Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins

Autism is a neurological disorder of childhood with poorly understood etiology and pathology. We compared lipid peroxidation status in the plasma of children with autism, and their developmentally normal non-autistic siblings by quantifying the levels of malonyldialdehyde, an end product of fatty acid oxidation. Lipid peroxidation was found to be elevated in autism indicating that oxidative stress is increased in this disease. Levels of major antioxidant proteins namely, transferrin (iron-binding protein) and ceruloplasmin (copper-binding protein) in the serum, were significantly reduced in autistic children as compared to their developmentally normal non-autistic siblings. A striking correlation was observed between reduced levels of these proteins and loss of previously acquired language skills in children with autism. These results indicate altered regulation of transferrin and ceruloplasmin in autistic children who lose acquired language skills. It is suggested that such changes may lead to abnormal iron and copper metabolism in autism, and that increased oxidative stress may have pathological role in autism.     

Autism-Specific Covariation in Perceptual Performances: “g” or “p” Factor?

Background

Autistic perception is characterized by atypical and sometimes exceptional performance in several low- (e.g., discrimination) and mid-level (e.g., pattern matching) tasks in both visual and auditory domains. A factor that specifically affects perceptive abilities in autistic individuals should manifest as an autism-specific association between perceptual tasks. The first purpose of this study was to explore how perceptual performances are associated within or across processing levels and/or modalities. The second purpose was to determine if general intelligence, the major factor that accounts for covariation in task performances in non-autistic individuals, equally controls perceptual abilities in autistic individuals.

Methods

We asked 46 autistic individuals and 46 typically developing controls to perform four tasks measuring low- or mid-level visual or auditory processing. Intelligence was measured with the Wechsler''s Intelligence Scale (FSIQ) and Raven Progressive Matrices (RPM). We conducted linear regression models to compare task performances between groups and patterns of covariation between tasks. The addition of either Wechsler''s FSIQ or RPM in the regression models controlled for the effects of intelligence.

Results

In typically developing individuals, most perceptual tasks were associated with intelligence measured either by RPM or Wechsler FSIQ. The residual covariation between unimodal tasks, i.e. covariation not explained by intelligence, could be explained by a modality-specific factor. In the autistic group, residual covariation revealed the presence of a plurimodal factor specific to autism.

Conclusions

Autistic individuals show exceptional performance in some perceptual tasks. Here, we demonstrate the existence of specific, plurimodal covariation that does not dependent on general intelligence (or “g” factor). Instead, this residual covariation is accounted for by a common perceptual process (or “p” factor), which may drive perceptual abilities differently in autistic and non-autistic individuals.     

Precocious realists: perceptual and cognitive characteristics associated with drawing talent in non-autistic children

A local processing bias in the block design task and in drawing strategy has been used to account for realistic drawing skill in individuals with autism. We investigated whether the same kind of local processing bias is seen in typically developing children with unusual skill in realistic graphic representation. Forty-three 5–11-year-olds who drew a still life completed a version of the block design task in both standard and segmented form, were tested for their memory for the block design items, and were given the Kaufmann Brief Intelligence Test-II. Children were classified as gifted, moderately gifted or typical on the basis of the level of realism in their drawings. Similar to autistic individuals, the gifted group showed a local processing bias in the block design task. But unlike autistic individuals, the gifted group showed a global advantage in the visual memory task and did not use a local drawing strategy; in addition, their graphic realism skill was related to verbal IQ. Differences in the extent of local processing bias in autistic and typically developing children with drawing talent are discussed.     

Accommodating Autistics and Treating Autism: Can We Have Both?

One of the central claims of the neurodiversity movement is that society should accommodate the needs of autistics, rather than try to treat autism. People have variously tried to reject this accommodation thesis as applicable to all autistics. One instance is Pier Jaarsma and Stellan Welin, who argue that the thesis should apply to some but not all autistics. They do so via separating autistics into high‐ and low‐functioning, on the basis of IQ and social effectiveness or functionings. I reject their grounds for separating autistics. IQ is an irrelevant basis for separating autistics. Charitably rendering it as referring to more general capacities still leaves us mistaken about the roles they play in supporting the accommodation thesis. The appeal to social effectiveness or functionings relies on standards that are inapplicable to autistics, and which risks being deaf to the point of their claims. I then consider if their remaining argument concerning autistic culture may succeed independently of the line they draw. I argue that construing autistics' claims as beginning from culture mistakes their status, and may even detract from their aims. Via my discussion of Jaarsma and Welin, I hope to point to why the more general strategy of separating autistics, in response to the accommodation thesis, does not fully succeed. Finally, I sketch some directions for future discussions, arguing that we should instead shift our attention to consider another set of questions concerning the costs and extent of change required to accommodate all autistics.     

Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder

1. Autism is a severe neurodevelopmental disorder with potential genetic and environmental etiologies. Recent genetic linkage reports and biochemical analysis of postmortem autistic cerebellum point to Reelin, an important secretory extracellular protein, as being involved in the pathology of autism.2. We hypothesized that blood levels of Reelin and its isoforms would be altered in autistic twins, and their first degree relatives versus normal controls.3. We measured blood levels of unprocessed Reelin (410 kDa) and its proteolytic cleavage products (Reelins 330 and 180 kDa) as well as albumin and ceruloplasmin in 28 autistic individuals, their parents (13 fathers, 13 mothers), 6 normal siblings, and 8 normal controls using SDS-PAGE and western blotting.4. Results indicated significant reductions in 410 kDa Reelin species in autistic twins (–70%, p < 0.01), their fathers (–62%, p < 0.01), their mothers (–72%, p < 0.01), and their phenotypically normal siblings (–70%, p < 0.01) versus controls. Reelin 330 kDa values did not vary significantly from controls. Reelin 180 kDa values for parents (fathers –32% p < 0.05 vs. controls, mothers –34%) declined when compared to controls. In contrast autistic Reelin 180 kDa increased, albeit nonsignificantly versus controls. Albumin and ceruloplasmin values for autistics and their first degree relatives did not vary significantly from controls. There were no significant meaningful correlations between Reelin, albumin and ceruloplasmin levels, age, sex, ADI scores, or age of onset.5. These results suggest that Reelin 410 deficiency may be a vulnerability factor in the pathology of autism.     

Abstract Spatial Reasoning as an Autistic Strength

Autistic individuals typically excel on spatial tests that measure abstract reasoning, such as the Block Design subtest on intelligence test batteries and the Raven’s Progressive Matrices nonverbal test of intelligence. Such well-replicated findings suggest that abstract spatial processing is a relative and perhaps absolute strength of autistic individuals. However, previous studies have not systematically varied reasoning level – concrete vs. abstract – and test domain – spatial vs. numerical vs. verbal, which the current study did. Autistic participants (N = 72) and non-autistic participants (N = 72) completed a battery of 12 tests that varied by reasoning level (concrete vs. abstract) and domain (spatial vs. numerical vs. verbal). Autistic participants outperformed non-autistic participants on abstract spatial tests. Non-autistic participants did not outperform autistic participants on any of the three domains (spatial, numerical, and verbal) or at either of the two reasoning levels (concrete and abstract), suggesting similarity in abilities between autistic and non-autistic individuals, with abstract spatial reasoning as an autistic strength.     

Fatty acid compositions of red blood cell phospholipids in children with autism

We compared the compositions of fatty acids including n-3, n-6 polyunsaturated fatty acids, trans- and cis-monounsaturated fatty acids, and saturated fatty acids in the red blood cell membranes of 40 children with autism (20 with early onset autism and 20 with developmental regression) and age-matched, 20 typically developing controls and 20 subjects with non-autistic developmental disabilities. The main findings include increased levels of eicosenoic acid (20:1n9) and erucic acid (22:1n9) in autistic subjects with developmental regression when compared with typically developing controls. In addition, an increase in 20:2n6 and a decrease in 16:1n7t were observed in children with clinical regression compared to those with early onset autism. Our results do not provide strong evidence for the hypothesis that abnormal fatty acid metabolism plays a role in the pathogenesis of autism spectrum disorder, although they suggest some metabolic or dietary abnormalities in the regressive form of autism.     

Towards an understanding of the mechanisms of weak central coherence effects: experiments in visual configural learning and auditory perception

The weak central coherence hypothesis of Frith is one of the most prominent theories concerning the abnormal performance of individuals with autism on tasks that involve local and global processing. Individuals with autism often outperform matched nonautistic individuals on tasks in which success depends upon processing of local features, and underperform on tasks that require global processing. We review those studies that have been unable to identify the locus of the mechanisms that may be responsible for weak central coherence effects and those that show that local processing is enhanced in autism but not at the expense of global processing. In the light of these studies, we propose that the mechanisms which can give rise to 'weak central coherence' effects may be perceptual. More specifically, we propose that perception operates to enhance the representation of individual perceptual features but that this does not impact adversely on representations that involve integration of features. This proposal was supported in the two experiments we report on configural and feature discrimination learning in high-functioning children with autism. We also examined processes of perception directly, in an auditory filtering task which measured the width of auditory filters in individuals with autism and found that the width of auditory filters in autism were abnormally broad. We consider the implications of these findings for perceptual theories of the mechanisms underpinning weak central coherence effects.     

