Neuroanatomical spread of amyloid β and tau in Alzheimer's disease: implications for primary prevention.

With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer's disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid β and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid β uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer's disease dementia patients) with available amyloid β and tau PET data. Amyloid β PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid β PET composite showed a 120% increase in the accumulation rate of amyloid β compared to the global composite (P < 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid β and tau pathology. To detect early changes in amyloid β pathology, focusing on the earliest sites of amyloid β accumulation results in more powerful and efficient study designs in early Alzheimer's disease. Targeted composites could be used to re-examine the thresholds for amyloid β-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid β treatments may benefit from the use of focal composites when estimating drug effects on amyloid β and tau changes in populations with minimal amyloid β and tau pathology and limited expected short-term accumulation

Neuroscience Networks: Data-sharing in an Information Age

To study the brain from molecules to behaviour, neuroscientists face the challenge of communicating an emerging wealth of information in coherent accessible form

The alimentary impact of the hemp seed

Hemp seed and hemp seed oil can supply us with many important substances. Their essential fatty acid compositions are favourable, but they may contain non-psychotropic cannabinoids. Emerging data show that these components can influence the health status of the population beneficially. Some data also showed trace amounts of tetrahydrocannabinol in seed oils, the main psychotropic cannabinoid that is contraindicated.Our aim was to examine cannabinoids and fatty acid composition as well as metal and non-metal element compositions in products, like hemp seed oil and chopped hemp seed capsule.The cannabinoids were separated by thin layer chromatography. Fatty acid composition was determined with gas chromatography, and elements (Al, B, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Mo, Na, Ni, P, Pb, S, Si, Sn, Sr, V, and Zn) were measured by inductively coupled plasma optical emission spectrometric method. Selenium was determined with polarographic analyser.Cannabinoids were not detectable by thin layer chromatography, so hemp seed oil, as well as the capsule, have no psychotropic adverse effect. Our data showed that hemp seed contains essential fatty acids close to the recommended ratio. The B and Se concentrations of the oils and the P concentration of the capsule are also relevant

Group interventions to improve health outcomes : a framework for their design and delivery

Peer reviewedPublisher PD

Cis and Trans Effects of Human Genomic Variants on Gene Expression

This work was funded by the Louis-Jeantet Foundation (http://www.jeantet.ch/), the European Research Council (Grant ID: 260927 http://erc.europa.eu/), the Swiss National Foundation (Grant ID: 130342 http://www.snf.ch), NCCR Frontiers In Genetics (http://www.frontiers-in-genetics.org), the UK Medical Research Council (http://www.mrc.ac.uk) and the Wellcome Trust (Grant ID: 092731).

Alterations of prolyl endopeptidase activity in the plasma of children with autistic spectrum disorders

BACKGROUND: Prolyl Endopeptidase (PEP, EC 3.4.21.26), a cytosolic endopeptidase, hydrolyses peptide bonds on the carboxyl side of proline residue in proteins with a relatively small molecular weight. It has been shown that altered PEP activity is associated with various psychological diseases such as schizophrenia, mania and depression. Autistic Spectrum Disorders (ASD) are neuropsychiatric and behavioural syndromes affecting social behaviours and communication development. They are classified as developmental disorders. The aim of this study was to examine the hypothesis that PEP activity is also associated with ASDs. METHODS: Fluorometric assay was used to measure PEP activity in EDTA plasma in children with ASD (n = 18) aged 4–12 years (mean ± SD: 7.9 ± 2.5). These results were then compared to PEP activity in a control group of non-ASD children (n = 15) aged 2–10 years (mean ± SD: 6.4 ± 2.2). RESULTS: An alteration in PEP activity was found in the children with ASD compared to the control group. There was much greater variation of PEP activity in the group of ASD children when compared to the controls (SD= 39.9 and SD 9.6, respectively). This variation was significant (p < 0.0005), although the mean level of PEP activity in the group of ASD children was slightly higher than in the control group (124.4 and 134.1, respectively). CONCLUSION: Our preliminary finding suggests a role for PEP enzyme in the pathophysiology of autism but further research should be conducted to establish its role in the aetiology of psychiatric and neurological disorders, including autism and related spectrum disorders

Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders

Personality is influenced by genetic and environmental factors1 and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci2,3, significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132–260,861). Of these genomewide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422–18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit– hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion–introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety)

Genomic and epigenetic evidence for oxytocin receptor deficiency in autism

<p>Abstract</p> <p>Background</p> <p>Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders.</p> <p>Methods</p> <p>We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR).</p> <p>Results</p> <p>Our analysis revealed a genomic deletion containing the oxytocin receptor gene, <it>OXTR </it>(MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate <it>OXTR </it>expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that <it>OXTR </it>mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls.</p> <p>Conclusion</p> <p>Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of <it>OXTR </it>in the development of the disorder.</p> <p>See the related commentary by Gurrieri and Neri: <url>http://www.biomedcentral.com/1741-7015/7/63</url></p