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1.
Am J Kidney Dis ; 79(5): 677-687.e1, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34543687

RESUMEN

RATIONALE & OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in individuals with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial (SPRINT) who underwent brain magnetic resonance imaging studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP <120 mm Hg) versus standard (systolic BP <140 mm Hg) BP lowering. OUTCOMES: The magnetic resonance imaging outcome measures were the 4-year change in global cerebral blood flow (CBF), white matter lesion (WML) volume, and total brain volume (TBV). RESULTS: A total of 716 randomized participants with a mean age of 68 years were enrolled; follow-up imaging occurred after a median 3.9 years. Among participants with eGFR <60 mL/min/1.73 m2 (n = 234), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 3.38 (95% CI, 0.32 to 6.44) mL/100 g/min, -0.06 (95% CI, -0.16 to 0.04) cm3 (inverse hyperbolic sine-transformed), and -3.8 (95% CI, -8.3 to 0.7) cm3, respectively. Among participants with UACR >30 mg/g (n = 151), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 1.91 (95% CI, -3.01 to 6.82) mL/100 g/min, 0.003 (95% CI, -0.13 to 0.13) cm3 (inverse hyperbolic sine-transformed), and -7.0 (95% CI, -13.3 to -0.3) cm3, respectively. The overall treatment effects on CBF and TBV were not modified by baseline eGFR or UACR; however, the effect on WMLs was attenuated in participants with albuminuria (P = 0.04 for interaction). LIMITATIONS: Measurement variability due to multisite design. CONCLUSIONS: Among adults with hypertension who have primarily early kidney disease, intensive versus standard BP treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive BP treatment targets on brain health in persons with early kidney disease. FUNDING: SPRINT was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Aging; and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with study number NCT01206062.


Asunto(s)
Hipertensión , Insuficiencia Renal Crónica , Anciano , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea/fisiología , Circulación Cerebrovascular , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Perfusión
2.
Cogn Behav Neurol ; 34(3): 220-225, 2021 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-34473674

RESUMEN

Variably protease-sensitive prionopathy (VPSPr) is a recently described sporadic prion disease with distinctive clinical and histopathological features. We report the clinical, imaging, and neuropathological features of VPSPr in a 46-year-old right-handed man who presented with progressive cognitive decline, behavior disturbances, and a 50-pound weight loss over 6 months. The initial evaluation revealed severe cognitive impairment with no focal neurologic deficits. His cognitive, psychiatric, and behavior symptoms progressed rapidly, and he died 12 months after the initial visit. Throughout his disease course, workup for rapid progressive dementia was unremarkable except that brain MRI diffusion-weighted imaging showed persistent diffuse cortical and thalamic signal abnormalities. Sporadic Creutzfeldt-Jakob disease was highly suspected; however, two EEGs (8 months apart) demonstrated only nonspecific cerebral dysfunction. The patient's CSF 14-3-3 protein was negative at the initial visit and again 8 months later. His CSF real-time quaking-induced conversion and total tau level were normal. An autopsy of his brain was performed, and the neuropathological findings confirmed VPSPr. Our case underlines the importance of considering VPSPr in the spectrum of prion disease phenotypes when evaluating individuals with rapidly progressive dementia.


Asunto(s)
Síndrome de Creutzfeldt-Jakob , Enfermedades por Prión , Priones , Encéfalo/diagnóstico por imagen , Síndrome de Creutzfeldt-Jakob/complicaciones , Síndrome de Creutzfeldt-Jakob/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Péptido Hidrolasas/metabolismo , Enfermedades por Prión/complicaciones , Priones/metabolismo
3.
Clin Sci (Lond) ; 135(15): 1929-1944, 2021 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-34374423

