Profiles of executive functioning and neuroticism in emerging adulthood: Concurrent associations with psychopathology and health-related quality of life.

Objective: We employed latent profile analysis (LPA) to discern configurations of executive functioning (EF) and neuroticism (NE) and tested their concurrent validity with respect to internalizing and externalizing problems and physical health. Participants: A total of 125 college students completed the study. Methods: Participants self-reported NE and EF on separate normed rating scales and completed computerized tests of EF. Self-reported internalizing problems, externalizing problems, and global physical health were collected. Results: LPA revealed four profiles: (1) Lower EF + Higher NE, (2) Higher EF + Lower NE, (3) Inconsistent EF + Higher NE, and (4) Inconsistent EF + Lower NE. Adjusting for covariates, profiles were differentially associated with internalizing problems, externalizing problems, and physical health. Conclusions: Screening EF and NE in college students may identify those at risk for psychopathology and physical health concerns. Tailored prevention and intervention efforts on college campuses targeting EF and NE may enhance well-being.

Childhood ADHD and Executive Functioning: Unique Predictions of Early Adolescent Depression.

Given the increasing prevalence of adolescent depression, identification of its early predictors and elucidation of the mechanisms underlying its individual differences is imperative. Controlling for baseline executive functioning (EF), we tested separate ADHD dimensions (i.e., inattention, hyperactivity-impulsivity) as independent predictors of early adolescent depression, including temporally-ordered causal mediation by academic functioning and social problems, using structural equation modeling. At baseline, participants consisted of 216 children (67% male) ages 6-9 years old with (n = 112) and without (n = 104) ADHD who subsequently completed Wave 2 and 3 follow-ups approximately two and four years later, respectively. Predictors consisted of separate parent and teacher ratings of childhood ADHD and laboratory-based assessments of key EF domains. At Wave 2, parents and teachers completed normed rating scales of youth academic and social functioning; youth completed standardized assessments of academic achievement. At Wave 3, youth self-reported depression. Baseline inattention positively predicted early adolescent depression whereas childhood hyperactivity-impulsivity and EF did not. Neither academic nor social functioning significantly mediated predictions of depression from baseline ADHD and EF. We consider prediction of early adolescent depression from inattention, including directions for future intervention and prevention research.

Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD) episodic memory impairments are common; however, it is not known whether these impairments are due to hippocampal pathology. Hippocampal Lewy-bodies emerge by Braak stage 4, but are not uniformly distributed. For instance, hippocampal CA1 Lewy-body pathology has been specifically associated with pre-mortem episodic memory performance in demented patients. By contrast, the dentate gyrus (DG) is relatively free of Lewy-body pathology. In this study, we used ultra-high field 7-Tesla to measure hippocampal subfields in vivo and determine if these measures predict episodic memory impairment in PD during life. METHODS: We studied 29 participants with PD (age 65.5 ±â€¯7.8 years; disease duration 4.5 ±â€¯3.0 years) and 8 matched-healthy controls (age 67.9 ±â€¯6.8 years), who completed comprehensive neuropsychological testing and MRI. With 7-Tesla MRI, we used validated segmentation techniques to estimate CA1 stratum pyramidale (CA1-SP) and stratum radiatum lacunosum moleculare (CA1-SRLM) thickness, dentate gyrus/CA3 (DG/CA3) area, and whole hippocampus area. We used linear regression, which included imaging and clinical measures (age, duration, education, gender, and CSF), to determine the best predictors of episodic memory impairment in PD. RESULTS: In our cohort, 62.1% of participants with PD had normal cognition, 27.6% had mild cognitive impairment, and 10.3% had dementia. Using 7-Tesla MRI, we found that smaller CA1-SP thickness was significantly associated with poorer immediate memory, delayed memory, and delayed cued memory; by contrast, whole hippocampus area, DG/CA3 area, and CA1-SRLM thickness did not significantly predict memory. Age-adjusted linear regression models revealed that CA1-SP predicted immediate memory (beta[standard error]10.895[4.215], p < .05), delayed memory (12.740[5.014], p < .05), and delayed cued memory (12.801[3.991], p < .05). In the fully-adjusted models, which included all five clinical measures as covariates, only CA1-SP remained a significant predictor of delayed cued memory (13.436[4.651], p < .05). CONCLUSIONS: In PD, we found hippocampal CA1-SP subfield thickness estimated on 7-Tesla MRI scans was the best predictor of episodic memory impairment, even when controlling for confounding clinical measures. Our results imply that ultra-high field imaging could be a sensitive measure to identify changes in hippocampal subfields and thus probe the neuroanatomical underpinnings of episodic memory impairments in patients with PD.

Negative Parenting Moderates the Prospective Association of ADHD Symptoms and Youth Social Problems.

