Because aggressive behavior during early childhood has been related to negative developmental outcomes, a further understanding of the underlying mechanisms of aggression during the first years of... Show moreBecause aggressive behavior during early childhood has been related to negative developmental outcomes, a further understanding of the underlying mechanisms of aggression during the first years of life is essential. Although the factors prenatal risk, parenting behavior, temperament and cognitive functions have consistently been related to externalizing behavior during preschool and school age, research focusing on their interplay in relation to aggressive behavior earlier in life is scarce. The aim of the current dissertation was to gain more insight into these associations during infancy and toddlerhood. Our studies indicated that impairments in children’s early cognitive regulation abilities play a role in the development of aggressive behavior. It can also be concluded that both adverse pre- and postnatal environmental influences have an impact on child aggression: higher prenatal risk and adverse parenting behavior were directly or indirectly (via poor cognitive functioning) related to higher levels of aggression. In addition, it was found that poor cognitive skills increased the risk of aggression in case of high prenatal risk or a highly reactive temperament during early development. These results suggest that early intervention programs to prevent aggression should focus on prenatal risk, parenting behavior and cognitive development during the first years of life. Show less
Anxiety disorders are globally one of the most prevalent and disabling forms of psychopathology in adults and children. Having a parent with an anxiety disorder multiplies the risk of anxiety... Show moreAnxiety disorders are globally one of the most prevalent and disabling forms of psychopathology in adults and children. Having a parent with an anxiety disorder multiplies the risk of anxiety disorders in the ofspring, although the specifc mechanisms and processes that play a role in this intergenerational transmission remain largely unknown. According to information processing theories, threat-related biases in cognitive processing are a causal mechanism in the development and maintenance of anxiety. These theories propose that individuals with anxiety are more likely to cognitively process novel stimuli in their environment as threatening. Creswell and colleagues proposed a theoretical model that highlighted the role of these cognitive biases as a mechanism in the intergenerational transmission of anxiety (Creswell et al., in Hadwin, Field (eds) Information processing biases and anxiety: a developmental perspective, Wiley, pp 279–295, 2010). This model postulated signifcant associations between (1) parents’ and children’s threat-related cognitive biases (2) parents’ threatrelated cognitive biases in their own and their child’s environment, (3) parents’ threat-related cognitive biases and parenting behaviors that convey anxiety risk to the ofspring (e.g., modeling of fear, and verbal threat information transmission), and (4) parenting behaviors and child threat-related biases. This theoretical review collated the recent empirical work testing these four core hypotheses of the model. Building on the reviewed empirical work, an updated conceptual model focusing on threat-related attention and interpretation is proposed. This updated model incorporates the links between cognition and anxiety in parents and children and addresses the potential bidirectional nature of parent–child infuences. Show less
Bruijnen, C.P.; Groot, L.G.R. de; Vondeling, A.M.; Bree, R. de; Bos, F. van den; Witteveen, P.O.; Emmelot-Vonk, M.H. 2021
Introduction: In addition to classical endpoints such as survival and complication rates, other outcomes such as quality of life and functional status are increasingly recognized as important... Show moreIntroduction: In addition to classical endpoints such as survival and complication rates, other outcomes such as quality of life and functional status are increasingly recognized as important endpoints, especially for elderly patients. However, little is known about the long-term effect of surgery with regard to these other outcomes. Our aim is to investigate the functional status and self-reported health status of patients > 70 years one year after surgery for head and neck cancer. Methods: We present one-year follow-up data of patients > 70 year who underwent surgery for HNC. During an interview by telephone, functional status was evaluated by using the Katz-15 Index of Independence questionnaire including six items covering basic Activities of Daily Living (ADL) and nine items covering Instrumental Activities of Daily Living (IADL). Measurements were compared with those obtained preoperatively. Results: In total, 126 patients were included and eventually we collected follow-up data of 68 patients. There was a statistically significant decrease in functional status on the total Katz-15 and on the IADL questionnaire scores one year after surgery (mean 1.34 versus 2.42, p -value 0.00 and mean 1.21 versus 1.94, p- value 0.00). There was no significant change concerning ADL dependence ( p -value 0.18) and cognitive status ( p -value 0.11). The self-reported health status improved postoperatively, although not statistically significantly so (mean 67.36 versus 71.25, p -value 0.12). Conclusion: Approximately-one year after surgery for HNC, there is a significant decline in functional status indicating a higher level of dependency. Show less
