D-KEFS trail making test as an embedded performance validity measure.

OBJECTIVE: The Delis-Kaplan Executive Function System (D-KEFS) Trail Making Test (TMT) is a commonly used measure of processing speed and executive functioning that may also be useful as an embedded performance validity test (PVT). We evaluated the utility of several multi-condition indices on the D-KEFS TMT in three independent samples to determine an optimal multi-condition index and cutoff on the D-KEFS TMT. METHOD: Classification accuracy statistics for multiple multi-condition indices on the D-KEFS TMT were evaluated in three independent samples, including a sample with history of mild traumatic brain injury (TBI; n = 267) classified into psychometrically defined performance-valid and performance-invalid subgroups, the D-KEFS national normative sample (n = 1713), and a sample of middle- and older-aged adults diagnosed with mild cognitive impairment (MCI; n = 70). RESULTS: The D-KEFS TMT Conditions 1-5 summation index maximized sensitivity at .31 while maintaining adequate specificity at ≥.9. This index also had acceptable classification accuracy in both the D-KEFS national normative and MCI cross-validation samples, with the exception of the oldest subgroup of the national norming sample (i.e., individuals' ages 80-89), in which the observed failure rates for all multi-condition indices tested were greater than 10%. CONCLUSION: Our study provides support for the use the D-KEFS TMT Conditions 1-5 summation index as an embedded PVT among individuals younger than 80 years-old and from a range of conditions spanning from cognitively normal to mildly impaired; however, further validation is necessary.

The Minnesota Multiphasic Personality Inventory-2-RF in Treatment-Seeking Veterans with History of Mild Traumatic Brain Injury.

OBJECTIVE: This study examined the Minnesota Multiphasic Personality Inventory-Second Edition-Restructured Form (MMPI-2-RF) to better understand symptom presentation in a sample of treatment-seeking Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans with self-reported history of mild traumatic brain injury (mTBI). METHOD: Participants underwent a comprehensive clinical neuropsychological battery including performance and symptom validity measures and self-report measures of depressive, posttraumatic, and post-concussive symptomatology. Those with possible symptom exaggeration (SE+) on the MMPI-2-RF were compared with those without (SE-) with regard to injury, psychiatric, validity, and cognitive variables. RESULTS: Between 50% and 87% of participants demonstrated possible symptom exaggeration on one or more MMPI-2-RF validity scales, and a large majority were elevated on content scales related to cognitive, somatic, and emotional complaints. The SE+ group reported higher depressive, posttraumatic, and post-concussive symptomatology, had higher scores on symptom validity measures, and performed more poorly on neuropsychological measures compared with the SE- group. There were no group differences with regard to injury variables or performance validity measures. Participants were more likely to exhibit possible symptom exaggeration on cognitive/somatic compared with traditional psychopathological validity scales. CONCLUSIONS: A sizable portion of treatment-seeking OEF/OIF Veterans demonstrated possible symptom exaggeration on MMPI-2-RF validity scales, which was associated with elevated scores on self-report measures and poorer cognitive performance, but not higher rates of performance validity failure, suggesting symptom and performance validity are distinct concepts. These findings have implications for the interpretation of clinical data in the context of possible symptom exaggeration and treatment in Veterans with persistent post-concussive symptoms.

Advanced neuroimaging to quantify myelin in vivo: Application to mild TBI.

BACKGROUND: Difficulty providing accurate diagnosis and prognosis, especially after mild forms of traumatic brain injury (TBI), has increased efforts to detect changes in white matter microstructure using advanced neuroimaging techniques. Although methods such as diffusion tensor imaging (DTI) have greatly increased knowledge of white matter changes resulting from TBI, several shortcomings limit the utility of these techniques particularly when applied to populations with mild TBI (mTBI) history. In vivo imaging of myelin may be particularly well suited to detect changes in white matter microstructure resulting from mTBI. REVIEW: This manuscript will briefly review the animal and histological data supporting the important role of myelin following TBI, contributions and shortcomings of the use of diffusion tensor imaging (DTI) in mild TBI and the utility of multi-component relaxometry (MCR) techniques as a method for improved visualizing of white matter microstructural integrity in myelin. CONCLUSION: The use of MCR-based techniques has potential as a clinical and research tool to assess and track changes in myelin as well as the common behavioural changes such as slowed processing speed following TBI.

A multivariate twin study of hippocampal volume, self-esteem and well-being in middle-aged men.

Self-esteem and well-being are important for successful aging, and some evidence suggests that self-esteem and well-being are associated with hippocampal volume, cognition and stress responsivity. Whereas most of this evidence is based on studies on older adults, we investigated self-esteem, well-being and hippocampal volume in 474 male middle-aged twins. Self-esteem was significantly positively correlated with hippocampal volume (0.09, P = 0.03 for left hippocampus, 0.10, P = 0.04 for right). Correlations for well-being were not significant (Ps > 0.05). There were strong phenotypic correlations between self-esteem and well-being (0.72, P < 0.001) and between left and right hippocampal volume (0.72, P < 0.001). In multivariate genetic analyses, a two-factor additive genetic and unique environmental (AE) model with well-being and self-esteem on one factor and left and right hippocampal volumes on the other factor fits the data better than Cholesky, independent pathway or common pathway models. The correlation between the two genetic factors was 0.12 (P = 0.03); the correlation between the environmental factors was 0.09 (P > 0.05). Our results indicate that largely different genetic and environmental factors underlie self-esteem and well-being on one hand and hippocampal volume on the other.