Although ADHD and negative parenting are established predictors of youth outcomes, their independent and interactive effects on youth social functioning remain unclear. We tested childhood ADHD symptoms and negative parenting as independent and interactive predictors of prospective change in social problems across a four-year follow-up. At baseline, families of 221 (33% female) children with (n = 94) and without ADHD were rigorously assessed including observed positive and negative parenting behavior, youth ADHD symptoms, as well as multi-informant ratings of youth social problems at multiple occasions. Based on multiple regression with robust standard errors and full-information maximum likelihood procedures to address missing data, ADHD symptoms positively predicted social problems, even with control of observed parenting behavior, child age and sex, oppositional defiant disorder symptoms, and baseline social problems. Additionally, a child ADHD symptoms x negative parenting interaction uniquely predicted separate parent- and teacher-rated social problems where ADHD symptoms positively predicted social problems exclusively in the context of high (+1SD) and very high (+2 SD) negative parenting, respectively. When ADHD was separated into distinct dimensions (i.e., inattention, hyperactivity), an interaction between inattention symptoms and negative parenting approached significance such that inattention symptoms positively predicted parent-rated social problems in the context of high negative parenting. We discuss the interaction between parenting and ADHD symptoms in predictions of youth social problems and implications for intervention.

Association of ADHD and Executive Functioning With Childhood Depression.

Objective: Despite its association with increased severity and treatment resistance, relatively little is known about the correlates of early-onset childhood depression. ADHD and executive functioning (EF) are each related to depression. Given their covariation, we tested the independent association of ADHD dimensions (i.e., inattention, hyperactivity) and EF with childhood depression using structural equation modeling to identify potential targets for intervention. Method: Participants were 225 five- to 10-year-old children (68% male) with (n = 117) and without (n = 108) ADHD. Youth completed laboratory assessments of EF, and parent, teacher, and youth reports of depression were gathered. Results: With control of EF and anxiety, across informants, inattention, but not hyperactivity, was positively related to child depression. EF was positively associated with depression according to parent ratings only. Conclusion: We consider the association of inattention and EF with childhood depression, including implications for intervention and prevention from a developmental psychopathology framework.

Executive Functioning Mediates Predictions of Youth Academic and Social Development from Parenting Behavior.

Using multiple mediation with bootstrapping, dimensions of executive functioning (i.e., inhibitory control, working memory, set shifting) were tested as mediators of predictions of academic and social outcomes from observed positive and negative parenting in 131 children followed prospectively into early adolescence. Inhibitory control and working memory mediated predictions of academic achievement, whereas inhibitory control meditated predictions of school competence from positive parenting. Additionally, working memory mediated predictions of negative social preference, but not social competence, from positive parenting. Executive functioning did not mediate predictions from negative parenting. The role of parenting in shaping youth outcomes through executive functioning is considered.

The effects of dopamine on digit span in Parkinson's disease.

BACKGROUND: Parkinson's disease patients are at an elevated risk of developing cognitive impairment. Although cognitive impairment is one of the strongest predictors of quality of life, dopaminergic anti-parkinsonian medications are designed to target motor symptoms. However, there is substantial evidence that dopamine also impacts cognition, in particular working memory. It is therefore critical for movement disorders physicians to understand the potential dopaminergic effects on working memory when prescribing these medications. Verbal digit span tasks offer a potentially straightforward and quick assessment of baseline working memory. Moreover, Digit Span Backward was recently validated as a screening tool for mild cognitive impairment in Parkinson's disease when participants were medicated. Research indicates that the interaction between dopamine and working memory follows an Inverted-U shaped curve, but the effect of dopamine on Digit Span has not been well studied. Our study seeks to: (1) determine the validity of verbal Digit Spans for detecting cognitive impairment in Parkinson's disease patients both ON and OFF medications; and (2) ascertain the effects of dopaminergic medications on verbal Digit Span. METHODS: We recruited 64 Parkinson's disease patients and 22 age-and education-matched controls. Parkinson's patients completed Digit Span Backward and Digit Span Forward ON and OFF medications, while healthy controls completed them once. All participants were categorized by cognitive diagnosis using level-II consensus criteria. RESULTS: Digit Span Backward successfully identified mild cognitive impairment in Parkinson's disease, both ON and OFF medications. Combining patients with and without cognitive impairment, we found that dopamine significantly improved performance on Digit Span Backward, but not Forward. In a secondary analysis, we found this dopaminergic improvement was restricted to the Low baseline working memory group; the High baseline working memory group was unaffected. CONCLUSIONS: This study provides evidence for Digit Span Backward as a screening tool for working memory impairment in Parkinson's disease and for its utility in measuring baseline working memory. Moreover, it reveals a partial beneficial effect of dopamine on Digit Span in Parkinson's disease patients.

Cross-species translation of the Morris maze for Alzheimer's disease.