The Level and Nature of Autistic Intelligence II: What about Asperger Syndrome?

A distinctively uneven profile of intelligence is a feature of the autistic spectrum. Within the spectrum, Asperger individuals differ from autistics in their early speech development and in being less likely to be characterized by visuospatial peaks. While different specific strengths characterize different autistic spectrum subgroups, all such peaks of ability have been interpreted as deficits: isolated, aberrant, and irreconcilable with real human intelligence. This view has recently been challenged by findings of autistic strengths in performance on Raven's Progressive Matrices (RPM), an important marker of general and fluid intelligence. We investigated whether these findings extend to Asperger syndrome, an autistic spectrum subgroup characterized by verbal peaks of ability, and whether the cognitive mechanisms underlying autistic and Asperger RPM performance differ. Thirty-two Asperger adults displayed a significant advantage on RPM over Wechsler Full-Scale and Performance scores relative to their typical controls, while in 25 Asperger children an RPM advantage was found over Wechsler Performance scores only. As previously found with autistics, Asperger children and adults achieved RPM scores at a level reflecting their Wechsler peaks of ability. Therefore, strengths in RPM performance span the autistic spectrum and imply a common mechanism advantageously applied to different facets of cognition. Autistic spectrum intelligence is atypical, but also genuine, general, and underestimated.     

Comparative analysis of neurological disorders focuses genome-wide search for autism genes

The behaviors of autism overlap with a diverse array of other neurological disorders, suggesting common molecular mechanisms. We conducted a large comparative analysis of the network of genes linked to autism with those of 432 other neurological diseases to circumscribe a multi-disorder subcomponent of autism. We leveraged the biological process and interaction properties of these multi-disorder autism genes to overcome the across-the-board multiple hypothesis corrections that a purely data-driven approach requires. Using prior knowledge of biological process, we identified 154 genes not previously linked to autism of which 42% were significantly differentially expressed in autistic individuals. Then, using prior knowledge from interaction networks of disorders related to autism, we uncovered 334 new genes that interact with published autism genes, of which 87% were significantly differentially regulated in autistic individuals. Our analysis provided a novel picture of autism from the perspective of related neurological disorders and suggested a model by which prior knowledge of interaction networks can inform and focus genome-scale studies of complex neurological disorders.     

Arthropod Distribution in a Tropical Rainforest: Tackling a Four Dimensional Puzzle

Quantifying the spatio-temporal distribution of arthropods in tropical rainforests represents a first step towards scrutinizing the global distribution of biodiversity on Earth. To date most studies have focused on narrow taxonomic groups or lack a design that allows partitioning of the components of diversity. Here, we consider an exceptionally large dataset (113,952 individuals representing 5,858 species), obtained from the San Lorenzo forest in Panama, where the phylogenetic breadth of arthropod taxa was surveyed using 14 protocols targeting the soil, litter, understory, lower and upper canopy habitats, replicated across seasons in 2003 and 2004. This dataset is used to explore the relative influence of horizontal, vertical and seasonal drivers of arthropod distribution in this forest. We considered arthropod abundance, observed and estimated species richness, additive decomposition of species richness, multiplicative partitioning of species diversity, variation in species composition, species turnover and guild structure as components of diversity. At the scale of our study (2km of distance, 40m in height and 400 days), the effects related to the vertical and seasonal dimensions were most important. Most adult arthropods were collected from the soil/litter or the upper canopy and species richness was highest in the canopy. We compared the distribution of arthropods and trees within our study system. Effects related to the seasonal dimension were stronger for arthropods than for trees. We conclude that: (1) models of beta diversity developed for tropical trees are unlikely to be applicable to tropical arthropods; (2) it is imperative that estimates of global biodiversity derived from mass collecting of arthropods in tropical rainforests embrace the strong vertical and seasonal partitioning observed here; and (3) given the high species turnover observed between seasons, global climate change may have severe consequences for rainforest arthropods.     

