Evidence for abnormal brain function as measured with diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) and cognitive dysfunction have been observed in inter-episode bipolar disorder (BD) patients. We aimed to create a joint statistical model of white matter integrity and functional response measures in explaining differences in working memory and processing speed among BD patients. Medicated inter-episode BD (n=26; age=45.2±10.1 years) and healthy comparison (HC; n=36; age=46.3±11.5 years) participants completed 51-direction DTI and fMRI while performing a working memory task. Participants also completed a processing speed test. Tract-based spatial statistics identified common white matter tracts where fractional anisotropy was calculated from atlas-defined regions of interest. Brain responses within regions of interest activation clusters were also calculated. Least angle regression was used to fuse fMRI and DTI data to select the best joint neuroimaging predictors of cognitive performance for each group. While there was overlap between groups in which regions were most related to cognitive performance, some relationships differed between groups. For working memory accuracy, BD-specific predictors included bilateral dorsolateral prefrontal cortex from fMRI, splenium of the corpus callosum, left uncinate fasciculus, and bilateral superior longitudinal fasciculi from DTI. For processing speed, the genu and splenium of the corpus callosum and right superior longitudinal fasciculus from DTI were significant predictors of cognitive performance selectively for BD patients. BD patients demonstrated unique brain-cognition relationships compared to HC. These findings are a first step in discovering how interactions of structural and functional brain abnormalities contribute to cognitive impairments in BD. (JINS, 2015, 21, 330–341)

While neuropsychological deficits in both “hot” and “cool” executive functions (EFs) have been documented among individuals with attention-deficit/hyperactivity disorder (ADHD), these EF deficits are not universal across all individuals with this diagnosis. One potential moderator of executive dysfunction may be the presence of comorbid oppositional defiant disorder (ODD). This study examined the association between “hot” and “cool” EFs and comorbid ODD in children with ADHD. Thirty-three children with ADHD and comorbid ODD (ADHD+ODD), 67 with ADHD without ODD (ADHD-ODD), and 30 typically developing controls participated. Children were 7–12 years of age. “Cool” EFs were assessed with a spatial span task and a card sorting test. “Hot” EFs were assessed using a delay discounting task and a gambling task. ADHD-ODD and ADHD+ODD groups performed more poorly on “cool” EF tasks than controls, but did not differ from each other. Furthermore, the number of ADHD symptoms, but not ODD symptoms, was associated with “cool” EF scores. The three groups did not differ on “hot” EF tasks and the number of ADHD or ODD symptoms was unrelated to “hot” EF scores. In sum, children with ADHD presented with “cool” EF deficits which appear to be unrelated to ODD comorbidity. However, “hot” EF deficits were not present among children with ADHD, irrespective of comorbid ODD status. (JINS, 2015, 21, 584–595)

White matter disruptions have been identified in individuals with congenital heart disease (CHD). However, no specific theory-driven relationships between microstructural white matter disruptions and cognition have been established in CHD. We conducted a two-part study. First, we identified significant differences in fractional anisotropy (FA) of emerging adults with CHD using Tract-Based Spatial Statistics (TBSS). TBSS analyses between 22 participants with CHD and 18 demographically similar controls identified five regions of normal appearing white matter with significantly lower FA in CHD, and two higher. Next, two regions of lower FA in CHD were selected to examine theory-driven differential relationships with cognition: voxels along the left uncinate fasciculus (UF; a tract theorized to contribute to verbal memory) and voxels along the right middle cerebellar peduncle (MCP; a tract previously linked to attention). In CHD, a significant positive correlation between UF FA and memory was found, r(20)=.42, p=.049 (uncorrected). There was no correlation between UF and auditory attention span. A positive correlation between MCP FA and auditory attention span was found, r(20)=.47, p=.027 (uncorrected). There was no correlation between MCP and memory. In controls, no significant relationships were identified. These results are consistent with previous literature demonstrating lower FA in younger CHD samples, and provide novel evidence for disrupted white matter integrity in emerging adults with CHD. Furthermore, a correlational double dissociation established distinct white matter circuitry (UF and MCP) and differential cognitive correlates (memory and attention span, respectively) in young adults with CHD. (JINS, 2015, 21, 22–33)

