domingo, 29 de julio de 2018
La enfermedad de Alzheimer presenta características diferenciadas en cada paciente
A Study of Amyloid-β and Phosphotau in Plaques and Neurons in the Hippocampus of Alzheimer’s Disease Patients
Abstract
The main pathological hallmarks in Alzheimer’s disease (AD) are the presence of extracellular amyloid plaques, primarily consisting of amyloid-β (Aβ) peptide, and the accumulation of paired helical filaments of hyperphosphorylated tau protein (PHF-Tau) within neurons. Since CA1 is one of the most affected regions in AD, mainly at early stages, we have performed a detailed analysis of the CA1 region from 11 AD patients (demented and clinically similar; Braak stages IV-VI) to better understand the possible relationship between the presence and distribution of different neurochemical types of Aβ plaques and PHF-Tau immunoreactive (- ir) neurons. Hence, we have examined hippocampal sections in confocal microscopy images from double and triple-immunostained sections, to study labeled plaques and PHF-Tau-ir neurons using specific software tools. There are four main findings in the present study. First, the pyramidal layer of proximal CA1 (close to CA2) contains the smallest number of both plaques and PHF-Tau-ir neurons. Second, a large proportion of Aβ-ir plaques were also characterized by the presence of PHF-Tau-ir. Third, all plaques containing one of the two PHF-Tau isoforms also express the other isoform, that is, if a plaque contains PHFpS396, it also contains PHFAT8, and vice versa. Fourth, the coexpression study of both PHF-Tau isoforms in CA1 neurons revealed that most of the labeled neurons express only PHFpS396. Our findings further support the idea that AD is not a unique entity even within the same neuropathological stage, since the microanatomical/neurochemical changes that occur in the hippocampus greatly vary from one patient to another.
INTRODUCTION
Alzheimer’s disease (AD) is a progressive brain disease and the most common cause of dementia [1]. The main pathological hallmarks in AD are the presence of extracellular amyloid plaques, primarily consisting of amyloid-β (Aβ) peptide, and the accumulation within neurons of paired helical filaments of hyperphosphorylated tau protein (PHF-Tau), which are known as neurofibrillary tangles (NFTs) [2–4].
La FDA aprueba el primer fármaco con un ingrediente derivado de la marihuana
Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut Syndrome
Abstract
BACKGROUND
Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox–Gastaut syndrome, a severe developmental epileptic encephalopathy.
METHODS
In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox–Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period.
RESULTS
A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations.
CONCLUSIONS
Among children and adults with the Lennox–Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560.)
sábado, 21 de julio de 2018
Confirman la evidencia de que la actividad física disminuye las posibilidades de desarrollar depresión
Physical Activity and Incident Depression: A Meta-Analysis of Prospective Cohort Studies
Abstract
Objective:
The authors examined the prospective relationship between physical activity and incident depression and explored potential moderators.
Method:
Prospective cohort studies evaluating incident depression were searched from database inception through Oct. 18, 2017, on PubMed, PsycINFO, Embase, and SPORTDiscus. Demographic and clinical data, data on physical activity and depression assessments, and odds ratios, relative risks, and hazard ratios with 95% confidence intervals were extracted. Random-effects meta-analyses were conducted, and the potential sources of heterogeneity were explored. Methodological quality was assessed using the Newcastle-Ottawa Scale.
Results:
A total of 49 unique prospective studies (N=266,939; median proportion of males across studies, 47%) were followed up for 1,837,794 person-years. Compared with people with low levels of physical activity, those with high levels had lower odds of developing depression (adjusted odds ratio=0.83, 95% CI=0.79, 0.88; I2=0.00). Furthermore, physical activity had a protective effect against the emergence of depression in youths (adjusted odds ratio=0.90, 95% CI=0.83, 0.98), in adults (adjusted odds ratio=0.78, 95% CI=0.70, 0.87), and in elderly persons (adjusted odds ratio=0.79, 95% CI=0.72, 0.86). Protective effects against depression were found across geographical regions, with adjusted odds ratios ranging from 0.65 to 0.84 in Asia, Europe, North America, and Oceania, and against increased incidence of positive screen for depressive symptoms (adjusted odds ratio=0.84, 95% CI=0.79, 0.89) or major depression diagnosis (adjusted odds ratio=0.86, 95% CI=0.75, 0.98). No moderators were identified. Results were consistent for unadjusted odds ratios and for adjusted and unadjusted relative risks/hazard ratios. Overall study quality was moderate to high (Newcastle-Ottawa Scale score, 6.3). Although significant publication bias was found, adjusting for this did not change the magnitude of the associations.
