RESUMEN

BACKGROUND: Targeted treatment is highly warranted for cerebral small vessel disease, a causal factor of one in four strokes and a major contributor to vascular dementia. Patients with cerebral small vessel disease have impaired cerebral blood flow and vessel reactivity. Tadalafil is a specific phosphodiesterase 5 inhibitor shown to improve vascular reactivity in the brain. METHODS: The ETLAS-2 trial is a phase 2 double-blind, randomized placebo-controlled, parallel trial with the feasibility of tadalafil as the primary outcome. The trial aims to include 100 patients with small vessel occlusion stroke or transitory ischemic attacks and signs of cerebral small vessel disease more than 6 months before administration of study medication. Patients are treated for 3 months with tadalafil 20 mg or placebo daily and undergo magnetic resonance imaging (MRI) to evaluate changes in small vessel disease according to the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria as well as cerebral blood flow, cerebrovascular reactivity, and neurovascular coupling in a functional MRI sub-study. The investigation includes comprehensive cognitive testing using paper-pencil tests and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests in a cognitive sub-study. DISCUSSION: The ETLAS-2 trial tests the feasibility of long-term treatment with tadalafil and explores vascular and cognitive effects in cerebral small vessel disease in trial sub-studies. The study aims to propose a new treatment target and improve the understanding of small vessel disease. Currently, 64 patients have been included and the trial is estimated to be completed in the year 2024. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05173896. Registered on 30 December 2021.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Circulación Cerebrovascular , Cognición , Inhibidores de Fosfodiesterasa 5 , Tadalafilo , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/fisiopatología , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Circulación Cerebrovascular/efectos de los fármacos , Ensayos Clínicos Fase II como Asunto , Cognición/efectos de los fármacos , Método Doble Ciego , Imagen por Resonancia Magnética , Pruebas Neuropsicológicas , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Tadalafilo/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

BACKGROUND: There are only a few recognized drug targets for cerebral small vessel disease (CSVD). Though inflammation is increasingly implicated in the development of CSVD, it remains unclear whether immunomodulation could become a therapeutic target. Accordingly, the Mendelian randomization (MR) method was used to assess the genetically proxied impacts of IL6 receptor (IL6R) inhibitor, IL1ß inhibitor, Tumor necrosis factor (TNF) inhibitor and ß-tubulin inhibitor on CSVD through. METHODS: Single nucleotide polymorphisms (SNPs) near the IL6R, IL1ß, TNFRSF1A and ß-tubulin genes were identified as genetic proxies for immunomodulatory drugs. These SNPs exhibited significant associations with serum C-reactive protein (CRP) levels in a large European genome-wide association study. The causal effects of immunomodulatory drugs on CSVD manifestations and the mediation influence of 731 peripheral blood immune phenotypes linking these drugs to CSVD manifestations were examined using a two-sample two-step MR approach. RESULTS: A total of 9, 18, 4 and 1 SNP were identified to proxy the effects of IL1ß inhibitor, IL6R inhibitor, TNF inhibitor and ß-tubulin inhibitor, respectively. MR analysis showed a significant causal relationship between IL1ß inhibition and reduced volume of periventricular white matter hyperintensity (PWMH). IL6R inhibition was associated with a reduced risk of small vessel stroke, decreased axial diffusivity and mean diffusivity. Genetically proxied TNF inhibition may decrease the occurrence of cerebral microbleeds (CMBs) and severe enlarged perivascular spaces located at white matter (WM-EPVS). It could also protect WM integrity, as evidenced by the reduced volumes of PWMH and deep white matter hyperintensity (DWMH). Various peripheral blood immune phenotypes exhibited significant associations with immunomodulatory drugs. Notably, the median fluorescence intensity (MFI) of CD45 on CD8br cells partially mediated the effects of IL1ß inhibitor on PWMH volume. Indirect effects of TNF inhibition on PWMH and DWMH volume through the MFI of CD127 on CD28- CD8br cells were observed. The effects of TNF inhibition on the occurrence of any CMBs were partially mediated by the MFI of CD45 on natural killer T cells, and the effects of TNF inhibition on the occurrence of lobar CMBs were partially mediated by the MFI of HLA DR on CD33- HLA DR+ cells. Furthermore, the MFI of HLA DR on CD33- HLA DR+ cells partially mediated the effects of TNF inhibition on WM-EPVS. CONCLUSIONS: IL1ß inhibitor, IL6R inhibitor and TNF inhibitor were associated with lower burden of CSVD while the activation of certain immune cells such as Tregs and myeloid cells partially mediated their protective effects.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Estudio de Asociación del Genoma Completo , Interleucina-1beta , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Humanos , Interleucina-1beta/genética , Agentes Inmunomoduladores/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/genética , Tubulina (Proteína)/genética

