Expression Changes in Mitochondrial Genes Affecting Mitochondrial Morphology, Transmembrane Potential, Fragmentation, Amyloidosis, and Neuronal Cell Death Found in Brains of Alzheimer's Disease Patients.

BACKGROUND: Alzheimer's disease (AD) is a neurological disease that has both a genetic and non-genetic origin. Mitochondrial dysfunction is a critical component in the pathogenesis of AD as deficits in oxidative capacity and energy production have been reported. OBJECTIVE: Nuclear-encoded mitochondrial genes were studied in order to understand the effects of mitochondrial expression changes on mitochondrial function in AD brains. These expression data were to be incorporated into a testable mathematical model for AD used to further assess the genes of interest as therapeutic targets for AD. METHODS: RT2-PCR arrays were used to assess expression of 84 genes involved in mitochondrial biogenesis in AD brains. A subset of mitochondrial genes of interest was identified after extensive Ingenuity Pathway Analysis (IPA) (Qiagen). Further filtering of this subset of genes of interest was achieved by individual qPCR analyses. Expression values from this group of genes were included in a mathematical model being developed to identify potential therapeutic targets. RESULTS: Nine genes involved in trafficking proteins to mitochondria, morphology of mitochondria, maintenance of mitochondrial transmembrane potential, fragmentation of mitochondria and mitochondrial dysfunction, amyloidosis, and neuronal cell death were identified as significant to the changes seen. These genes include TP53, SOD2, CDKN2A, MFN2, DNM1L, OPA1, FIS1, BNIP3, and GAPDH. CONCLUSION: Altered mitochondrial gene expression indicates that a subset of nuclear-encoded mitochondrial genes compromise multiple aspects of mitochondrial function in AD brains. A new mathematical modeling system may provide further insights into potential therapeutic targets.

Incorporating Mitochondrial Gene Expression Changes Within a Testable Mathematical Model for Alzheimer's Disease: Stress Response Modulation Predicts Potential Therapeutic Targets.

BACKGROUND: Alzheimer's disease is a specific form of dementia characterized by the aggregation of amyloid-ß plaques and tau tangles. New research has found that the formation of these aggregates occurs after dysregulation of cellular respiration and the production of radical oxygen species. Proteomic data shows that these changes are also related to unique gene expression patterns. OBJECTIVE: This study is designed to incorporate both proteomic and gene expression data into a testable mathematical model for AD. Manipulation of this new model allows the identification of potential therapeutic targets for AD. METHODS: We investigate the impact of these findings on new therapeutic targets via metabolic flux analysis of sirtuin stress response pathways while also highlighting the importance of metabolic enzyme activity in maintaining proper respiratory activity. RESULTS: Our results indicate that protective changes in SIRT1 and AMPK expression are potential avenues for therapeutics. CONCLUSION: Combining our mitochondrial gene expression analyses with available protein data allowed the construction of a new mathematical model for AD that provides a useful approach to test the efficacy of potential AD therapeutic targets.

The T9861C Mutation in the mtDNA-Encoded Cytochrome C Oxidase Subunit III Gene Occurs in High Frequency but with Unequal Distribution in the Alzheimer's Disease Brain.

Mitochondrial dysfunction is recognized as a critical component in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Deficits in oxidative capacity and, specifically, cytochrome c oxidase (CO) activity have been reported in AD brains and platelets. We previously identified a point mutation at np 9861 in AD brain mitochondrial DNA (mtDNA) that alters amino acid 219 of subunit III of CO from phenylalanine to leucine. We rapidly screened and quantitated levels of T9861C in samples using mismatched PCR-RFLP and nucleotide extension assays. Six of 40 AD brains possessed the T9861C mutation (designated AD+) compared to zero of 40 age-matched control brains. The 15% frequency of T9861C in AD brain is 115-fold higher than the frequency (0.13%) reported in 9,986 human mtDNA samples queried in world-wide databases. T9861C is heteroplasmic, with mutant load varying from 11% to >95%. Detected initially in parietal cortex, T9861C is not localized to that region but is also found in temporal cortex and caudate but not in hippocampus. The mutant load is unequally distributed throughout these brain regions with the highest load occurring in the parietal or temporal cortex. CO activity normalized to citrate synthase (CS) is reduced an average of 48.5% in AD+ brains. CO/CS ratios amongst controls and the two AD populations (AD and AD+) were significantly different (p = 0.001). Post hoc differences were also significant between controls and AD+ (p = 0.001) and controls and AD (p = 0.019). There was no significant difference between AD and AD+ (p = 0.317).