Conclusions:
Available evidence supports the notion that physical activity can confer protection against the emergence of depression regardless of age and geographical region.
Pacientes con cardiopatías congénitas graves muestran retraso psicomotor con mayor frecuencia
Psychomotor development in patients with severe congenital heart disease.
Abstract
AIM:
Retrospective analysis of the neurodevelopment in the first two years of life in patients with severe congenital heart disease.
PATIENTS AND METHODS:
Out of 89 patients with severe congenital heart disease 19 were excluded due to a history of prematurity and/or chromosomopathy, four due to a history of ischemic stroke and two due to lack of medical history. Denver Test (DT) results at 2, 6, 12, 15 and 18 months, and results in motor, language and social interaction fields were achieved.
RESULTS:
59.4% were male and 40.6% female. The mean age of patients undergoing extracorporeal membrane oxygenation with pathological DT at 18 months was 3 months, compared to 11.88 months in those with normal DT. DT at 2 months was normal in 98.4% of patients, 87.5% at 6 and 12 months, 81.3% at 15 months and 85% at 18 months. Two patients with abnormal neurodevelopment normalized the DT before 24 months. The field of neurodevelopment most affected was language (15.6%), followed by motor (10.9%) and social interaction (8%).
CONCLUSIONS:
Psychomotor development delay, especially in the area of language, is more frequent in patients with severe congenital heart disease. The presence of cyanosis and the need for extracorporeal membrane oxygenation were the variables that are most associated with this type of pathology.
Efectos de la restricción calórica sobre el envejecimiento y la memoria
Caloric restriction and memory during aging.
NTRODUCTION:
To understand the underlying brain mechanisms involved in the aging process and mental deterioration could be key to the development of behavioral patterns that guarantee reaching advanced ages with the highest possible quality of life and reduce the cognitive loss associated with senescence.
AIM:
To describe and analyze different animal and human studies that demonstrate that a caloric restriction diet may rescue cerebral aging and the cognitive decline associated to aging.
DEVELOPMENT:
For more than 100 years it has been known that caloric restriction extends life span in many laboratory animal. This effect seems to derive from the reduction of age-related symptoms, such as obesity, the onset of cancerous tumors and some metabolic diseases. However, while the consequences of caloric restriction on health are well-established, their ability to reverse age-dependent memory deficits remains a controversial issue. The analyses of the effects of caloric restriction on different animals provides progress for the understanding of its beneficial effects on the neurobiology of cognitive processes during aging.
CONCLUSIONS:
Caloric restriction attenuates the normal or pathological aging of the brain and reduces age-related memory problems. Dietary intervention could become a very effective method to promote a better quality of life and prevent the age-related cognitive deficits.
Un nuevo estudio respalda la conexión entre virus del herpes y enfermedad de Alzheimer
Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus
Summary
Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer’s disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD.
Figure 1
Multiomic Evaluation of Alzheimer’s Disease-Associated Virome
(A) This study was performed in two phases, an initial exploration into the earliest network changes associated with preclinical AD, which identified multiple shifts in network biology consistent with viral perturbations and prompted a systematic, multiomic evaluation of viral biology on larger datasets focused on clinical AD.
(B–E) Regulatory networks built across EC and HIP samples showed differences in gene drivers for preclinical AD versus control networks (B) including many AD associated genes (C), although drivers exclusive to each network shared functional characteristics, such as association with viral biology (D), and promoter enrichments for the same C2H2 zinc finger transcription factors binding motifs (E).
