariable binary logistic regression was used to identify the relationship between HRV parameters and CSVD. Participants were invited to further undergo three-dimensional brain volume scan, and the voxel based morphometry (VBM) analysis was used to identify gray matter atrophy. RESULTS: Among 109 participants enrolled in this study, 63 were assigned to the arteriosclerotic CSVD group and 46 to the control group. Lower standard deviation of normal-to-normal intervals (SDNN, OR = 0.943, 95% CI 0.903 to 0.985, P = 0.009) and higher ratio of low to high frequency power (LF/HF, OR = 4.372, 95% CI 1.033 to 18.508, P = 0.045) during the sleep period were associated with CSVD, independent of traditional cerebrovascular risk factors and sleep disordered breathing. A number of 24 CSVD patients and 21 controls further underwent three-dimensional brain volume scan and VBM analysis. Based on VBM results, SDNN during the awake time (ß = 0.544, 95% CI 0.211 to 0.877, P = 0.001) and the sleep period (ß = 0.532, 95% CI 0.202 to 0.862, P = 0.001) were both positively related with gray matter volume within the right inferior frontal gyrus only among CSVD patients. CONCLUSIONS: Decreased nocturnal HRV is associated with arteriosclerotic CSVD independent of traditional cerebrovascular risk factors and sleep disordered breathing. The structural atrophy of some brain regions associated with cardiac autonomic regulation sheds light on the potential relationship. TRIAL REGISTRATION: Trial registration number: ChiCTR1800017902 . Date of registration: 20 Aug 2018.
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Enfermedades de los Pequeños Vasos Cerebrales , Anciano , Anciano de 80 o más Años , Sistema Nervioso Autónomo , Encéfalo/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Frecuencia Cardíaca , Humanos , Imagen por Resonancia Magnética , Persona de Mediana EdadRESUMEN
Whether white matter lesion (WML) is associated with vascular cognitive impairment in cerebral small vessel disease (CSVD) remains controversial; some severe CSVD patients retain normal cognitive function, and cortical thinning associated with WMLs has also been recently reported. The contribution of cortical atrophy to vascular cognitive impairment in severe CSVD and whether WML affects cortical atrophy remain unknown. From November 2012 to January 2015, 50- to 80-year-old patients with moderate to severe WMLs or more than four lacunar infarctions and cognitive complaints, excluding those with large vascular diseases diagnosed by transcranial cerebral Doppler, were recruited. The patients were divided into CSVD groups with or without vascular cognitive impairment-no dementia (VCIND) according to scores on neuropsychological tests that evaluated five cognitive domains. Based on these results, 16 patients were included in the CSVD with VCIND group, and 12 were included in the CSVD without VCIND group. T1, T2, 3D-MPRAGE, and diffusion tensor imaging were performed, and gray matter volume and fractional anisotropy (FA) values were compared between the two groups. Gray matter volume, especially in the frontal cortex, bilateral calcarine sulcus, and fusiform gyrus, was considerably lower in the CSVD with VCIND patients, with 24,619 fewer voxels. In addition, the FA values of 1,583 voxels were lower in the CSVD patients with VCIND than in those without. In conclusion, cortical atrophy is associated with cognitive impairment in moderate to severe WML or lacunar infarction patients, suggesting that cortical atrophy might be secondary to white matter damage in vascular cognitive impairment caused by CSVD.
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Corteza Cerebral/patología , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Disfunción Cognitiva/complicaciones , Anciano , Atrofia , Enfermedades de los Pequeños Vasos Cerebrales/patología , Disfunción Cognitiva/patología , Demografía , Femenino , Sustancia Gris/patología , Humanos , Masculino , Sustancia Blanca/patologíaRESUMEN
BACKGROUND: Many scoring systems exist for clock drawing task variants. However, none of them are reliable in evaluating longitudinal changes of cognitive function. The purpose of this study is to create a simple yet optimal scoring procedure to evaluate cognitive decline using a clinic-based sample. METHODS: Clock-drawings from 121 participants (76 individuals with no dementia and later did not develop dementia after a mean 41.2-month follow-up, 45 individuals with no dementia became demented after a mean 42.3-month follow-up) were analyzed using t-test to determine a new and simplified CDT scoring system. The new scoring method was then compared with other commonly used systems. RESULTS: In the converters, there were only 7 items that are significantly different between the initial visits and the second visits. We propose a new scoring system that includes the seven critical items: numbers are equally spaced (12-3-6-9) (pâ=â0.031), the other eight numbers are marked (pâ=â0.022), numbers are clockwise (pâ=â0.002), all numbers are correct (pâ=â0.030), distance between numbers is constant (pâ=â0.016), clock has two hands (pâ=â0.000), arrows are drawn (pâ=â0.003). Compared with other traditionally used scoring methods, this based change clock drawing test (BCCDT) has one of the most balanced sensitivities/specificities with a clinic-based sample. CONCLUSIONS: The new CDT scoring system provides further evidence in support of a simple and reliable clock-drawing scoring system in follow-up studies to evaluate cognitive decline, which can be used in assessing the efficacy of medicine.
