The role of COMT and plasma proline in the variable penetrance of autistic spectrum symptoms in 22q11.2 deletion syndrome.

This paper examines how COMT158 genotypes and plasma proline levels are associated with variable penetrance of social behavioural and social cognitive problems in 22q11.2 deletion syndrome (22q11DS). Severity of autistic spectrum symptoms of 45 participants with 22q11DS was assessed using the Autism Diagnostic Interview Revised. Face and facial emotion recognition was evaluated using standardized computer-based test-paradigms. Associations with COMT158 genotypes and proline levels were examined. High proline levels and poor face recognition in individuals with the COMTMET allele, and poor facial emotion recognition, explained almost 50% of the variance in severity of autism symptomatology in individuals with 22q11DS. High proline levels and a decreased capacity to break down dopamine as a result of the COMTMET variant are both relevant in the expression of the social phenotype in patients. This epistatic interaction effect between the COMT158 genotype and proline on the expression of social deficits in 22q11DS shows how factors other than the direct effects of the deletion itself can modulate the penetrance of associated cognitive and behavioural outcomes. These findings are not only relevant to our insight into 22q11DS, but also provide a model to better understand the phenomenon of variable penetrance in other pathogenic genetic variants.

Intellectual functioning in relation to autism and ADHD symptomatology in children and adolescents with 22q11.2 deletion syndrome.

BACKGROUND: The 22q11.2 deletion syndrome (22q11DS; velo-cardio-facial syndrome) is associated with an increased risk of various disorders, including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). With this study, we aimed to investigate the relation between intellectual functioning and severity of ASD and ADHD symptomatology in 22q11DS. METHOD: A sample of 102 individuals (62 females) with 22q11DS aged 9 to 18.5 years were assessed using age appropriate Wechsler scales of intelligence as well as psychological and psychiatric assessment to evaluate the presence of ASD and ADHD symptomatology. RESULTS: Intelligence profiles were characterised by lower scores on the factor perceptual organisation and higher scores on the factor processing speed, with on subtest level higher scores on digit span and lower scores on arithmetic and vocabulary as compared with the mean factor or subtest score respectively. No differences in intelligence profiles were found between subgroups with and without ASD and/or ADHD. Low scores on coding were associated with higher severity of ASD symptomatology, while lower scores on block design were associated with more severe ADHD symptomatology. CONCLUSIONS: On several sub-domains of intelligence, poorer performance was associated with higher severity of ASD and ADHD symptomatology. The impact of developmental disorders in 22q11DS can be traced in specific domains of intellectual functioning as well as in severity of symptomatology.

Interventions to improve adherence to antipsychotic medication in patients with schizophrenia--a review of the past decade.

OBJECTIVE: Nonadherence to antipsychotic medication is highly prevalent in patients with schizophrenia and has a deleterious impact on the course of the illness. This review seeks to determine the interventions that were examined in the past decade to improve adherence rates. METHOD: The literature between 2000 and 2009 was searched for randomized controlled trials which compared a psychosocial intervention with another intervention or with treatment as usual in patients with schizophrenia. RESULTS: Fifteen studies were identified, with a large heterogeneity in design, adherence measures and outcome variables. Interventions that offered more sessions during a longer period of time, and especially those with a continuous focus on adherence, seem most likely to be successful, as well as pragmatic interventions that focus on attention and memory problems. The positive effects of adapted forms of Motivational Interviewing found in earlier studies, such as compliance therapy, have not been confirmed. CONCLUSION: Nonadherence remains a challenging problem in schizophrenia. The heterogeneity of factors related to nonadherence calls for individually tailored approaches to promote adherence. More evidence is required to determine the effects of specific interventions.

In search for significant cognitive features in Klinefelter syndrome through cross-species comparison of a supernumerary X chromosome.

The behavioral characterization of animals that carry genetic disorder abnormalities in a controlled genetic and environmental background may be used to identify human deficits that are significant to understand underlying neurobiological mechanisms. Here, we studied whether previously reported object recognition impairments in mice with a supernumerary X chromosome relate to specific cognitive deficits in Klinefelter syndrome (47,XXY). We aimed to optimize face validity by studying temporal object recognition in human cognitive assays. Thirty-four boys with Klinefelter syndrome (mean age 12.01) were compared with 90 age-matched normal controls, on a broad range of visual object memory tasks, including tests for pattern and temporal order discrimination. The results indicate that subjects with Klinefelter syndrome have difficulty in the processing of visual object and pattern information. Visual object patterns seem difficult to discriminate especially when temporal information needs to be processed and reproduced. On the basis of cross-species comparison, we propose that impaired temporal processing of object pattern information is an important deficit in Klinefelter syndrome. The current study shows how cross-species behavioral characterization may be used as a starting point to understand the neurobiology of syndromal phenotypic expression. The features of this study may serve as markers for interventions in Klinefelter syndrome. Similar cross-species evaluations of standard mouse behavioral paradigms in different genetic contexts may be powerful tools to optimize genotype-phenotype relationships.

Cognitive slowing in multiple sclerosis is strongly associated with brain volume reduction.

INTRODUCTION: In this study, we investigated the influence of in vivo disease pathology (measured as magnetic resonance imaging (MRI) lesion load and brain volume reduction) on cognitive functioning, especially the speed of processing, in multiple sclerosis (MS) patients. Since MS is characterized by cognitive slowing rather than impaired accuracy, we used the Amsterdam Neuropsychological Tasks (ANT) program, a computerized test proven to be very sensitive to cognitive slowing in MS patients. METHODS: Thirty-two patients performed the ANT and underwent MRI scanning. Using the ANT computerized tests, we investigated focused, divided, sustained attention, executive function and psychomotor function, and examined associations of speed, speed fluctuation and accuracy of performance of these tests with MRI lesion load and brain volume parameters. RESULTS: A decrease in the speed of processing and response speed stability, and a decrease in psychomotor accuracy and stability were clearly associated with less brain volume, and with higher lesion loads, in particular at frontal and occipital areas. Correlations with brain volume reduction were found for all domains, except for visuo-spatial processing. In particular, speed and speed fluctuation scores correlated with brain volume reduction, while accuracy of performance, in general, did not correlate. Only some test speed scores and speed fluctuation scores correlated with lesion load measurements. CONCLUSION: This study shows that, in MS patients, accuracy of processing is not compromised unless high working memory demands are involved. Problems in neurocognitive functioning in MS are mainly modulated by speed and stability of speed processing, in particular when attention-demanding controlled information processing is required. Abnormalities in these domains are most strongly associated with brain volume loss, confirming that pathology beyond focal lesions is important in MS.

Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS.

OBJECTIVE: To investigate the cognitive skills of patients with relapsing remitting multiple sclerosis (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) relative to healthy control subjects and to assess whether there is heterogeneity in the type of cognitive disabilities demonstrated by patients with different MS phenotypes. METHODS: RRMS patients (n = 108), SPMS patients (n = 71), PPMS patients (n = 55), and healthy control subjects (n = 67) underwent neuropsychological assessment with the Brief Repeatable Battery of Neuropsychological Tests. RESULTS: Relative to controls, cognitive performance of RRMS patients was deficient when tasks required higher-order working memory (WM) processes (Word List Generation, 10/36 Spatial Recall Test, Symbol Digit Modalities Test). PPMS and SPMS patients performed poorer than control subjects on all tasks. SPMS patients performed more poorly than PPMS patients when tasks required higher-order WM processes, except when speed of information processing played a relatively important role (Symbol Digit Modalities Test, Paced Auditory Serial Addition Test). Whereas RRMS patients generally performed better than the progressive subtypes, they showed relatively poor verbal fluency. CONCLUSION: MS patients with different disease courses have different cognitive profiles.

Motor function under lower and higher controlled processing demands in early and continuously treated phenylketonuria.

This study examined motor control in 61 early and continuously treated patients with phenylketonuria (PKU) and 69 control participants, aged 7 to 14 years. The pursuit task demanded concurrent planning and execution of unpredictable movements, whereas the tracking task required a highly automated circular movement that could be planned in advance. PKU patients showed significantly poorer motor control in both tasks compared with control participants. Deficits were particularly observed for younger patients (age < 11 years). Differences between control participants and PKU patients were significantly greater in the pursuit task compared with the tracking task, indicating more serious deficits when a higher level of controlled processing is required. Correlations with historical phenylalanine levels indicated a later maturation of the level of control required by the pursuit task compared with the tracking task.

Face recognition in children with a pervasive developmental disorder not otherwise specified.

This study investigates the accuracy and speed of face recognition in children with a Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS; DSM-IV, American Psychiatric Association [APA], 1994). The study includes a clinical group of 26 nonretarded 7- to 10-year-old children with PDDNOS and a control group of 65 normally developing children of the same age. Two computerized reaction time tasks were administered: a face recognition task and a control task designed to measure the recognition of abstract visuospatial patterns. The latter were either easy or difficult to distinguish from a set of alternative patterns. The normally developing children recognized the faces much faster than the hardly distinguishable abstract patterns. The children in the PDDNOS group needed an amount of time to recognize the faces that almost equalled the time they needed to recognize the abstract patterns that were difficult to distinguish. The results suggest that, when processing faces, children with PDDNOS use a strategy that is more attention-demanding and, hence, less automatic or "Gestalt-like" than the one used by the control children. The results are discussed in the light of a theory that explains the development of coherent mental representations.