(F and G) G-quadruplex sequence motifs were strongly enriched in the promoters of the drivers “lost in preclinical AD,” and those “gained in preclinical AD” (F); however, drivers “lost in preclinical AD” had much higher G-Quadruplex density in introns, exons, and 3′-UTR (G).
(H) Genes with high G-Quadruplex density in these locations were uniformly downregulated in the EC of preclinical AD and AD samples, suggesting some significant alteration of G-Quadruplex regulation.
(I–L) To investigate the possibility of an AD-associated virome, we incorporated clinical, neuropathological, RNA, DNA, and proteomic data from individuals with clinical AD (and controls) (I) across four brain regions to identify and characterize viral activity associated with AD biology (J and K), highlighting Roseoloviruses HHV-6A and HHV7 (L).
Region abbreviations: EC, entorhinal cortex; HIP, hippocampus; MTG, medial temporal gyrus; PC, posterior cingulate cortex; SFG, superior frontal gyrus; VCX, visual cortex.
sábado, 14 de julio de 2018
Alteraciones de conducta en los trastornos del espectro autista
Conduct disorders in autism spectrum disorders
Abstract
Autism spectrum disorders (ASD) are neurodevelopmental disorders that affect social communication and present stereotypic behaviours. Comorbidity associated to conduct disorders is frequent, starts in infancy and, in general, continues into adulthood. It is sometimes associated with aggressiveness, negativism, self-harm and breaking social norms. It causes a high degree of dysfunctionality in persons with ASD, their family, professionals and those around them, and is the main cause of pharmacological treatment, hospitalisation and special education. Factors related to the symptoms of ASD, comorbidity and social factors are associated with an increased risk of conduct disorders. In many cases it would be necessary to perform a detailed examination that includes a functional analysis and a combination of psychoeducational, social and pharmacological interventions.To review the precipitating factors, causes, evaluation and treatment of the conduct disorders associated with ASD.The study outlines what is understood by conduct disorders in ASD, the different clinical and cognitive mechanisms associated with it, and the most effective strategies for intervention.Comorbid ASD with conduct disorders is frequent, begins in early infancy and continues throughout life. A detailed evaluation that includes a functional analysis of the behaviour to be eliminated and treatment with different psychological, social educational and pharmacological strategies are essential.
Asocian el tabaquismo y la diabetes con calcificaciones en el hipocampo
Hippocampal Calcifications: Risk Factors and Association with Cognitive Function
Abstract
Purpose
To identify risk factors for hippocampal calcifications and to investigate the association between hippocampal calcifications and cognitive function.
Materials and Methods
For this retrospective study, consecutive patients visiting a memory clinic at a Dutch general hospital between April 2009 and April 2015 were identified. All individuals underwent a standard diagnostic work-up including cognitive tests and brain CT. The following vascular risk factors were assessed: hypertension, diabetes mellitus, hyperlipidemia, and smoking. Cognitive screening consisted of the Cambridge Cognitive Examination, which includes the Mini-Mental State Examination. CT scans were analyzed for the presence and severity (absent, mild, moderate, severe) of hippocampal calcifications. One measure per patient, only the most severe score, was used. Logistic regression was used to identify risk factors for hippocampal calcifications, and linear regression was used for the association between hippocampal calcifications (patient level) and cognitive function.
Results
A total of 1991 patients (mean age, 78 years; range, 45–96 years) were included. The mean age of women was 79 years (range, 47–96 years), and the mean age of men was 77 years (range, 45–95 years). Of the 1991 patients, 380 (19.1%) had hippocampal calcifications. Older age (odds ratio [OR] per year, 1.05; 95% confidence interval [CI]: 1.03, 1.06), diabetes mellitus (OR, 1.50; 95% CI: 1.12, 2.00), and smoking (OR, 1.49; 95% CI: 1.05, 2.10) were associated with the presence of hippocampal calcifications. No associations were found between presence and severity of hippocampal calcifications and cognitive function.
Conclusion
Older age, diabetes mellitus, and smoking were associated with an increased risk of hippocampal calcifications. A greater degree of hippocampal calcifications was not associated with lower cognitive function in patients with memory complaints.
