Counting on random number generation: Uncovering mild executive dysfunction in congenital heart disease.

Congenital heart disease (CHD) is associated with various neurocognitive deficits, particularly targeting executive functions (EFs), of which random number generation (RNG) is one indicator. RNG has, however, never been investigated in CHD. We administered the Mental Dice Task (MDT) to 67 young adults with CHD and 55 healthy controls. This 1-minute-task requires the generation of numbers 1 to 6 in a random sequence. RNG performance was correlated with a global EF score. Participants underwent MRI to examine structural-volumetric correlates of RNG. Compared to controls, CHD patients showed increased backward counting, reflecting deficient inhibition of automatized behavior. They also lacked a small-number bias (higher frequency of small relative to large numbers). RNG performance was associated with global EF scores in both groups. In CHD patients, MRI revealed an inverse association of counting bias with most of the volumetric measurements and the amount of small numbers was positively associated with corpus callosum volume, suggesting callosal involvement in the "pseudoneglect in number space". In conclusion, we found an impaired RNG performance in CHD patients, which is associated with brain volumetric measures. RNG, reportedly resistant to learning effects, may be an ideal task for the longitudinal assessment of EFs in patients with CHD.

Association of cerebellar volume with cognitive and motor function in adults with congenital heart disease.

INTRODUCTION: Patients with congenital heart disease (CHD) are at risk for cognitive and motor function impairments, brain injury, and smaller total brain volumes. The specific vulnerability of the cerebellum and its role in cognitive and motor functions in adults with congenital heart disease is not well defined. METHODS: Forty-three patients with CHD and 53 controls between 18 and 32 years underwent brain magnetic resonance imaging and cognitive, executive (EF), and motor function assessment. Cerebellar volumes were obtained using EasyMeasure and SUIT Toolbox. Associations between cerebellar volumes and cognitive and motor function were calculated using linear models. RESULTS: General cognitive and pure motor functions were lower in patients compared to controls (P < 0.05). Executive functions were within the normal range. While total cerebellar volumes and the anterior lobes were similar in patients and controls (P > 0.1), the posterior cerebellar lobe was smaller in patients with more complex CHD (P = 0.006). Smaller posterior cerebellar gray matter was not associated with cognitive functions. Smaller anterior cerebellar gray matter was not significantly related to motor functions (P > 0.1). CONCLUSION: In adults with CHD, cerebellar volume was largely unimpaired. Patients with more complex CHD may be vulnerable to changes in the posterior cerebellar gray matter. We found no significant contribution of cerebellar gray matter to cognitive and motor impairments. More advanced imaging techniques are necessary to clarify the contribution of the cerebellum to cognitive and motor functions.

Successful weaning versus permanent cerebrospinal fluid diversion after aneurysmal subarachnoid hemorrhage: post hoc analysis of a Swiss multicenter study.

OBJECTIVE: Acute hydrocephalus is a frequent complication after aneurysmal subarachnoid hemorrhage (aSAH). Among patients needing CSF diversion, some cannot be weaned. Little is known about the comparative neurological, neuropsychological, and health-related quality-of-life (HRQOL) outcomes in patients with successful and unsuccessful CSF weaning. The authors aimed to assess outcomes of patients by comparing those with successful and unsuccessful CSF weaning; the latter was defined as occurring in patients with permanent CSF diversion at 3 months post-aSAH. METHODS: The authors included prospectively recruited alert (i.e., Glasgow Coma Scale score 13-15) patients with aSAH in this retrospective study from six Swiss neurovascular centers. Patients underwent serial neurological (National Institutes of Health Stroke Scale), neuropsychological (Montreal Cognitive Assessment), disability (modified Rankin Scale), and HRQOL (EuroQol-5D) examinations at < 72 hours, 14-28 days, and 3 months post-aSAH. RESULTS: Of 126 included patients, 54 (42.9%) developed acute hydrocephalus needing CSF diversion, of whom 37 (68.5%) could be successfully weaned and 17 (31.5%) required permanent CSF diversion. Patients with unsuccessful weaning were older (64.5 vs 50.8 years, p = 0.003) and had a higher rate of intraventricular hemorrhage (52.9% vs 24.3%, p = 0.04). Patients who succeed in restoration of physiological CSF dynamics improve on average by 2 points on the Montreal Cognitive Assessment between 48-72 hours and 14-28 days, whereas those in whom weaning fails worsen by 4 points (adjusted coefficient 6.80, 95% CI 1.57-12.04, p = 0.01). They show better neuropsychological recovery between 48-72 hours and 3 months, compared to patients in whom weaning fails (adjusted coefficient 7.60, 95% CI 3.09-12.11, p = 0.02). Patients who receive permanent CSF diversion (ventriculoperitoneal shunt) show significant neuropsychological improvement thereafter, catching up the delay in neuropsychological improvement between 14-28 days and 3 months post-aSAH. Neurological, disability, and HRQOL outcomes at 3 months were similar. CONCLUSIONS: These results show a temporary but clinically meaningful cognitive benefit in the first weeks after aSAH in successfully weaned patients. The resolution of this difference over time may be due to the positive effects of permanent CSF diversion and underlines its importance. Patients who do not show progressive neuropsychological improvement after weaning should be considered for repeat CT imaging to rule out chronic (untreated) hydrocephalus.

