Higher blood-brain barrier permeability is associated with higher white matter hyperintensities burden.

The pathogenesis of white matter hyperintensities (WMH) is incompletely understood but blood-brain barrier (BBB) dysfunction may play a key role. This study aimed to investigate the relationship between BBB permeability and the severity of WMH burden. Consecutive participants without symptomatic stroke history presented for physical examination were recruited in this cross-sectional study and divided into three WMH burden groups according to total Fazekas scores. They received dynamic contrast-enhanced-magnetic resonance imaging to measure BBB permeability, and received Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). A total of 102 participants aged 49-90 years (mean age of 69.82 years) were enrolled (36 with low WMH burden, 35 with medium WMH burden, and 31 with high WMH burden). Multivariable linear regression analyses revealed that participants with higher WMH burden had significantly higher BBB leakage rate and area under the leakage curve in normal-appearing white matter, WMH, cortical gray matter, and deep gray matter (DGM) after adjustment for age, sex, and vascular risk factors. Scores on MMSE and MoCA decreased with increasing leakage rate in WMH and DGM after adjustment for age, sex, WMH burden, and education years. We found that higher BBB permeability is associated with higher WMH burden and cognitive decline. The compromised BBB integrity may be a critical contributor to the pathogenesis of WMH and part of a series of pathological processes that finally lead to cognitive impairment.

The use of computed tomography scans and the Bender Gestalt Test in the assessment of competency to stand trial and criminal responsibility in the field of mental health and law.

computed tomography and the Bender Gestalt Test are some of the tests used routinely for the assessment of alleged offenders referred under Sections 77 and 78 of the Criminal Procedure Act 51 of 1977. An exploratory retrospective study was conducted at the Free State Psychiatric Complex. The aim of this study was to identify the extent to which the Bender Gestalt Test results and the computed tomography scans are associated with outcomes in the assessment of competency to stand trial and criminal responsibility in individuals referred to the Free State Psychiatric Complex (FSPC) observation unit. This was a cross-sectional study and the entire population of patients admitted in 2013 was included in the study. The clinical and demographic data were obtained from patient files. The majority of participants were black, males, single and unemployed. The most common diagnosis was schizophrenia. The current study showed no statistically significant association between the Bender Gestalt Test Hain's scores and the outcome of criminal responsibility and competency to stand trial. Similarly, the study also showed no statistically significant association between the presence of a brain lesion and the outcome of criminal responsibility and competency to stand trial. It was also concluded that as CT scans are expensive, patients should be referred for that service only when there is a clear clinical indication to do so.

Understanding the Impact of Brain Disorders: Towards a 'Horizontal Epidemiology' of Psychosocial Difficulties and Their Determinants.

OBJECTIVE: To test the hypothesis of 'horizontal epidemiology', i.e. that psychosocial difficulties (PSDs), such as sleep disturbances, emotional instability and difficulties in personal interactions, and their environmental determinants are experienced in common across neurological and psychiatric disorders, together called brain disorders. STUDY DESIGN: A multi-method study involving systematic literature reviews, content analysis of patient-reported outcomes and outcome instruments, clinical input and a qualitative study was carried out to generate a pool of PSD and environmental determinants relevant for nine different brain disorders, namely epilepsy, migraine, multiple sclerosis, Parkinson's disease, stroke, dementia, depression, schizophrenia and substance dependency. Information from these sources was harmonized and compiled, and after feedback from external experts, a data collection protocol including PSD and determinants common across these nine disorders was developed. This protocol was implemented as an interview in a cross-sectional study including a convenience sample of persons with one of the nine brain disorders. PSDs endorsed by at least 25% of patients with a brain disorder were considered associated with the disorder. PSD were considered common across disorders if associated to 5 out of the 9 brain disorders and if among the 5 both neurological and psychiatric conditions were represented. SETTING: The data collection protocol with 64 PSDs and 20 determinants was used to collect data from a convenience sample of 722 persons in four specialized health care facilities in Europe. RESULTS: 57 of the PSDs and 16 of the determinants included in the protocol were found to be experienced across brain disorders. CONCLUSION: This is the first evidence that supports the hypothesis of horizontal epidemiology in brain disorders. This result challenges the brain disorder-specific or vertical approach in which clinical and epidemiological research about psychosocial difficulties experienced in daily life is commonly carried in neurology and psychiatry and the way in which the corresponding health care delivery is practiced in many countries of the world.