Neuropsychological assessment aims to identify individual performance profiles in multiple domains of cognitive functioning; however, substantial variation exists in how deficits are defined and what cutoffs are used, and there is no universally accepted definition of neuropsychological impairment. The aim of this study was to derive and validate a clinical case definition rule to identify neuropsychological impairment in children and adolescents. An existing normative pediatric sample was used to calculate base rates of abnormal functioning on eight measures covering six domains of neuropsychological functioning. The dataset was analyzed by varying the range of cutoff levels [1, 1.5, and 2 standard deviations (SDs) below the mean] and number of indicators of impairment. The derived rule was evaluated by bootstrap, internal and external clinical validation (orthopedic and traumatic brain injury). Our neuropsychological impairment (NPI) rule was defined as “two or more test scores that fall 1.5 SDs below the mean.” The rule identifies 5.1% of the total sample as impaired in the assessment battery and consistently targets between 3 and 7% of the population as impaired even when age, domains, and number of tests are varied. The NPI rate increases in groups known to exhibit cognitive deficits. The NPI rule provides a psychometrically derived method for interpreting performance across multiple tests and may be used in children 6–18 years. The rule may be useful to clinicians and scientists who wish to establish whether specific individuals or clinical populations present within expected norms versus impaired function across a battery of neuropsychological tests. (JINS, 2015, 21, 596–609)

Although there is mounting evidence that greater PTSD symptoms are associated with reduced executive functioning, it is not fully understood whether this association is more global or specific to certain executive function subdomains, such as inhibitory control. We investigated the generality of the association between PTSD symptoms and executive function by administering a broad battery of sensitive executive functioning tasks to a cohort of returning Operation Enduring Freedom/Operation Iraqi Freedom Veterans with varying PTSD symptoms. Only tasks related to inhibitory control explained significant variance in PTSD symptoms as well as symptoms of depression, while measures of working memory, measures of switching, and measures simultaneously assessing multiple executive function subdomains did not. Notably, the two inhibitory control measures that showed the highest correlation with PTSD and depressive symptoms, measures of response inhibition and distractor suppression, explained independent variance. These findings suggest that greater posttraumatic psychological symptoms are not associated with a general decline in executive functioning but rather are more specifically related to stopping automatic responses and resisting internal and external distractions. (JINS, 2015, 21, 342–352)

Individuals with amnestic mild cognitive impairment (aMCI) show minor decrements in their instrumental activities of daily living (IADL). Sensitive measures of IADL performance are needed to capture the mild difficulties observed in aMCI groups. Routine naturalistic actions (NAs) are familiar IADL-type activities that require individuals to enact everyday tasks such as preparing coffee. In the current study we examined the extent to which NAs could be used to help facilitate differential diagnosis of aMCI relative to composite measures of episodic memory, semantic knowledge, and executive function. Healthy older adults (n=24) and individuals with aMCI (n=24) enacted two highly familiar NAs and completed tests of episodic memory, semantic knowledge, and executive function. Binary logistic regression was used to predict group membership (aMCI vs. control participants). The regression analyses indicated that NA performance could reliably predict group membership, over and above measures of cognitive functioning. These findings indicated that NA performance can be used to help facilitate differential diagnosis of healthy aging and aMCI and used as an outcome measure in intervention studies. (JINS, 2015, 21, 419–428)

Racially patterned disadvantage in Southern states, especially during the formative years of primary school, may contribute to enduring disparities in adult cognitive outcomes. Drawing on a lifecourse perspective, we examine whether state of school attendance affects cognitive outcomes in older adults and partially contributes to persistent racial disparities. Using data from older African American and white participants in the national Health and Retirement Study (HRS) and the New York based Washington Heights Inwood Cognitive Aging Project (WHICAP), we estimated age-and gender-adjusted multilevel models with random effects for states predicting years of education and cognitive outcomes (e.g., memory and vocabulary). We summarized the proportion of variation in outcomes attributable to state of school attendance and compared the magnitude of racial disparities across states. Among WHICAP African Americans, state of school attendance accounted for 9% of the variance in years of schooling, 6% of memory, and 12% of language. Among HRS African Americans, state of school attendance accounted for 13% of the variance in years of schooling and also contributed to variance in cognitive function (7%), memory (2%), and vocabulary (12%). Random slope models indicated state-level African American and white disparities in every Census region, with the largest racial differences in the South. State of school attendance may contribute to racial disparities in cognitive outcomes among older Americans. Despite tremendous within-state heterogeneity, state of school attendance also accounted for some variability in cognitive outcomes. Racial disparities in older Americans may reflect historical patterns of segregation and differential access to resources such as education. (JINS, 2015, 21, 677–687)