El núcleo accumbens reforzaría las redes cerebrales de la memoria
Finding influential nodes for integration in brain networks using optimal percolation theory
Abstract
Global integration of information in the brain results from complex interactions of segregated brain networks. Identifying the most influential neuronal populations that efficiently bind these networks is a fundamental problem of systems neuroscience. Here, we apply optimal percolation theory and pharmacogenetic interventions in vivo to predict and subsequently target nodes that are essential for global integration of a memory network in rodents. The theory predicts that integration in the memory network is mediated by a set of low-degree nodes located in the nucleus accumbens. This result is confirmed with pharmacogenetic inactivation of the nucleus accumbens, which eliminates the formation of the memory network, while inactivations of other brain areas leave the network intact. Thus, optimal percolation theory predicts essential nodes in brain networks. This could be used to identify targets of interventions to modulate brain function.
La terapia asistida con caballos mejora la calidad de vida de personas con esclerosis múltiple
Effects of hippotherapy in multiple sclerosis: pilot study on quality of life, spasticity, gait, pelvic floor, depression and fatigue.
NTRODUCTION AND OBJECTIVE:
Hippotherapy is being used as a promising method in the physical treatment of multiple sclerosis (MS).
MATERIAL AND METHOD:
Comparative open clinical pre-post study into hippotherapy intervention during a 6-month period in patients with MS (n=6). Not randomised and with control group (n=4). The study was performed by MHG Foundation.
RESULTS:
A statistically significant improvement was observed in the therapy group in: spasticity pre-post measured by the modified Ashworth scale (P=.01). Statistically significant improvement in fatigue impact (P<.0001) measured with FIS; in general, perception of heath outcome in urinary quality of life scale KHQ (P=.033), and in subscales 2, 3 and 4 of MSQOL-54 (P=.011). Control group showed no improvement in any scale.
CONCLUSIONS:
This study reinforces current literature that supports hippotherapy as an adequate intervention for MS patients. Further studies with more participants, control groups and blinded research would be logical steps for future research in this field.
KEYWORDS:
Calidad de vida; Esclerosis múltiple; Espasticidad; Fatiga; Fatigue; Hipoterapia; Hippotherapy; Multiple sclerosis; Pelvic floor; Quality of life; Spasticity; Suelo pélvico
Nueva concepción del continuo TEA-TDAH con una base neuroevolutiva común
Concordances between autism spectrum disorders and attention deficit hyperactivity disorder
Abstract
The current literature acknowledges an overlap of genetic, clinical and neuropsychological aspects between autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), suggesting that there may be a common pattern that covers features ranging from the common genetic and structural aetiology to shared patterns of symptoms. To review the current advances in these common aspects. Several studies have pointed out preschool attentional difficulties as the basis of both disorders. From the genetic perspective, it is estimated that 50-72% of the genetic factors overlap between the two disorders. They also share a decrease in the volume of the corpus callosum and left frontal grey matter, as well as functional alterations such as dorsolateral prefrontal, striato-thalamic and superior parietal hypoactivation. Results are also found regarding executive functioning, with differential profiles for the two conditions, and also concerning the relationship between the repetitive and impulsive behaviours in the early stages of ASD and ensuing problems of hyperactivity. This new conception of the ASD-ADHD continuum, with a common neurodevelopmental basis and associated clinical features, could be of great use in clinical practice. It is suggested that this association should be taken into account when it comes to deciding on the treatment.
Un sistema robótico facilita el diagnóstico de trastornos neurodegenerativos a través del movimiento ocular
OSCANN: Technical Characterization of a Novel Gaze Tracking Analyzer
Abstract
Eye-movement analysis has grown exponentially in recent decades. The reason is that abnormalities in oculomotor movements are usually symptoms of injuries in the nervous system. This paper presents a novel regulated solution named OSCANN. OSCANN aims at providing an innovative tool for the control, management and visualization of oculomotor neurological examinations. This solution utilizes an eye-tracker sensor based on video electro-oculography (VOG) technology to capture eye movements and store them in video files. Such a sensor can store images at a rate of 100 frames per second. A characterization study was performed using twenty-two volunteers (13 male, 9 female, ages 22–45 years, mean 29.3 years, SD = 6.7) to assess the accuracy and precision specifications of OSCANN during oculomotor movement analysis. The accuracy was evaluated based on the offset, whereas precision was estimated with Root Means Square (RMS). Such a study reported values lower than 0.4 and 0.03 of accuracy and precision, respectively. These results suggest that OSCANN can be considered as a powerful tool to measure oculomotor movement alterations involved in some neurological disease progression.