An investigation of intra-individual variability in children with fetal alcohol spectrum disorder (FASD).

Intra-individual variability (IIV) is defined as systematic within-person variation in performance either across test sessions (e.g., test/retest performance on the same task) or in one session (e.g., variations in performance on multiple trials of a single task). Higher levels of IIV have been noted as a characteristic of neurodevelopmental disorders such as attention deficit/hyperactivity disorder​ (ADHD), but IIV is yet to be investigated in fetal alcohol spectrum disorder (FASD). FASD is a term used to describe a range of conditions resulting from prenatal exposure to alcohol. As part of a comprehensive neuropsychological battery, four study groups (1. fetal alcohol syndrome/partial fetal alcohol syndrome; 2. static encephalopathy/alcohol exposed; 3. neurobehavioral disorder/alcohol exposed as diagnosed using the University of Washington FASD 4-Digit Code; 4. typically-developing (TD) age-matched children with no prenatal alcohol exposure) were administered measures of motor response and inhibitory control, attention, and adaptive behavior. The results indicate increased levels of IIV in those with FASD compared to the TD controls. It was found that IIV uniquely contributes to predicting adaptive behavior above and beyond attention, while attention partially mediates the relationship between IIV and adaptive behavior. This is the first study to the authors' knowledge to show the presence of increased IIV in children with FASD. It additionally provides evidence that IIV measures some inherent variability in performance independent of poor attention in children with FASD.

Prospective memory in children with attention deficit hyperactivity disorder: a review.

OBJECTIVE: The objective of the paper is to synthesize the research on prospective memory (PM) in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: Research on PM and ADHD in youth was synthesized according to the PRISMA guidelines and a summary of the types of PM deficits typically seen in these children, as well as the methods currently available to assess and treat these deficits is provided. Suggestions on ways to better manage PM deficits in children's everyday lives are also discussed. RESULTS: Six studies have investigated PM in children with ADHD. The majority of these studies found a deficit in time-based PM, but not event-based PM. The mechanisms underlying this deficit, however, are still unknown. There are currently no specific measures available to clinically assess PM in children and there are no specific evidence-based interventions available that specifically target PM deficits in children with ADHD. CONCLUSION: Remediation strategies aimed at compensating for these PM deficits in daily life may be most useful. Nevertheless, more research is necessary to better understand PM in children with ADHD.

Assessment of executive function in young children with and without ASD using parent ratings and computerized tasks of executive function.

OBJECTIVE: The current study investigated executive function (EF) in young children with and without autism spectrum disorder (ASD) using multiple methods of assessment. METHOD: Young children (M = 63.2 months) with and without ASD, matched on age, IQ, and maternal education, were assessed on computerized measures of working memory, inhibition, flexibility, and planning. Parents completed a behavior rating scale assessing children's EF within everyday contexts. RESULTS: There were no significant group differences on working memory, inhibition, flexibility, or planning. The mean difference on one aspect of the planning task (number of correct trials), however, approached significance and showed a medium to large effect size. There was also a significant difference between groups on the EF behavior rating scale, indicating that participants with ASD demonstrated greater executive dysfunction, as indexed by parent report. CONCLUSIONS: The results suggest that in young children with ASD, EF difficulties may only become apparent when situational demands require coordinating multiple abilities, as assessed with scales indexing children's abilities to manage their day-to-day EF-related behavior. We suggest that multiple methods are needed to achieve a comprehensive and valid EF assessment in young children with ASD.