RESUMEN

The accumulation of extracellular amyloid-ß (Aß) and intracellular hyperphosphorylated τ proteins in the brain are the hallmarks of Alzheimer's disease (AD). Much of the research into the pathogenesis of AD has focused on the amyloid or τ hypothesis. These hypotheses propose that Aß or τ aggregation is the inciting event in AD that leads to downstream neurodegeneration, inflammation, brain atrophy and cognitive impairment. Multiple drugs have been developed and are effective in preventing the accumulation and/or clearing of Aß or τ proteins. However, clinical trials examining these therapeutic agents have failed to show efficacy in preventing or slowing the progression of the disease. Thus, there is a need for fresh perspectives and the evaluation of alternative therapeutic targets in this field. Epidemiology studies have revealed significant overlap between cardiovascular and cerebrovascular risk factors such as hypertension, diabetes, atherosclerosis and stroke to the development of cognitive impairment. This strong correlation has given birth to a renewed focus on vascular contributions to AD and related dementias. However, few genes and mechanisms have been identified. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that plays a complex role in hypertension, autoregulation of cerebral blood flow and blood-brain barrier (BBB) integrity. Multiple human genome-wide association studies have linked mutations in the cytochrome P450 (CYP) 4A (CYP4A) genes that produce 20-HETE to hypertension and stroke. Most recently, genetic variants in the enzymes that produce 20-HETE have also been linked to AD in human population studies. This review examines the emerging role of 20-HETE in AD and related dementias.


Asunto(s)
Arterias Cerebrales/metabolismo , Circulación Cerebrovascular , Cognición , Disfunción Cognitiva/metabolismo , Demencia Vascular/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Animales , Arterias Cerebrales/fisiopatología , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Demencia Vascular/epidemiología , Demencia Vascular/fisiopatología , Demencia Vascular/psicología , Hemodinámica , Humanos , Pronóstico , Medición de Riesgo , Factores de Riesgo , Transducción de Señal
4.
Hypertension ; 77(4): 1391-1398, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33583199
6.
Lancet Neurol ; 19(11): 899-907, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33098800

RESUMEN

BACKGROUND: Results from the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive control of systolic blood pressure significantly reduced the occurrence of mild cognitive impairment, but not probable dementia. We investigated the effects of intensive lowering of systolic blood pressure on specific cognitive functions in a preplanned substudy of participants from SPRINT. METHODS: SPRINT was an open-label, multicentre, randomised controlled trial undertaken at 102 sites, including academic medical centres, Veterans Affairs medical centres, hospitals, and independent clinics, in the USA and Puerto Rico. Participants were adults aged 50 years or older with systolic blood pressure higher than 130 mm Hg, but without diabetes, history of stroke, or dementia. Participants were randomly assigned (1:1) to a systolic blood pressure goal of less than 120 mm Hg (intensive treatment) versus less than 140 mm Hg (standard treatment). All major classes of antihypertensive agents were included. A subgroup of randomly assigned participants including, but not limited to, participants enrolled in an MRI substudy was then selected for a concurrent substudy of cognitive function (target 2800 participants). Each individual was assessed with a screening cognitive test battery and an extended cognitive test battery at baseline and biennially during the planned 4-year follow-up. The primary outcomes for this substudy were standardised composite scores for memory (Logical Memory I and II, Modified Rey-Osterrieth Complex Figure [immediate recall], and Hopkins Verbal Learning Test-Revised [delayed recall]) and processing speed (Trail Making Test and Digit Symbol Coding). SPRINT was registered with ClinicalTrials.gov, NCT01206062. FINDINGS: From Nov 23, 2010, to Dec 28, 2012, 2921 participants (mean age 68·4 years [SD 8·6], 1080 [37%] women) who had been randomly assigned in SPRINT were enrolled in the substudy (1448 received intensive treatment and 1473 received standard treatment). SPRINT was terminated early due to benefit observed in the primary outcome (composite of cardiovascular events). After a median follow-up of 4·1 years (IQR 3·7-5·8), there was no between-group difference in memory, with an annual decline in mean standardised domain score of -0·005 (95% CI -0·010 to 0·001) in the intensive treatment group and -0·001 (-0·006 to 0·005) in the standard treatment group (between-group difference -0·004, 95% CI -0·012 to 0·004; p=0·33). Mean standardised processing speed domain scores declined more in the intensive treatment group (between-group difference -0·010, 95% CI -0·017 to -0·002; p=0·02), with an annual decline of -0·025 (-0·030 to -0·019) for the intensive treatment group and -0·015 (-0·021 to 0·009) for the standard treatment group. INTERPRETATION: Intensive treatment to lower systolic blood pressure did not result in a clinically relevant difference compared with standard treatment in memory or processing speed in a subgroup of participants from SPRINT. The effect of blood pressure lowering might not be evident in specific domains of cognitive function, but instead distributed across multiple domains. FUNDING: National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Alzheimer's Association.