Measurement of cerebral blood flow by transcranial Doppler ultrasonography in children presenting with autistic behavior. Preliminary results

Transcranial Doppler ultrasonographic recordings of the middle cerebral arteries were performed on eight children with autistic behavior compared to eight controls. Blood flow measurements were assessed at rest and during auditory and visual stimulations. The main result was obtained during the auditory stimulations and concerned the left artery blood flow which is lower in autistics than in controls in these conditions (p less than .02). This result confirms the possibility of a left hemisphere dysfunctioning in autistics and may be related to clinical features as language disabilities and paradoxical reactivity to auditory stimuli.     

Alteration in amino-glycerophospholipids levels in the plasma of children with autism: a potential biochemical diagnostic marker

Currently, there is no biochemical test to assist in the behavioral diagnosis of autism. We observed that levels of phosphatidylethanolamine (PE) were decreased while phosphatidylserine (PS) were increased in the erythrocyte membranes of children with autism as compared to their non-autistic developmentally normal siblings. A new method using Trinitrobenezene sulfonic acid (TNBS) for the quantification of PE and PS (amino-glycerophospholipids, i.e., AGP) in the plasma of children was developed and standardized. Wavelength scans of TNBS-PE and TNBS-PS complexes gave two peaks at 320 nm and 410 nm. When varying concentrations of PS and PE were used, a linear regression line was observed at 410 nm with TNBS. Using this assay, the levels of AGP were found to be significantly increased in the plasma of children with autism as compared to their non-autistic normal siblings. It is proposed that plasma AGP levels may function as a potential diagnostic marker for autism.     

Brain region-specific decrease in the activity and expression of protein kinase A in the frontal cortex of regressive autism

Autism is a severe neurodevelopmental disorder that is characterized by impaired language, communication, and social skills. In regressive autism, affected children first show signs of normal social and language development but eventually lose these skills and develop autistic behavior. Protein kinases are essential in G-protein-coupled, receptor-mediated signal transduction and are involved in neuronal functions, gene expression, memory, and cell differentiation. We studied the activity and expression of protein kinase A (PKA), a cyclic AMP-dependent protein kinase, in postmortem brain tissue samples from the frontal, temporal, parietal, and occipital cortices, and the cerebellum of individuals with regressive autism; autistic subjects without a clinical history of regression; and age-matched developmentally normal control subjects. The activity of PKA and the expression of PKA (C-α), a catalytic subunit of PKA, were significantly decreased in the frontal cortex of individuals with regressive autism compared to control subjects and individuals with non-regressive autism. Such changes were not observed in the cerebellum, or the cortices from the temporal, parietal, and occipital regions of the brain in subjects with regressive autism. In addition, there was no significant difference in PKA activity or expression of PKA (C-α) between non-regressive autism and control groups. These results suggest that regression in autism may be associated, in part, with decreased PKA-mediated phosphorylation of proteins and abnormalities in cellular signaling.     

Novel plasma phospholipid biomarkers of autism: Mitochondrial dysfunction as a putative causative mechanism

Autism is a neurological disorder that manifests as noticeable behavioral and developmental abnormalities predominantly in males between the ages of 2 and 10. Although the genetics, biochemistry and neuropathology of this disease have been extensively studied, underlying causal factors to this disease have remained elusive. Using a longitudinal trial design in which three plasma samples were collected from 15 autistic and 12 non-autistic age-matched controls over the course of 1 year, universal and unambiguous alterations in lipid metabolism were observed. Biomarkers of fatty acid elongation and desaturation (poly-unsaturated long chain fatty acids (PUFA) and/or saturated very long chain fatty acids (VLCFA)-containing ethanolamine phospholipids) were statistically elevated in all autistic subjects. In all 8 of the affected/non-affected sibling pairs, the affected sibling had higher levels of these biomarkers than the unaffected sibling. Exposure of neurons, astrocytes and hepatocytes in vitro to elevated extracellular glutamate levels resulted in lipid biomarker changes indistinguishable from those observed in autistic subjects. Glutamate stress also resulted in in vitro decreased levels of reduced glutathione (GSH), methionine and cysteine, in a similar way to the decreases we observed in autism plasma. Impaired mitochondrial fatty acid oxidation, elevated plasma VLCFAs, and glutamate toxicity as putative causal factors in the biochemistry, neuropathology, and gender bias in autism are discussed.     