Attention and working memory training: A feasibility study in children with neurodevelopmental disorders.

The current study investigated the efficacy of a game-based process specific intervention for improving attention and working memory in children with Fetal Alcohol Spectrum Disorders (FASD) and Autism Spectrum Disorders (ASD). The Caribbean Quest (CQ) is a 'serious game' that consists of five hierarchically structured tasks, delivered in an adaptive format, targeting different aspects of attention and/or working memory. In addition to game play, the intervention incorporates metacognitive strategies provided by trained educational assistants (EAs), to facilitate generalization and far transfer to academic and daily skills. EAs delivered the intervention to children (ages 6-13) during their regular school day, providing children with instruction in metacognitive strategies to improve game play, with participants completing approximately 12 hours of training over an 8 to 12 school week period. Pre- and post-test analyses revealed significant improvement on measures of working memory and attention, including reduced distractibility and improved divided attention skills. Additionally, children showed significant gains in performance on an academic measure of reading fluency, suggesting that training-related gains in attention and working memory transferred to classroom performance. Exit interviews with EAs revealed that the intervention was easily delivered within the school day, that children enjoyed the intervention, and that children transferred metacognitive strategies learned in game play into the classroom. Preliminary results support this game-based process specific intervention as a potentially effective treatment and useful tool for supporting cognitive improvements in children with FASD or ASD, when delivered as part of an overall treatment plan.

The effect of task complexity on planning in preterm-born children.

OBJECTIVE: Planning is an important executive function (EF) skill that is fundamental to the capacity to achieve everyday goals that require a series of intermediate steps. This study examined the effect of preterm birth on planning skills in early and middle childhood using Tower problems that made different cognitive workload demands. METHOD: We administered a novel touchscreen Tower of Hanoi task (Monkey Tree Task; MTT) in three age cohorts (3, 6, and 9 years) to 485 children born between 2000 and 2010 (105 extremely low birth weight [ELBW], 248 late preterm [LP], and 132 term-born [Term]). RESULTS: Children born with ELBW completed significantly fewer Tower problems with higher cognitive demands than children born at Term or LP. Likewise, Term- and LP-born children completed more Tower problems than children born with ELBW. In the youngest cohort, Term-born children solved Tower problems more efficiently than either preterm group, and LP-born children solved problems more efficiently than those born with ELBW. However, there were no group differences in efficiency in the older age cohorts. Significant correlations between our MTT measures and performance on other EF tasks were found. CONCLUSIONS: The MTT captured significant performance differences in planning skills between children born term vs. preterm. This study provides important information on the impact that cognitive workload, as a function of Tower problem complexity, has on planning skills in preterm children. This study adds to a growing body of research that distinguishes LP birth as having subtle, but distinguishable, adverse neuropsychological outcomes at earlier ages.

Effects of working memory training on children born preterm.

Researchers have reported benefits of working memory training in various populations, however, the training gains in preterm population is still inadequately studied. This study aimed to investigate the transfer and lasting effects of an online working memory training program on a group of preterm children aged between 4 and 6 years (mean gestational age = 28.3 weeks; mean birth weight = 1153 grams). Children were asked to perform the Cogmed JM at home for approximately 15 minutes a day, 5 days a week for 5 weeks. Their nontrained working memory and attention were assessed pre-training, post-training, and at 5-week follow-up. Parent ratings on children's executive functions were obtained at the three time points. Results revealed that significant improvements in verbal working memory was emerging in preterm children at 5-week follow-up, while significant gains in visuospatial working memory was found post-training and at 5-week follow-up in age-matched term-born children. These results indicated that working memory training has benefits on preterm children; however, the gains are different from those observed in term-born children. No significant differences in attention and parent-rated EF were found in either group across time. The possible explanations for the training benefits observed in preterm children were discussed.

