Neuropsychological Outcome One Year after Carotid Revascularization : A before-and-after Study

Altres ajuts: This study was supported by a grant from the Fundación Mútua Madrileña.The aim of our study was to determine the clinical profile of patients considered cognitive 'responders' to surgery in order to establish clinical variables associated with a favorable cognitive performance. A total of 70 patients were included in the study. A well-validated, comprehensive standardized neurocognitive battery of tests of about 2 hours was administered. Patients were examined twice, 1-week before surgery and 1-year postoperatively. The criterion to be included in the 'responder' group was the following: to obtain a positive difference between post-revascularization and pre-revascularization neuropsychological assessment ≥1 standard deviation in ≥2 tests. Twenty-seven patients (38.6%) were cognitive responders to treatment. In bivariate analysis between responders and non-responders, presence of atrophy (P=0.003), small vessels (P=0.577), symptoms (P=0.046), and age (P=0.030) were the factors statistically significant. When comparing cognitive performance before and after carotid revascularization, significant differences were observed in semantic fluency with a lower performance after 12 months (P=0.004, d=0.29), and in the Language index (Repeatable Battery for the Assessment of Neuropsychological Status) (P=0.005, d=0.34). Patients without neurological symptoms, of a younger age and without atrophy and white matter small vessel lesions are better cognitive responders 1-year after carotid revascularization

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Trastorno cognitivo en la estenosis carotídea: evaluación neuropsicológica y efecto del tratamiento quirúrgico

Introducción: el deterioro cognitivo tras un accidente cerebrovascular es frecuente. Alrededor del 55% de los pacientes que lo padece desarrollan déficits en la memoria episódica, un 40% en las funciones ejecutivas, y los déficits del lenguaje afectan a un 23% de ellos. La estenosis carotídea (EC) se identifica como etiología del 20-30% de los accidentes cerebrales isquémicos. El diagnóstico y el tratamiento quirúrgico de la EC han ocupado en los últimos años un papel relevante en la literatura médica. Sin embargo, la contribución de la EC por sí misma en la cognición de pacientes asintomáticos o sintomáticos es poco conocida. En este trabajo, proponemos: 1) estudiar si los pacientes con estenosis grave (>70%) de la arteria carótida, sin clínica cerebrovascular importante ni demencia, presentan un deterioro cognitivo superior a la población general; 2) describir qué funciones cognitivas se ven alteradas y analizar si existen diferencias cognitivas en base a la gravedad de la estenosis, el lado del que van a ser revascularizados o la presencia de clínica neurológica; 3) identificar el perfil clínico predictor de aquellos sujetos que desarrollará una mejor respuesta cognitiva tras la revascularización. Estudio 1 Método: se incluyeron 106 sujetos: 53 pacientes con EC grave sin demencia y 53 controles extraídos de la población general emparejados uno a uno según edad, sexo, nivel de escolaridad y dominancia manual. La evaluación cognitiva se realizó mediante la Repeatable Battery Assessment for Neuropsychological Status (RBANS). Resultados: Observamos que los pacientes con EC obtuvieron un rendimiento cognitivo inferior a los controles en atención, memoria verbal, capacidad visuoespacial y fluencia verbal. El análisis según el grado de EC mostraba que los pacientes con mayor grado de EC total presentaban peores puntuaciones en aprendizaje y memoria. Además, hallamos que los pacientes con EC izquierda presentaban un peor rendimiento en tareas cognitivas frontales que los pacientes con EC derecha. Estudio 2 Método: se incluyeron 70 pacientes candidatos a revascularización carotídea que fueron valorados en dos ocasiones, una semana antes de la cirugía y un año después de la intervención, mediante una extensa batería normalizada para la población española. Resultados: El 38.6% de los pacientes fueron clasificados como “respondedores” cognitivamente. Las variables preoperatorias relacionadas con un mejor resultado cognitivo fueron una menor edad, la ausencia de sintomatología neurológica previa y la no detección en las pruebas de neuroimagen de atrofia cerebral y lesiones de pequeño vaso. El rendimiento cognitivo de los pacientes tras 12 meses de la intervención se mantuvo estable en todas las áreas evaluadas excepto en lenguaje. Se observó un peor rendimiento a los 12 meses en los sujetos con sintomatología neurológica, en funciones visuoperceptivas y tareas ejecutivas respecto a los asintomáticos. Los pacientes revascularizados del lado izquierdo obtuvieron peores resultados cognitivos a los 12 meses de la revascularización en atención, tanto verbal como visual, y en fluencia fonética. Conclusiones: Los pacientes con EC grave presentan una función cognitiva basal inferior a la población general de las mismas características. El deterioro cognitivo hallado se asoció con el grado de EC. Aquellos pacientes con EC sin síntomas neurológicos, jóvenes y sin lesiones periventriculares de la sustancia blanca ni atrofia cerebral, presentaron una mejor respuesta cognitiva al año de ser revascularizados.Introduction: Cognitive decline after an acute cerebrovascular event is frequent, and it has been estimated that around 55% of stroke subjects develop episodic memory deficits, 40% executive function deficits and up to 23% language function deficits. Carotid artery stenosis (CAS) causes between 20% and 30% of ischemic cerebral infarctions. In recent years, diagnosis and surgical treatment of CAS has been a relevant focus of interest in the medical literature. However, the contribution of CAS per se to cognitive function in asymptomatic patients or in patients with transient ischemic attacks is poorly understood. The objectives of the studies reported in the present Doctoral Thesis were as follows: 1) to assess whether persons with severe CAS (> 70%) without cerebrovascular symptoms and without dementia showed a greater cognitive decline as compared to healthy individuals; 2) to describe which cognitive functions were altered and whether there were cognitive differences according to severity of stenosis, side of surgical repair, and presence or absence of neurological symptoms; and 3) to identify a predictive clinical and neuropsychological profile for patients which will present a improvement of their cognitive profileg after revascularization. Study 1 Method: 106 subjects were included: 53 patients with severe CAS and without dementia and 53 healthy controls matched by age, sex, education level and manual dominance. Cognitive assessment was performed using the Repeatable Battery Assessment for Neuropsychological Status (RBANS). Results: It was found that patients with CAS showed a lower cognitive performance than controls in attention, verbal memory, visuospatial capacity and verbal fluency. Analysis according to the degree of stenosis showed that patients with higher degree of total CAS showed lower scores on learning and memory. Also, patients with left CAS showed lower performance on frontal cognitive tasks as compared to patients with right CAS. Study 2 Method: 70 patients who were scheduled for carotid revascularization were evaluated on two occasions, one week before the intervention (baseline) and one year after the surgical procedure using a large battery of neuropsychological tests normalized for the Spanish population. Results: 38.6% of patients were classified as “responders” as they presented an improvement of at least one standard deviation in at least two tests after the surgical procedure. Predictive factors of positive response were younger patient’s age as well as absence of neurological symptoms, and no detection of cerebral atrophy and small-vessel lesions on imaging studies. Cognitive performance at 12 months after surgery remained stable in all areas evaluated, except for language. A worse performance in visuospatial functions and executive tasks at 12 months was observed in patients with neurological symptoms as compared with asymptomatic patients. Patients undergoing revascularization procedures of the left side showed worse cognitive performance at 12 months after the surgical procedure in verbal and visual attention as well as in verbal fluency. Conclusions: Patients with severe CAS showed a lower baseline cognitive status as compared with a general population of the same sociodemographic characteristics. Cognitive decline was associated with the degree of CAS. Patients without neurological symptoms, of younger age and without white matter periventricular lesions and cerebral atrophy showed a better cognitive response at one year after carotid artery revascularization

Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trialResearch in context

Summary: Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589

Optimization of adsorptive removal of α-toluic acid by CaO2 nanoparticles using response surface methodology

The present work addresses the optimization of process parameters for adsorptive removal of α-toluic acid by calcium peroxide (CaO2) nanoparticles using response surface methodology (RSM). CaO2 nanoparticles were synthesized by chemical precipitation method and confirmed by Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) analysis which shows the CaO2 nanoparticles size range of 5–15 nm. A series of batch adsorption experiments were performed using CaO2 nanoparticles to remove α-toluic acid from the aqueous solution. Further, an experimental based central composite design (CCD) was developed to study the interactive effect of CaO2 adsorbent dosage, initial concentration of α-toluic acid, and contact time on α-toluic acid removal efficiency (response) and optimization of the process. Analysis of variance (ANOVA) was performed to determine the significance of the individual and the interactive effects of variables on the response. The model predicted response showed a good agreement with the experimental response, and the coefficient of determination, (R2) was 0.92. Among the variables, the interactive effect of adsorbent dosage and the initial α-toluic acid concentration was found to have more influence on the response than the contact time. Numerical optimization of process by RSM showed the optimal adsorbent dosage, initial concentration of α-toluic acid, and contact time as 0.03 g, 7.06 g/L, and 34 min respectively. The predicted removal efficiency was 99.50%. The experiments performed under these conditions showed α-toluic acid removal efficiency up to 98.05%, which confirmed the adequacy of the model prediction

Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study

Background: People with Huntington's disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis