Cognitive mediators of adaptive functioning outcomes in survivors of pediatric brain tumors treated with proton radiotherapy.

BACKGROUND: Cranial radiotherapy (RT) is associated with risk for cognitive and adaptive dysfunction. Proton RT (PRT) is a technique hypothesized to spare cognition by reducing exposure to nontarget brain tissue. However, little is known regarding functional outcomes in survivors of pediatric brain tumor (BT) treated with PRT. The present study examined the relationship between cognitive and adaptive outcomes in pediatric BT survivors post-PRT. METHODS: Survivors treated with either focal (n = 33) or craniospinal irradiation (CSI; n = 37) PRT completed neurocognitive evaluations approximately 5 years post-treatment. Results of intelligence testing and ratings of adaptive functioning are reported. Mediation models examined the relationship among radiation field, cognition, and adaptive functioning. RESULTS: The PRT CSI group demonstrated worse cognitive outcomes than the PRT Focal group across each cognitive index (Cohen's d = 0.56-0.70). Parent ratings of adaptive functioning were also worse in the PRT CSI group than the PRT Focal group (Global Adaptive Composite, d = 0.53; conceptual skills, d = 0.67). Cognitive performance fully mediated the relationship between radiation field and adaptive outcomes, while controlling for group differences in tumor histology and RT dose. CONCLUSIONS: Focal PRT survivors demonstrated generally positive outcomes with weaknesses in processing speed and aspects of adaptive functioning. CSI exposure was associated with more consistently poor cognitive and adaptive outcomes. The increased risk for adaptive dysfunction in the PRT CSI group appeared due to the effects of CSI on cognition. Efforts to reduce the volume of tissue exposure to RT remain important.

Cognition in older patients with multiple sclerosis compared to patients with amnestic mild cognitive impairment and healthy older adults.

OBJECTIVE: Progress in the treatment of multiple sclerosis (MS) has resulted in larger numbers of patients living to an advanced age, but little is known about the cognitive status of these individuals. The primary purpose of this study was to identify differences in the cognitive performance between elderly individuals with MS and those with amnestic mild cognitive impairment (aMCI). METHOD: Three groups ranging in age from 60 to 80 were compared: patients with MS (n = 64), patients with aMCI (n = 58), and healthy adults (n = 70). All participants completed a standard neuropsychological test battery that evaluated domains of attention, processing speed, executive function, memory, language, and visual spatial function. RESULTS: Compared to age- and gender-matched healthy controls, elderly MS patients exhibited a pattern of cognitive impairment centering on information processing speed and memory that was consistent with the deficits observed in other studies of MS patients regardless of age. Compared to aMCI patients, the MS patients exhibited worse performance on measures of processing speed, but better performance on a measure of memory under cued conditions (Selective Reminding Test), a nonspeeded measure of language (Boston Naming Test), and measures of executive function with processing speed statistically controlled (Trail Making Test, Stroop Test). CONCLUSIONS: Differences on neuropsychological measures can serve to distinguish aMCI from MS-related cognitive impairment in older patients, but it is essential that these measures control for the deficit in processing speed that is such a primary feature of MS. (PsycINFO Database Record

Information processing speed and attention in multiple sclerosis: Reconsidering the Attention Network Test (ANT).

OBJECTIVE: The Attention Network Test (ANT) assesses attention in terms of discrepancies between response times to items that differ in the burden they place on some facet of attention. However, simple arithmetic difference scores commonly used to capture these discrepancies fail to provide adequate control for information processing speed, leading to distorted findings when patient and control groups differ markedly in the speed with which they process and respond to stimulus information. This study examined attention networks in patients with multiple sclerosis (MS) using simple difference scores, proportional scores, and residualized scores that control for processing speed through statistical regression. METHOD: Patients with relapsing-remitting (N = 20) or secondary progressive (N = 20) MS and healthy controls (N = 40) of similar age, education, and gender completed the ANT. RESULTS: Substantial differences between patients and controls were found on all measures of processing speed. Patients exhibited difficulties in the executive control network, but only when difference scores were considered. When deficits in information processing speed were adequately controlled using proportional or residualized score, deficits in the alerting network emerged. The effect sizes for these deficits were notably smaller than those for overall information processing speed and were also limited to patients with secondary progressive MS. CONCLUSIONS: Deficits in processing speed are more prominent in MS than those involving attention, and when the former are properly accounted for, differences in the latter are confined to the alerting network.

Incidental learning during rapid information processing on the symbol-digit modalities test.