Asunto(s)
Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Cognición/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Pruebas de Estado Mental y Demencia , Anciano , Anciano de 80 o más Años , Antihipertensivos/farmacología , Presión Sanguínea/fisiología , Monitoreo Ambulatorio de la Presión Arterial/métodos , Monitoreo Ambulatorio de la Presión Arterial/tendencias , Cognición/fisiología , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/psicología , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/psicología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Estados Unidos/epidemiología , United States Department of Veterans Affairs/tendencias
7.
IEEE Trans Vis Comput Graph ; 26(9): 2818-2833, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-30763242

RESUMEN

We report empirical study results on the color encoding of ensemble scalar and orientation to visualize diffusion magnetic resonance imaging (DMRI) tubes. The experiment tested six scalar colormaps for average fractional anisotropy (FA) tasks (grayscale, blackbody, diverging, isoluminant-rainbow, extended-blackbody, and coolwarm) and four three-dimensional (3D) spherical colormaps for tract tracing tasks (uniform gray, absolute, eigenmaps, and Boy's surface embedding). We found that extended-blackbody, coolwarm, and blackbody remain the best three approaches for identifying ensemble average in 3D. Isoluminant-rainbow colormap led to the same ensemble mean accuracy as other colormaps. However, more than 50 percent of the answers consistently had higher estimates of the ensemble average, independent of the mean values. The number of hues, not luminance, influences ensemble estimates of mean values. For ensemble orientation-tracing tasks, we found that both Boy's surface embedding (greatest spatial resolution and contrast) and absolute colormaps (lowest spatial resolution and contrast) led to more accurate answers than the eigenmaps scheme (medium resolution and contrast), acting as the uncanny-valley phenomenon of visualization design in terms of accuracy. Absolute colormap broadly used in brain science is a good default spherical colormap. We could conclude from our study that human visual processing of a chunk of colors differs from that of single colors.

8.
JAMA ; 322(6): 524-534, 2019 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-31408137

RESUMEN

Importance: The effect of intensive blood pressure lowering on brain health remains uncertain. Objective: To evaluate the association of intensive blood pressure treatment with cerebral white matter lesion and brain volumes. Design, Setting, and Participants: A substudy of a multicenter randomized clinical trial of hypertensive adults 50 years or older without a history of diabetes or stroke at 27 sites in the United States. Randomization began on November 8, 2010. The overall trial was stopped early because of benefit for its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. Brain magnetic resonance imaging (MRI) was performed on a subset of participants at baseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up date was July 1, 2016. Interventions: Participants were randomized to a systolic blood pressure (SBP) goal of either less than 120 mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standard treatment, n = 315). Main Outcomes and Measures: The primary outcome was change in total white matter lesion volume from baseline. Change in total brain volume was a secondary outcome. Results: Among 670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years; 40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 years after randomization, after a median intervention period of 3.40 years. In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm3 (difference, 0.92 cm3 [95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3 [95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, -0.54 cm3 [95% CI, -0.87 to -0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm3 (difference, -30.6 cm3 [95% CI, -32.3 to -28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3 (difference, -26.9 cm3 [95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, -3.7 cm3 [95% CI, -6.3 to -1.1]). Conclusions and Relevance: Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.