Background and Purpose Cerebral amyloid angiopathy (CAA) is a common pathology of the leptomeningeal and cortical small vessels associated with hemorrhagic and non-hemorrhagic brain injury. Given... Show moreBackground and Purpose Cerebral amyloid angiopathy (CAA) is a common pathology of the leptomeningeal and cortical small vessels associated with hemorrhagic and non-hemorrhagic brain injury. Given previous evidence for CAA-related loss of cortical thickness and white matter volume, we hypothesized that CAA might also cause tissue loss in the basal ganglia. Methods We compared basal ganglia volumes expressed as a percentage of total intracranial volume (pBGV) of non-demented patients with sporadic and hereditary CAA to age-matched healthy control (HC) and Alzheimer's disease (AD) cohorts.Results Patients with sporadic CAA had lower pBGV (n=80, 1.16%+/- 0.14%) compared to HC (n=80, 1.30%+/- 0.13%, P<0.0001) and AD patients (n=80, 1.23%+/- 0.11%, P=0.001). Similarly, patients with hereditary CAA demonstrated lower pBGV (n=25, 1.26%+/- 0.17%) compared to their matched HC (n=25, 1.36%+/- 0.15%, P=0.036). Using a measurement of normalized basal ganglia width developed for analysis of clinical-grade magnetic resonance images, we found smaller basal ganglia width in patients with CAA-related lobar intracerebral hemorrhage (ICH; n=93, 12.35 +/- 1.47) compared to age-matched patients with hypertension-related deep ICH (n=93, 13.46 +/- 1.51, P<0.0001) or HC (n=93, 15.45 +/- 1.22, P<0.0001). Within the sporadic CAA research cohort, decreased basal ganglia volume was independently correlated with greater cortical gray matter atrophy (r=0.45, P<0.0001), increased basal ganglia fractional anisotropy (r=-0.36, P=0.001), and worse performance on language processing (r=0.35, P=0.003), but not with cognitive tests of executive function or processing speed.Conclusions These findings suggest an independent effect of CAA on basal ganglia tissue loss, indicating a novel mechanism for CAA-related brain injury and neurologic dysfunction. Show less
Objective: A downside of Deep Brain Stimulation (DBS) for Parkinson's Disease (PD) is that cognitive function may deteriorate postoperatively. Electroencephalography (EEG) was explored as biomarker... Show moreObjective: A downside of Deep Brain Stimulation (DBS) for Parkinson's Disease (PD) is that cognitive function may deteriorate postoperatively. Electroencephalography (EEG) was explored as biomarker of cognition using a Machine Learning (ML) pipeline.Methods: A fully automated ML pipeline was applied to 112 PD patients, taking EEG time-series as input and predicted class-labels as output. The most extreme cognitive scores were selected for class differentiation, i.e. best vs. worst cognitive performance (n = 20 per group). 16,674 features were extracted per patient; feature-selection was performed using a Boruta algorithm. A random forest classifier was modelled; 10-fold cross-validation with Bayesian optimization was performed to ensure generalizability. The predicted class-probabilities of the entire cohort were compared to actual cognitive performance.Results: Both groups were differentiated with a mean accuracy of 0.92; using only occipital peak frequency yielded an accuracy of 0.67. Class-probabilities and actual cognitive performance were negatively linearly correlated (b =-0.23 (95% confidence interval (-0.29,-0.18))).Conclusions: Particularly high accuracies were achieved using a compound of automatically extracted EEG biomarkers to classify PD patients according to cognition, rather than a single spectral EEG feature.Significance: Automated EEG assessment may have utility for cognitive profiling of PD patients during the DBS screening. (c) 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Background: The cholinergic system and M-1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M-1 receptor partial agonist HTL0018318 is under... Show moreBackground: The cholinergic system and M-1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M-1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects.Methods: This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15-35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions.Results: HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15-35 mg. Maximum plasma concentrations were achieved after 1-2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (+/- 4.61) in younger adult subjects and 14.3 h (+/- 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes.Conclusion: Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB. Show less
Meer, P.B. van der; Koekkoek, J.A.F.; Bent, M.J. van den; Dirven, L.; Taphoorn, M.J.B. 2021