Design and methods of the NiCK study: neurocognitive assessment and magnetic resonance imaging analysis of children and young adults with chronic kidney disease.

BACKGROUND: Chronic kidney disease is strongly linked to neurocognitive deficits in adults and children, but the pathophysiologic processes leading to these deficits remain poorly understood. The NiCK study (Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease) seeks to address critical gaps in our understanding of the biological basis for neurologic abnormalities in chronic kidney disease. In this report, we describe the objectives, design, and methods of the NiCK study. DESIGN/METHODS: The NiCK Study is a cross-sectional cohort study in which neurocognitive and neuroimaging phenotyping is performed in children and young adults, aged 8 to 25 years, with chronic kidney disease compared to healthy controls. Assessments include (1) comprehensive neurocognitive testing (using traditional and computerized methods); (2) detailed clinical phenotyping; and (3) multimodal magnetic resonance imaging (MRI) to assess brain structure (using T1-weighted MRI, T2-weighted MRI, and diffusion tensor imaging), functional connectivity (using functional MRI), and blood flow (using arterial spin labeled MRI). Primary analyses will examine group differences in neurocognitive testing and neuroimaging between subjects with chronic kidney disease and healthy controls. Mechanisms responsible for neurocognitive dysfunction resulting from kidney disease will be explored by examining associations between neurocognitive testing and regional changes in brain structure, functional connectivity, or blood flow. In addition, the neurologic impact of kidney disease comorbidities such as anemia and hypertension will be explored. We highlight aspects of our analytical approach that illustrate the challenges and opportunities posed by data of this scope. DISCUSSION: The NiCK study provides a unique opportunity to address key questions about the biological basis of neurocognitive deficits in chronic kidney disease. Understanding these mechanisms could have great public health impact by guiding screening strategies, delivery of health information, and targeted treatment strategies for chronic kidney disease and its related comorbidities.

Global cortical atrophy (GCA) associates with worse performance in the Montreal Cognitive Assessment (MoCA). A population-based study in community-dwelling elders living in rural Ecuador.

BACKGROUND/OBJECTIVE: Increasing numbers of individuals with cognitive impairment are posing economic threads to the developing world. Proper assessment of this condition may be complicated by illiteracy and cross-cultural factors. We conducted a population-based study in elders living in rural Ecuador to evaluate whether the MoCA associated with structural brain damage in less-educated populations. METHODS: Atahualpa residents aged ≥60 years were identified during a door-to-door survey and invited to undergo MRI for grading GCA. Using a multivariate generalized linear model, we evaluated whether MoCA scores correlates with GCA, after adjusting for demographics, education, cardiovascular health (CVH) status, depression and edentulism. RESULTS: Out of 311 eligible persons, 241 (78%) were enrolled. Mean age was 69.2±7.5 years, 141 (59%) were women, 199 (83%) had primary school education, 175 (73%) had poor CVH status, 30 (12%) had symptoms of depression and 104 (43%) had edentulism. Average MoCA scores were 18.5±4.7 points. GCA was mild in 108, moderate in 95, and severe in 26 persons. Total and most domain-specific MoCA scores were significantly worse in persons with moderate to severe GCA. In the multivariate model, mean MoCA score was associated with GCA severity (ß=2.38, SE=1.07, p=0.027). CONCLUSIONS: MoCA scores associate with severity of GCA after adjusting for potential confounders, and may be used as reliable estimates of structural brain damage. However, a lower cut-off than that recommended for developed countries, would be better for recognizing cognitive impairment in less educated populations.