Testosterone modifies the effect of APOE genotype on hippocampal volume in middle-aged men.

BACKGROUND: The APOE epsilon4 allele is an established risk factor for Alzheimer disease (AD), yet findings are mixed for how early its effects are manifest. One reason for the mixed results could be the presence of interaction effects with other AD risk factors. Increasing evidence indicates that testosterone may play a significant role in the development of AD. The aim of the present study was to examine the potential interaction of testosterone and APOE genotype with respect to hippocampal volume in middle age. METHODS: Participants were men from the Vietnam Era Twin Study of Aging (n = 375). The mean age was 55.9 years (range 51-59). Between-group comparisons were performed utilizing a hierarchical linear mixed model that adjusted for the nonindependence of twin data. RESULTS: A significant interaction was observed between testosterone and APOE genotype (epsilon4-negative vs epsilon4-positive). Those with both low testosterone (> or =1 SD below the mean) and an epsilon4-positive status had the smallest hippocampal volumes, although comparisons with normal testosterone groups were not significant. However, individuals with low testosterone and epsilon4-negative status had significantly larger hippocampal volumes relative to all other groups. A main effect of APOE genotype on hippocampal volume was observed, but only when the APOE-by-testosterone interaction was present. CONCLUSIONS: These findings demonstrate an interaction effect between testosterone and the APOE epsilon4 allele on hippocampal volume in middle-aged men, and they may suggest 2 low testosterone subgroups. Furthermore, these results allude to potential gene-gene interactions between APOE and either androgen receptor polymorphisms or genes associated with testosterone production.

Elevated pulse pressure is associated with age-related decline in language ability.

Recent research suggests that pulse pressure (PP), a putative marker of vascular integrity, may be associated with brain microvascular damage and age-related cognitive decline. Thus, the present study examined the relationship between PP and cognition in a sample of healthy nondemented older adults. One hundred nine participants were administered neurological and neuropsychological evaluations and determined to be nondemented. Regression analyses were used to examine the relationships among pulse pressure (PP) [systolic blood pressure (SBP)--diastolic blood pressure (DBP)], age, and cognition. PP and related measures were inversely correlated with global cognitive functioning and scores on a composite measure of language function, even after adjusting for age, education, and relevant vascular risk factors. Results indicate that increases in the pulsatile component of blood pressure may convey added risk of global cognitive decline and specific impairment in language abilities.

Use of the multiple sclerosis functional composite as an outcome measure in a phase 3 clinical trial.

BACKGROUND: The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of interferon beta-1a (Avonex) in patients with secondary progressive MS. OBJECTIVE: To assess the practice effects, reliability, and validity of the MSFC clinical outcome measure. DESIGN: Examining technicians underwent formal training using standardized materials. The MSFC was performed according to a standardized protocol. The 436 patients enrolled in the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial underwent 3 prebaseline MSFC testing sessions before randomization. RESULTS: Practice effects were evident initially for the MSFC but stabilized by the fourth administration. The Paced Auditory Serial Addition Test demonstrated the most prominent practice effects. The reliability of the MSFC was excellent, with an intraclass correlation coefficient for session 3 (final prebaseline session) vs session 4 (baseline) of 0.90. The MSFC at baseline correlated moderately strongly with the Kurtzke Expanded Disability Status Scale. Among the MSFC components, the Timed 25-Foot Walk correlated most closely. Correlations among the 3 MSFC components were weak, suggesting they assess distinct aspects of neurologic function in patients with MS. CONCLUSIONS: The MSFC demonstrated excellent intrarater reliability in this multinational phase 3 trial. Three prebaseline testing sessions were sufficient to compensate for practice effects. The pattern of correlations among the MSFC, its components, and the Kurtzke Expanded Disability Status Scale supported the validity of the MSFC.

Intrarater and interrater reliability of the MS functional composite outcome measure.

OBJECTIVE: To assess practice effects, and intrarater and interrater reliability of the MS functional composite (MSFC) outcome measure. BACKGROUND: To address the poor reliability and insensitivity to change of available MS clinical rating scales, the National MS Society's Clinical Outcomes Assessment Task Force developed the MSFC, a multidimensional quantitative clinical outcome measure that includes tests of leg function/ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). METHODS: Ten patients with secondary progressive MS underwent six testing sessions over a 2-week period. The MSFC was administered by the same examining technician in the first five sessions and by the other technician in the sixth. Patients were reassessed by both technicians after 6 months (sessions 7 and 8). The MSFC score was calculated as the mean of the Z scores of the three components. A pooled dataset derived from secondary progressive MS patients in the placebo arms of previous clinical trials and natural history studies served as the reference population to standardize scores. RESULTS: Practice effects were evident initially but stabilized by the fourth administration. The intraclass correlation coefficient (ICC) was 0.97 for the MSFC for session 4 versus session 5 (intrarater reliability). The ICC was 0.95 for session 5 versus session 6 (interrater reliability), and was 0.96 for session 7 versus session 8 when patients were reassessed 6 months later. CONCLUSIONS: The MS functional composite (MSFC) outcome measure had excellent intrarater and interrater reliability when standardized procedures were used to train examining technicians and to assess patients. Prebaseline testing sessions should be included in clinical trials employing the MSFC to compensate for practice effects.