Introduction AEDs have been associated with depression, anxiety, and cognitive impairment, all frequent complications of glioma and its subsequent treatment, with considerable morbidity and an... Show moreIntroduction AEDs have been associated with depression, anxiety, and cognitive impairment, all frequent complications of glioma and its subsequent treatment, with considerable morbidity and an adverse effect on health-related quality of life. This study aimed to determine the independent association between AED use and self-reported depression, anxiety, and subjective cognitive impairment in glioma patients. Methods In this multicenter cross-sectional study, depression and anxiety were assessed with the HADS and subjective cognitive impairment was assessed with the MOS-CFS. Univariable logistic regression analyses were performed on all potential confounding predictor variables. Potential confounders were included in the multivariable analyses if p-value < 0.1, to evaluate whether use of AEDs was independently related to depression, anxiety, and/or subjective cognitive impairment. Results A total of 272 patients were included. Prevalence of depression differed significantly between patients not using (10%) and using AEDs (21%, unadjusted Odds Ratio [uOR] = 2.29 [95%CI 1.05-4.97], p = 0.037), but after correction for confounders the statistical significant difference was no longer apparent (adjusted Odds Ratio [aOR] = 1.94 [95%CI 0.83-4.50], p = 0.125). Prevalences of anxiety (aOR = 1.17 [95%CI 0.59-2.29], p = 0.659) and subjective cognitive impairment (aOR = 0.83 [95%CI 0.34-2.04], p = 0.684) did not differ significantly before or after adjustment of confounders between patients not using (19% and 16%, respectively) and using AEDs (26% and 21%, respectively). Conclusions Our results indicate AED use was not independently associated with concurrent depression, anxiety, or subjective cognitive impairment in glioma patients. Alternative factors seem to have a greater contribution to the risk of developing neuropsychiatric symptoms in glioma patients. Show less
Patients with Parkinson's Disease may be eligible for Deep Brain Stimulation (DBS) in case of severe motor complications. This thesis provides indications for improving patient selection for DBS,... Show morePatients with Parkinson's Disease may be eligible for Deep Brain Stimulation (DBS) in case of severe motor complications. This thesis provides indications for improving patient selection for DBS, as well as describing new biomarkers based on Electroencephalography (EEG) to aid during the DBS selection process. Show less
Buhrmann, A.; Brands, A.M.A.; Grond, J. van der; Schilder, C.; Mast, R.C. van der; Ottenheim, N.R.; ... ; Berg, E. van den 2020
The cerebellum is increasingly recognised for its role in modulation of cognition, behaviour, and affect. The present study examined the relation between structural cerebellar damage (grey matter... Show moreThe cerebellum is increasingly recognised for its role in modulation of cognition, behaviour, and affect. The present study examined the relation between structural cerebellar damage (grey matter volume (GMV), white matter hyperintensities (WMHs), lacunar infarcts (LIs) and microbleeds (MBs)) and measures of cognitive, psychological (i.e. symptoms of depression and apathy) and general daily functioning in a population of community-dwelling older persons with mild cognitive deficits, but without dementia. In 194 participants of the Discontinuation of Antihypertensive Treatment in Elderly People (DANTE) Study Leiden, the association between cerebellar GMV, WMHs, LIs and MBs and measures of cognitive, psychological and general daily functioning was analysed with linear regression analysis, adjusted for age, sex, education and cerebral volume. Cerebellar GMV was associated with the overall cognition score (standardised beta 0.20 [95% CI, 0.06-0.33]). Specifically, posterior cerebellar GMV was associated with executive function (standardised beta 0.18 [95% CI, 0.03-0.16]). No relation was found between vascular pathology and cognition. Also, no consistent associations were found on the cerebellar GMV and vascular pathology measures and psychological and general daily functioning. In this population of community-dwelling elderly, less posterior cerebellar GMV but not vascular pathology was associated with worse cognitive function, specifically with poorer executive function. No relation was found between cerebellar pathology and psychological and general daily functioning. Show less
Haverkamp, B.F.; Wiersma, R.; Vertessen, K.; Ewijk, H. van; Oosterlaan, J.; Hartman, E. 2020