Analogous behavioral assays are needed across animal models and human patients to improve translational research. Here, we examined the extent to which performance in the Morris water maze - the most frequently used behavioral assay of spatial learning and memory in rodents - translates to humans. We designed a virtual version of the assay for human subjects that includes the visible-target training, hidden-target learning, and probe trials that are typically administered in the mouse version. We compared transgenic mice that express human amyloid precursor protein (hAPP) and patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) to evaluate the sensitivity of performance measures in detecting deficits. Patients performed normally during visible-target training, while hAPP mice showed procedural learning deficits. In hidden-target learning and probe trials, hAPP mice and MCI-AD patients showed similar deficits in learning and remembering the target location. In addition, we have provided recommendations for selecting performance measures and sample sizes to make these assays sensitive to learning and memory deficits in humans with MCI-AD and in mouse models. Together, our results demonstrate that with careful study design and analysis, the Morris maze is a sensitive assay for detecting AD-relevant impairments across species.

APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory.

OBJECTIVES: Using high-resolution structural MRI, we endeavored to study the relationships among APOE ε4, hippocampal subfield and stratal anatomy, and episodic memory. METHODS: Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE ε4 carrier status. Each subject underwent ultra-high-field 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment. RESULTS: We found a selective, dose-dependent association of APOE ε4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in Alzheimer disease. The relationship between the ε4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE ε4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers. In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE ε4 allele to its phenotypic effects on memory. CONCLUSIONS: The APOE ε4 allele segregated dose-dependently and selectively with CA1-SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation.

Shared vulnerability of two synaptically-connected medial temporal lobe areas to age and cognitive decline: a seven tesla magnetic resonance imaging study.

The medial temporal lobe (MTL) is the first brain area to succumb to neurofibrillary tau pathology in Alzheimer's disease (AD). Postmortem human tissue evaluation suggests that this pathology propagates in an ordered manner, with the entorhinal cortex (ERC) and then CA1 stratum radiatum and stratum lacunosum-moleculare (CA1-SRLM)--two monosynaptically connected structures--exhibiting selective damage. Here, we hypothesized that, if ERC and CA1-SRLM share an early vulnerability to AD pathology, then atrophy should occur in a proportional manner between the two structures. We tested this hypothesis in living humans, using ultra-high field 7.0 T MRI to make fine measurements of MTL microstructure. Among a pool of age-matched healthy controls and patients with amnestic mild cognitive impairment and mild AD, we found a significant correlation between ERC and CA1-SRLM size that could not be explained by global atrophy affecting the MTL. Of the various structures that contribute axons or dendrites into the CA1-SRLM neuropil, only ERC emerged as a significant predictor of CA1-SRLM size in a linear regression analysis. In contrast, other synaptically connected elements of the MTL did not exhibit size correlations. CA1-SRLM and ERC structural covariance was significant for older controls and not patients, whereas the opposite pattern emerged for a correlation between CA1-SRLM and episodic memory performance. Interestingly, CA1-SRLM and ERC were the only MTL structures to atrophy in older controls relative to a younger comparison group. Together, these findings suggest that ERC and CA1-SRLM share vulnerability to both age and AD-associated atrophy.

Altered cortico-striatal-thalamic connectivity in relation to spatial working memory capacity in children with ADHD.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) captures a heterogeneous group of children, who are characterized by a range of cognitive and behavioral symptoms. Previous resting-state functional connectivity MRI (rs-fcMRI) studies have sought to understand the neural correlates of ADHD by comparing connectivity measurements between those with and without the disorder, focusing primarily on cortical-striatal circuits mediated by the thalamus. To integrate the multiple phenotypic features associated with ADHD and help resolve its heterogeneity, it is helpful to determine how specific circuits relate to unique cognitive domains of the ADHD syndrome. Spatial working memory has been proposed as a key mechanism in the pathophysiology of ADHD. METHODS: We correlated the rs-fcMRI of five thalamic regions of interest (ROIs) with spatial span working memory scores in a sample of 67 children aged 7-11 years [ADHD and typically developing children (TDC)]. In an independent dataset, we then examined group differences in thalamo-striatal functional connectivity between 70 ADHD and 89 TDC (7-11 years) from the ADHD-200 dataset. Thalamic ROIs were created based on previous methods that utilize known thalamo-cortical loops and rs-fcMRI to identify functional boundaries in the thalamus. RESULTS/CONCLUSION: Using these thalamic regions, we found atypical rs-fcMRI between specific thalamic groupings with the basal ganglia. To identify the thalamic connections that relate to spatial working memory in ADHD, only connections identified in both the correlational and comparative analyses were considered. Multiple connections between the thalamus and basal ganglia, particularly between medial and anterior dorsal thalamus and the putamen, were related to spatial working memory and also altered in ADHD. These thalamo-striatal disruptions may be one of multiple atypical neural and cognitive mechanisms that relate to the ADHD clinical phenotype.