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

¿Revascularización completa en el infarto de miocardio con elevación del ST?: Sí, no lo dude

Primary angioplasty is now clearly established as the best reperfusion strategy for patients with ST-segment elevation myocardial infarction (STEMI), but the best strategy for significant stenosis at non-culprit vessels has not been adequately studied. Several randomized trials have been previously performed, but all of them with soft primary endpoints and consequently a low number of patients. The COMPLETE trial, for the first time, provides us with solid scientific evidence about what we should do in patients with STEMI and multi-vessel disease. This study included more than 4000 patients and has shown that complete revascularization reduces significantly the risk of cardiovascular death or myocardial infarction.La angioplastia primaria está reconocida como la mejor estrategia de reperfusión en el infarto de miocardio con elevación del segmento ST. No obstante, la mejor estrategia para el tratamiento de las lesiones coronarias significativas en arterias no relacionadas con el infarto no se había estudiado convenientemente. Hasta la fecha se habían realizado varios estudios aleatorizados pero con objetivos de beneficio clínico de gravedad menor o «blandos» y pocos pacientes. Por primera vez, el estudio COMPLETE proporciona evidencia científica sólida sobre la estrategia terapéutica en pacientes con infarto de miocardio con elevación del segmento ST y enfermedad multivaso. Este estudio, que incluyó a más de 4.000 pacientes, ha demostrado que la revascularización completa reduce significativamente el riesgo combinado de mortalidad o infarto de miocardio

Sensibilidad de biomarcadores en el líquido cefalorraquídeo en enfermedades neurodegenerativas

Recent advances in the pathophysiology of Alzheimer�s disease has prompted the clinical development of biomarkers that would expand research in early diagnosis, rate of disease progression and monitoring the effect of therapies. Cerebrospinal fluid measures (CSF) of beta-amyloid 42, total tau and phospo- tau proteins have shown a high diagnostic accuracy in differenciating Alzheimer�s dementia from healthy controls, even at very early stages of the disease. Diagnostic accuracy of the biomarkers between Alzheimer�s disease and other dementia types is not as good, although the specificity of phospo-tau levels remains high. Clinical usefulness is limited by the invasiveness of the procedure, and by strict adhesion to a well-defined protocol and sample handling. The type of technical method for determination is not widely established, and variability between centres is high. Nevertheless, there is an important role of CSF biomarkers in selected cases, and in the research of timing the events of Alzheimer�s disease.El avance en el conocimiento de la biología de la enfermedad de Alzheimer ha favorecido el desarrollo clínico de biomarcadores que permitan un diagnóstico temprano, monitoricen la progresión y puedan servir parar la evaluación de terapias. Las determinaciones en el líquido cefalorraquídeo (LCR) de beta-amiloide 42 (BA42), proteína tau total y proteína tau fosforilada han mostrado tener un rendimiento diagnóstico elevado para diferenciar la demencia tipo Alzheimer respecto a controles, incluso en fases incipientes de la misma. El rendimiento respecto a otros tipos de enfermedades neurodegenerativas es más bajo, aunque la especificidad de la tau fosforilada se mantiene para diferenciar la demencia tipo Alzheimer de las otras. La aplicabilidad clínica se encuentra limitada por la necesidad de un procedimiento invasivo, y de un protocolo y adiestramiento técnico en la determinación de específicos. La tecnología de medida todavía no está estandarizada a nivel global y la variabilidad entre centros es alta. Sin embargo, en casos clínicos seleccionados y en la investigación de la patocronia de la enfermedad de Alzheimer, los biomarcadores de LCR juegan un papel importante