Genetic influences on prefrontal activation during a verbal fluency task in adults: a twin study based on multichannel near-infrared spectroscopy.

Near-infrared spectroscopy (NIRS) studies have reported that prefrontal hemodynamic dysfunction during executive function tasks may be a promising biomarker of psychiatric disorders, because its portability and noninvasiveness allow easy measurements in clinical settings. Here, we investigated the degree to which prefrontal NIRS signals are genetically determined. Using a 52-channel NIRS system, we monitored the oxy-hemoglobin (oxy-Hb) signal changes in 38 adult pairs of right-handed monozygotic (MZ) twins and 13 pairs of same-sex right-handed dizygotic (DZ) twins during a letter version of the verbal fluency task. Heritability was estimated based on a classical twin paradigm using structured equation modeling. Significant genetic influences were estimated in the right dorsolateral prefrontal cortex and left frontal pole. The degrees of heritability were 66% and 75% in the variances, respectively. This implies that the prefrontal hemodynamic dysfunction observed during an executive function task measured by NIRS may be an efficient endophenotype for large-scale imaging genetic studies in psychiatric disorders.

Costs explained by function rather than diagnosis--results from the SNAC Nordanstig elderly cohort in Sweden.

BACKGROUND: Because the prevalence of many brain disorders rises with age, and brain disorders are costly, the economic burden of brain disorders will increase markedly during the next decades. AIM: The purpose of this study is to analyze how the costs to society vary with different levels of functioning and with the presence of a brain disorder. METHODS: Resource utilization and costs from a societal viewpoint were analyzed versus cognition, activities of daily living (ADL), instrumental activities of daily living (IADL), brain disorder diagnosis and age in a population-based cohort of people aged 65 years and older in Nordanstig in Northern Sweden. Descriptive statistics, non-parametric bootstrapping and a generalized linear model (GLM) were used for the statistical analyses. RESULTS: Most people were zero users of care. Societal costs of dementia were by far the highest, ranging from SEK 262,000 (mild) to SEK 519,000 per year (severe dementia). In univariate analysis, all measures of functioning were significantly related to costs. When controlling for ADL and IADL in the multivariate GLM, cognition did not have a statistically significant effect on total cost. The presence of a brain disorder did not impact total cost when controlling for function. The greatest shift in costs was seen when comparing no dependency in ADL and dependency in one basic ADL function. CONCLUSION: It is the level of functioning, rather than the presence of a brain disorder diagnosis, which predicts costs. ADLs are better explanatory variables of costs than Mini mental state examination. Most people in a population-based cohort are zero users of care.

The use of serial testing in evaluating the need for comprehensive neuropsychological testing of adults.

The aim of this study was to develop brief neuropsychological testing procedures that would identify adults (aged 15 and older) who need comprehensive neuropsychological evaluation. The tests used for screening were selected to (1) initially provide a broad catchment procedure followed by (2) a more diversified basis for prediction. The total time required to administer the screening measures is about 45 minutes. The criterion for the need for comprehensive testing was based on the General Neuropsychological Deficit Scale (GNDS), which summarizes 42 variables derived from the complete Halstead-Reitan Battery. The results indicated that the brief testing battery permitted accurate identification of persons who showed neuropsychological impairment based on comprehensive testing. Cutoff points were determined and guidelines were provided for use of the brief testing results.

Health problems due to long working hours in Japan: working hours, workers' compensation (Karoshi), and preventive measures.