Cortical atrophy is a biomarker of Alzheimer’s disease (AD) that correlates with clinical symptoms. This study examined changes in cortical thickness from before to after an exercise intervention in mild cognitive impairment (MCI) and healthy elders. Thirty physically inactive older adults (14 MCI, 16 healthy controls) underwent MRI before and after participating in a 12-week moderate intensity walking intervention. Participants were between the ages of 61 and 88. Change in cardiorespiratory fitness was assessed using residualized scores of the peak rate of oxygen consumption (V̇O2peak) from pre- to post-intervention. Structural magnetic resonance images were processed using FreeSurfer v5.1.0. V̇O2peak increased an average of 8.49%, which was comparable between MCI and healthy elders. Overall, cortical thickness was stable except for a significant decrease in the right fusiform gyrus in both groups. However, improvement in cardiorespiratory fitness due to the intervention (V̇O2peak) was positively correlated with cortical thickness change in the bilateral insula, precentral gyri, precuneus, posterior cingulate, and inferior and superior frontal cortices. Moreover, MCI participants exhibited stronger positive correlations compared to healthy elders in the left insula and superior temporal gyrus. A 12-week moderate intensity walking intervention led to significantly improved fitness in both MCI and healthy elders. Improved V̇O2peak was associated with widespread increased cortical thickness, which was similar between MCI and healthy elders. Thus, regular exercise may be an especially beneficial intervention to counteract cortical atrophy in all risk groups, and may provide protection against future cognitive decline in both healthy elders and MCI. (JINS, 2015, 21, 757–767)

HIV-associated cognitive impairments are prevalent, and are consistent with injury to both frontal cortical and subcortical regions of the brain. The current study aimed to assess the association of HIV infection with functional connections within the frontostriatal network, circuitry hypothesized to be highly vulnerable to HIV infection. Fifteen HIV-positive and 15 demographically matched control participants underwent 6 min of resting-state functional magnetic resonance imaging (RS-fMRI). Multivariate group comparisons of age-adjusted estimates of connectivity within the frontostriatal network were derived from BOLD data for dorsolateral prefrontal cortex (DLPFC), dorsal caudate and mediodorsal thalamic regions of interest. Whole-brain comparisons of group differences in frontostriatal connectivity were conducted, as were pairwise tests of connectivity associations with measures of global cognitive functioning and clinical and immunological characteristics (nadir and current CD4 count, duration of HIV infection, plasma HIV RNA). HIV – associated reductions in connectivity were observed between the DLPFC and the dorsal caudate, particularly in younger participants (<50 years, N=9). Seropositive participants also demonstrated reductions in dorsal caudate connectivity to frontal and parietal brain regions previously demonstrated to be functionally connected to the DLPFC. Cognitive impairment, but none of the assessed clinical/immunological variables, was also associated with reduced frontostriatal connectivity. In conclusion, our data indicate that HIV is associated with attenuated intrinsic frontostriatal connectivity. Intrinsic connectivity of this network may therefore serve as a marker of the deleterious effects of HIV infection on the brain, possibly via HIV-associated dopaminergic abnormalities. These findings warrant independent replication in larger studies. (JINS, 2015, 21, 1–11)

