El cerebelo en el Autismo

Autism is considered as a neurodevelopmental disorder which affects boys more than girls, in a proportion 4:1 respectively. Autism presents neuroanatomical abnormalities located in the frontal cortex, the amygdala and the cerebellum. Autistic cerebellar postmortem studies have revealed a reduced number of Purkinje cells as well as a reduced Purkinje cell size when compared with non-autistic subjects. These anatomical alterations compromise the role of the cerebellum in cognitive, motor, emotional, learning and memory neural processes resulting in a different interpretation of the world, and therefore a different way to respond and behave. There are both biological and environmental insults causing the behavioral and neuroanatomical autistic phenotype. Valproic acid, an antiepileptic drug, has been related to some autistic cases after mothers were under medication with this drug during the first trimester of gestation and given birth autistic children. Therefore, in this brief review we analyzed the most recent advances of autism research in humans, with a primary focus on the use of valproic acid as a teratogen that mimics in rats some of the neuroanatomical alterations seen in autistic humans. In addition to the peculiar cerebellar pathology, all of this to shed light on a better understating of this disorder.El autismo es un trastorno generalizado del desarrollo que afecta más a varones que mujeres, con una proporción de 4 a 1, respectivamente. Dentro de sus características neuropatológicas más sobresalientes se encuentran la alteración anatómica de diversas estructuras del sistema nervioso central como la corteza frontal, la amígdala y el cerebelo. Estudios post mórtem en cerebelos de sujetos autistas han mostrado una notable disminución en el número de neuronas de Purkinje así como en su tamaño, comparado con las de sujetos sanos. Estas alteraciones anatómicas comprometen la participación del cerebelo en los procesos neurales como la cognición, actividad motora, la emoción, el aprendizaje y la memoria, dando como resultado una interpretación diferente del mundo que impacta sobre la respuesta y el comportamiento de los sujetos autistas. Actualmente se desconoce la causa de estas alteraciones anatómicas y aunque se avanza rápido en la ciencia se tiene la limitante de los sujetos experimentales, que en este caso son humanos. Por lo tanto, en esta revisión analizamos los hallazgos más relevantes de la patología cerebelar en el autismo, así como el uso del ácido valproico en ratas como teratógeno para simular alteraciones cerebelares como las observadas en autistas, contribuyendo a un mejor entendimiento de su neuropatología

Prenatal exposure to sodium valproate alters androgen receptor expression in the developing cerebellum in a region and age specific manner in male and female rats

Valproic acid (VPA) is an anti-epileptic drug with teratogenicity activity that has been related to autism. In rodents, exposure to VPA in utero leads to brain abnormalities similar than those reported in the autistic brain. Particularly, VPA reduces the number of Purkinje neurons in the rat cerebellum parallel to cerebellar abnormalities found in autism. Thus, we injected pregnant females on embryonic day 12 either with VPA (600 mg/kg, i.p.) or 0.9% saline solution and obtained the cerebellum from their offspring at different postnatal time points. Testosterone has been linked to autism and plays an important role during brain development. Therefore, we identified and analyzed the androgen receptor (AR) by immunohistochemistry and densitometry, respectively. We found VPA decreases AR density in the superficial Purkinje layer only in cerebellar lobule 8 at PN7, but increased it at PN14 compared to control in males. In females, VPA decreased AR density in the superficial Purkinje layer in cerebellar lobule 6 at PN14, but increased it in lobule 9 at the same time point. No differences were found in the deep Purkinje layer of any cerebellar lobule in terms of AR density neither in males nor females. We additionally found a particular AR density decreasing in both superficial and deep regions across development in the majority of cerebellar lobules in males, but in all cerebellar lobules in females. Thus, our results indicate that VPA disrupts the AR ontogeny in the developing cerebellum in an age and region specific manner in male and female rats. Future epigenetic studies including the evaluation of histone deacetylases (HDAC’s) might shed light these results as HDAC’s are expressed by Purkinje neurons, interact with the AR and are VPA targets. This work contributes to the understanding of the cerebellar development and it might help to understand the role of the cerebellum in neurodevelopmental disorders such as autism.This research was supported by CONACYT (Consejo Nacional de Ciencia y Tecnologia of Mexico Grant 106531 to Maria Elena Hernandez (MEH) and CONACYT Doctorate scholarship 205779 to Miguel Perez Pouchoulen (MPP). Authors thank M.S. Dulce Mariely Alvarez-Croda for her valuable comments to the manuscript

Increase of angiotensin II type 1 receptor auto-antibodies in Huntington’s disease