domingo, 8 de julio de 2018
Factores de riesgo en la aparición de conductas violentas en adultos
Violent aggression predicted by multiple pre-adult environmental hits
Abstract
Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Follow-up of matched extreme group individuals (≤1 vs. ≥3 risks) unexpectedly revealed that high-risk subjects had >5 times greater probability of forensic hospitalization. In line with longstanding sociological theories, we hypothesized that risk accumulation before adulthood induces violent aggression and criminal conduct, independent of mental illness. We determined in 6 independent cohorts (4 schizophrenia and 2 general population samples) pre-adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. All single hits by themselves were marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted violent aggression (odds ratio 10.5). An epigenome-wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely, determination in peripheral blood mononuclear cells of histone-deacetylase1 mRNA as ‘umbrella mediator’ of epigenetic processes revealed an increase in the high-risk group, suggesting lasting epigenetic alterations. Together, we provide sound evidence of a disease-independent unfortunate relationship between well-defined pre-adult environmental hits and violent aggression, calling for more efficient prevention.
Cognición social y funciones cognitivas en pacientes con epilepsia tratados con eslicarbacepina
Social cognition and cognitive functions in patients with epilepsy treated with eslicarbazepine acetatehttps://europepmc.org/abstract/med/29790568
INTRODUCTION:
Epilepsy is accompanied by cognitive disorders, frequently aggravated by the use of antiepileptic drugs, which can affect social empathy.
AIM:
To analyse the impact of treatment with eslicarbazepine acetate (ESL) on social cognition and prefrontal cognitive functions in adults with focal epilepsy.
PATIENTS AND METHODS:
We conducted a prospective single-centre study with patients aged between 18 and 65 years with focal seizures treated with ESL. The patients were evaluated in their baseline visit and at six months after starting ESL treatment by means of tasks designed for theory of mind, executive and attentional functions, auditory-verbal memory, quality of life, and anxiety and depression.
RESULTS:
Forty-one patients were treated with ESL, and 30 completed the follow-up. A significant improvement was observed in the theory of mind tasks. In the analysis stratified by sex, the men showed greater improvement. A cognitive improvement was observed in the Wisconsin Card Sorting Test, Symbol Digit, Backward Digit Span and Stroop tests. No differences were found in the Quality of Life in Epilepsy-31 Inventory or in the Hospital Anxiety and Depression Scale. These results were independent of the reduction in the number of seizures and the ESL dosage.
CONCLUSION:
Treatment with ESL could improve some aspects of theory of mind in patients with epilepsy, especially in men and independently of the control of seizures, with no changes in quality of life, anxiety or depression.
Un biomaterial promueve la regeneración del tejido destruido por un derrame cerebral
Dual-function injectable angiogenic biomaterial for the repair of brain tissue following stroke
Abstract
Stroke is the primary cause of disability due to the brain's limited ability to regenerate damaged tissue. After stroke, an increased inflammatory and immune response coupled with severely limited angiogenesis and neuronal growth results in a stroke cavity devoid of normal brain tissue. In the adult, therapeutic angiogenic materials have been used to repair ischaemic tissues through the formation of vascular networks. However, whether a therapeutic angiogenic material can regenerate brain tissue and promote neural repair is poorly understood. Here we show that the delivery of an engineered immune-modulating angiogenic biomaterial directly to the stroke cavity promotes tissue formation de novo, and results in axonal networks along thee generated blood vessels. This regenerated tissue produces functional recovery through the established axonal networks. Thus, this biomaterials approach generates a vascularized network of regenerated functional neuronal connections within previously dead tissue and lays the groundwork for the use of angiogenic materials to repair other neurologically diseased tissues.
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