Microstructural degeneration and cerebrovascular risk burden underlying executive dysfunction after stroke

Executive functions are commonly disrupted in people with a traumatic brain injury (TBI), with executive dysfunction having potentially devastating functional consequences. Neuropsychologists are increasingly being asked to make predictions regarding patients’ everyday functional abilities. Despite this, traditional neuropsychological measures of executive function lack sensitivity and ecological validity, whilst administration of newer functional measures such as the Multiple Errands Test can be time consuming, costly, difficult to standardize across settings, and may potentially violate patient privacy or create safety concerns for the patient, therapist, or general public. Virtual reality (VR) assessment paradigms that simulate real world environments and scenarios on computers have been suggested as a potential solution; however studies to date have lacked psychometric rigour. The overall aim of the present thesis was to develop a VR measure of executive function; the Virtual Library Task (VLT) and to compare the ecological and construct validity of this measure with existing neuropsychological measures of executive function. Thirty TBI participants and thirty control participants were administered the VLT, and a real life analogous task - the Real Library Task (RLT), and several neuropsychological measures of executive function: Verbal Fluency, Wisconsin Card Sorting Test – 64: Computer Version (WCST-64CV), the Brixton Spatial Anticipation Test and two more recent tests designed with ecological validity in mind; Zoo Map subtest and Modified Six Elements Test (MSET) from the Behavioural Assessment of the Dysexecutive Syndrome. Significant others for each participant also completed the Dysexecutive Questionnaire (DEX); a behavioural rating scale of everyday executive functioning. Results indicated that performances on the VLT and the RLT were significantly positively correlated. In addition the VLT measures (but none of the neuropsychological measures of executive function) were significant predictors of RLT scores. Despite the TBI group experiencing more everyday executive problems as reported by significant other DEX scores, only one of the five neuropsychological measures, the MSET, was able to differentiate the groups. The VLT successfully differentiated the groups, and was moderately correlated with neuropsychological measures of executive function and not correlated with a theoretically unrelated construct (immediate attention). Results indicated that only the VLT and the MSET were significantly correlated with DEX scores and both these measures significantly predicted everyday executive functioning. Overall the results across studies raise concerns regarding the use of the Verbal Fluency Test, WCST-64CV2, Brixton Spatial Anticipation Test and Zoo Map Test to accurately identify and predict executive function impairments in people with moderate to severe TBI. This is particularly concerning given that these measures are commonly used in clinical practice, with many clinicians interpreting adequate performance on them as patients’ having intact or unimpaired executive functions. In contrast the MSET appears to be both sensitive to executive dysfunction and capable of predicting everyday executive functioning. Results indicate that the VLT is also an ecologically valid measure of executive functioning and provide initial support for the construct validity of this test. The VLT has the advantage over the MSET by providing objective measurement of individual components of executive function. Further investigation of the VLT’s reliability and construct validity is recommended.

Potentially incongruent research literatures suggest three divergent hypotheses about depressive symptomatology: (1) symptoms are recurrent; (2) later-life depression results from high cerebrovascular burden (CVB); and (3) depressive symptoms contribute to comorbidities causing vascular burden. Past vascular depression research assumes that later-life depressive symptoms relate uniquely to high CVB and not to prior, recurrent depression. This study examines these divergent hypotheses. Data include 5175 participants across 18years from the Wisconsin Longitudinal Study (mean age at 1993 baseline was 53years; follow-ups in 2004 and 2011). Depressive symptomatology was measured using the Center for Epidemiological Studies Depression. CVB was operationalized as hypertension, high blood sugar, diabetes, and other heart problems. Hypotheses were examined via a cross-lagged structural equation model and logistic regression. Model fit was acceptable (root mean square error of approximation (RMSEA)=0.047; comparative fit index=0.963). Hypotheses 1 and 2 were supported. Depressive symptomatology at 2004 and 2011 follow-ups was predicted by earlier depressive symptomatology and prior CVB. Hypothesis 3 was partially supported; depressive symptomatology in 2004 predicted subsequent CVB. Logistic regression results were that CVB predicted clinically significant depressive symptoms based on the Center for Epidemiological Studies Depression clinical cutoff. Cerebrovascular burden in midlife predicts depressive symptomatology in later-life, even after accounting for prior depressive symptomatology, supporting a fundamental assumption of the vascular depression hypothesis. Midlife depressive symptomatology also predicted escalation of CVB in later-life. Results suggest a process model of later-life depressive symptom development that interrelates CVB and depressive symptoms throughout the life span and have clinical implications for the interruption of this process through the integration of primary care and behavioral health specialists. Copyright © 2017 John Wiley & Sons, Ltd.