A Double Dissociation Between Inattentive and Impulsive Traits, on Tasks of Visual Processing and Emotion Regulation.

OBJECTIVE: To dissociate between inattentive and impulsive traits common in attention deficit hyperactivity disorder (ADHD) using a non-dichotomous measurment of these traits. METHOD: 120 university students who completed the Conner's adult ADHD rating scales (CAARS) were also tested on the Microgenesis task which requires visual attention and on the Cyber Cruiser task which requires emotion regulation. RESULTS: Results show that a measure of inattention was specifically related to a measure of effortful visual processing condition. In addition, a measure of impulsivity was specifically related to the tendency to fail in refueling one's car on time, although this relation was opposite to the predicted direction. Furthermore, by using exploratory and confirmatory factor analyses, the CAARS' factor structure was confirmed to be relevant to an Israeli population. CONCLUSION: The current experiment supports the idea that visual attention may play a part in inattentive symptoms, and that emotion regulation may play a part in impulsivity symptoms.

Evidence of motor-control difficulties in children with attention deficit hyperactivity disorder, explored through a hierarchical motor-systems perspective.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) may reflect a disorder of neural systems that regulate motor control. The current study investigates motor dysfunction in children with ADHD using a hierarchical motor-systems perspective where frontal-striatal/"medial" brain systems are viewed as regulating parietal/"lateral" brain systems in a top down manner, to inhibit automatic environmentally driven responses in favor of goal-directed behavior. It was hypothesized that due to frontal-striatal hypoactivation, children with ADHD would have difficulty with higher order motor control tasks felt to be dependent on these systems, yet have preserved general motor function. METHOD: A total of 63 children-ADHD and matched controls-completed experimental motor tasks that required maintenance of internal motor representations and the ability to inhibit visually driven responses. Children also completed a measure of motor inhibition, and a portion of the sample completed general motor function tasks. RESULTS: On motor tasks that required them to maintain internal motor representations and to inhibit automatic motor responses, children with ADHD had significantly greater difficulty than controls, yet on measures of general motor dexterity, their performance was comparable. Children with ADHD displayed significantly greater intraindividual (subject) variability than controls. Intraindividual variability (IIV) contributed to variations in performance across the motor tasks, but did not account for all of the variance on all tasks. CONCLUSIONS: These findings suggest that children with ADHD may be more controlled by external stimuli than by internally represented information, possibly due to dysfunction of the medial motor system. However, it is likely that children with ADHD also display general motor-execution problems (as evidenced by IIV findings), suggesting that atypicalities may extend to both medial and lateral motor systems. Findings are interpreted within the context of contemporary theories regarding motor dysfunction in ADHD, and implications for understanding externalizing behaviors in ADHD are discussed.

Emotion recognition in children with Fetal Alcohol Spectrum Disorders.

There is a limited amount of research that examines social-emotional functioning in children with Fetal Alcohol Spectrum Disorder (FASD), and the majority of it relies on parent and teacher reports of social impairments. Because these provide broad measures of social function, they fail to elucidate the underlying specific skills with which this group of children has difficulty. The current study examines emotion-recognition abilities in children with FASD, as it plays a central role in social interaction. Participants were 22 children with diagnosed FASD (ages 8-14), and age- and gender-matched typically developing controls. Tasks included measures of emotion recognition from three nonlinguistic modalities: facial expressions, emotional tone of voice, and body positioning and movement. Participant's parents completed measures of adaptive and behavioral function that were related to children's performance on aspects of emotion recognition. Overall, the results show that children with FASD have more difficulties with emotion recognition than typically developing age-matched peers, but these difficulties may not be clinically significant (e.g., smaller effect size) or may be specific to the age of the individual exhibiting the emotion (i.e., child vs. adult). These results are discussed in the context of previous studies.

Confirmatory factor analysis of the Reynolds Intellectual Assessment Scales (RIAS) in Canadian children.