The aim was to provide a meta-analysis of studies investigating the effects of physical activity interventions on cognitive outcomes and academic performance in adolescents or young adults. A... Show moreThe aim was to provide a meta-analysis of studies investigating the effects of physical activity interventions on cognitive outcomes and academic performance in adolescents or young adults. A systematic review with meta-analysis was performed using the following databases: Embase, ERIC, MEDLINE, PsycINFO and Web of Science. Studies had to meet the following criteria: controlled study design, investigating the effects of physical activity interventions on cognitive outcomes and academic performance in healthy adolescents or young adults (12-30 years). Results showed that acute interventions (n=44) significantly improved processing speed (ES=0.39), attention (ES=0.34) and, inhibition (ES=0.32). In a subsequent meta-regression, shorter duration of intervention was significantly associated with greater improvements in attention (beta=-0.02) and cognitive flexibility (beta=-0.04), whereas age, percentage of boys, intensity and dose were not. Chronic interventions (n=27) significantly improved processing speed (ES=0.30), attention (ES=0.50), cognitive flexibility (ES=0.19), working memory (ES=0.59) and language skills (ES=0.31). In the meta-regression, higher percentage of boys was significantly associated with greater improvements in attention (beta=0.02) and working memory (beta=0.01) whereas age, duration, frequency, dose and load were not. In conclusion, acute and chronic physical activity interventions might be a promising way to improve several cognitive outcomes and language skills in adolescents and young adults. Show less
Duchenne muscular dystrophy is a multifactorial disease including a cognitive phenotype. It is caused by mutations in the X-chromosomal DMD gene from which dystrophin is synthesized. Multiple... Show moreDuchenne muscular dystrophy is a multifactorial disease including a cognitive phenotype. It is caused by mutations in the X-chromosomal DMD gene from which dystrophin is synthesized. Multiple isoforms of dystrophin have been identified. The full length dystrophin isoform Dp427 m is expressed predominantly in muscle. Other isoforms include: Dp427(c), Dp427(p), Dp260, Dp140, Dp116, Dp71 and Dp40. The majority of these isoforms are expressed in brain and several hypotheses exist on their role in subtypes of neurons and astrocytes. However, their function in relation to cognition remains unclear. Unlike progressive muscle wasting, cognitive involvement is not seen in all DMD patients and the severity varies greatly. To achieve a better understanding of brain involvement in DMD, a multidisciplinary approach is required. Here, we review the latest findings on dystrophin isoform expression in the brain; specific DMD-associated learning and behavioural difficulties; and imaging and spectroscopy findings relating to brain structure, networks, perfusion and metabolism. The main challenge lies in determining links between these different findings. If we can determine which factors play a role in the differentiation between severe and minor cognitive problems in DMD in the near future, we can both provide better advise for the patients and also develop targeted therapeutic interventions. (C) 2020 The Author(s). Published by Elsevier B.V. Show less
There is a lack of reliable, repeatable, and non-invasive clinical endpoints when investigating treatments for intellectual disability (ID). The aim of this study is to explore a novel approach... Show moreThere is a lack of reliable, repeatable, and non-invasive clinical endpoints when investigating treatments for intellectual disability (ID). The aim of this study is to explore a novel approach towards developing new endpoints for neurodevelopmental disorders, in this case for ARID1B-related ID. In this study, twelve subjects with ARID1B-related ID and twelve age-matched controls were included in this observational case-control study. Subjects performed a battery of non-invasive neurobehavioral and neurophysiological assessments on two study days. Test domains included cognition, executive functioning, and eye tracking. Furthermore, several electrophysiological assessments were performed. Subjects wore a smartwatch (Withings (R) Steel HR) for 6 days. Tests were systematically assessed regarding tolerability, variability, repeatability, difference with control group, and correlation with traditional endpoints. Animal fluency, adaptive tracking, body sway, and smooth pursuit eye movements were assessed as fit-for-purpose regarding all criteria, while physical activity, heart rate, and sleep parameters show promise as well. The event-related potential waveform of the passive oddball and visual evoked potential tasks showed discriminatory ability, but EEG assessments were perceived as extremely burdensome. This approach successfully identified fit-for-purpose candidate endpoints for ARID1B-related ID and possibly for other neurodevelopmental disorders. Next, results could be replicated in different ID populations or the assessments could be included as exploratory endpoint in interventional trials in ARID1B-related ID. Show less
Dirven, L.; Luerding, R.; Beier, D.; Bumes, E.; Reinert, C.; Seidel, C.; ... ; Hau, P. 2020
Background Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult... Show moreBackground Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL). Methods Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL. Results 28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (>= 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below - 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range. Conclusions This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment. Show less