Research in amyotrophic lateral sclerosis (ALS) suggests that executive dysfunction, a prevalent cognitive feature of the disease, is associated with abnormal structural connectivity and white matter integrity. In this exploratory study, we investigated the white matter constructs of executive dysfunction, and attempted to detect structural abnormalities specific to cognitively impaired ALS patients. Eighteen ALS patients and 22 age and education matched healthy controls underwent magnetic resonance imaging on a 4.7 Tesla scanner and completed neuropsychometric testing. ALS patients were categorized into ALS cognitively impaired (ALSci, n = 9) and ALS cognitively competent (ALScc, n = 5) groups. Tract-based spatial statistics and connectomics were used to compare white matter integrity and structural connectivity of ALSci and ALScc patients. Executive function performance was correlated with white matter FA and network metrics within the ALS group. Executive function performance in the ALS group correlated with global and local network properties, as well as FA, in regions throughout the brain, with a high predilection for the frontal lobe. ALSci patients displayed altered local connectivity and structural integrity in these same frontal regions that correlated with executive dysfunction. Our results suggest that executive dysfunction in ALS is related to frontal network disconnectivity, which potentially mediates domain-specific, or generalized cognitive impairment, depending on the degree of global network disruption. Furthermore, reported co-localization of decreased network connectivity and diminished white matter integrity suggests white matter pathology underlies this topological disruption. We conclude that executive dysfunction in ALSci is associated with frontal and global network disconnectivity, underlined by diminished white matter integrity. Hum Brain Mapp 38:1249-1268, 2017. © 2016 Wiley Periodicals, Inc.

Studies evaluating the effect of apolipoprotein E (APOE) on vascular depression are sparse, employ heterogeneous methods, and yield inconsistent results. One possibility is that APOE is a moderator of another predictor such as cerebrovascular burden. This longitudinal study examines the relationships between APOE, cerebrovascular burden, and depressive symptomatology in a large cohort sample from midlife to later life. Data include 3,203 participants across 18 years (1993-2011) from the Wisconsin Longitudinal Study (baseline mean age = 53 years). Depressive symptomatology was measured using the Center for Epidemiologic Studies Depression scale. Cerebrovascular burden was operationalized as hypertension, high blood sugar or diabetes, and other heart problems. APOE genotyping was completed using saliva samples. Hypotheses were examined via a moderated path model and binary logistic regression. Results supported the hypothesized path model (root mean square error of approximation = 0.041; comparative fit index = 0.959); however, APOE-conferred risk was not a significant moderator of the 2004 or 2011 vascular depression effect and only approached significance as a predictor of depression in 2011 (P = .079). The logistic regression yielded APOE as a significant predictor of clinically significant depressive symptoms in 2011 (P = .02, Exp(B) = 1.197). The present findings suggest that APOE may influence expression of depressive symptomatology as adults age into and beyond their mid-70s but do not indicate APOE as a moderator of vascular depression. Results posit a potential explanation for inconsistent past findings.

Heterogeneity in downstream atrophy in Alzheimer's disease (AD) is predominantly investigated in relation to pathological hallmarks (Aβ, tau) and co-pathologies (cerebrovascular burden) independently. However, the proportional contribution of each pathology in determining atrophy pattern remains unclear. We assessed heterogeneity in atrophy using two recently conceptualized dimensions: typicality (typical AD atrophy at the center and deviant atypical atrophy on either extreme including limbic predominant to hippocampal sparing patterns) and severity (overall neurodegeneration spanning minimal atrophy to diffuse typical AD atrophy) in relation to Aβ, tau, and cerebrovascular burden. We included 149 Aβ + individuals on the AD continuum (cognitively normal, prodromal AD, AD dementia) and 163 Aβ- cognitively normal individuals from the ADNI. We modeled heterogeneity in MRI-based atrophy with continuous-scales of typicality (ratio of hippocampus to cortical volume) and severity (total gray matter volume). Partial correlation models investigated the association of typicality/severity with (a) Aβ (global Aβ PET centiloid), tau (global tau PET SUVR), cerebrovascular (total white matter hypointensity volume) burden (b) four cognitive domains (memory, executive function, language, visuospatial composites). Using multiple regression, we assessed the association of each pathological burden and typicality/severity with cognition. (a) In the AD continuum, typicality (r = -0.31, p < 0.001) and severity (r = -0.37, p < 0.001) were associated with tau burden after controlling for Aβ, cerebrovascular burden and age. Findings imply greater tau pathology in limbic predominant atrophy and diffuse atrophy. (b) Typicality was associated with memory (r = 0.49, p < 0.001) and language scores (r = 0.19, p = 0.02). Severity was associated with memory (r = 0.26, p < 0.001), executive function (r = 0.24, p = 0.003) and language scores (r = 0.29, p < 0.001). Findings imply better cognitive performance in hippocampal sparing and minimal atrophy patterns. Beyond typicality/severity, tau burden but not Aβ and cerebrovascular burden explained cognition. In the AD continuum, atrophy-based severity was more strongly associated with tau burden than typicality after accounting for Aβ and cerebrovascular burden. Cognitive performance in memory, executive function and language domains was explained by typicality and/or severity and additionally tau pathology. Typicality and severity may differentially reflect burden arising from tau pathology but not Aβ or cerebrovascular pathologies which need to be accounted for when investigating AD heterogeneity.

Healthy cognitive ageing is a societal and public health priority. Cerebrovascular risk factors increase the likelihood of dementia in older people but their impact on cognitive ageing in younger, healthy brains is less clear. The UK Biobank provides cognition and brain imaging measures in the largest population cohort studied to date. Here we show that cognitive abilities of healthy individuals (N = 22,059) in this sample are detrimentally affected by cerebrovascular risk factors. Structural equation modelling revealed that cerebrovascular risk is associated with reduced cerebral grey matter and white matter integrity within a fronto-parietal brain network underlying executive function. Notably, higher systolic blood pressure was associated with worse executive cognitive function in mid-life (44–69 years), but not in late-life (>70 years). During mid-life this association did not occur in the systolic range of 110–140 mmHg. These findings suggest cerebrovascular risk factors impact on brain structure and cognitive function in healthy people.

The development and decline of brain structure and function throughout adulthood is a complex issue, with cognitive aging trajectories influenced by a host of factors including cerebrovascular risk. Neuroimaging studies of age-related cognitive decline typically reveal a linear decrease in gray matter (GM) volume/density in frontal regions across adulthood. However, white matter (WM) tracts mature later than GM, particularly in regions necessary for executive functions and memory. Therefore, it was predicted that a middle-aged group (MC: 35-45 years) would perform best on a verbal working memory task and reveal greater regional WM integrity, compared with both young (YC: 18-25 years) and elder groups (EC: 60+ years). Diffusion tensor imaging (DTI) and magnetoencephalography (MEG) were obtained from 80 healthy participants. Objective measures of cerebrovascular risk and cognition were also obtained. As predicted, MC revealed best verbal working memory accuracy overall indicating some maturation of brain function between YC and MC. However, contrary to the prediction fractional anisotropy values (FA), a measure of WM integrity, were not greater in MC (i.e., there were no significant differences in FA between YC and MC but both groups showed greater FA than EC). An overall multivariate model for MEG ROIs showed greater peak amplitudes for MC and YC, compared with EC. Subclinical cerebrovascular risk factors (systolic blood pressure and blood glucose) were negatively associated with FA in frontal callosal, limbic, and thalamic radiation regions which correlated with executive dysfunction and slower processing speed, suggesting their contribution to age-related cognitive decline. Hum Brain Mapp 38:3472-3490, 2017. © 2017 Wiley Periodicals, Inc.