The purpose of the current study was to assess the validity of the Reynolds Intellectual Assessment Scale's (RIAS) index and subtest scores by examining whether the RIAS conforms to Carroll's ( 1993 ) three-stratum theory of cognitive ability and the Cattell-Horn Gf-Gc (Horn & Cattell, 1966 ) theory of intelligence upon which it was based. Factor structures of RIAS scores from typically developing (n = 187) and mixed clinical groups (n = 164), 4-18 years old, were compared using confirmatory factor analysis. The results were mixed, with some findings supporting the validity of the Composite Intelligence Index (CIX), Nonverbal Intelligence Index (NIX), and Verbal Intelligence Index (VIX) while others suggested that the CIX and NIX in particular should be interpreted with caution, depending on the population in which the RIAS is being used. The functioning of the two nonverbal subtests in all analyses suggested that the RIAS's nonverbal subtests are most problematic, with the greatest impact on the RIAS's validity as a measure of overall, verbal, and nonverbal intelligence. The RIAS's use as a general cognitive screener is supported but caution is recommended if the RIAS is being used to make important diagnostic, qualification for services, forensic, or placement decisions.

Event- and time-triggered remembering: the impact of attention deficit hyperactivity disorder on prospective memory performance in children.

The current study examined prospective memory (PM, both time-based and event-based) and time estimation (TR, a time reproduction task) in children with and without attention deficit hyperactivity disorder (ADHD). This study also investigated the influence of task performance and TR on time-based PM in children with ADHD relative to controls. A sample of 69 children, aged 8 to 13 years, completed the CyberCruiser-II time-based PM task, a TR task, and the Super Little Fisherman event-based PM task. PM performance was compared with children's TR abilities, parental reports of daily prospective memory disturbances (Prospective and Retrospective Memory Questionnaire for Children, PRMQC), and ADHD symptomatology (Conner's rating scales). Children with ADHD scored more poorly on event-based PM, time-based PM, and TR; interestingly, TR did not appear related to performance on time-based PM. In addition, it was found that PRMQC scores and ADHD symptom severity were related to performance on the time-based PM task but not to performance on the event-based PM task. These results provide some limited support for theories that propose a distinction between event-based PM and time-based PM.

Impaired reward processing by anterior cingulate cortex in children with attention deficit hyperactivity disorder.

Decades of research have examined the neurocognitive mechanisms of cognitive control, but the motivational factors underlying task selection and performance remain to be elucidated. We recently proposed that anterior cingulate cortex (ACC) utilizes reward prediction error signals carried by the midbrain dopamine system to learn the value of tasks according to the principles of hierarchical reinforcement learning. According to this position, disruption of the ACC-dopamine interface can disrupt the selection and execution of extended, task-related behaviors. To investigate this issue, we recorded the event-related brain potential (ERP) from children with attention deficit hyperactivity disorder (ADHD), which is strongly associated with ACC-dopamine dysfunction, and from typically developing children while they navigated a simple "virtual T-maze" to find rewards. Depending on the condition, the feedback stimuli on each trial indicated that the children earned or failed to earn either money or points. We found that the reward positivity, an ERP component proposed to index the impact of dopamine-related reward signals on ACC, was significantly larger with money feedback than with points feedback for the children with ADHD, but not for the typically developing children. These results suggest that disruption of the ACC-dopamine interface may underlie the impairments in motivational control observed in childhood ADHD.

Test-retest reliability and practice effects of executive function tasks in preschool children.

This study examined the test-retest reliability of executive function tasks in preschool children. Measures of working memory, response inhibition, attentional flexibility, and planning were administered to thirty three preschool children between the ages of 36 and 72 months (M = 54.75 months) on two testing occasions approximately three weeks apart (M interval = 21.64 days). Working memory tasks showed higher test-retest reliability than measures of response inhibition. There were significant practice effects on three measures of complex working memory. Implications of these findings for the assessment of executive function in preschool children are discussed.