Ellis, N.; Tee, A.; McAllister, B.; Massey, T.; McLauchlan, D.; Stone, T.; ... ; Holmans, P. 2020
BACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized examination of motor... Show moreBACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized examination of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown.METHODS: We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by 1) constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders and of intelligence and 2) testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n = 5160) of patients with HD.RESULTS: Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence.CONCLUSIONS: Polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD. Show less
Since Antiquity, “active cognition” has been a problematic notion in Aristotelian scholarship. Part of the problem is the definition of what counts as “active”. In the first part of this paper I... Show moreSince Antiquity, “active cognition” has been a problematic notion in Aristotelian scholarship. Part of the problem is the definition of what counts as “active”. In the first part of this paper I shall offer a short survey on various contenders for “active” perceptual cognition defended in recent interpretations of Aristotle, by way of introduction to the more complicated problems of “active” intellectual cognition. In the second part of the paper I will offer—in outline—my interpretation of Aristotle’s theory of intellectual cognition, which takes the most recent findings in the area of perceptual cognition as a starting point. Here I pursue the analogy that Aristotle sets up between perception and intellection throughout the De anima. In the third part of the paper I shall examine a number of influential accounts of active intellectual cognition found in the corpus of Alexander of Aphrodisias, in particular Mantissa 2–5 (also known as De intellectu). These accounts each develop the analogies offered in Aristotle’s De anima III.5 in their own way. Show less
Neurocognitive deficits are frequently described in Duchenne muscular dystrophy (DMD), but it is unknown how these progress over time. Our aim was to longitudinally assess verbal span capacity and... Show moreNeurocognitive deficits are frequently described in Duchenne muscular dystrophy (DMD), but it is unknown how these progress over time. Our aim was to longitudinally assess verbal span capacity and information processing speed in DMD and to explore a genotype-phenotype relation. Verbal span and processing speed scores were available of 28 males with DMD on two time-points, with a mean time interval of 28.34 months (SD = 16.09). The cohort contained of six patients missing only dystrophin isoform Dp427, sixteen missing Dp427 and Dp140, and six were undeterminable. A lower verbal span capacity was found at the first and second assessment, whereas processing speed was normal at both time-points. Post-hoc analyses suggested lower scores on verbal span and processing speed for patients missing Dp427 and Dp140. In DMD, a developmental stagnation in verbal span capacity, irrespective of normal processing speed, is detected through longitudinal follow-up. This appears more pronounced in patients missing Dp427 and Dp140. (C) 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. Show less
We aimed to expand our knowledge about the level of neurocognitive functioning (NCF) and health-related quality of life (HRQoL) in patients with primary and secondary brain tumors during the... Show moreWe aimed to expand our knowledge about the level of neurocognitive functioning (NCF) and health-related quality of life (HRQoL) in patients with primary and secondary brain tumors during the disease course. We found that the tumor itself has the largest negative impact on NCF and HRQoL. At group level, treatment (surgery, radiotherapy and/or chemotherapy) did not seem to have a large extra detrimental effect on the short term. However, subgroups of patients, e.g. patients with tumors in the non-dominant hemisphere and long-term survivors, appeared to be vulnerable for cognitive decline after treatment. At the individual patient level, HRQoL varied to a large degree in the first months after treatment, confirming this is a multidimensional concept and that the impact of treatment differs for the different aspects. With the results from the studies described in this thesis, treatment and individual patient care can be optimized by minimizing the negative impact of treatment, e.g. by intraoperative monitoring of cognition during awake surgery, and by counseling and rehabilitation of patients. Besides, investigators should pay attention to methodological challenges in reporting of neurocognitive outcomes in research, as reporting of these outcomes is currently not sufficient, while evidence can be of value in clinical decision-making. Show less