RESUMEN

BACKGROUND AND OBJECTIVE: Cerebral small vessel disease (CSVD) often coexists with cognitive dysfunction in patients, leading to significant challenges in treatment and management. This study aimed to examine the efficacy of combined application of donepezil and nimodipine on patients with comorbid CSVD and cognitive dysfunction and the effects on patients' albumin and prealbumin levels. METHODS: The records of 112 patients with comorbid CSVD and cognitive dysfunction treated at the People's Hospital of Suzhou New District from January 2019 to December 2022 were analysed retrospectively. A total of 50 patients receiving donepezil were allocated to the control group, and 62 patients receiving both nimodipine and donepezil to the study group. Outcomes compared between the two groups included serum homocysteine (Hcy), high sensitivity C-reactive protein (hs-CRP), albumin, and prealbumin before and after therapy, efficacy, and adverse reactions. Additionally, logistic regression was performed to analyze the risk factors impacting patient prognosis. RESULTS: Prior to therapy, the two groups did not differ significantly in Hcy and hs-CRP levels (p > 0.05), whereas after therapy, the levels in both groups dropped significantly (p < 0.01), with more obvious lower levels in the study group (p < 0.05). After treatment, the study group presented significantly higher albumin and prealbumin levels than the control group (p < 0.001). An obvious higher overall response rate was observed in the study group compared to the control group (p = 0.012). No significant inter-group discrepancy was found regarding the total incidence of adverse reactions (p = 0.752). Univariate analysis identified age, course of disease, heart rate (HR), Montreal Cognitive Assessment (MoCA) score, diastolic blood pressure (DBP), systolic blood pressure (SBP), drinking history, as well as medication regimen as risk factors impacting patient prognosis. Multivariate logistic regression analysis identified SBP, DBP, and medication regimen as the independent risk factors. CONCLUSION: Combined application of donepezil and nimodipine can effectively treat patients with comorbid CSVD and cognitive dysfunction. It can significantly lower the Hcy and hs-CRP levels and improve the nutritional status without increasing the frequency of adverse reactions. In addition, for CSVD patients with cognitive dysfunction, age, course of disease, MoCA score, HR, SBP, DBP, drinking history, and medication regimen are risk factors impacting patient prognosis, while SBP, DBP, and medication regimen are independent risk factors.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Disfunción Cognitiva , Donepezilo , Quimioterapia Combinada , Nimodipina , Estado Nutricional , Humanos , Femenino , Masculino , Donepezilo/administración & dosificación , Donepezilo/uso terapéutico , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Disfunción Cognitiva/tratamiento farmacológico , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Nimodipina/administración & dosificación , Nimodipina/uso terapéutico , Resultado del Tratamiento , Nootrópicos/administración & dosificación , Nootrópicos/uso terapéutico , Nootrópicos/efectos adversos , Homocisteína/sangre

RESUMEN

Cerebral small vessel disease (CSVD) is one of the most common nervous system diseases. Hypertension and neuroinflammation are considered important risk factors for the development of CSVD and white matter (WM) lesions. We used the spontaneously hypertensive rat (SHR) as a model of early-onset CSVD and administered epimedium flavonoids (EF) for three months. The learning and memorization abilities were tested by new object recognition test. The pathological changes of WM were assessed using magnetic resonance imaging, transmission electron microscopy (TEM), Luxol fast blue and Black Gold staining. Oligodendrocytes (OLs) and myelin basic protein were detected by immunohistochemistry. The ultrastructure of the tight junctions was examined using TEM. Microglia and astrocytes were detected by immunofluorescence. RNA-seq was performed on the corpus callosum of rats. The results revealed that EF could significantly improve the learning and memory impairments in SHR, alleviate the injury and demyelination of WM nerve fibers, promote the differentiation of oligodendrocyte precursor cells (OPCs) into mature OLs, inhibit the activation of microglia and astrocytes, inhibit the expression of p38 MAPK/NF-κB p65/NLRP3 and inflammatory cytokines, and increase the expression of tight-junction related proteins ZO-1, occludin, and claudin-5. RNA-seq analysis showed that the neurotrophin signaling pathway played an important role in the disease. RT-qPCR and WB results showed that EF could regulate the expression of nerve growth factor and brain-derived neurotrophic factor and their downstream related proteins in the neurotrophin signaling pathway, which might explain the potential mechanism of EF's effects on the cognitive impairment and WM damage caused by hypertension.

Asunto(s)

Epimedium , Flavonoides , Enfermedades Neuroinflamatorias , Ratas Endogámicas SHR , Transducción de Señal , Sustancia Blanca , Animales , Transducción de Señal/efectos de los fármacos , Masculino , Ratas , Flavonoides/farmacología , Flavonoides/uso terapéutico , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/patología , Sustancia Blanca/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/genética , Modelos Animales de Enfermedad , Microglía/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Astrocitos/efectos de los fármacos

RESUMEN

BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Circulación Cerebrovascular , Estudios Cruzados , Citrato de Sildenafil , Humanos , Citrato de Sildenafil/uso terapéutico , Citrato de Sildenafil/farmacología , Citrato de Sildenafil/efectos adversos , Masculino , Femenino , Anciano , Método Doble Ciego , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/fisiopatología , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Circulación Cerebrovascular/efectos de los fármacos , Persona de Mediana Edad , Cilostazol/uso terapéutico , Cilostazol/farmacología , Cilostazol/efectos adversos , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Inhibidores de Fosfodiesterasa 5/efectos adversos , Inhibidores de Fosfodiesterasa 5/farmacología , Resultado del Tratamiento , Flujo Pulsátil/efectos de los fármacos , Imagen por Resonancia Magnética , Arteria Cerebral Media/efectos de los fármacos , Arteria Cerebral Media/diagnóstico por imagen , Arteria Cerebral Media/fisiopatología