Forest carbon in lowland Papua New Guinea: Local variation and the importance of small trees

Efforts to incentivize the reduction of carbon emissions from deforestation and forest degradation require accurate carbon accounting. The extensive tropical forest of Papua New Guinea (PNG) is a target for such efforts and yet local carbon estimates are few. Previous estimates, based on models of neotropical vegetation applied to PNG forest plots, did not consider such factors as the unique species composition of New Guinea vegetation, local variation in forest biomass, or the contribution of small trees. We analysed all trees >1 cm in diameter at breast height (DBH) in Melanesia's largest forest plot (Wanang) to assess local spatial variation and the role of small trees in carbon storage. Above‐ground living biomass (AGLB) of trees averaged 210.72 Mg ha^?1 at Wanang. Carbon storage at Wanang was somewhat lower than in other lowland tropical forests, whereas local variation among 1‐ha subplots and the contribution of small trees to total AGLB were substantially higher. We speculate that these differences may be attributed to the dynamics of Wanang forest where erosion of a recently uplifted and unstable terrain appears to be a major source of natural disturbance. These findings emphasize the need for locally calibrated forest carbon estimates if accurate landscape level valuation and monetization of carbon is to be achieved. Such estimates aim to situate PNG forests in the global carbon context and provide baseline information needed to improve the accuracy of PNG carbon monitoring schemes.     

Transforming growth factor beta 1 869T/C and 915G/C polymorphisms and risk of autism spectrum disorders

Background:

Transforming growth factor-β1 (TGF-β1) has been found to play a crucial role in early central nervous system development. Several studies have illustrated decreased TGF-β1 levels in sera and brains of autistic children. Two point mutations in the TGF-β1 signal peptide at 869T/C and 915G/C have been reported to influence TGF-β1 expression. The aim of the present study was to investigate the correlation of TGF-β1 polymorphisms and their haplotypes with autism.

Methods:

This study was performed on 39 autistic patients and 35 age- and sex-matched normal controls in an Iranian population, using the sequence specific primed-polymerase chain reaction (PCR-SSP) technique. Patients were divided into mild-to-moderate and severe groups according to the childhood autism rating scale.

Results:

No significant differences were observed for allele, genotype, or haplotype frequencies between the autistics and controls. Only a slight difference was observed in GC25 between the controls and all children with autism.

Conclusion:

Thus, these results indicate that the polymorphisms in TGF-β1 gene may not play an important role in the development of autism.Key Words: Autism spectrum disorders, Development, Polymorphism, Transforming Growth Factor beta 1     

Autistic Traits in Neurotypical Adults: Correlates of Graph Theoretical Functional Network Topology and White Matter Anisotropy Patterns

Attempts to explicate the neural abnormalities behind autism spectrum disorders frequently revealed impaired brain connectivity, yet our knowledge is limited about the alterations linked with autistic traits in the non-clinical population. In our study, we aimed at exploring the neural correlates of dimensional autistic traits using a dual approach of diffusion tensor imaging (DTI) and graph theoretical analysis of resting state functional MRI data. Subjects were sampled from a public neuroimaging dataset of healthy volunteers. Inclusion criteria were adult age (age: 18–65), availability of DTI and resting state functional acquisitions and psychological evaluation including the Social Responsiveness Scale (SRS) and Autistic Spectrum Screening Questionnaire (ASSQ). The final subject cohort consisted of 127 neurotypicals. Global brain network structure was described by graph theoretical parameters: global and average local efficiency. Regional topology was characterized by degree and efficiency. We provided measurements for diffusion anisotropy. The association between autistic traits and the neuroimaging findings was studied using a general linear model analysis, controlling for the effects of age, gender and IQ profile. Significant negative correlation was found between the degree and efficiency of the right posterior cingulate cortex and autistic traits, measured by the combination of ASSQ and SRS scores. Autistic phenotype was associated with the decrease of whole-brain local efficiency. Reduction of diffusion anisotropy was found bilaterally in the temporal fusiform and parahippocampal gyri. Numerous models describe the autistic brain connectome to be dominated by reduced long-range connections and excessive short-range fibers. Our finding of decreased efficiency supports this hypothesis although the only prominent effect was seen in the posterior limbic lobe, which is known to act as a connector hub. The neural correlates of the autistic trait in neurotypicals showed only limited similarities to the reported findings in clinical populations with low functioning autism.     

Origin of the blood hyperserotonemia of autism

Background  

Research in the last fifty years has shown that many autistic individuals have elevated serotonin (5-hydroxytryptamine, 5-HT) levels in blood platelets. This phenomenon, known as the platelet hyperserotonemia of autism, is considered to be one of the most well-replicated findings in biological psychiatry. Its replicability suggests that many of the genes involved in autism affect a small number of biological networks. These networks may also play a role in the early development of the autistic brain.