Background To date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive... Show moreBackground To date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI), we investigated whether a single dose of a monoaminergic drug (methylphenidate) improves executive functioning and whether a single dose of a cholinergic drug (galantamine) improves memory in VCI patients. Methods STREAM-VCI is a single-center, double-blind, three-way crossover trial. We included 30 VCI patients (Mini-Mental State Examination (MMSE) >= 16 and Clinical Dementia Rating score 0.5-1.0) with cerebrovascular pathology on MRI. All patients received single doses of methylphenidate (10 mg), galantamine (16 mg), and placebo in random order on three separate study visits. We used the NeuroCart (R), a computerized test battery, to assess drug-sensitive cognitive effects. Predefined main outcomes, measured directly after a single dose of a study drug, were (i) change in performance on the adaptive tracker for executive functioning and (ii) performance on the Visual Verbal Learning Test-15 (VVLT-15) for memory, compared to placebo. We performed mixed model analysis of variance. Results The study population had a mean age of 67 +/- 8 years and MMSE 26 +/- 3, and 9 (30%) were female. Methylphenidate improved performance on the adaptive tracker more than placebo (mean difference 1.40%; 95% confidence interval [CI] 0.56-2.25; p = 0.002). In addition, methylphenidate led to better memory performance on the VVLT-15 compared to placebo (mean difference in recalled words 0.59; 95% CI 0.03-1.15; p = 0.04). Galantamine did not improve performance on the adaptive tracker and led to worse performance on delayed recall of the VVLT-15 (mean difference - 0.84; 95% CI - 1.65, - 0.03; p = 0.04). Methylphenidate was well tolerated while galantamine produced gastrointestinal side effects in a considerable number of patients. Conclusions In this proof-of-principle study, methylphenidate is well tolerated and improves executive functioning and immediate recall in patients with VCI. Galantamine did not improve memory or executive dysfunction. Results might be influenced by the considerable amount of side effects seen. Show less
The ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve... Show moreThe ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve the mesocortical circuitry. Coping with stress increases VTA-DA excitability, but when the stressor becomes chronic the VTA-DA circuit is less active, which may lead to degeneration and local microglial activation. This switch between activation and inhibition of VTA-DA neurons is modulated by e.g. corticotropin-releasing hormone (CRH), opioids, brain-derived neurotrophic factor (BDNF), and the adrenal glucocorticoids. These actions are coordinated with energy-demanding stress-coping styles to promote behavioral adaptation. The VTA circuits show sexual dimorphism that is programmed by sex hormones during perinatal life in a manner that can be affected by glucocorticoid exposure. We conclude that insight in the role of stress in VTA-DA plasticity and connectivity, during reward processing and stress-coping, will be helpful to better understand the mechanism of resilience to breakdown of adaptation. Show less
Coppen, E.M.; Jacobs, M.; Zwaan, K.F. van der; Middelkoop, H.A.M.; Roos, R.A.C. 2019
Objective: In Huntington's disease (HD), a hereditary neurodegenerative disorder, cognitive impairment in early disease stages mainly involves executive dysfunction. However, visual cognitive... Show moreObjective: In Huntington's disease (HD), a hereditary neurodegenerative disorder, cognitive impairment in early disease stages mainly involves executive dysfunction. However, visual cognitive deficits have additionally been reported and are of clinical relevance given their influence on daily life and overall cognitive performance. This study aimed to assess visual perceptual skills in HD gene carriers.Methods: Subtasks of the Visual Object and Space Perception battery and Groningen Intelligence Test were administered in 62 participants (18 healthy controls, 22 participants with a genetic confirmation of HD without symptoms, i.e., premanifest HD, and 22 participants with a genetic confirmation of HD with symptoms, i.e., manifest HD). Group differences in task performance were measured using analysis of covariance with and without correction for age. Receiver Operating Characteristics (ROC) analysis was performed to examine which task best discriminated between groups and cut-off scores were provided.Results: Manifest HD performed significantly worse compared to both controls and premanifest HD on all visual perceptional tasks. Premanifest HD did not differ in task performance from controls. Besides the Shape Detection, all tasks were robust in discriminating between groups. The Animal Silhouettes test was most accurate in discriminating manifest HD from premanifest HD (AUC = 0.90, SE = 0.048, p < .001).Conclusion: Visual perceptual deficits are present in early manifest HD, especially an impaired recognition of animals and objects from sketched silhouettes, and not in premanifest HD. This suggests that decline in visual processing only occurs in clinical disease stages. The visual cognitive battery, especially the Silhouettes tasks used in this study is sensitive in discriminating manifest HD from premanifest HD and controls. Show less