The authors reviewed neuroimaging studies of obstructive sleep apnea (OSA) to summarize findings, evaluate their contribution to a current understanding of the neurophysiology of the disorder, and propose directions for future research. Manuscripts were identified using the National Institutes of Health PubMed literature search system. Search terms included obstructive sleep apnea, sleep apnea, imaging, neuroimaging, magnetic resonance imaging, MRI, functional magnetic resonance imaging, fMRI, magnetic resonance spectroscopy, and MRS. Inclusion criteria required that research articles (1) were written in English, (2) examined an adult population, and (3) focused on imaging of the brain. Support for structural abnormalities is mixed, but converging evidence suggests the hippocampus may be atrophic in patients with OSA. Neurochemical evidence is supportive of white-matter impairment in OSA, particularly in the frontal lobes. Functional studies utilizing respiratory challenges report widespread neural differences in motor, sensory, and autonomic brain regions. Functional neuroimaging cognitive challenges have reported either a lack of brain activation in dorsolateral prefrontal cortex or increased neural response in frontal lobe, cingulate, thalamus, cerebellum, and juncture of parietal and temporal lobes, depending on the cognitive task employed. The current literature examining neuroimaging-derived neural correlates in patients with OSA has made many important preliminary contributions. Future studies would be strengthened by consideration of potential moderating participant characteristics, such as sex, age, education, OSA severity, and comorbid conditions. Additional investigation employing neuroimaging techniques is needed to advance our understanding of the neurophysiology of OSA.

Processing speed predicts functional outcome and is a potential endophenotype for schizophrenia. Establishing the neural basis of processing speed impairment may inform the treatment and etiology of schizophrenia. Neuroimaging investigations in healthy subjects have linked processing speed to brain anatomical connectivity. However, the relationship between processing speed impairment and white matter (WM) integrity in schizophrenia is unclear. Individuals with schizophrenia and healthy subjects underwent diffusion tensor imaging (DTI) and completed a brief neuropsychological assessment that included measures of processing speed, verbal learning, working memory and executive functioning. Group differences in WM integrity, inferred from fractional anisotropy (FA), were examined throughout the brain and the hypothesis that processing speed impairment in schizophrenia is mediated by diminished WM integrity was tested. WM integrity of the corpus callosum, cingulum, superior and inferior frontal gyri, and precuneus was reduced in schizophrenia. Average FA in these regions mediated group differences in processing speed but not in other cognitive domains. Diminished WM integrity in schizophrenia was accounted for, in large part, by individual differences in processing speed. Cognitive impairment in schizophrenia was mediated by reduced WM integrity. This relationship was strongest for processing speed because deficits in working memory, verbal learning and executive functioning were not mediated by WM integrity. Larger sample sizes may be required to detect more subtle mediation effects in these domains. Interventions that preserve WM integrity or ameliorate WM disruption may enhance processing speed and functional outcome in schizophrenia.