Neurocognitive functioning in young adults with congenital heart disease: insights from a case-control study.

BACKGROUND: While there is evidence that cognitive impairment of children with congenital heart disease (CHD) may persist into adolescence, little is known about the spectrum of neurocognitive functioning of young adults with this disorder. The aim of this study was to assess neurocognitive functioning in a population of young adults with different types of CHD. METHODS: Cross-sectional cohort study in young adults with CHD and a group-matched healthy control group. We assessed neurocognitive and general intellectual functioning with a comprehensive battery of standardised neuropsychological tests. In addition to task-based assessments, questionnaire data of executive dysfunctions in everyday life were measured with the Behaviour Rating Inventory of Executive Function - Adult Version. RESULTS: A total of 67 patients (55% men) with CHD and 55 healthy controls (51% men) were included for analysis. Mean age at assessment was 26.9 (3.68) and 26.0 (3.32) years, respectively. The CHD group performed poorer in the domains of Executive Functions, Memory, Attention & Speed, and general intellectual functioning. Patients with a CHD of severe complexity were more affected than patients with simple or moderate complexity. Behaviour Rating Inventory of Executive Function - Adult Version scores indicated that patients' self-rated deficits in behaviour regulation in everyday life was higher compared with healthy controls. CONCLUSION: Our findings indicate lower neurocognitive functioning in young adults with a CHD, particularly in those with severe defect complexity. In view of the potentially enhanced risk for cerebrovascular and neurodegenerative disease in this patient group as reported in the literature, systematic longitudinal monitoring of cognitive functioning is recommended.

White matter microstructure and executive functions in congenital heart disease from childhood to adulthood: A pooled case-control study.

Congenital heart disease (CHD) patients are at risk for alterations in the cerebral white matter microstructure (WMM) throughout development. It is unclear whether the extent of WMM alterations changes with age, especially during adolescence when the WMM undergoes rapid maturation. We investigated differences in WMM between patients with CHD and healthy controls from childhood until early adulthood in a pooled sample of children, adolescents, and young adults. The association between WMM and EF was assessed. Patients with CHD (N=78) and controls (N=137) between 9 and 32 years of age underwent diffusion tensor imaging and an executive function test-battery. Mean fractional anisotropy (FA) was calculated for each white matter tract. Linear regression tested age and group effects (CHD vs control) and their interaction on FA. Relative Variable Importance (RI) estimated the independent contribution of tract FA, presence of CHD, CHD complexity, and parental education to the variability in EF. Mean FA was lower in patients compared to controls in almost all tracts (p between 0.057 and <0.001). WMM alterations in patients were not different depending on age (all interaction effects p>0.074). Predictors of EF were CHD group (RI=43%), parental education (RI=23%), CHD complexity (RI=10%), FA of the hippocampal cingulum (RI=6%) and FA of the corticospinal tract (RI=6%). The lack of group-FA-interactions indicates that the extent of altered FA remains similar across age. Altered FA is associated with EF impairments. CHD is a chronic disease with cerebral and neurocognitive impairments persisting into adulthood and, thus, long-term follow-up programs may improve overall outcome for this population.

Anticholinergic and Sedative Medications Are Associated With Neurocognitive Performance of Well Treated People With Human Immunodeficiency Virus.