Asunto(s)
Antihipertensivos/uso terapéutico , Encéfalo/fisiología , Hipertensión/tratamiento farmacológico , Sustancia Blanca/patología , Anciano , Presión Sanguínea , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Factores de Riesgo
9.
JAMA ; 321(6): 553-561, 2019 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-30688979

RESUMEN

Importance: There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia. Objective: To evaluate the effect of intensive blood pressure control on risk of dementia. Design, Setting, and Participants: Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018. Interventions: Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683). Main Outcomes and Measures: The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. Results: Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97). Conclusions and Relevance: Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.


Asunto(s)
Antihipertensivos/uso terapéutico , Disfunción Cognitiva/prevención & control , Demencia/prevención & control , Hipertensión/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Presión Sanguínea/efectos de los fármacos , Enfermedades Cardiovasculares/prevención & control , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales
10.
Stroke ; 48(11): 3078-3085, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28954920

RESUMEN

BACKGROUND AND PURPOSE: The visual analogue scale is a self-reported, validated tool to measure quality of life (QoL). Our purpose was to determine whether baseline QoL predicted strokes in the ALLHAT study (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial) and evaluate determinants of poststroke change in QoL. In the ALLHAT study, among the 33 357 patients randomized to treatment arms, 1525 experienced strokes; 1202 (79%) strokes were nonfatal. This study cohort includes 32 318 (97%) subjects who completed the baseline visual analogue scale QoL estimate. METHODS: QoL was measured on a visual analogue scale and adjusted using a Torrance transformation (transformed QoL [TQoL]). Kaplan-Meier curves and adjusted proportional hazards analyses were used to estimate the effect of TQoL on the risk of stroke, on a continuous scale (0-1) and by quartiles (≤0.81, >0.81≤0.89, >0.89≤0.95, >0.95). We analyzed the change from baseline to first poststroke TQoL using adjusted linear regression. RESULTS: After adjusting for multiple stroke risk factors, the hazard ratio for stroke events for baseline TQoL was 0.93 (95% confidence interval, 0.89-0.98) per 0.1 U increase. The lowest baseline TQoL quartile had a 20% increased stroke risk (hazard ratio=1.20 [95% confidence interval, 1.00-1.44]) compared with the reference highest quartile TQoL. Poststroke TQoL change was significant within all treatment groups (P≤0.001). Multivariate regression analysis revealed that baseline TQoL was the strongest predictor of poststroke TQoL with similar results for the untransformed QoL. CONCLUSIONS: The lowest baseline TQoL quartile had a 20% higher stroke risk than the highest quartile. Baseline TQoL was the only factor that predicted poststroke change in TQoL. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000542.


Asunto(s)
Antihipertensivos/administración & dosificación , Dislipidemias , Calidad de Vida , Accidente Cerebrovascular , Anciano , Antihipertensivos/efectos adversos , Supervivencia sin Enfermedad , Método Doble Ciego , Dislipidemias/sangre , Dislipidemias/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/inducido químicamente , Accidente Cerebrovascular/mortalidad , Tasa de Supervivencia
11.
Am J Kidney Dis ; 70(3): 357-367, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28606731

RESUMEN

BACKGROUND: Chronic kidney disease is common and is associated with cardiovascular disease, cerebrovascular disease, and cognitive function, although the nature of this relationship remains uncertain. STUDY DESIGN: Cross-sectional cohort using baseline data from the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING & PARTICIPANTS: Participants in SPRINT, a randomized clinical trial of blood pressure targets in older community-dwelling adults with cardiovascular disease, chronic kidney disease, or high cardiovascular disease risk and without diabetes or known stroke, who underwent detailed neurocognitive testing in the cognition substudy, SPRINT-Memory and Cognition in Decreased Hypertension (SPRINT-MIND). PREDICTORS: Urine albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). OUTCOMES: Cognitive function, a priori defined as 5 cognitive domains based on 11 cognitive tests using z scores, and abnormal white matter volume quantified by brain magnetic resonance imaging. RESULTS: Of 9,361 SPRINT participants, 2,800 participated in SPRINT-MIND and 2,707 had complete data; 637 had brain imaging. Mean age was 68 years, 37% were women, 30% were black, and 20% had known cardiovascular disease. Mean eGFR was 70.8±20.9mL/min/1.73m2 and median urine ACR was 9.7 (IQR, 5.7-22.5) mg/g. In adjusted analyses, higher ACR was associated with worse global cognitive function, executive function, memory, and attention, such that each doubling of urine ACR had the same association with cognitive performance as being 7, 10, 6, and 14 months older, respectively. Lower eGFR was independently associated with worse global cognitive function and memory. In adjusted models, higher ACR, but not eGFR, was associated with larger abnormal white matter volume. LIMITATIONS: Cross-sectional only, no patients with diabetes were included. CONCLUSIONS: In older adults, higher urine ACR and lower eGFR have independent associations with global cognitive performance with different affected domains. Albuminuria concurrently identifies a higher burden of abnormal brain white matter disease, suggesting that vascular disease may mediate these relationships.