Introduction: Alzheimer’s disease (AD) is a neurodegenerative disorder with a clinical presentation characterized by memory impairment and executive dysfunction. Our group previously demonstrated significant alterations in white matter microstructural metrics in AD compared to healthy older adults. We aimed to further investigate the relationship between white matter microstructure in AD and cognitive function, including memory and executive function.Methods: Diffusion tensor imaging (DTI) and neuropsychological data were downloaded from the AD Neuroimaging Initiative database for 49 individuals with AD and 48 matched healthy older adults. The relationship between whole-brain fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD), radial diffusivity (RD), and composite scores of memory and executive function was examined. We also considered voxel-wise relationships using Tract-Based Spatial Statistics.Results: As expected, individuals with AD had lower composite scores on tests of memory and executive function, as well as disrupted white matter integrity (low FA, high MD, AxD, and RD) relative to healthy older adults in widespread regions, including the hippocampus. When the AD and healthy older adult groups were combined, we found significant relationships between DTI metrics (FA/MD/AxD/RD) and memory scores across widespread regions of the brain, including the medial temporal regions. We also found significant relationships between DTI metrics (FA/MD/AxD/RD) and executive function in widespread regions, including the frontal areas in the combined group. However, when the groups were examined separately, no significant relationships were found between DTI metrics (FA/MD/AxD/RD) and memory performance for either group. Further, we did not find any significant relationships between DTI metrics (FA/MD/AxD/RD) and executive function in the AD group, but we did observe significant relationships between FA/RD, and executive function in healthy older adults.Conclusion: White matter integrity is disrupted in AD. In a mixed sample of AD and healthy elderly persons, associations between measures of white matter microstructure and memory and executive cognitive test performance were evident. However, no significant linear relationship between the degree of white matter disruption and level of cognitive functioning (memory and executive abilities) was found in those with AD. Future longitudinal studies of the relations between DTI metrics and cognitive function in AD are required to determine whether DTI has potential to measure progression of AD and/or treatment efficacy.

Executive dysfunction is common following brain injury, with impairments involving attention, social pragmatics, higher-order thinking, judgment, and reasoning. Executive function impairments may have a direct impact on an individual's ability to return to instrumental activities of daily living (IADL), including employment, money management, driving, and maintaining a residence. Research has shown that neuropsychological executive function measures may be able to predict daily-living skills. There is limited research evaluating the relationship between executive functions and IADLs in adults with acquired brain injuries (ABI), with none investigating levels of proficiency as related to specific test scores. We hypothesize that neuropsychological executive function measures will have significant and moderate-to-strong correlations with participant-rated proficiency on functional tasks as measured by the Mayo-Portland Adaptability Inventory. Results support that IQ and some of the executive function measures (Processing Speed, Working Memory, and Trail-Making Test-Part B) correlated significantly and strongly and explained unique variance in all IADLs in this study. Data suggest that individuals with ABI who performed in the higher end of the low-average range or higher on measures of executive functioning tend to require little or no assistance to be independent with transportation, money management, living without support, and employment. Results also suggest that individuals with less executive dysfunction are likely to have greater overall community participation.

The association between higher order abilities, processing speed, and age are variably mediated by white matter integrity during typical aging

To examine the association between brain magnetic resonance imaging (MRI) characteristics and executive function and bimanual performance in children with unilateral cerebral palsy (CP). Clinical MRI brain scans were classified as: (1) predominant pathological pattern (normal, white matter injury [WMI]; grey matter injury; focal vascular insults [FVI]; malformations; or miscellaneous); and (2) focal lesions (frontal, basal ganglia, and/or thalamus). Assessments included: (1) bimanual performance; (2) unimanual dexterity; and (3) executive function tasks (information processing, attention control, cognitive flexibility, and goal setting) and behavioural ratings (parent). From 131 recruited children, 60 were ineligible for analysis, leaving 71 children (47 males, 24 females) in the final sample (mean age 9y [SD 2y], 6y-12y 8mo). Brain MRIs were WMI (69%) and FVI (31%); and frontal (59%), thalamic (45%), basal ganglia (37%), and basal ganglia plus thalamic (21%). Bimanual performance was lower in FVI versus WMI (p<0.003), and with frontal (p=0.36), basal ganglia (p=0.032), and thalamic/basal ganglia lesions (p=0.013). Other than information processing, executive function tasks were not associated with predominant pattern. Frontal lesions predicted attention control (p=0.049) and cognitive flexibility (p=0.009) but not goal setting, information processing, or behavioural ratings. Clinical brain MRI predicts cognitive and motor outcomes when focal lesions and predominate lesion patterns are considered. What this paper adds Early brain magnetic resonance imaging (MRI) predicts bimanual performance and cognitive outcomes. Brain MRI may identify children requiring targeted interventions. Basal ganglia with/without thalamic lesions predicted bimanual performance. Frontal lesions were associated with attention control and cognitive flexibility. Brain MRI predominant patterns predicted motor, not cognitive outcomes, other than information processing.