RESUMEN

BACKGROUND: Cerebral small vessel disease is a common cause of vascular cognitive impairment and dementia. There is an urgent need for preventative treatments for vascular cognitive impairment and dementia, and reducing vascular dysfunction may provide a therapeutic route. Here, we investigate whether the chronic administration of nimodipine, a central nervous system-selective dihydropyridine calcium channel blocking agent, protects vascular, metabolic, and cognitive function in an animal model of cerebral small vessel disease, the spontaneously hypertensive stroke-prone rat. METHODS: Male spontaneously hypertensive stroke-prone rats were randomly allocated to receive either a placebo (n=24) or nimodipine (n=24) diet between 3 and 6 months of age. Animals were examined daily for any neurological deficits, and vascular function was assessed in terms of neurovascular and neurometabolic coupling at 3 and 6 months of age, and cerebrovascular reactivity at 6 months of age. Cognitive function was evaluated using the novel object recognition test at 6 months of age. RESULTS: Six untreated control animals were terminated prematurely due to strokes, including one due to seizure, but no treated animals experienced strokes and so had a higher survival (P=0.0088). Vascular function was significantly impaired with disease progression, but nimodipine treatment partially preserved neurovascular coupling and neurometabolic coupling, indicated by larger (P<0.001) and more prompt responses (P<0.01), and less habituation upon repeated stimulation (P<0.01). Also, animals treated with nimodipine showed greater cerebrovascular reactivity, indicated by larger dilation of arterioles (P=0.015) and an increase in blood flow velocity (P=0.001). This protection of vascular and metabolic function achieved by nimodipine treatment was associated with better cognitive function (P<0.001) in the treated animals. CONCLUSIONS: Chronic treatment with nimodipine protects from strokes, and vascular and cognitive deficits in spontaneously hypertensive stroke-prone rat. Nimodipine may provide an effective preventive treatment for stroke and cognitive decline in cerebral small vessel disease.

Asunto(s)

Bloqueadores de los Canales de Calcio , Enfermedades de los Pequeños Vasos Cerebrales , Cognición , Modelos Animales de Enfermedad , Nimodipina , Ratas Endogámicas SHR , Animales , Nimodipina/farmacología , Nimodipina/uso terapéutico , Masculino , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Ratas , Cognición/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Circulación Cerebrovascular/efectos de los fármacos , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/prevención & control

RESUMEN

BACKGROUND: Previous studies yielded conflicting results about the influence of blood pressure (BP) and antihypertensive treatment on cerebral small vessel disease. Here, we conducted a Mendelian randomization study to investigate the effect of BP and antihypertensive drugs on cerebral small vessel disease. METHODS: We extracted single-nucleotide polymorphisms for systolic BP and diastolic BP from a genome-wide association study (N=757 601) and screened single-nucleotide polymorphisms associated with calcium channel blockers, thiazides, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and ß-blockers from public resources as instrumental variables. Then, we chose the genome-wide association study of white matter hyperintensity (WMH; N=18 381), cerebral microbleed (3556 cases, 22 306 controls), white matter perivascular space (9317 cases, 29 281 controls), basal ganglia perivascular space (BGPVS; 8950 cases, 29 953 controls), hippocampal perivascular space (HIPPVS; 9163 cases, 29 708 controls), and lacunar stroke (6030 cases, 248 929 controls) as outcome data sets. Subsequently, we conducted a 2-sample Mendelian randomization analysis. RESULTS: We found that elevated systolic BP significantly increases the risk of BGPVS (odds ratio [OR], 1.05 [95% CI, 1.04-1.07]; P=1.72×10-12), HIPPVS (OR, 1.04 [95% CI, 1.02-1.05]; P=2.71×10-7), and lacunar stroke (OR, 1.41 [95% CI, 1.30-1.54]; P=4.97×10-15). There was suggestive evidence indicating that elevated systolic BP is associated with higher WMH volume (ß=0.061 [95% CI, 0.018-0.105]; P=5.58×10-3) and leads to an increased risk of cerebral microbleed (OR, 1.16 [95% CI, 1.04-1.29]; P=7.17×10-3). Elevated diastolic BP was significantly associated with higher WMH volume (ß=0.087 [95% CI, 0.049-0.124]; P=5.23×10-6) and significantly increased the risk of BGPVS (OR, 1.05 [95% CI, 1.04-1.06]; P=1.20×10-16), HIPPVS (OR, 1.03 [95% CI, 1.02-1.04]; P=2.96×10-6), and lacunar stroke (OR, 1.31 [95% CI, 1.21-1.41]; P=2.67×10-12). The use of calcium channel blocker to lower BP was significantly associated with lower WMH volume (ß=-0.287 [95% CI, -0.408 to -0.165]; P=4.05×10-6) and significantly reduced the risk of BGPVS (OR, 0.85 [95% CI, 0.81-0.89]; P=8.41×10-19) and HIPPVS (OR, 0.88 [95% CI, 0.85-0.92]; P=6.72×10-9). CONCLUSIONS: Our findings contribute to a better understanding of the pathogenesis of cerebral small vessel disease. Additionally, the utilization of calcium channel blockers to decrease BP can effectively reduce the likelihood of WMH, BGPVS, and HIPPVS. These findings offer valuable insights for the management and prevention of cerebral small vessel disease.