Asunto(s)
Trastornos del Conocimiento , Cognición/fisiología , Insuficiencia Renal Crónica , Anciano , Determinación de la Presión Sanguínea/métodos , Enfermedades Cardiovasculares/epidemiología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/fisiopatología , Estudios Transversales , Femenino , Tasa de Filtración Glomerular , Humanos , Hipertensión/diagnóstico , Hipertensión/psicología , Pruebas de Inteligencia , Pruebas de Función Renal/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/psicología , Factores de Riesgo , Estadística como Asunto , Sustancia Blanca/diagnóstico por imagen
12.
Lancet Neurol ; 16(5): 360-368, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28320635

RESUMEN

BACKGROUND: Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery. METHODS: We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18-83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8-20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24-48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov, number NCT01436487. FINDINGS: The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 [95% CI 0·55-2·09], p=0·83). INTERPRETATION: Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke (<36 h) are planned. FUNDING: Athersys Inc.


Asunto(s)
Células Madre Adultas/trasplante , Trasplante de Médula Ósea/métodos , Células Madre Multipotentes/trasplante , Accidente Cerebrovascular/terapia , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuperación de la Función , Resultado del Tratamiento
13.
Stroke ; 42(4): 883-8, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21330625

RESUMEN

BACKGROUND AND PURPOSE: There is some evidence that poststroke dementia, cognitive impairment no dementia (CIND), and mild cognitive impairment predict for poor outcomes such as dementia, death, and institutionalization. However, few studies have examined the prognostic value of CIND, CIND severity, and domain impairments in a poststroke cohort. METHODS: A cohort of ischemic stroke patients with baseline cognitive assessments 3 months poststroke were followed up annually for outcomes of dependency, vascular events, and death for up to 5 years. Univariate and multivariate Cox proportional regression was performed to determine the ability CIND, CIND severity, and domain impairments to predict dependency, vascular outcomes, and death. RESULTS: Four-hundred nineteen patients without dementia (mean age 60±11 years, 32% female) were followed for a mean of 3.2 years. Older age, diabetes, more severe strokes, CIND-mild, and CIND-moderate were independently predictive of dependency. There were no independent predictors of recurrent vascular events. Older age, diabetes, and CIND-moderate were independently predictive of death. In analyses of individual cognitive domains, impairments in visuomotor speed were independently predictive of dependency. CONCLUSIONS: In poststroke patients, CIND predicts dependency and death, while CIND severity discriminates patients with poor survival. Impairments in visuomotor speed independently predict dependency. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique Identifier: NCT00161070.