Background: We previously showed that anticholinergic (ACH) medications contribute to self-reported neurocognitive impairment (NCI) in elderly people with human immunodeficiency virus (PWH). The current cross-sectional study further evaluated the effect of ACH and sedative drugs on neurocognitive function in PWH who underwent comprehensive neuropsychological evaluation. Methods: A medication review was performed in PWH enrolled in the prospective Neurocognitive Assessment in Metabolic and Aging Cohort within the Swiss HIV Cohort Study. Neurocognitive functions were analyzed in 5 domains (motor skills, speed of information, attention/working memory, executive functions, and verbal learning memory). The effect of ACH and sedative medications on neurocognitive functioning was evaluated using linear regression models for the continuous (mean z-score) outcome and multivariable logistic regression models for the binary (presence/absence) outcome. Results: A total of 963 PWH (80% male, 92% Caucasian, 96% virologically suppressed, median age 52) were included. Fourteen percent of participants were prescribed ≥1 ACH medication and 9% were prescribed ≥1 sedative medication. Overall, 40% of participants had NCI. Sedative medication use was associated with impaired attention/verbal learning and ACH medication use with motor skills deficits both in the continuous (mean z-score difference -0.26 to -0.14, P < .001 and P = .06) and binary (odds ratio [OR], ≥1.67; P < .05) models. Their combined use was associated with deficits in overall neurocognitive functions in both models (mean z-score difference -0.12, P = .002 and OR = 1.54, P = .03). These associations were unchanged in a subgroup analysis of participants without depression (n = 824). Conclusions: Anticholinergic and sedative medications contribute to NCI. Clinicians need to consider these drugs when assessing NCI in PWH.

Longitudinal neuropsychological assessment after aneurysmal subarachnoid hemorrhage and its relationship with delayed cerebral ischemia: a prospective Swiss multicenter study.

OBJECTIVE: While prior retrospective studies have suggested that delayed cerebral ischemia (DCI) is a predictor of neuropsychological deficits after aneurysmal subarachnoid hemorrhage (aSAH), all studies to date have shown a high risk of bias. This study was designed to determine the impact of DCI on the longitudinal neuropsychological outcome after aSAH, and importantly, it includes a baseline examination after aSAH but before DCI onset to reduce the risk of bias. METHODS: In a prospective, multicenter study (8 Swiss centers), 112 consecutive alert patients underwent serial neuropsychological assessments (Montreal Cognitive Assessment [MoCA]) before and after the DCI period (first assessment, < 72 hours after aSAH; second, 14 days after aSAH; third, 3 months after aSAH). The authors compared standardized MoCA scores and determined the likelihood for a clinically meaningful decline of ≥ 2 points from baseline in patients with DCI versus those without. RESULTS: The authors screened 519 patients, enrolled 128, and obtained complete data in 112 (87.5%; mean [± SD] age 53.9 ± 13.9 years; 66.1% female; 73% World Federation of Neurosurgical Societies [WFNS] grade I, 17% WFNS grade II, 10% WFNS grades III-V), of whom 30 (26.8%) developed DCI. MoCA z-scores were worse in the DCI group at baseline (-2.6 vs -1.4, p = 0.013) and 14 days (-3.4 vs -0.9, p < 0.001), and 3 months (-0.8 vs 0.0, p = 0.037) after aSAH. Patients with DCI were more likely to experience a decline of ≥ 2 points in MoCA score at 14 days after aSAH (adjusted OR [aOR] 3.02, 95% CI 1.07-8.54; p = 0.037), but the likelihood was similar to that in patients without DCI at 3 months after aSAH (aOR 1.58, 95% CI 0.28-8.89; p = 0.606). CONCLUSIONS: Aneurysmal SAH patients experiencing DCI have worse neuropsychological function before and until 3 months after the DCI period. DCI itself is responsible for a temporary and clinically meaningful decline in neuropsychological function, but its effect on the MoCA score could not be measured at the time of the 3-month follow-up in patients with low-grade aSAH with little or no impairment of consciousness. Whether these findings can be extrapolated to patients with high-grade aSAH remains unclear. Clinical trial registration no.: NCT03032471 (ClinicalTrials.gov).

Altered white matter microstructure is related to cognition in adults with congenital heart disease.

Adults with congenital heart disease are at risk for persisting executive function deficits, which are known to affect academic achievement and quality of life. Alterations in white -matter microstructure are associated with cognitive impairments in adolescents with congenital heart disease. This study aimed to identify microstructural alterations potentially associated with executive function deficits in adults with congenital heart disease. Diffusion tensor imaging and tract-based spatial statistics were conducted in 45 patients (18 females) and 54 healthy controls (26 females) aged 18-32 years. Fractional anisotropy of white matter diffusion was compared between groups and correlated with an executive function score, derived from an extensive neuropsychological test battery. Patients showed widespread bilateral reduction in fractional anisotropy (P < 0.05, multiple comparison corrected) compared to controls. Lower fractional anisotropy was driven by patients with moderate and severe defect complexity (compared to controls: P < 0.001). Executive function scores were lower in patients (P < 0.05) and associated with lower fractional anisotropy in the left superior corona radiata and the corticospinal tract (corrected P < 0.05). Our findings confirm alterations of white matter microstructure in adults with congenital heart disease, mainly in those patients of moderate to severe complexity. These alterations are associated with impairments in executive functioning. A better understanding of the neurocognitive deficits may help counselling and care of patients with congenital heart disease across their lifespan and have the potential to improve their outcome and quality of life.