Late in the 1970s, serious social concern over health problems due to long working hours has arisen in Japan. This report briefly summarizes the Japanese circumstances about long working hours and what the Government has achieved so far. The national statistics show that more than 6 million people worked for 60 h or more per week during years 2000 and 2004. Approximately three hundred cases of brain and heart diseases were recognized as labour accidents resulting from overwork (Karoshi) by the Ministry of Health, Labour and Welfare (MHLW) between 2002 and 2005. Consequently, the MHLW has been working to establish a more appropriate compensation system for Karoshi, as well as preventive measures for overwork related health problems. In 2001, the MHLW set the standards for clearly recognizing Karoshi in association with the amount of overtime working hours. These standards were based on the results of a literature review and medical examinations indicating a relationship between overwork and brain and heart diseases. In 2002, the MHLW launched the program for the prevention of health impairment due to overwork, and in 2005 the health guidance through an interview by a doctor for overworked workers has been enacted as law. Long working hours are controversial issues because of conflicts between health, safety, work-life balance, and productivity. It is obvious that we need to continue research regarding the impact on worker health and the management of long working hours.

Improving the ecological validity of executive functioning assessment.

The current study investigated ways to improve the ecological validity of the neuropsychological assessment of executive functioning through the formal assessment of compensatory strategies and environmental cognitive demands. Results indicated that the group of executive functioning tests (i.e., Trail Making Test, Wisconsin Card Sorting Test, Stroop, and Controlled Oral Word Association Test) accounted for 18-20% of the variance in everyday executive ability as measured by the Dysexecutive Questionnaire and Brock Adaptive Functioning Questionnaire. The addition of extra-test variables significantly increased the variance in everyday executive ability accounted for. The current study adds to the literature on the ecological validity of executive functioning assessment by highlighting the importance of extra-test variables when trying to understand the complex relationship between cognitive testing and real world performance.

Neural systems responding to degrees of uncertainty in human decision-making.

Much is known about how people make decisions under varying levels of probability (risk). Less is known about the neural basis of decision-making when probabilities are uncertain because of missing information (ambiguity). In decision theory, ambiguity about probabilities should not affect choices. Using functional brain imaging, we show that the level of ambiguity in choices correlates positively with activation in the amygdala and orbitofrontal cortex, and negatively with a striatal system. Moreover, striatal activity correlates positively with expected reward. Neurological subjects with orbitofrontal lesions were insensitive to the level of ambiguity and risk in behavioral choices. These data suggest a general neural circuit responding to degrees of uncertainty, contrary to decision theory.

Longitudinal assessment of adaptive behavior in infants and young children with newly diagnosed epilepsy: influences of etiology, syndrome, and seizure control.

OBJECTIVES: The outcomes of childhood-onset epilepsy are highly varied and have several potential determinants. We examined the independent effects of syndrome type, seizure control, and etiology over time on adaptive behavior as measured by the Vineland Scales of Adaptive Behavior. METHODS: As part of a prospective community-based study of newly diagnosed epilepsy, parents of children who were younger than 3 years at the time of initial onset of epilepsy completed the Vineland Adaptive Behavior Scales screener version at entry into the study and once a year thereafter for up to 3 years. Longitudinal analyses were performed on the composite score as the primary outcome and on the 4 domain scores (communication, socialization, motor, and daily living) as confirmatory/secondary outcomes to determine the effects of syndrome (epileptic encephalopathy or other), seizure control (intractable or not), and etiology (symptomatic or not) on adaptive behavior at the time of initial diagnosis and over time. RESULTS: A total of 613 children were enrolled in the study, and 191 (31%) of these children met the age criterion for this analysis. Of these, 172 (90%) had adequate follow-up and had completed baseline and at least 1 subsequent Vineland assessment. Overall, Vineland scores (composite and individual domains) were somewhat below average at baseline (initial diagnosis). All declined significantly over time. All of the effects at baseline, however, were limited to children with epileptic encephalopathies and symptomatic etiology. Substantial declines over time occurred in these children, and there was an independent effect of intractable seizures as well. In children with none of these factors ( approximately 75% of the study group), baseline scores were consistent with average performance for the test norms and there was no evidence of any decline over time. CONCLUSIONS: Children with an underlying symptomatic etiology or a syndrome that can be characterized as 1 of the epileptic encephalopathies demonstrate impaired adaptive behavior at the time of initial diagnosis and experience additional declines in assessments of age-adjusted performance over time. Our results suggest that future seizure outcome is not strongly reflected in adaptive behavior at initial diagnosis but that it takes its toll on the child over time. Understanding how each of these factors affects development and how they interact with each other is the next step in designing effective interventions for lessening the impact of these disorders on the child. In the majority of children with onset of epilepsy during infancy or early childhood, adaptive behavior is within the normal range and does not show any evidence of declining over time. Although this is encouraging, it does not contradict other studies that have demonstrated behavioral and relatively subtle cognitive difficulties in school-aged children with epilepsy. Long-term follow-up in this cohort will permit us to examine the predictive value of the Vineland for later behavioral and cognitive difficulties in this group that, so far, seems to be doing well.