Asunto(s)

Antihipertensivos , Presión Sanguínea , Enfermedades de los Pequeños Vasos Cerebrales , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Femenino , Masculino , Accidente Vascular Cerebral Lacunar/genética , Accidente Vascular Cerebral Lacunar/tratamiento farmacológico , Bloqueadores de los Canales de Calcio/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Persona de Mediana Edad

RESUMEN

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD. METHODS: Genetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations. RESULTS: A lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively. CONCLUSIONS: SGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.

Asunto(s)

Biomarcadores , Enfermedades de los Pequeños Vasos Cerebrales , Análisis de la Aleatorización Mendeliana , Transportador 1 de Sodio-Glucosa , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Transportador 2 de Sodio-Glucosa , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Transportador 1 de Sodio-Glucosa/genética , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Transportador 1 de Sodio-Glucosa/metabolismo , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/sangre , Enfermedades de los Pequeños Vasos Cerebrales/metabolismo , Factores de Riesgo , Transportador 2 de Sodio-Glucosa/metabolismo , Transportador 2 de Sodio-Glucosa/genética , Biomarcadores/sangre , Medición de Riesgo , Hemoglobina Glucada/metabolismo , Variantes Farmacogenómicas , Resultado del Tratamiento , Fenotipo , Hemorragia Cerebral/genética , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/epidemiología , Factores Protectores , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Predisposición Genética a la Enfermedad

RESUMEN

INTRODUCTION: Cerebral small vessel disease (SVD) is a common cause of stroke/vascular dementia with few effective treatments. Neuroinflammation and increased blood-brain barrier (BBB) permeability may influence pathogenesis. In rodent models, minocycline reduced inflammation/BBB permeability. We determined whether minocycline had a similar effect in patients with SVD. METHODS: MINERVA was a single-center, phase II, randomized, double-blind, placebo-controlled trial. Forty-four participants with moderate-to-severe SVD took minocycline or placebo for 3 months. Co-primary outcomes were microglial signal (determined using 11C-PK11195 positron emission tomography) and BBB permeability (using dynamic contrast-enhanced MRI). RESULTS: Forty-four participants were recruited between September 2019 and June 2022. Minocycline had no effect on 11C-PK11195 binding (relative risk [RR] 1.01, 95% confidence interval [CI] 0.98-1.04), or BBB permeability (RR 0.97, 95% CI 0.91-1.03). Serum inflammatory markers were not affected. DISCUSSION: 11C-PK11195 binding and increased BBB permeability are present in SVD; minocycline did not reduce either process. Whether these pathophysiological mechanisms are disease-causing remains unclear. INTERNATIONAL CLINICAL TRIALS REGISTRY PORTAL IDENTIFIER: ISRCTN15483452 HIGHLIGHTS: We found focal areas of increased microglial signal and increased blood-brain barrier permeability in patients with small vessel disease. Minocycline treatment was not associated with a change in these processes measured using advanced neuroimaging. Blood-brain barrier permeability was dynamic but MRI-derived measurements correlated well with CSF/serum albumin ratio. Advanced neuroimaging is a feasible outcome measure for mechanistic clinical trials.

Asunto(s)

Barrera Hematoencefálica , Enfermedades de los Pequeños Vasos Cerebrales , Minociclina , Tomografía de Emisión de Positrones , Humanos , Minociclina/farmacología , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Masculino , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Método Doble Ciego , Femenino , Anciano , Imagen por Resonancia Magnética , Inflamación/tratamiento farmacológico , Persona de Mediana Edad

RESUMEN

Intracerebral hemorrhage (ICH) is generally considered to be closely related to cerebral small vessel disease (CSVD), leading to a poor prognosis. However, the coexistence of ICH in general CSVD patients and related factors remain underreported. In our cross-sectional study, we screened 414 CSVD patients from a database at the Department of Neurology, First Affiliated Hospital of Zhengzhou University (September 2018 to April 2022). Imaging biomarkers of CSVD and coexisting ICH lesion were assessed. Factors associated with coexisting ICH in CSVD were determined using multivariate logistic regression analysis. ICH was observed in 59 patients (14.3%). Multivariate logistic regression showed that previous history of ischemic stroke or transient ischemic attack (OR 5.189, 95%CI 2.572-10.467, P < 0.001), high-grade perivascular space in the basal ganglia (n > 10) (OR 2.051, 95%CI 1.044-4.027, P = 0.037) and low adjusted calcium-phosphorus product (OR 0.728 per 1 [mmol/L]2 increase, 95%CI 0.531-0.998, P = 0.049) were associated with coexisting ICH in CSVD patients. The considerable proportion of coexisting ICH and revelation of associated factors in general CSVD patients alert physicians of the potential risk of the reoccurrence of ICH, and might have a significant impact on therapeutic strategies.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Ataque Isquémico Transitorio , Humanos , Estudios Transversales , Imagen por Resonancia Magnética/métodos , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Ataque Isquémico Transitorio/complicaciones