Background In the recent years, a role of the immune system in Huntington’s disease (HD) is increasingly recognized. Here we investigate the presence of T cell activating auto-antibodies against angiotensin II type 1 receptors (AT1R) in all stages of the disease as compared to healthy controls and patients suffering from multiple sclerosis (MS) as a prototype neurologic autoimmune disease. Results As compared to controls, MS patients show higher titers of anti-AT1R antibodies, especially in individuals with active disease. In HD, anti-AT1R antibodies are more frequent than in healthy controls or even MS and occur in 37.9% of patients with relevant titers ≥ 20 U/ml. In a correlation analysis with clinical parameters, the presence of AT1R antibodies in the sera of HD individuals inversely correlated with the age of onset and positively with the disease burden score as well as with smoking and infection. Conclusions These data suggest a dysfunction of the adaptive immune system in HD which may be triggered by different stimuli including autoimmune responses, infection and possibly also smoking

Bupropion for the treatment of apathy in Huntington's disease:A multicenter, randomised, double-blind, placebo-controlled, prospective crossover trial

OBJECTIVE:To evaluate the efficacy and safety of bupropion in the treatment of apathy in Huntington's disease (HD). METHODS:In this phase 2b multicentre, double-blind, placebo-controlled crossover trial, individuals with HD and clinical signs of apathy according to the Structured Clinical Interview for Apathy-Dementia (SCIA-D), but not depression (n = 40) were randomized to receive either bupropion 150/300mg or placebo daily for 10 weeks. The primary outcome parameter was a significant change of the Apathy Evaluation Scale (AES) score after ten weeks of treatment as judged by an informant (AES-I) living in close proximity with the study participant. The secondary outcome parameters included changes of 1. AES scores determined by the patient (AES-S) or the clinical investigator (AES-C), 2. psychiatric symptoms (NPI, HADS-SIS, UHDRS-Behavior), 3. cognitive performance (SDMT, Stroop, VFT, MMSE), 4. motor symptoms (UHDRS-Motor), 5. activities of daily function (TFC, UHDRS-Function), and 6. caregiver distress (NPI-D). In addition, we investigated the effect of bupropion on brain structure as well as brain responses and functional connectivity during reward processing in a gambling task using magnetic resonance imaging (MRI). RESULTS:At baseline, there were no significant treatment group differences in the clinical primary and secondary outcome parameters. At endpoint, there was no statistically significant difference between treatment groups for all clinical primary and secondary outcome variables. Study participation, irrespective of the intervention, lessened symptoms of apathy according to the informant and the clinical investigator. CONCLUSION:Bupropion does not alleviate apathy in HD. However, study participation/placebo effects were observed, which document the need for carefully controlled trials when investigating therapeutic interventions for the neuropsychiatric symptoms of HD. TRIAL REGISTRATION:ClinicalTrials.gov 01914965

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

Tall and short enrollees posing side-by-side. SCS-01, C-1503

Tall and short enrollees posing side-by-side. SCS-01, C-1503. From the Paul Saft photographic album, SCS-1, C-1503, 1938-39, depicting camp life, taken mostly in the Moscow, Lewiston, Robinson Lake areas.SCS-1C-150

Two men in western hats posing as a hold-up, SCS-1, C-1503.

Two men in western hats posing as a hold-up, SCS-1, C-1503. From the Paul Saft photographic album, SCS-1, C-1503, 1938-39, depicting camp life, taken mostly in the Moscow, Lewiston, Robinson Lake areas.SCS-1C-150

Four men with truck hauling a large loaded flatbed. SCS-1, C-1503

Four men with truck hauling a large loaded flatbed. SCS-1, C-1503. From the Paul Saft photographic album, SCS-1, C-1503, 1938-39, depicting camp life, taken mostly in the Moscow, Lewiston, Robinson Lake areas.SCS-1C-150

Batter and catcher at the plate. Captioned 'Lewiston 'Tour'.' Lewiston, Idaho. SCS-1, C-1503.

Batter and catcher at the plate. Captioned 'Lewiston 'Tour'.' Lewiston, Idaho. SCS-1, C-1503. From the Paul Saft photographic album, SCS-1, C-1503, 1938-39, depicting camp life, taken mostly in the Moscow, Lewiston, Robinson Lake areas.SCS-1C-150

Shallow lake, captioned: 'Good duck hunting.' SCS-1, C-1503.

Shallow lake, captioned 'Good duck hunting.' SCS-1, C-1503. From the Paul Saft photographic album, SCS-1, C-1503, 1938-39, depicting camp life, taken mostly in the Moscow, Lewiston, Robinson Lake areas.SCS-1C-150