Using Games to Improve Functioning in Children with Fetal Alcohol Spectrum Disorders.

Researchers from the University of Victoria (Victoria, BC, Canada) and the University of Alberta (Edmonton, AB, Canada) partnered in a study aimed at improving attention abilities and executive functioning in children diagnosed with fetal alcohol spectrum disorders through administration of a computerized process approach training program. Early results are promising, and next steps involve school-based implementation.

Executive functions in extremely low birth weight and late-preterm preschoolers: effects on working memory and response inhibition.

Executive function (EF) refers to fundamental capacities that underlie more complex cognition and have ecological relevance across the individual's lifespan. However, emerging executive functions have rarely been studied in young preterm children (age 3) whose critical final stages of fetal development are interrupted by their early birth. We administered four novel touch-screen computerized measures of working memory and inhibition to 369 participants born between 2004 and 2006 (52 Extremely Low Birth Weight [ELBW]; 196 late preterm; 121 term-born). ELBW performed worse than term-born on simple and complex working memory and inhibition tasks and had the highest percentage of incomplete performance on a continuous performance test. The latter finding indicates developmental immaturity and the ELBW group's most at-risk preterm status. Additionally, late-preterm participants performed worse compared with term-born on measures of complex working memory but did not differ from those term-born on response inhibition measures. These results are consistent with a recent literature that identifies often subtle but detectable neurocognitive deficits in late-preterm children. Our results support the development and standardization of computerized touch-screen measures to assess EF subcomponent abilities during the formative preschool period. Such measures may be useful to monitor the developmental trajectory of critical executive function abilities in preterm children, and their use is necessary for timely recognition of deficit and application of appropriate interventional strategies.

Reinforcement learning in children with FASD.

BACKGROUND: It is often said that children with Fetal Alcohol Spectrum Disorder (FASD) have difficulty learning from reinforcement. However, there is little empirical evidence to support or deny this claim. OBJECTIVES: To examine reinforcement learning in children with FASD, specifically: (1) the rate of learning from reinforcement; and (2) the impact of concreteness of the reinforcer. METHODS: Participants included 18 children with FASD (IQ ≥ 70), ages 11-17, and 18 age- and sex-matched controls. Participants each completed a novel reinforcement learning discrimination task that involved visual probabilistic learning (70% contingent feedback). The task was completed twice, once with tokens, and once with points (counterbalanced). RESULTS: The control group demonstrated significantly stronger overall reinforcement learning, although rates of improvement and effect of concreteness of the reinforcer (tokens vs. points) were not different between groups. The FASD group's responses were more likely to be guided by the most recent information, rather than based on integration of reward status over multiple trials. CONCLUSIONS: Reinforcement learning does not appear to occur in a functionally different manner in children with FASD, but does take longer, and is more impacted by recent reward than an integration of overall reinforcement information. Children with FASD without an intellectual disability may be able to learn from reinforcement given sufficient consistent repetition. However, other failures associated with learning difficulties such as the complexity of the material, transfer of learning, or impulsivity were not addressed in this study.

Investigating the efficacy of an attention training programme in children with foetal alcohol spectrum disorder.

OBJECTIVE: The current study investigated the efficacy of a direct intervention programme aimed at improving attention abilities in children with foetal alcohol spectrum disorder (FASD). METHODS: The Computerized Progressive Attention Training (CPAT) program is an intervention which targets proposed attention networks. CPAT task difficulty automatically adjusts based on participant performance. Ten children aged 6-15 with FASD completed an average of 16 hours of intervention over ~9 weeks at school, aided by a research assistant providing metacognitive strategies and support. RESULTS: Pre- and post-intervention assessments indicate significant improvement on several attention measures including sustained attention and selective attention. In addition, several measures of spatial working memory, math fluency, and reading fluency also significantly increased, suggesting that better attention leads to better cognitive performance. CONCLUSION: Results provide support for the use of computerized attention training materials as part of an effective intervention for cognitive performance in children with FASD.