The Symbol--Digit Modalities Test (SDMT) is widely used to assess processing speed in MS patients. We developed a computerized version of the SDMT (c-SDMT) that scored participants' performance during subintervals over the course of the usual 90-s time period and also added an incidental learning test (c-ILT) to assess how well participants learned the symbol-digit associations while completing the c-SDMT. Patients with MS (n = 65) achieved lower scores than healthy controls (n = 38) on both the c-SDMT and c-ILT, and the scores on the two tests were correlated. However, no increase in the rate of item completion occurred for either group over the course of the c-SDMT, and the difference between groups was the same during each subinterval. Therefore, it seems implausible that controls completed more items on the c-SDMT because they were more adept at learning the symbol-digit associations as the test ensued. Instead, MS patients' poorer incidental learning performance appears to reflect the greater attentional burden that tasks requiring rapid serial processing of information impose upon them.

Dairy intake is associated with brain glutathione concentration in older adults.

BACKGROUND: A reduction in key antioxidants such as glutathione has been noted in brain tissue undergoing oxidative stress in aging and neurodegeneration. To date, no dietary factor has been linked to a higher glutathione concentration. However, in an earlier pilot study, we showed evidence of a positive association between cerebral glutathione and dairy intake. OBJECTIVE: We tested the hypothesis that dairy food consumption is associated with cerebral glutathione concentrations in older adults. DESIGN: In this observational study, we measured cerebral glutathione concentrations in 60 healthy subjects (mean ± SD age: 68.7 ± 6.2 y) whose routine dairy intakes varied. Glutathione concentrations were measured by using a unique, noninvasive magnetic resonance chemical shift imaging technique at 3 T and compared with dairy intakes reported in 7-d food records. RESULTS: Glutathione concentrations in the frontal [Spearman's rank-order correlation (rs) = 0.39, P = 0.013], parietal (rs = 0.50, P = 0.001), and frontoparietal regions (rs = 0.47, P = 0.003) were correlated with average daily dairy servings. In particular, glutathione concentrations in all 3 regions were positively correlated with milk servings (P ≤ 0.013), and those in the parietal region were also correlated with cheese servings (P = 0.015) and calcium intake (P = 0.039). Dairy intake was related to sex, fat-free mass, and daily intakes of energy, protein, and carbohydrates. However, when these factors were controlled through a partial correlation, correlations between glutathione concentrations and dairy and milk servings remained significant. CONCLUSIONS: Higher cerebral glutathione concentrations were associated with greater dairy consumption in older adults. One possible explanation for this association is that dairy foods may serve as a good source of substrates for glutathione synthesis in the human brain.

Effects of clonidine and methylphenidate on motor activity in Fmr1 knockout mice.

Fragile X syndrome (FXS), a disorder caused by a mutation in the FMR1 gene, is often associated with Attention Deficit Hyperactivity Disorder (ADHD). Common treatments for the hyperactivity often seen in ADHD involve the use of stimulants and α2-adrenergic agonists. The Fmr1 knockout (KO) mouse has been found to be a valid model for FXS both biologically and behaviorally. Of particular interest to our research, the Fmr1 KO mouse has been demonstrated to show increased locomotion in comparison to wild type (WT) littermates. In the present study, we assessed the effects of clonidine (0.05 mg/kg) and methylphenidate (5 mg/kg) on motor activity in Fmr1 KO mice and their WT littermates in the open field test. Results showed that methylphenidate increased motor activity in both genotypes. Clonidine decreased motor activity in both genotypes, but the effect was delayed in the Fmr1 KO mice.

Brief report: altered social behavior in isolation-reared Fmr1 knockout mice.

Social behavior abnormalities in Fragile X syndrome (FXS) are characterized by social withdrawal, anxiety, and deficits in social cognition. To assess these deficits, a model of FXS, the Fmr1 knockout mouse (Fmr1 KO), has been utilized. This mouse model has a null mutation in the fragile X mental retardation 1 gene (Fmr1) and displays physical and behavioral characteristics similar to humans with FXS. Several studies have investigated the social behavior of this model, but the results on the behavioral phenotype have not been consistent. In order to further characterize the social behavior in the knockout, isolation-reared Fmr1 KO were evaluated to determine if they differ in their social behavior compared to wild-type littermate controls. Differences by genotype were not observed in social approach behavior; however, the knockout mice showed a significantly reduced preference for social novelty and decreased sniff time in the sociability phase. These findings add to the growing body of knowledge on the subtle differences in social behavior shown by the Fmr1 knockout mice, and that differences occur when the subjects are isolation-reared. Validity of the model and possible changes to methodology are discussed.