The neuropsychological profile of early and continuously treated phenylketonuria: orienting, vigilance, and maintenance versus manipulation-functions of working memory.

In this paper, we review neuropsychological test results of early and continuously treated Phenylketonuria (PKU) patients. To increase insight into the neuropsychological profile of this population, we have attempted to place the results within an attentional network model [Images of the mind, 1994], which proposes interacting but dissociable attentional networks for orienting, vigilance, and executive control of attention. Executive control of attention is discussed against the background of the process-specific theory of working memory (WM) [Handbook of neuropsychology, 1994], which postulates a distinction between the 'maintenance'-function of WM and the 'manipulation and monitoring'-function. Neuropsychological results are presented for 67 early and continuously treated PKU patients and 73 controls aged 7-14 years. Four neuropsychological tasks were employed to measure orienting, mnemonic processing, interference suppression, and top-down control in visual search. No differences were found in orienting and the maintenance-function of WM. In addition to previously reported impairments in sustained attention/vigilance and inhibition of prepotent responding, PKU patients exhibited deficits when top-down control was required in a visual search task, but showed no impairment when interference suppression was required. It is discussed how the specific neuropsychological impairments in PKU may be a consequence of mid-dorsolateral prefrontal cortex (DLPFC) dysfunctioning due to deficiencies in catecholamine modulation.

Information processing characteristics in subtypes of multiple sclerosis.

The purpose of this study was to evaluate information processing characteristics in patients with multiple sclerosis (MS). We selected 53 patients with MS and 58 matched healthy controls. Using computerized tests, we investigated focused, divided, sustained attention, and executive function, and attempted to pinpoint deficits in attentional control to peripheral or central processing stages. The results substantiate the hypothesis that the slowing of attention-demanding (controlled) information processing underlying more complex cognitive skills is general, i.e. irrespective of type of controlled processing, with MS patients being 40% slower than controls. MS patients may suffer from focused, and divided and sustained attention deficits, as well as from compromised central processing stages, with secondary progressive (SP) patients showing the most extensive range of deficits, closely followed by primary progressive (PP) patients, while relapsing-remitting (RR) patients appear to be much less affected. General slowing appears to be highest in PP and SP type MS patients (50% slower) versus relapsing-remitting MS (24% slower). In contrast to most previous results, (complex) processing speed appeared to be robustly correlated with severity of MS as measured by the expanded disability status scale and with disease duration. Patients did much less differ in accuracy of processing from controls, suggesting the importance of using time strategies in planning everyday life and job activities to compensate for or alleviate MS-related speed handicaps.

Facial identity and facial emotions: speed, accuracy, and processing strategies in children and adults.

As yet, nearly all studies in face and facial affect recognition typically provide only data on the accuracy of processing, invariably also in the absence of reference data on abstract information processing. In this study, accuracy and speed of abstract visuo-spatial processing, face recognition, and facial emotion recognition were investigated in normal school children (7-10 years) and adults (25+/-4 years). In the age range of 7-10 years, accuracy of facial processing hardly increased, while speed did substantially increase with age. Adults, however, were substantially more accurate and faster than children. Differences between facial and abstract information processing were related to type of processing strategy, that is, configural or holistic processing versus featural or piecemeal processing. Improvement in task performance with age is discussed in terms of an enhanced efficiency of the configural organization of facial knowledge (facial information processing tasks), together with a further increase in processing capacity (all tasks). The differential developmental course of speed and accuracy levels indicates that speed is a more sensitive measure when children get older. Moreover, it also suggests that speed of performance, in addition to accuracy, might be successfully used in the assessment of clinical deficits, as has recently been demonstrated in children with autistic disorders of social contact.

Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations.