RESUMEN

OBJECTIVES: Small vessel cerebrovascular disease (SVCVD) accounts for 35% to 67% of vascular dementias, and may be overlooked by healthcare providers due to its insidious onset. SVCVD involves chronic cerebral ischemia and hypoperfusion, endothelial dysfunction, blood-brain barrier disruption, and interstitial fluid reflux. The purpose of this study was to investigate the clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with donepezil hydrochloride compared to donepezil alone in the treatment of mild-to-moderate cognitive impairment in patients with SVCVD. MATERIAL AND METHODS: A cohort of 115 individuals with mild-to-moderate cognitive impairment due to SVCVD was purposefully selected and randomized into two groups: a test group and a control group. The test group received a combination of repetitive transcranial magnetic stimulation (rTMS) and oral donepezil hydrochloride (10 mg/day), while the control group received oral donepezil alone (10 mg/day). The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores were evaluated in both groups prior to and following the interventions. RESULTS: Following 6 weeks of treatment, both groups demonstrated enhancement in cognitive function. However, a statistically significant difference was observed between the test group and the control group (p < .05 on both the MMSE and the MOCA), favoring the test group. CONCLUSIONS: Compared to donepezil alone, the combination of repetitive transcranial magnetic stimulation (rTMS) and donepezil has a significantly greater effect on enhancing cognitive function among individuals experiencing mild-to-moderate cognitive impairment resulting from SVCVD.

Asunto(s)

Disfunción Cognitiva , Donepezilo , Estimulación Magnética Transcraneal , Humanos , Donepezilo/uso terapéutico , Masculino , Estimulación Magnética Transcraneal/métodos , Disfunción Cognitiva/etiología , Disfunción Cognitiva/terapia , Disfunción Cognitiva/tratamiento farmacológico , Femenino , Anciano , Terapia Combinada , Persona de Mediana Edad , Nootrópicos/uso terapéutico , Trastornos Cerebrovasculares/complicaciones , Trastornos Cerebrovasculares/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/terapia , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Inhibidores de la Colinesterasa/administración & dosificación , Indanos/uso terapéutico

RESUMEN

BACKGROUND: Cerebral small vessel disease is characterized by white matter hyperintensities (WMH) and acute small vessel occlusion (SVO) stroke. We investigated the effect of prior antiplatelet use (APU) on stroke outcome in 1151 patients with acute SVO stroke patients and moderate to severe WMH. METHODS: Using a multicenter database, this retrospective study used quantitative WMH volume measurements and propensity score matching (PSM) for comparisons between patients with prior APU and without APU. Primary outcomes were stroke progression and poor functional outcome (modified Rankin Scale>2) at 3 months. Logistic regression analyses assessed associations between prior APU, WMH burden, and stroke outcomes. RESULTS: Stroke progression was lower in the prior APU group in both the total cohort (14.8% vs. 6.9%, p < 0.001) and the PSM cohort (16.3% vs. 6.9%, p < 0.001). The proportion of poor functional outcomes at 3 months was not significantly different in the total cohort, but the PSM cohort showed a lower proportion in the prior APU group (30.8% vs. 20.2%, p = 0.002). Logistic regression analysis confirmed that prior APU was associated with a reduced risk of stroke progression (OR, 0.39; 95% CI, 0.22-0.70; p = 0.001) and poor functional outcome at 3 months (OR, 0.37; 95% CI, 0.23-0.59; p < 0.001). CONCLUSION: Prior APU is associated with reduced stroke progression and improved functional outcome at 3 months in acute SVO stroke patients with moderate to severe WMH. Early treatment of WMH and acute SVO stroke may have potential benefits in improving stroke outcomes.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Sustancia Blanca , Humanos , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Imagen por Resonancia Magnética , Estudios Retrospectivos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/tratamiento farmacológico , Sustancia Blanca/diagnóstico por imagen , Estudios Multicéntricos como Asunto