Patient assessment based on a theory of visual attention (TVA): subtle deficits after a right frontal-subcortical lesion.

We report on a patient who complained of reduced awareness in the left visual field, but showed no visual neglect or extinction in clinical testing. By MR scanning, the brain damage was localized to the right basal ganglia, also involving structures in right frontal cortex. Using psychophysical testing and mathematical modeling based on Bundesen's theory of visual attention [TVA; Psychol. Rev. 97 (1990) 523], the patient's subjective experience of attentional disturbance was confirmed, and the deficit was specified into several components. At very short exposure durations, two effects were shown. The detection threshold was elevated, particularly in the left visual field, and stimuli in this side were given less attentional weight. In addition, the capacity of visual short-term memory (VSTM) was markedly reduced in both visual fields. The robustness of the test results was evaluated by bootstrap analysis. The study demonstrates the sensitivity and specificity gained by combining psychophysical testing with TVA modeling in the analysis of visual attention disorders. Extending the results of a pioneer study of parietal neglect patients by Duncan et al. [J. Exp. Psychol.: Gen. 128 (1999) 450], this study demonstrates the strength of the method in a single case, with a lesion outside parietal cortex, and only minor clinical symptoms.

Sensitivity and specificity of WAIS-III/WMS-III demographically corrected factor scores in neuropsychological assessment.

This study explored the neurodiagnostic utility of 6 factor scores identified by recent exploratory and confirmatory factor analyses of the WAIS-III and WMS-III: Verbal Comprehension, Perceptual Organization, Processing Speed, Working Memory, Auditory Memory and Visual Memory. Factor scores were corrected for age. education, sex and ethnicity to minimize their influences on diagnostic accuracy. Cut-offs at 1, 1.5 and 2 standard deviations (SDs) below the standardization sample mean were applied to data from the overlapping test normative samples (N = 1073) and 6 clinical samples described in the WAIS-III/WMS-III Technical Manual (N = 126). The analyses suggest that a I SD cut-off yields the most balanced levels of sensitivity and specificity; more strict (1.5 or 2 SD) cut-offs generally result in trading modest gains in specificity for larger losses in sensitivity. Finally, using combinations of WAIS-III/WMS-III factors together as test batteries, we explored the sensitivity and specificity implications of varying diagnostic decision rules (e.g.,1 vs. 2 impaired factors = "impairment"). For most of the disorders considered here, even a small (e.g., 3 factor) WAIS-III/WMS-III battery provides quite good overall diagnostic accuracy.

The FAB: a Frontal Assessment Battery at bedside.

OBJECTIVE: To devise a short bedside cognitive and behavioral battery to assess frontal lobe functions. METHODS: The designed battery consists of six subtests exploring the following: conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. It takes approximately 10 minutes to administer. The authors studied 42 normal subjects and 121 patients with various degrees of frontal lobe dysfunction (PD, n = 24; multiple system atrophy, n = 6; corticobasal degeneration, n = 21; progressive supranuclear palsy, n = 47; frontotemporal dementia, n = 23). RESULTS: The Frontal Assessment Battery scores correlated with the Mattis Dementia Rating Scale scores (rho = 0.82, p < 0.01) and with the number of criteria (rho = 0.77, p < 0.01) and perseverative errors (rho = 0.68, p < 0.01) of the Wisconsin Card Sorting Test. These variables accounted for 79% of the variance in a stepwise multiple regression, whereas age or Mini-Mental State Examination scores had no significant influence. There was good interrater reliability (kappa = 0.87, p < 0.001), internal consistency (Cronbach's coefficient alpha = 0.78), and discriminant validity (89.1% of cases correctly identified in a discriminant analysis of patients and controls). CONCLUSION: The Frontal Assessment Battery is easy to administer at bedside and is sensitive to frontal lobe dysfunction.