Fifty-seven 7-14-year-old early- and continuously treated phenylketonuria (PKU) patients and 65 matched controls performed a sustained attention task. PKU patients with plasma phenylalanine (phe) levels higher than 360 micromol/l at the time of testing exhibited, compared to controls, lower speed of information processing, a lower ability to inhibit task-induced cognitive interference, less consistent performance, and a stronger decrease of performance level over time. Patients with concurrent phe levels lower than 360 micromol/l did not differ from controls and were significantly better than patients with levels higher than 360 micromol/l. Strong relationships were found with task performance for phe levels during the pre-school years and between ages 5 and 7. These correlations were stronger than those between concurrent phe level and task performance. Significant multiple regression models were found with age accounting for the largest proportion of variance of tempo and tempo fluctuation, and lifetime phe levels (particularly phe level between ages 5 and 7) accounting for the largest proportion of variance of the relative number of inhibition errors and its increase over time. Phe level between ages 5 and 7 also contributed significantly to the variance of tempo and tempo fluctuation. Neuropsychological outcome was independent of IQ. The results indicate that strict dietary adherence during these periods is beneficial to attentional control later in life. We suggest that phe levels should be maintained under 360 micromol/l until approximately age 12, when development of attentional control approaches an adult level.

Short-term dietary interventions in children and adolescents with treated phenylketonuria: effects on neuropsychological outcome of a well-controlled population.

This study addressed two questions: is there an effect of dietary interventions that induce relatively small changes in phenylalanine (Phe) concentration on neuropsychological outcome of early- and continuously treated phenylketonuria (PKU) patients, and are there differences in effects for PKU children and adolescents? To answer the first question, the effect of a short-term dietary intervention (1-2 weeks) was compared for patients whose Phe concentrations increased vs those whose Phe concentrations decreased. Controls were tested twice to control for learning effects. To answer the second question, the effect of dietary interventions was examined in younger patients (aged 7-10 years) and older patients (aged 11-14 years). The effect of dietary interventions was determined with three neuropsychological tasks: one requiring sustained attention; a second demanding maintenance in working memory; and a third in which complex operations were performed in working memory. Relatively small fluctuations in Phe concentration were found to influence neuropsychological task performance of PKU patients. Patients whose Phe concentrations decreased at the second assessment showed generally more improvement than controls. Patients whose Phe concentrations had increased showed minimal improvement or deterioration of task performance. The strongest effects were observed when sustained attention and manipulation of working memory content were required. There were some indications of a greater sensitivity of younger patients to fluctuations in Phe concentration.

The brief repeatable battery of neuropsychological tests: normative values allow application in multiple sclerosis clinical practice.

The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) is a sensitive measure of cognitive impairment in multiple sclerosis (MS) patients. It consists of the Selective Reminding Test, the 10/36 Spatial Recall Test, the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Test and the Word List Generation Test. We administered one of two parallel versions of the test battery to 140 healthy subjects to produce normative values for both versions. As expected, test scores were influenced by certain variables like age, gender and education. Although constructed as two equivalent versions, for some tests the two versions showed significant differences in test scores, which could not be explained by differences in these variables.

[Phenylketonuria: a children's disease in adulthood]. / Een kinderziekte op de volwassen leeftijd: fenylketonurie.

The prognosis for patients with phenylketonuria (PKU) has improved greatly with early institution of treatment after birth. It was assumed that the diet could be terminated after adolescence but there are strong indications that hyperphenylalaninaemia can have detrimental effects in adult patients. Hyperphenylalaninaemia can cause reversible white matter abnormalities, and is also associated with psychiatric illness, which improves with lowering of the plasma phenylalanine level. Even optimally treated patients generally have a decreased performance with neuropsychological tests compared with subjects without PKU. Elevation of the plasma phenylalanine level leads to worsening of neuropsychological performance, lowering of the level leads to improved performance. Strict metabolic control is necessary during pregnancy in women with PKU in view of the increasing frequency of congenital abnormalities with increasing phenylalanine level. The complexity and demanding nature of the diet treatment make specialised facilities for optimal medical and paramedical care mandatory.

Evaluation of attention before and after 2 years of growth hormone treatment in intrauterine growth retarded children.

The objective of this study was to assess attention in children with short stature following intrauterine growth retardation (IUGR), at baseline and after 2 years of growth hormone (hGH) treatment. At baseline, all of the children had a birth height and a current height below the third centile. The attention measures (Sonneville Visual Attention Tasks: SVAT) of the IUGR group were compared with those of a comparison sample. In the baseline analyses, 48 children with IUGR and 119 comparison children were included; the 2-year follow-up analyses involved 41 children with IUGR and 68 comparison children. At baseline, children with IUGR showed deficits in divided, focused, and sustained attention. They were less accurate, exhibited more variability in reaction time, and performed more slowly and more impulsively than did the children in the comparison sample. After 2 years of hGH treatment, the IUGR group exhibited deficits in divided and sustained attention. They were still less accurate and showed more variability in reaction time and more impulsiveness. Current head circumference, the type of delivery, and global intelligence of children with IUGR were significantly correlated with attention measures. We hypothesize that short stature following IUGR and attention deficits are related, and that hGH treatment seems to have some beneficial effect on attentional capacity.