RESUMEN

OBJECTIVE: This study aimed to investigate the effects of intensive blood pressure control on cognitive function in elderly patients with cerebral small vessel disease (CSVD). METHODS: From May 2020 to June 2022, 140 outpatients and inpatients with CSVD and hypertension in the Department of Neurology of Beijing Shijingshan Hospital were selected. They were randomly divided into the standard and intensive blood pressure control groups, and the dosage of antihypertensive drugs was adjusted to reduce the blood pressure to the target level. The patients were followed up for 2 years. The medical records or data at "enrollment" and "2-year follow-up" were analyzed and evaluated. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to evaluate cognitive function. Cranial magnetic resonance imaging was performed to evaluate lacunar infarctions (LIs) and white matter hyperintensity (WMH). Multiple linear regression was used to analyze the correlation between MMSE scores and blood pressure, WMH, and LIs. RESULTS: (1) The MMSE and MoCA scores in the standard group were significantly lower than those at enrollment. The WMH score in the standard group was significantly higher than that at enrollment. (2) After the 2-year follow-up, the 24-h systolic blood pressure (SBP), 24-h diastolic blood pressure (DBP), daytime mean SBP, daytime mean DBP, and nighttime mean SBP in the two groups significantly decreased, which had significant statistical significance (P < 0.05). (3) The correlation between blood pressure and MMSE score was analyzed using multiple linear regression analysis. The WMH score, LIs, 24-h SBP, and 24-h DBP were independently correlated with MMSE scores. CONCLUSION: In elderly patients with hypertension, a decrease in SBP to 126 mmHg, compared with 134 mmHg, can delay cognitive impairment as well as reduce LIs and cerebral WMH lesions in patients with CSVD.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Disfunción Cognitiva , Hipertensión , Accidente Vascular Cerebral Lacunar , Humanos , Anciano , Presión Sanguínea/fisiología , Cognición , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Hipertensión/complicaciones , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico

RESUMEN

AIMS: This study assesses the association of antihypertensive medication use on the severities of neuropathological cerebrovascular disease (CVD excluding lobar infarction) in older individuals. METHODS: Clinical and neuropathological data were retrieved for 149 autopsy cases >75 years old with or without CVD or Alzheimer's disease and no other neuropathological diagnoses. Clinical data included hypertension status, hypertension diagnosis, antihypertensive medication use, antihypertensive medication dose (where available) and clinical dementia rating (CDR). Neuropathological CVD severity was evaluated for differences with anti-hypertensive medication usage. RESULTS: Antihypertensive medication use was associated with less severe white matter small vessel disease (SVD, mainly perivascular dilatation and rarefaction), with a 5.6-14.4 times greater likelihood of less severe SVD if medicated. No significant relationship was detected between infarction (presence, type, number and size), lacunes or cerebral amyloid angiopathy and antihypertensive medication use. Only increased white matter rarefaction/oedema and not perivascular dilation was associated with Alzheimer's pathology, with a 4.3 times greater likelihood of reduced Aß progression through the brain if white matter rarefaction severity was none or mild. Antihypertensive medication use was associated with reduced Aß progression but only in those with moderate to severe white matter SVD. CONCLUSIONS: This histopathological study provides further evidence that antihypertensive medication use in older individuals is associated with white matter SVD and not with other CVD pathologies. This is mainly due to a reduction in white matter perivascular dilation and rarefaction/oedema. Even in those with moderate to severe white matter SVD, antihypertensive medication use reduced rarefaction and Aß propagation through the brain.

Asunto(s)

Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Enfermedades de los Pequeños Vasos Cerebrales , Hipertensión , Leucoencefalopatías , Sustancia Blanca , Humanos , Anciano , Antihipertensivos/uso terapéutico , Encéfalo/patología , Enfermedad de Alzheimer/patología , Angiopatía Amiloide Cerebral/patología , Sustancia Blanca/patología , Leucoencefalopatías/patología , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipertensión/patología , Infarto/complicaciones , Infarto/patología , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/patología , Imagen por Resonancia Magnética

RESUMEN

OBJECTIVE: To study the effect of the drug Cellex on the severity of cognitive impairment in patients with small vessel disease (SVD). MATERIAL AND METHODS: A non-interventional observational controlled prospective observational study in parallel groups was conducted. 118 patients with CHEM who received unified therapy were under observation. Group 1 consisted of 40 patients who, in addition to basic therapy, received 10 injections of Cellex subcutaneously (0.2 ml 1 time/day), group 2 - 39 patients who received 2 courses of injections of Cellex subcutaneously (0.1 ml 1 time/day) with an interval of one month, patients 3-both groups (n=39) received only basic therapy. The examination included an assessment of the clinical status and neuropsychological testing (the MOS questionnaire and the clock drawing test - TRCH), analysis of the results of MRI of the brain. The blood levels of homocysteine (HC), C-reactive protein (CRP), asymmetric dimethylarginin (ADMA), and von Willebrand factor (FW) were determined in dynamics. RESULTS: A statistically significant improvement in the performance of the MoCA and TRP questionnaire tests in groups 1 and 2 was demonstrated, with a more pronounced and persistent effect in patients who received repeated courses of treatment. Clinical improvement was accompanied by normalization of the concentration of studied markers of inflammation (CRP) and endothelial dysfunction (HC, ADMA, FW) in the blood, while the dynamics was most pronounced in patients of group 2. The treatment was characterized by good tolerability, low frequency and insignificant severity of adverse events. CONCLUSION: The drug Cellex has demonstrated significant effectiveness in the treatment of patients with SVD with cognitive impairment, against the background of treatment, there was a decrease in markers of inflammation and endothelial dysfunction, therapy was characterized by good tolerability.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Disfunción Cognitiva , Accidente Cerebrovascular , Humanos , Encéfalo , Inflamación , Pruebas Neuropsicológicas , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico

RESUMEN

Balancing the risks of recurrent ischemia and antithrombotic-associated bleeding, particularly intracranial hemorrhage (ICH), is a key challenge in the secondary prevention of ischemic stroke and transient ischemic attack. In hyperacute ischemic stroke, the use of acute reperfusion therapies is determined by the balance of anticipated benefit and the risk of ICH. Cerebral small vessel disease (CSVD) causes most spontaneous ICH. Here, we review the evidence linking neuroimaging markers of CSVD to antithrombotic and thrombolytic-associated ICH, with emphasis on cerebral microbleeds (CMB). We discuss their role in the prediction of ICH, and practical implications for clinical decision making. Although current observational data suggest CMB presence should not preclude antithrombotic therapy in patients with ischemic stroke or TIA, they are useful for improving ICH risk prediction with potential relevance for determining the optimal secondary prevention strategy, including the use of left atrial appendage occlusion. Following ICH, recommencing antiplatelets is probably safe in most patients, while the inconclusive results of recent randomized controlled trials of anticoagulant use makes recruitment to ongoing trials (including those testing left atrial appendage occlusion) in this area a high priority. Concern regarding CSVD and ICH risk after hyperacute stroke treatment appears to be unjustified in most patients, though some uncertainty remains regarding patients with very high CMB burden and other risk factors for ICH. We encourage careful phenotyping for underlying CSVD in future trials, with the potential to enhance precision medicine in stroke.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/tratamiento farmacológico , Pronóstico , Fibrinolíticos/uso terapéutico , Hemorragias Intracraneales/complicaciones , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Factores de Riesgo , Enfermedades de los Pequeños Vasos Cerebrales/terapia , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Hemorragia Cerebral/terapia , Hemorragia Cerebral/tratamiento farmacológico

RESUMEN

BACKGROUND AND PURPOSE: Cerebral small vessel disease (CSVD) is a clinically commonly-seen slow-progressing cerebral vascular disease. As a classic Chinese formula for the treatment of stroke, Daqinjiao Decoction (DQJD) is now used to treat CSVD with desirable effect. Since the mechanism of action is still unclear, this article will explore the therapeutic effect and mechanism of action of the formula using network pharmacology technology. METHODS: The major chemical components and potential target genes of DQJD were screened by bioinformatics. The key targets in CSVD were identified based on network modules. Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Pharmacodynamics of the decoction was evaluated by establishing a rat model with bilateral common carotid artery occlusion in the brain. Molecular docking, Western blot analysis and quantitative real-time polymerase chain reaction (QRT-PCR) were performed to confirm the effectiveness of targets in related pathways. RESULTS: Network pharmacology showed that 16 targets and 30 pathways were involved in the DQJD-targeted pathway network. Results revealed that DQJD might play a role by targeting the key targets including Caspse3 and P53 and regulating the P53 signaling pathway. Cognitive function and neuronal cell changes of rats were evaluated using Morris water maze, open field test and HE staining. It was indicated that DQJD could keep the nerve cells intact and neatly arranged. The decoction could improve the memory and learning ability of rats compared with the model group. It decreased the protein and mRNA expression levels of Caspse3 and P53 significantly (p<0.01). CONCLUSION: The study shows that baicalein, quercetin and wogonin, the effective components of DQJD, may regulate multiple signaling pathways by targeting the targets like Caspse3 and P53 and treat CSVD by reducing the damage to brain nerve cells.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Medicamentos Herbarios Chinos , Animales , Ratas , Simulación del Acoplamiento Molecular , Medicamentos Herbarios Chinos/química , Farmacología en Red , Proteína p53 Supresora de Tumor , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Tecnología

RESUMEN

OBJECTIVE: Cerebral small vessel disease (CSVD) commonly coexists with intracranial atherosclerotic stenosis (ICAS). In-stent restenosis (ISR) affects the nonprocedural outcome of severe symptomatic ICAS after intracranial stenting. However, only 8%-27% of ISR patients are symptomatic, which highlights the importance of the investigation of risk factors associated with symptomatic ISR (SISR) to improve long-term functional outcome. Whether CSVD is associated with SISR remains unclear. The authors tested the hypothesis that CSVD is associated with SISR in ICAS patients after intracranial stenting. METHODS: This retrospective study enrolled 97 patients who were symptomatic due to severe anterior circulation ICAS treated with intracranial stenting. SISR was evaluated with clinical and vascular imaging follow-up. CSVD subtypes, including white matter hyperintensities (WMHs), enlarged perivascular spaces, and chronic lacunar infarctions, were evaluated. Cox regression analysis was used to compare the incidence of SISR between patients with and without CSVD. RESULTS: Of the enrolled patients, 58.8% had CSVD. The 1- and 2-year ISR rates were 24.7% and 37.1%, respectively. Of the CSVD subtypes, SISR was associated with deep WMHs (DWMHs; HR 5.39, 95% CI 1.02-28.44). DWMH Fazekas scale grades 2 (HR 85.54, 95% CI 2.42-3018.93) and 3 (HR 66.24, 95% CI 1.87-2352.32) were associated with SISR, but DWMH Fazekas grades 0 and 1 were not. The proportions of SISR in patients with DWMH Fazekas grades 0, 1, 2, and 3 were 16.7%, 33.3%, 50%, and 100%, respectively. CONCLUSIONS: Patients with CSVD have a higher risk of SISR than those without CSVD. Of the CSVD subtypes, patients with DWMHs are associated with SISR. The DWMH Fazekas scale score is considered to be a predictor for SISR.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Reestenosis Coronaria , Arteriosclerosis Intracraneal , Humanos , Estudios Retrospectivos , Constricción Patológica , Reestenosis Coronaria/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Imagen por Resonancia Magnética