Cognitive and emotional sequellae are commonly observed in stroke patients and these symptoms often co-occur. Diagnosis can be difficult since symptoms of depression and executive dysfunction overlap. To study the longitudinal relationship between depressive symptoms and executive dysfunction in stroke patients. The study comprises of 116 first-ever stroke patients who were followed-up for 2 years and who were assessed for emotional and cognitive sequellae after 1, 6, 12, and 24 months. Emotional disturbances were evaluated using the SCL-90 depression subscale. Executive functions were assessed using compound scores of a combination of the interference scores of the Stroop Colour Word Test and the Concept Shifting Test. Twenty-five patients suffered from both depressive symptoms and executive dysfunction, 28 patients were depressed with no signs of executive dysfunction, and 13 patients showed executive dysfunction with no depressive symptoms. Patients with executive dysfunction had higher mean SCL-90-D scores compared to patients with no executive dysfunction (30.9 (SD 11.7) versus 26.2 (SD 11.1, p = 0.037). Depressive symptoms were predictive for executive dysfunction in a regression analysis corrected for age, sex, and diabetes mellitus but not after additional correction for pre-existent brain damage and other vascular risk factors. After 2 years 66.6 and 53.3% of patients with both depressive symptoms and executive dysfunction at baseline still had depressive symptoms and executive dysfunctions respectively and had worse prognostic outcome than patients with depressive symptoms or executive dysfunction alone. Symptoms of depression and executive dysfunction are highly prevalent in stroke patients and often co-occur. These patients are more at risk for poor stroke outcome, chronic depression, and cognitive deterioration.

Results from recent studies addressing the vascular depression hypothesis have been mixed, with cerebrovascular risk factors (CVRFs) predicting depression in some geriatric patients but not in others. The current study seeks to examine executive dysfunction as a potential moderator of the relationship between CVRFs and depressive symptoms. Data concerning CVRFs, executive functioning, and depressive symptoms from 77 geriatric rehabilitation patients were incorporated to test the hypothesis that patients with executive dysfunction and greater CVRFs would demonstrate the highest levels of depression over time. CVRFs (diabetes, hypertension, atrial fibrillation) were measured via diagnosis by treating physician. Depression was assessed using the 15-item Geriatric Depression Scale (GDS) at baseline and at 6-month and 18-month follow-ups. Executive functioning was measured at baseline using the Initiation/Perseveration (IP) Subtest of the Mattis Dementia Rating Scale. Multivariate analysis of variance demonstrated a significant statistical interaction between the number of CVRFs and scores on the IP Subtest on depressive symptoms. Patients with two or more CVRFs and lower IP scores demonstrated significantly greater depressive symptoms at baseline and at 18-month follow-up than patients with fewer CVRFs and higher IP scores. The univariate effect at 6 months was not significant. The current data suggest that scores on an index of executive functioning may moderate the relationship between CVRFs and depressive symptoms. Interpretation of these findings is provided in the context of the vascular depression hypothesis and related frontostriatal dysfunction. Patients with greater CVRF burden and poor executive functioning may be at particularly high risk for depression.