Microstructural alterations of the corticospinal tract are associated with poor motor function in patients with severe congenital heart disease.

Congenital heart disease (CHD) patients are at risk for neurodevelopmental impairments, including altered motor function. However, little is known about the neuroanatomical correlates of persistent motor deficits in CHD. Thus, we examined the link between corticospinal tract (CST) microstructure and motor function in adolescent and adult CHD patients compared to healthy controls. This study investigated 89 CHD patients (N(adolescents) = 47, N(adults) = 42, mean age = 19.9 years) and 97 age-matched healthy controls (N(adolescents) = 44, N(adults) = 53, mean age = 20.6 years). Diffusion tensor imaging was conducted and fractional anisotropy (FA) of the left and right CST was extracted for each participant. Fine (pegboard) and pure motor (repeated finger, hand and foot movements) performance was evaluated with a standardized test battery. FA and motor performance were correlated and the effect of CHD complexity was tested using multivariate linear regression. Clinically relevant motor impairments (>2SD below normative mean) were evident in 24% of patients and 9% of controls. On average, motor performance was lower in CHD patients compared to controls, particularly in those with more complex CHD (fine motor: p = 0.023; pure motor: p < 0.001). FA CST was lower in patients compared to controls, particularly in those with more complex CHD (left: p < 0.001, right: p = 0.003). There was a significant interaction between CHD complexity and FA CST (left: p = 0.025, right: p = 0.025), indicating that FA correlates significantly with pure motor in patients with severe CHD, while there is only a weak association in moderate CHD and no association in patients with simple CHD and controls. Microstructure of the CST is altered in CHD patients, and is associated with pure motor impairments in patients with severe CHD. This indicates that persistent motor impairments may arise from atypical development of the primary motor pathway in the presence of a complex CHD. Early interventions promoting brain maturation in infancy may prevent persisting impairments across the lifetime.

Brain volumes in adults with congenital heart disease correlate with executive function abilities.

Congenital heart disease is the most common birth defect, and patients are at risk for neurodevelopmental impairment and brain abnormalities. Yet, little is known about the link between brain volumes and cognitive function in adults with congenital heart disease. Forty-four patients and 53 controls between 18 and 32 years underwent brain magnetic resonance imaging and cognitive testing, assessed with an intelligence quotient and executive function global score. Associations between brain volumes and cognitive function were calculated using linear models. Cognitive function in patients was within the normal range (intelligence quotient: 97.74 (10.76)). Total brain volume was significantly smaller in patients compared to controls (1067.26 (113.53) vs 1113.04 (97.88) cm3, P < 0.01), irrespective of cardiac factors (heart defect complexity, cyanosis, cardiopulmonary bypass: all P > 0.4). After adjusting for total brain volume, only corpus callosum volume remained significantly smaller (P = 0.03). Smaller total brain volume was associated with poorer overall executive functioning (P = 0.02) and inhibition (P < 0.01), in both patients and controls. The association between total brain volume and overall executive functioning was moderated by parental socioeconomic status (lower socioeconomic status was associated with a stronger association between brain volume and EF; interaction P = 0.03). In adults with congenital heart disease, despite normal intelligence quotient, brain volume alterations persist into adulthood and are related to executive functioning, in particular inhibitory control. Adults coming from low socioeconomic background and with altered brain volumes are especially vulnerable and should thus be followed-up during adulthood to ensure optimal social and educational support.

Neurocognitive course at 2-year follow-up in a Swiss cohort of people with well-treated HIV.