This study explored effects of the metabolic syndrome (MetS) on language in aging. MetS is a constellation of five vascular and metabolic risk factors associated with the development of chronic diseases and increased risk of mortality, as well as brain and cognitive impairments. We tested 281 English-speaking older adults aged 55–84, free of stroke and dementia. Presence of MetS was based on the harmonized criteria (Alberti et al., 2009). Language performance was assessed by measures of accuracy and reaction time on two tasks of lexical retrieval and two tasks of sentence processing. Regression analyses, adjusted for age, education, gender, diabetes, hypertension, and heart disease, demonstrated that participants with MetS had significantly lower accuracy on measures of lexical retrieval (action naming) and sentence processing (embedded sentences, both subject and object relative clauses). Reaction time was slightly faster on the test of embedded sentences among those with MetS. MetS adversely affects the language performance of older adults, impairing accuracy of both lexical retrieval and sentence processing. This finding reinforces and extends results of earlier research documenting the negative influence of potentially treatable medical conditions (diabetes, hypertension) on language performance in aging. The unanticipated finding that persons with MetS were faster in processing embedded sentences may represent an impairment of timing functions among older individuals with MetS. (JINS, 2015, 21, 116–125)

Adult survivors of childhood brain tumors are at risk for cognitive performance deficits that require the core cognitive skill of working memory. Our goal was to examine the neural mechanisms underlying working memory performance in survivors. We studied the working memory of adult survivors of pediatric posterior fossa brain tumors using a letter n-back paradigm with varying cognitive workload (0-, 1-, 2-, and 3-back) and functional magnetic resonance imaging as well as neuropsychological measures. Survivors of childhood brain tumors evidenced lower working memory performance than demographically matched healthy controls. Whole-brain analyses revealed significantly greater blood-oxygen level dependent (BOLD) activation in the left superior / middle frontal gyri and left parietal lobe during working memory (2-back versus 0-back contrast) in survivors. Left frontal BOLD response negatively correlated with 2- and 3-back working memory performance, Auditory Consonant Trigrams (ACT), and Digit Span Backwards. In contrast, parietal lobe BOLD response negatively correlated with 0-back (vigilance task) and ACT. The results revealed that adult survivors of childhood posterior fossa brain tumors recruited additional cognitive control resources in the prefrontal lobe during increased working memory demands. This increased prefrontal activation is associated with lower working memory performance and is consistent with the allocation of latent resources theory. (JINS, 2015, 21, 494–505)

There is currently some debate as to whether hippocampus mediates contextual cueing. In the present study, we examined contextual cueing in patients diagnosed with mild cognitive impairment (MCI) and healthy older adults, with the main goal of investigating the role of hippocampus in this form of learning. Amnestic MCI (aMCI) patients and healthy controls completed the contextual cueing task, in which they were asked to search for a target (a horizontal T) in an array of distractors (rotated L’s). Unbeknownst to them, the spatial arrangement of elements on some displays was repeated thus making the configuration a contextual cue to the location of the target. In contrast, the configuration for novel displays was generated randomly on each trial. The difference in response times between repeated and novel configurations served as a measure of contextual learning. aMCI patients, as a group, were able to learn spatial contextual cues as well as healthy older adults. However, better learning on this task was associated with higher hippocampal volume, particularly in right hemisphere. Furthermore, contextual cueing performance was significantly associated with hippocampal volume, even after controlling for age and MCI status. These findings support the role of the hippocampus in learning of spatial contexts, and also suggest that the contextual cueing paradigm can be useful in detecting neuropathological changes associated with the hippocampus. (JINS, 2015, 21, 285–296)

Non-right handedness (NRH) is reportedly more common in very preterm (VPT; <32 weeks’ gestation) children compared with term-born peers, but it is unclear whether neonatal brain injury or altered brain morphology and microstructure underpins NRH in this population. Given that NRH has been inconsistently reported to be associated with cognitive and motor difficulties, this study aimed to examine associations between handedness and neurodevelopmental outcomes in VPT 7-year-olds. Furthermore, the relationship between neonatal brain injury and integrity of motor tracts (corpus callosum and corticospinal tract) with handedness at age 7 years in VPT children was explored. One hundred seventy-five VPT and 69 term-born children completed neuropsychological and motor assessments and a measure of handedness at 7 years’ corrected age. At term-equivalent age, brain injury on MRI was assessed and diffusion tensor measures were obtained for the corpus callosum and posterior limb of the internal capsule. There was little evidence of stronger NRH in the VPT group compared with term controls (regression coefficient [b] −1.95, 95% confidence interval [−5.67, 1.77]). Poorer academic and working memory outcomes were associated with stronger NRH in the VPT group. While there was little evidence that neonatal unilateral brain injury was associated with stronger NRH, increased area and fractional anisotropy of the corpus callosum splenium were predictive of stronger NRH in the VPT group. VPT birth may alter the relationship between handedness and academic outcomes, and neonatal corpus callosum integrity predicts hand preference in VPT children at school age. (JINS, 2015, 21, 610–621)