RESUMEN

BACKGROUND AND OBJECTIVES: Diffusion tensor imaging (DTI) networks integrate damage from a variety of pathologic processes in cerebral small vessel disease (SVD) and may be a sensitive marker to detect treatment effects. We determined whether brain network analysis could detect treatment effects in the PRESERVE trial data set, in which intensive vs standard blood pressure (BP) lowering was compared. The primary end point of DTI had not shown treatment differences. METHODS: Participants with lacunar stroke were randomized to standard (systolic 130-140 mm Hg) or intensive (systolic ≤ 125 mm Hg) BP lowering and followed for 2 years with MRI at baseline and at 2 years. Graph theory-based metrics were derived from DTI data to produce a measure of network integrity weighted global efficiency and compared with individual MRI markers of DTI, brain volume, and white matter hyperintensities. RESULTS: Data were available in 82 subjects: standard n = 40 (mean age 66.3 ± 1.5 years) and intensive n = 42 (mean age 69.6 ± 1.0 years). The mean (SD) systolic BP was reduced by 13(14) and 23(23) mm Hg in the standard and intensive groups, respectively (p < 0.001 between groups). Significant differences in diffusion network metrics were found, with improved network integrity (weighted global efficiency, p = 0.002) seen with intensive BP lowering. In contrast, there were no significant differences in individual MRI markers including DTI histogram metrics, brain volume, or white matter hyperintensities. DISCUSSION: Brain network analysis may be a sensitive surrogate marker in trials in SVD. This work suggests that measures of brain network efficiency may be more sensitive to the effects of BP control treatment than conventional DTI metrics. TRIAL REGISTRATION INFORMATION: The trial is registered with the ISRCTN Registry (ISRCTN37694103; doi.org/10.1186/ISRCTN37694103) and the NIHR Clinical Research Network (CRN 10962; public-odp.nihr.ac.uk/QvAJAXZfc/opendoc.htm?document=crncc_users%5Cfind%20a%20clinical%20research%20study.qvw&lang=en-US&host=QVS%40crn-prod-odp-pu&anonymous=true). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that intensive BP lowering in patients with SVD results in improved brain network function when assessed by DTI-based brain network metrics.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Sustancia Blanca , Humanos , Persona de Mediana Edad , Anciano , Sustancia Blanca/patología , Imagen de Difusión Tensora/métodos , Presión Sanguínea , Citocromo P-450 CYP2B1 , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Imagen por Resonancia Magnética , Encéfalo/patología

RESUMEN

BACKGROUND: Cerebral small vessel disease (CSVD) is a common syndrome in the older population, with a prevalence ranging from 5% in subjects aged 50 years to almost 100% in those aged 90 years and older. It is regarded to be a major cause of vascular cognitive impairment. Existing prevention and treatment approaches have not yet shown ideal clinical outcomes. Dengyinnaotong Capsule has shown great potential for improving cognitive function. This trial (De-CSVD trial) is designed to investigate the efficacy and safety of Dengyinnaotong Capsule on cognitive function in patients with CSVD . METHODS: This multicenter, randomized, open-label, controlled trial is planned to recruit at least 270 patients with mild cognitive impairment related to CSVD in 25 centers in China. Recruitment started on 10 May 2021 and is foreseen to end on 31 December 2022. The final follow-up of participants will be completed by the end of March 2023. Participants will be randomized in a ratio of 1:1 to the experimental group (routine basic treatment plus Dengyinnaotong Capsule) or the control group (routine basic treatment). The primary outcome is the change in the Montreal Cognitive Assessment score from baseline to week 12. Secondary outcomes are changes in Shape Trail Test, Activities of Daily Living, Geriatric Depression Scale, and Dizziness Handicap Inventory score from baseline to week 12, new vascular events, and the changes in serum level of homocysteine, high-sensitivity C-reactive protein, and D-dimer from baseline to week 4 and 12, respectively. The exploratory outcome is the changes in the Tinetti performance-oriented mobility assessment score from baseline to week 12. Safety assessment is performed by monitoring vital signs, general biochemical examinations, 12-lead electrocardiogram examinations, and incidence of cardiovascular and cerebrovascular ischemia or bleeding events. Visits will be performed at week 0 (baseline, pre-randomization), week 4, and week 12 in the treatment period (post-randomization). DISCUSSION: This trial is the first to investigate the efficacy and safety of Dengyinnaotong Capsule on cognitive impairment in patients with CSVD. The findings of this study might provide convincing evidence regarding the efficacy of Dengyinnaotong Capsule in patients with mild cognitive impairment related to CSVD. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100045831. Registered on 25 April 2021.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Disfunción Cognitiva , Actividades Cotidianas , Anciano , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , China , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/tratamiento farmacológico , Humanos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Investigación