OBJECTIVE: The aim of this study was to examine neurocognitive course over time among people with well treated HIV. DESIGN: The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study is an ongoing, prospective, longitudinal, multicenter and multilingual study within the Swiss HIV Cohort Study (SHCS). Participants undergo neuropsychological assessment at baseline and two-yearly follow-up. SETTING: Seven SHCS centres. PARTICIPANTS: Patients aged at least 45 years enrolled in the SHCS with fluency in the local language (French, German or Italian) and agreeing to participate in the NAMACO study: 981 participants at baseline, 720 at 2-year follow-up of whom 644 had complete data sets. INTERVENTION: Standardized neuropsychological assessment at baseline and 2-year follow-up. MAIN OUTCOME MEASURE: Neurocognitive performance using Frascati criteria and mean z-scores. RESULTS: Four participants (of 644, 0.6%) had plasma HIV-1 RNA more than 50 copies/ml; median CD4+ cell count was 660 cells/µl. According to Frascati criteria, 204 participants (31.7%) had neurocognitive impairment (NCI) at baseline. NCI severity in these participants changed little over 2 years and comprehensive models based on Frascati criteria were not feasible. Examining mean z-scores, however, we observed neurocognitive stability or improvement over two years in five of seven neurocognitive domains assessed. Age at least 65 years (P = 0.02) and cognitive complaints (P = 0.004) were associated with neurocognitive decline, while black race (P = 0.01) and dolutegravir treatment (P = 0.002) were associated with improvement. CONCLUSION: Frascati criteria were less sensitive in measuring NCI change and therefore unsuitable for following neurocognitive course in our cohort of people with well treated HIV. Examining neurocognitive course by mean z-score change, we observed stability or improvement.

Structural brain abnormalities in adults with congenital heart disease: Prevalence and association with estimated intelligence quotient.

BACKGROUND: Little is known about the prevalence of structural brain abnormalities and cognitive functioning in the growing population of patients with adult congenital heart disease (ACHD). Thus, our aim was to assess structural abnormalities on brain magnetic resonance imaging (MRI) and their association with intelligence quotient (IQ) in ACHD patients. METHODS: Cross-sectional study in ACHD patients and healthy controls as comparison group. Brain MRI was performed on a 3 T MR scanner, and inspection of structural abnormalities was performed blinded to ACHD or control status. IQ was estimated using the vocabulary and matrix reasoning subtests from the Wechsler Adult Intelligence Scale, Fourth Edition. RESULTS: A total number of 67 (55% males) ACHD patients and 55 (51% males) controls were included (mean age 26.9 and 26.0 years respectively). Abnormalities on brain MRI were detected in 29 of 46 (63%) ACHD patients and in none of the controls. Abnormalities consisted of focal infarction or atrophy, white matter lesions, microhemorrhages, and global atrophy. Mean estimated IQ was significantly lower in ACHD patients than in controls (98.51 versus 104.38; 95% CI: -10.09 to -1.66; P value = 0.007). Comparison between patients with and without cerebral abnormalities revealed no significant difference in estimated IQ. CONCLUSION: Our findings indicate a high prevalence and wide spectrum of structural brain abnormalities in ACHD patients. Furthermore, this population is at a higher risk of impaired intellectual functioning than healthy controls. However, the present study could not establish a statistically significant association between MRI findings and estimated IQ. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04041557; URL: https://clinicaltrials.gov/ct2/show/NCT04041557?term=NCT04041557&rank=1.

Influence of the Intensive Care Unit Environment on the Reliability of the Montreal Cognitive Assessment.

Background: Neuropsychological screening becomes increasingly important for the evaluation of subarachnoid hemorrhage (SAH) and stroke patients. It is often performed during the surveillance period on the intensive (ICU), while it remains unknown, whether the distraction in this environment influences the results. We aimed to study the reliability of the Montreal Cognitive Assessment (MoCA) in the ICU environment. Methods: Consecutive stable patients with recent brain injury (tumor, trauma, stroke, etc.) were evaluated twice within 36 h using official parallel versions of the MoCA (ΔMoCA). The sequence of assessment was randomized into (a) busy ICU first or (b) quiet office first with subsequent crossover. For repeated MoCA, we determined sequence, period, location effects, and the intraclass correlation coefficient (ICC). Results: N = 50 patients were studied [n = 30 (60%) male], with a mean age of 57 years. The assessment's sequence ["ICU first" mean ΔMoCA -1.14 (SD 2.34) vs. "Office first" -0.73 (SD 1.52)] did not influence the MoCA (p = 0.47). On the 2nd period, participants scored 0.96 points worse (SD 2.01; p = 0.001), indicating no MoCA learning effect but a possible difference in parallel versions. There was no location effect (p = 0.31) with ΔMoCA between locations (Office minus ICU) of -0.32 (SD 2.21). The ICC for repeated MoCA was 0.87 (95% CI 0.79-0.92). Conclusions: The reliability of the MoCA was excellent, independent from the testing environment being ICU or office. This finding is helpful for patient care and studies investigating the effect of a therapeutic intervention on the neuropsychological outcome after SAH, stroke or traumatic brain injury.