Review of neuropsychological functioning in treated phenylketonuria: an information processing approach.

Phenylketonuria is no longer associated with mental retardation and other devastating neurological effects. Nonetheless, learning disabilities and IQ loss are common, even in early-treated individuals. Until recently, IQ was used as the sole measure of mental functioning in this population. As specific academic deficits were recognized and as a greater variety of tests became available, evaluation of children with phenylketonuria has included neuropsychological testing. A review of the 21 published reports highlights the areas of consensus and the need for additional well designed studies in the future. Problem solving, particularly abstract reasoning and executive functions, appears to be impaired in children with phenylketonuria. Reaction time, or speed of mental processing, appears to be the other important area affected in PKU. An information processing model is presented as a paradigm for further research and development of remedial strategies for children with phenylketonuria.

Methylphenidate and information processing. Part 1: Differentiation between responders and nonresponders; Part 2: Efficacy in responders.

Part 1 of this study attempted to discriminate clinical responders and nonresponders to methylphenidate (MPH) on the basis of neuropsychological deficit profiles. Part 2 addressed the question to what extent MPH might ameliorate these deficits. Hyperactive clinical responders (n = 30) and nonresponders (n = 28) to MPH, were compared to normal controls (n = 27) on selective and sustained attention tasks and on conventional psychological and neurological measures. The responders took part in a randomized double-blind placebo-controlled crossover study. They ingested a placebo (PL) or MPH (0.3-0.6 mg/kg/day) during 4 weeks, and were then tested. After crossover, another period of 4 weeks was concluded by a second test series. Compared to controls, both responders and nonresponders showed attention deficits in encoding, memory search, and decision operations, as well as in focused and sustained attention, vigilance, and use of feedback. These deficits were the most severe in the responders. Anamnestic data, IQ scores, and neurological variables did not discriminate between groups. MPH selectively alleviates attention deficits. MPH did not affect divided attention, except for an increased accuracy of response organization. The drug, however, greatly improved focused and sustained attention, vigilance, impulsivity, and the behavioral adaptivity to feedback.

Disturbed frontal regulation of attention in Parkinson's disease.

Parkinson's disease is characterized not only by tremor, akinesia and rigidity, but also by frontal cognitive dysfunction, that can be understood as a disturbance in the 'Supervisory Attentional System' (SAS). This concept refers to a system, located in the frontal cortex, that regulates attentional processes under novel, non-routine conditions. The hypothesis that cognitive dysfunction in Parkinson's disease results from a disturbance in the SAS was investigated by recording 'processing negativity' in 33 parkinsonian patients and 17 controls. Processing negativity is an event-related potential that reflects neuronal activity during selective attention. The contribution of the frontal cortex to selective attention can be studied directly using processing negativity. Parkinsonian patients were also scored for clinical symptoms and subjected to a neuropsychological test battery. Processing negativity was clearly disturbed in the parkinsonian patients. Moreover, parkinsonian patients with the lowest scores on 'frontal' neuropsychological tests such as Stroop, Trail Making and Word Fluency, also had the lowest processing negativity. Our results support the hypothesis that cognitive dysfunction in Parkinson's disease might be understood as a disturbance in the frontal regulation of attentional processes. Degeneration of the dopaminergic mesocortical innervation of the frontal cortex in Parkinson's disease is a possible neurochemical substrate of these frontal attentional disturbances.

Information processing in children with minor neurological dysfunction: behavioural and neurophysiological indices.

Minor neurological dysfunction (MND) refers to deviant function of the central nervous system in the absence of localizable neurological disorders. Children with no signs (n = 28) and with varying grades of MND (n = 48), classified according to failure on circumscript neurological subsystems, were administered selective and sustained attention tasks at the age of twelve. During the execution of one of the tasks, electrocortical activity of the brain was recorded at the Fz, Cz, Pz and Oz scalp locations. Of main interest were behavioural and electrophysiological indices of deficits in attentional control. With respect to the latter category, the investigation was focused on differences in event-related potential amplitudes reflecting subprocesses of cognitive processing (processing negativity, P300). Following a linear stage model of information processing, it was found that children who failed on three or more neurological subsystems (in particular on fine manipulation and coordination), exhibited deficits in the encoding, search and decision stages of processing. Furthermore, the children with MND showed a reduced positive parietal shift on target presentation. Under complex task conditions, children without MND showed a decrease in P300 amplitude which reflects the impact of processing negativity as a result of increased task demands; this effect was absent in children with MND. These electrocortical differences suggest imbalances in the external and internal neural regulation of the flow of information in the brain.