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Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/fisiopatología , Pruebas Neuropsicológicas , Anciano , Anciano de 80 o más Años , Cognición , Femenino , Estudios de Seguimiento , Evaluación Geriátrica , Humanos , Masculino , Persona de Mediana Edad , Desempeño Psicomotor , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Calcium toxicity remains the central focus of ischemic brain injury. Calcium channel antagonists have been reported to be neuroprotective in ischemic animal models but have failed in clinical trials. Rather than block the calcium channels, calbindin proteins can buffer excessive intracellular Ca2+, and as a result, maintain the calcium homeostasis. In the present study, we investigated the effect of calbindin D 28k (CaBD) in ischemic brain using the novel technique protein transduction domain (PTD)-mediated protein transduction. We generated PTD-CaBD in Escherichia coli, tested its biologic activity in N-methyl-D-aspartate (NMDA)- and oxygen-glucose deprivation (OGD)-induced hippocampal injury models, and examined the protection of the fusion protein using a rat brain focal ischemia model. Infarct volume was determined using 2,3,5-triphenyl-tetrazolium chloride staining; neuronal injury was examined using terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining and cleaved caspase-3 assay. The results showed that the PTD-CaBD was efficiently delivered into Cos7 cells, hippocampal slice cells, and brain tissue. Pretreatment with PTD-CaBD decreased intracellular free calcium concentration and reduced cell death in NMDA- or OGD-exposed hippocampal slices (P<0.05). Intraperitoneal administration of PTD-CaBD before transient middle cerebral artery occlusion decreased brain infarct volume (280+/-47 versus 166+/-70 mm3, P<0.05), and improved neurologic outcomes compared with the control. Further studies showed that, compared with the control animals, PTD-CaBD decreased TUNEL (58%+/-7% versus 29%+/-3%, P<0.05)- and cleaved caspase-3 (62+/-4/field versus 31+/-6/field, P<0.05)-positive cells in the ischemic boundary zone. These results indicate that systemic administration of PTD-CaBD could attenuate ischemic brain injury, suggesting that PTD-mediated protein transduction might provide a promising and effective approach for the therapies of brain diseases, including cerebral ischemia.
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Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Encéfalo/patología , Fármacos Neuroprotectores , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patología , Proteína G de Unión al Calcio S100/farmacología , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Células COS , Calbindinas , Calcio/metabolismo , Calcio/farmacología , Membrana Celular/metabolismo , Chlorocebus aethiops , Citosol/efectos de los fármacos , Citosol/metabolismo , Escherichia coli/metabolismo , Agonistas de Aminoácidos Excitadores/farmacología , Glucosa/deficiencia , Hipocampo/metabolismo , Hipocampo/patología , Hipoxia Encefálica/patología , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Técnicas In Vitro , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/prevención & control , N-Metilaspartato/farmacología , Ratas , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/farmacología , Proteína G de Unión al Calcio S100/biosíntesis , Proteína G de Unión al Calcio S100/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVE: To study the change of regional cerebral blood flow (rCBF) around hematoma in acute intracerebral hemorrhage. METHODS: Xenon-CT was performed on 5 patients of basal ganglia hemorrhage with the hematoma volume less than 30 ml, 3 males and 2 females, aged 56.8 +/- 5.6. within 36 hours of the onset and 13 days after to measure the rCBF was measured by 27 pixel rings respectively in the core of hematoma, edema region around the hematoma and compared with rCBF in the uninvolved hemisphere. RESULTS: (1) all the 5 patients had a history of hypertension, the mean intracerebral hemorrhage volume was 13 ml +/- 7 ml (6.4 approximately 23.7 ml). The first examination was conducted 23 h +/- 6 h (19 approximately 34 h) after the onset and the second examination was conducted 13.0 d +/- 0.7 d (12 approximately 14 d) after the onset. (2) Within 36 hours of the onset, the mean rCBF in the core of hematoma was 15 ml.100 g(-1).min(-1) +/- 8 ml.100 g(-1).min(-1), and the mean rCBF in edema region around the hematoma was 30 ml.100 g(-1).min(-1) +/- 8 ml.100 g(-1).min(-1). Thirteen days after the onset the mean rCBF in the core of hematoma was 9 ml.100 g(-1).min(-1) +/- 4 ml.100 g(-1).min(-1), significantly reduced in comparison with that measured in the first examination (P = 0.014), and the mean rCBF in the edema region around the hematoma was 23 ml.100 g(-1).min(-1) +/- 13 ml.100 g(-1).min(-1), reduced in comparison with those measured in the first examination too, however, not significantly (P = 0.055). The rCBF reduction was more significant in the edema region adjacent to the hematoma (P = 0.004), but not in the distant edema region. During the first examination the rCBF in the edema region around the hematoma was lower than the enantiomorph rCBF by 20.9%. Thirteen days after, the rCBF in the edema region around the hematoma was lower than the enantiomorph rCBF by 46.3%, significantly greater than the reduction during the first examination (P = 0.324). There was no difference between the values of enantiomorph rCBF during the first and second examinations (P = 0.038). CONCLUSION: There exists reduced perihematoma rCBF after intracerebral hemorrhage by xenon-CT examination, this phenomenon lasts 14 days and have the tendency of further reduced.