Children and adolescents with critical cyanotic congenital heart disease (CHD) are at risk for deficits in aspects of executive function (EF). The primary aim of this investigation was to compare EF outcomes in three groups of children/adolescents with severe CHD and controls (ages 10–19 years). Participants included 463 children/adolescents with CHD [dextro-transposition of the great arteries (TGA), n=139; tetralogy of Fallot (TOF), n=68; and, single-ventricle anatomy requiring Fontan procedure (SVF), n=145] and 111 controls, who underwent laboratory and informant-based evaluation of EF skills. Rates of EF impairment on D-KEFS measures were nearly twice as high for CHD groups (75–81%) than controls (43%). Distinct EF profiles were documented between CHD groups on D-KEFS tasks. Deficits in flexibility/problem-solving and verbally mediated EF skills were documented in all three CHD groups; visuo-spatially mediated EF abilities were impaired in TOF and SVF groups, but preserved in TGA. Parent, teacher, and self-report ratings on the BRIEF highlighted unique patterns of metacognitive and self-regulatory concerns across informants. CHD poses a serious threat to EF development. Greater severity of CHD is associated with worse EF outcomes. With increased understanding of the cognitive and self-regulatory vulnerabilities experienced by children and adolescents with CHD, it may be possible to identify risks early and provide individualized supports to promote optimal neurodevelopment. (JINS, 2014, 20, 34–49)

To compare neuropsychological test performance of Veterans with and without mild traumatic brain injury (MTBI), blast exposure, and posttraumatic stress disorder (PTSD) symptoms. We compared the neuropsychological test performance of 49 Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans diagnosed with MTBI resulting from combat blast-exposure to that of 20 blast-exposed OEF/OIF Veterans without history of MTBI, 23 OEF/OIF Veterans with no blast exposure or MTBI history, and 40 matched civilian controls. Comparison of neuropsychological test performance across all four participant groups showed a complex pattern of mixed significant and mostly nonsignificant results, with omnibus tests significant for measures of attention, spatial abilities, and executive function. The most consistent pattern was the absence of significant differences between blast-exposed Veterans with MTBI history and blast-exposed Veterans without MTBI history. When blast-exposed Veteran groups with and without MTBI history were aggregated and compared to non–blast-exposed Veterans, there were significant differences for some measures of learning and memory, spatial abilities, and executive function. However, covariation for severity of PTSD symptoms eliminated all significant omnibus neuropsychological differences between Veteran groups. Our results suggest that, although some mild neurocognitive effects were associated with blast exposure, these neurocognitive effects might be better explained by PTSD symptom severity rather than blast exposure or MTBI history alone. (JINS, 2015, 21, 353–363)

Older adults with early forms of neurodegenerative disease are at risk for functional disability, which is often defined by the loss of independence in instrumental activities of daily living (IADLs). The current study investigated the influence of mild changes in everyday functional abilities (referred to as functional limitations) on risk for development of incident functional disability. A total of 407 participants, who were considered cognitively normal or diagnosed with mild cognitive impairment (MCI) at baseline, were followed longitudinally over an average 4.1 years (range=0.8–9.2 years). Informant-based ratings from the Everyday Cognition (ECog; Farias et al., 2008) and the Instrumental Activities of Daily Living (Lawton & Brody, 1969) scales assessed the degree of functional limitations and incident IADL disability, respectively. Cox proportional hazards models revealed that more severe functional limitations (as measured by the Total ECog score) at baseline were associated with approximately a four-fold increased risk of developing IADL disability a few years later. Among the ECog domains, functional limitations in Everyday Planning, Everyday Memory, and Everyday Visuospatial domains were associated with the greatest risk of incident functional disability. These results remained robust even after controlling for participants’ neuropsychological functioning on tests of executive functions and episodic memory. Current findings indicate that early functional limitations have prognostic value in identifying older adults at risk for developing functional disability. Findings highlight the importance of developing interventions to support everyday abilities related to memory, executive function, and visuospatial skills in an effort to delay loss of independence in IADLs. (JINS, 2015, 21, 688–698)