[Effectiveness and usefulness of neuropsychological rehabilitation methods]. / Effektivität und Anwendbarkeit neuropsychologischer Rehabilitationsverfahren.

Every year, more than half a million people in Germany experience a stroke or a traumatic brain injury. A high percentage of them leave the hospital with neuropsychological deficiencies of attention, memory, speech or perception preventing them from returning to work. The German rehabilitation system is primarily funded by the statutory pension insurance system and is hospital-based, but only very few brain-damaged patients have the opportunity to be treated there. Hospital rehabilitation programmes often integrate neuropsychological trainings whereas neuropsychologically based outpatient programmes do not exist. Therefore two questions are crucial. First, are those separate neuropsychological trainings effective? Second, are positive effects generalized? Studies concerning these questions are reviewed. Not many of them, however, meet the usual requirements for valid intervention research, and their findings are equivocal. Nevertheless, they suggest that neuropsychological rehabilitation should be undertaken more frequently, which would offer a framework for future efficacy research.

[Assessment of cognitive suitability to drive after brain injury]. / Vurdering av kognitiv egnethet for bilkjøring etter hjerneskade.

There is an increasing interest in methods for assessing fitness to hold a driver's licence among patients with traumatic brain injury, cerebrovascular accidents and other central nervous system diseases which present cognitive impairments. This article describes a multimodal approach including medical, neuropsychological and open-road evaluations. We also present a study of 135 patients with cognitive deficits, 29 females and 106 males, mean age 48. Data from neuropsychological assessments are compared to scores on the Mini Mental State Examination and to results from the open-road tests. We recommend that patients with Mini Mental State scores > 20 are referred for further neuropsychological assessments, while patients with scores < 20 are usually unfit for driving. We regard the Mini Mental State Examination as unsuited for patients with aphasia. Our recommendation is that patients who present a complicated picture are referred to regional interdisciplinary centres.

A study of the performance of patients with frontal lobe lesions in a financial planning task.

It has long been argued that patients with lesions in the prefrontal cortex have difficulties in decision making and problem solving in real-world, ill-structured situations, particularly problem types involving planning and look-ahead components. Recently, several researchers have questioned our ability to capture and characterize these deficits adequately using just the standard neuropsychological test batteries, and have called for tests that reflect real-world task requirements more accurately. We present data from 10 patients with focal lesions to the prefrontal cortex and 10 normal control subjects engaged in a real-world financial planning task. We also introduce a theoretical framework and methodology developed in the cognitive science literature for quantifying and analysing the complex data generated by problem-solving tasks. Our findings indicate that patient performance is impoverished at a global level but not at the local level. Patients have difficulty in organizing and structuring their problem space. Once they begin problem solving, they have difficulty in allocating adequate effort to each problem-solving phase. Patients also have difficulty dealing with the fact that there are no right or wrong answers nor official termination points in real-world planning problems. They also find it problematic to generate their own feedback. They invariably terminate the session before the details are fleshed out and all the goals satisfied. Finally, patients do not take full advantage of the fact that constraints on real-world problems are negotiable. However, it is not necessary to postulate a 'planning' deficit. It is possible to understand the patients' difficulties in real world planning tasks in terms of the following four accepted deficits: inadequate access to 'structured event complexes', difficulty in generalizing from particulars, failure to shift between 'mental sets', and poor judgment regarding adequacy and completeness of a plan.