Asunto(s)
Isquemia Encefálica/mortalidad , Trastornos del Conocimiento/mortalidad , Accidente Cerebrovascular/mortalidad , Anciano , Isquemia Encefálica/psicología , Estudios de Cohortes , Evaluación de la Discapacidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas/normas , Pronóstico , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/psicología
14.
Dement Geriatr Cogn Disord ; 25(1): 17-22, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18025825

RESUMEN

BACKGROUND/AIMS: Previous work combining the Mini-Mental State Examination (MMSE) and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) has been conducted in western populations. We ascertained, in an Asian population, (1) the best method of combining the tests, (2) the effects of educational level, and (3) the effect of different dementia etiologies. METHODS: Data from 576 patients were analyzed (407 nondemented controls, 87 Alzheimer's disease and 82 vascular dementia patients). Sensitivity, specificity and AUC values were obtained using three methods, the 'And' rule, the 'Or' rule, and the 'weighted sum' method. RESULTS: The 'weighted sum' rule had statistically superior AUC and specificity results, while the 'Or' rule had the best sensitivity results. The IQCODE outperformed the MMSE in all analyses. Patients with no education benefited more from combined tests. There was no difference between Alzheimer's disease and vascular dementia populations in the predictive value of any of the combined methods. CONCLUSION: We recommend that the IQCODE be used to supplement the MMSE whenever available and that the 'weighted sum' method be used to combine the MMSE and the IQCODE, particularly in populations with low education. As the study population selected may not be representative of the general population, further studies are required before generalization to nonclinical samples.


Asunto(s)
Pueblo Asiatico/estadística & datos numéricos , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etnología , Demencia/diagnóstico , Demencia/etnología , Pruebas Neuropsicológicas , Encuestas y Cuestionarios , Anciano , Demografía , Escolaridad , Femenino , Humanos , Masculino , Tamizaje Masivo/métodos , Prevalencia , Singapur/epidemiología
15.
Ann N Y Acad Sci ; 1097: 259-64, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17413027

RESUMEN

Diffusion tensor imaging (DTI) was used to examine the microstructural integrity of normal appearing white matter (NAWM) in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Significant frontal, temporal, and parietal white matter diffusion tensor changes were demonstrated in MCI and AD compared with normal controls. These changes were correlated with cognitive functioning, and are consistent with a hypothesized loss of axonal processes in affected regions.


Asunto(s)
Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/psicología , Anciano , Axones/patología , Encéfalo/patología , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Pruebas Neuropsicológicas , Desempeño Psicomotor/fisiología
16.
Alzheimer Dis Assoc Disord ; 19(4): 184-5, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16327344

RESUMEN

The diversity of Singapore's population affords a unique opportunity to study ethnic variability in the dementias. We sought to explore the effects of ethnicity on the frequency of Alzheimer disease and vascular dementia in a large Singaporean sample. A total of 357 patients were studied: 190 with vascular dementia and 167 with Alzheimer disease. Vascular dementia was more common among Chinese and Malays, whereas Alzheimer disease was more common in Indians and Eurasians. Factors that may contribute to the observed ethnic variability in dementia etiologies include differential frequency of the ApoE-e4 allele, frequency of vascular risk factors, lifestyle choices, and cultural attitudes toward health care utilization.


Asunto(s)
Enfermedad de Alzheimer/etnología , Demencia Vascular/etnología , Adulto , Anciano , Anciano de 80 o más Años , China/etnología , Escolaridad , Europa (Continente)/etnología , Femenino , Humanos , India/etnología , Malasia/etnología , Masculino , Persona de Mediana Edad , Prevalencia , Singapur
17.
Alzheimer Dis Assoc Disord ; 17(2): 129-31, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12794392

RESUMEN

The 2nd Asia-Pacific regional meeting of the International Working Group on Harmonization of Dementia Drug Guidelines (IWGH) was held in Beijing, China in late 2002. Representatives from over a dozen countries convened to present data on dementia within the region and to share information on locally adapted outcome measures for use in dementia clinical trials. The IWGH recognized the competency and capability of many Asian sites and endorsed their inclusion in future multicenter clinical dementia research activities.