Better performance due to repeated testing can bias long-term trajectories of cognitive aging and correlates of change. We examined whether retest effects differ as a function of individual differences pertinent to cognitive aging: race/ethnicity, age, sex, language, years of education, literacy, and dementia risk factors including apolipoprotein E ε4 status, baseline cognitive performance, and cardiovascular risk. We used data from the Washington Heights-Inwood Columbia Aging Project, a community-based cohort of older adults (n=4073). We modeled cognitive change and retest effects in summary factors for general cognitive performance, memory, executive functioning, and language using multilevel models. Retest effects were parameterized in two ways, as improvement between the first and subsequent testings, and as the square root of the number of prior testings. We evaluated whether the retest effect differed by individual characteristics. The mean retest effect for general cognitive performance was 0.60 standard deviations (95% confidence interval [0.46, 0.74]), and was similar for memory, executive functioning, and language. Retest effects were greater for participants in the lowest quartile of cognitive performance (many of whom met criteria for dementia based on a study algorithm), consistent with regression to the mean. Retest did not differ by other characteristics. Retest effects are large in this community-based sample, but do not vary by demographic or dementia-related characteristics. Differential retest effects may not limit the generalizability of inferences across different groups in longitudinal research. (JINS, 2015, 21, 506–518)

The objective of this study was to describe the neuropsychological profiles of the three variants of primary progressive aphasia (PPA). Based on a comprehensive speech and language evaluation, 91 subjects were classified as logopenic (lvPPA=51), semantic (svPPA=13), or agrammatic (agPPA=27). All subjects completed a separate neuropsychological evaluation assessing verbal and visual memory, processing speed, executive function, and visuospatial function. The groups did not differ on demographic variables or on measures of disease duration or aphasia severity. There were group differences on aspects of learning and memory, as well as aspects of executive and visuospatial functions, primarily with the lvPPA group performing lower than the agPPA and svPPA groups. The agPPA group showed subtle deficits consistent with frontal lobe impairment, whereas neurocognitive weaknesses in the svPPA group were restricted to temporal lobe functions. The pattern of neurocognitive dysfunction in lvPPA suggests disease involvement of frontal lobe functions in addition to temporoparietal functions. These neurocognitive findings emphasize the value of a comprehensive neuropsychological evaluation of individuals who present with primary language disturbance, given the pattern of cognitive deficits may provide additive information for differentiating these clinical syndromes. (JINS, 2015, 21, 429–435)

Dementia cases are increasing worldwide; thus, investigators seek to identify interventions that might prevent or ameliorate cognitive decline in later life. Extensive research confirms the benefits of physical exercise for brain health, yet only a fraction of older adults exercise regularly. Interactive mental and physical exercise, as in aerobic exergaming, not only motivates, but has also been found to yield cognitive benefit above and beyond traditional exercise. This pilot study sought to investigate whether greater cognitive challenge while exergaming would yield differential outcomes in executive function and generalize to everyday functioning. Sixty-four community based older adults (mean age=82) were randomly assigned to pedal a stationary bike, while interactively engaging on-screen with: (1) a low cognitive demand task (bike tour), or (2) a high cognitive demand task (video game). Executive function (indices from Trails, Stroop and Digit Span) was assessed before and after a single-bout and 3-month exercise intervention. Significant group × time interactions were found after a single-bout (Color Trails) and after 3 months of exergaming (Stroop; among 20 adherents). Those in the high cognitive demand group performed better than those in the low cognitive dose condition. Everyday function improved across both exercise conditions. Pilot data indicate that for older adults, cognitive benefit while exergaming increased concomitantly with higher doses of interactive mental challenge. (JINS, 2015, 21, 768–779)