Asunto(s)
Demencia/tratamiento farmacológico , Cooperación Internacional , Guías de Práctica Clínica como Asunto , Asia , Ensayos Clínicos como Asunto , Medicina Basada en la Evidencia , Humanos
18.
J Neurol Sci ; 203-204: 49-52, 2002 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-12417356

RESUMEN

BACKGROUND AND PURPOSE: Vascular dementia accounts for 40-50% of dementia cases in Singapore. The aim of this study is to examine the prevalence and natural history of cognitive impairment in a cohort of Singaporean post-stroke patients. METHODS: The Vascular Dementia Battery (VDB) was offered to 252 patients with a transient ischaemic attack (TIA) or non-disabling ischaemic stroke at baseline (within 6 months post index stroke) and annually thereafter. The VDB assesses six cognitive domains: attention, language, verbal memory (recall and recognition), visual memory (recall and recognition), visuoconstruction and visuomotor speed. Dementia was diagnosed using the DSM-IV criteria. Patients who did not meet the DSM-IV criteria but were impaired in one or more cognitive domains were classified as 'cognitively impaired but not demented'. Those who were unimpaired in all cognitive domains were classified as 'cognitively intact'. RESULTS: At baseline, 56% of patients were 'cognitively intact', 40% were 'cognitively impaired but not demented' and 4% were 'demented'. At 1-year follow-up, 33% patients had a changed classification from baseline. While 31% of those who were 'cognitively impaired but not demented' at baseline improved to 'cognitively intact', 10% of the 'cognitively intact' group deteriorated to 'cognitively impaired but not demented' and 11% deteriorated from 'cognitively impaired but not demented' to 'demented'. Cognitive performance at baseline predicted for deterioration. CONCLUSIONS: This study suggests that the long-term cognitive performance in stroke patients change over time. Further studies are required to identify risk factors and effective treatment for cognitive deterioration after stroke.


Asunto(s)
Trastornos del Conocimiento/psicología , Accidente Cerebrovascular/psicología , Factores de Edad , Anciano , Trastornos del Conocimiento/clasificación , Estudios de Cohortes , Progresión de la Enfermedad , Educación , Femenino , Estudios de Seguimiento , Humanos , Ataque Isquémico Transitorio/psicología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Factores de Riesgo , Singapur , Accidente Cerebrovascular/clasificación
19.
J Neurol Sci ; 203-204: 85-9, 2002 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-12417363

RESUMEN

BACKGROUND: Vascular dementia (VaD) is occasionally caused by a single, strategically located stroke. In this report, we describe the clinical and anatomical features of 12 cases of strategic single infarct dementia (SSID) from Singapore. METHODS: Each patient completed a standardized diagnostic evaluation including history, neurological and neuropsychological examination, laboratory testing, and brain imaging. Dementia was diagnosed using the Diagnostic and Statistical Manual, 3rd edition, revised (DSM-III-R) criteria, and VaD was diagnosed using the National Institute of Neurologic Disorders and Stroke and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria. VaD patients whose brain imaging study revealed a single cerebrovascular event were diagnosed with SSID. RESULTS: We identified 12 cases of SSID among 125 VaD patients (9.6%). Stroke mechanism was lacunar infarction in five cases, embolism in four cases, large vessel thrombosis in two cases, and parenchymal hemorrhage in one case. The most commonly impaired cognitive domains on neuropsychological testing were visual memory, visuoconstruction, and language. In 11 of the 12 SSID cases, the stroke was located in the left hemisphere. The thalamus, either alone or as the proximal portion of a posterior cerebral artery infarction, was involved in 8 of the 12 cases. Stroke locations in the nonthalamic SSID cases included left angular gyrus, subcortical left frontal lobe including minor forceps, left basal forebrain and medial frontal lobe plus anterior corpus callosum (proximal anterior cerebral artery infarction), and anterior corpus callosum alone. CONCLUSIONS: Various stroke mechanisms may produce SSID. In our SSID cases, vascular damage almost always involved the left hemisphere and frequently involved the thalamus and major interhemispheric or intrahemispheric white matter pathways.


Asunto(s)
Demencia/etiología , Demencia/psicología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/psicología , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Bases de Datos Factuales , Demencia/patología , Femenino , Lateralidad Funcional/fisiología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Singapur , Accidente Cerebrovascular/patología
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