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Introduction Differences in brain network connectivity may reflect the capability of the neurological substrate to compensate for brain damage and preserve cognitive function (cognitive reserve). We examined the associations between white matter connectivity, brain damage markers, and cognition in a population sample of middle-aged individuals. Methods A total of 4759 participants from The Maastricht Study (mean age = 59.2, SD = 8.7, 50.2% male) underwent cognitive testing and diffusion magnetic resonance imaging (dMRI), from which brain volume, structural connectivity, and vascular damage were quantified. Multivariable linear regression was used to investigate whether connectivity modified the association between brain damage and cognition, adjusted for demographic and cardiometabolic risk factors. Results More atrophic and vascular brain damage was associated with worse cognition scores. Increasing connectivity moderated the negative association between damage and cognition (chi(2) = 8.64, df = 3, p

Introduction Autopsy studies recognize the locus coeruleus (LC) as one of the first sites accumulating tau in Alzheimer's disease (AD). Recent AD work related in vivo LC magnetic resonance imaging (MRI) integrity to tau and cognitive decline; however, relationships of LC integrity to age, tau, and cognition in autosomal dominant AD (ADAD) remain unexplored. Methods We associated LC integrity (3T-MRI) with estimated years of onset, cortical amyloid beta, regional tau (positron emission tomography [PET]) and memory (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word-List-Learning) among 27 carriers and 27 non-carriers of the presenilin-1 (PSEN1) E280A mutation. Longitudinal changes between LC integrity and tau were evaluated in 10 carriers. Results LC integrity started to decline at age 32 in carriers, 12 years before clinical onset, and 20 years earlier than in sporadic AD. LC integrity was negatively associated with cortical tau, independent of amyloid beta, and predicted precuneus tau increases. LC integrity was positively associated with memory. Discussion These findings support LC integrity as marker of disease progression in preclinical ADAD.

White matter signal abnormalities (WMSA), either hypo- or hyperintensities in MRI imaging, are considered a proxy of cerebrovascular pathology and contribute to, and modulate, the clinical presentation of Alzheimer's disease (AD), with cognitive dysfunction being apparent at lower levels of amyloid and/or tau pathology when lesions are present. To what extent the topography of cortical thinning associated with AD may be explained by WMSA remains unclear. Cortical thickness group difference maps and subgroup analyses show that the effect of WMSA on cortical thickness in cognitively normal participants has a higher overlap with the canonical pattern of AD, compared to AD participants. (Age and sex-matched group of 119 NC (AV45 PET negative, CDR = 0) versus 119 participants with AD (AV45 PET-positive, CDR > 0.5). The canonical patterns of cortical atrophy thought to be specific to Alzheimer's disease are strongly linked to cerebrovascular pathology supporting a reinterpretation of the classical models of AD suggesting that a part of the typical AD pattern is due to co-localized cortical loss before the onset of AD.

Background: the biomedical model of medicine was replaced by the biopsychosocial model in order to better accommodate psychological and social aspects of illness. The introduction of machine learning techniques provides the perspective of truly personalized medicine. This poses new challenges to our medical model.Aim: to explore the implications of personalized medicine for the biopsychosocial model.Methods: scholarly reflection.Results: The ability of machine learning technology to integrate a wide diversity of data makes it possible to develop predictive models for presentation, course and treatment response in individual patients. Such models are based on individual risk factors and protective factors that may have diverging influences in different in-dividuals. In a medical model adjusted to accommodate the possibilities of personalized medicine, it should be possible to highlight the importance and impact of each single factor in each individual patient. At present, the biopsychosocial model is not well prepared for this. When adopting machine learning technology in clinical practice, new skills and expertise will be required from physicians. They should be able to weigh and explain algorithms supported decisions to their patients. Moreover, new research should be designed in such a way that data will be suited for machine learning and can be inte-grated with existing databases in order to increase their size and scope.Conclusion: Currently, the biopsychosocial model is not well prepared to accommodate the possibilities of personalized medicine. Adaptations are needed to deal with the highly individual aspects of the patient's disease.

BACKGROUND: Substance use is overrepresented in patients with psychosis. Maladaptive coping has been proposed as one of the mechanisms which might underlie this high prevalence. Patients are known to apply more maladaptive coping compared to the healthy population. However, it is unknown whether coping is associated with the use of different substances across those with different vulnerability for psychosis, and whether coping mediates the possible association between life events and substance use.METHODS: In this multicenter, cohort study, 429 patients, 504 siblings, and 220 controls were included. We determined whether coping was associated with tobacco smoking, cannabis use, or alcohol consumption. Multivariable logistic regression models were applied whilst correcting for potential confounders. We performed post-hoc analyses to explore the association between negative life events, tobacco smoking, and the role of coping as a mediator in patients with psychosis.RESULTS: A positive association was found in patients between passive coping and tobacco smoking (fully adjusted OR 1.65, 95% CI 1.18-2.31). Tobacco smoking patients experienced more negative life events compared to non-smoking patients and passive coping mediated this association. In siblings and controls, none of the coping strategies were associated with substance use.CONCLUSIONS: The coping style of patients with psychosis is associated with tobacco smoking and mediates the association between negative events and tobacco smoking. No significant associations were found in siblings, controls or concerning other substance use. Future research is required to examine whether enhancing healthy coping strategies decreases tobacco use in patients with psychosis.

INTRODUCTION: Early health-technology assessment can support discussing scarce resource allocation among stakeholders. We explored the value of maintaining cognition in patients with mild cognitive impairment (MCI) by estimating: (1) the innovation headroom and (2) the potential cost effectiveness of roflumilast treatment in this population.METHODS: The innovation headroom was operationalized by a fictive 100% efficacious treatment effect, and the roflumilast effect on memory word learning test was assumed to be associated with 7% relative risk reduction of dementia onset. Both were compared to Dutch setting usual care using the adapted International Pharmaco-Economic Collaboration on Alzheimer's Disease (IPECAD) open-source model.RESULTS: The total innovation headroom expressed as net health benefit was 4.2 (95% bootstrap interval: 2.9-5.7) quality-adjusted life years (QALYs). The potential cost effectiveness of roflumilast was k€34 per QALY.DISCUSSION: The innovation headroom in MCI is substantial. Although the potential cost effectiveness of roflumilast treatment is uncertain, further research on its effect on dementia onset is likely valuable.

Primary prevention trials have shifted their focus to the earliest stages of Alzheimer's disease (AD). Autopsy data indicates that the neuromodulatory subcortical systems' (NSS) nuclei are specifically vulnerable to initial tau pathology, indicating that these nuclei hold great promise for early detection of AD in the context of the aging brain. The increasing availability of new imaging methods, ultra-high field scanners, new radioligands, and routine deep brain stimulation implants has led to a growing number of NSS neuroimaging studies on aging and neurodegeneration. Here, we review findings of current state-of-the-art imaging studies assessing the structure, function, and molecular changes of these nuclei during aging and AD. Furthermore, we identify the challenges associated with these imaging methods, important pathophysiologic gaps to fill for the AD NSS neuroimaging field, and provide future directions to improve our assessment, understanding, and clinical use of in vivo imaging of the NSS.

The neural correlates of subjective cognitive decline (SCD; i.e., without objectifiable deficit) remain to be elucidated. Possible causes of SCD include early neurodegeneration related to Alzheimer's disease or functional and structural changes related to sub-clinical depression. We investigated the relationship between episodic memory performance or memory complaints and structural or functional magnetic resonance imaging (MRI) measures in participants with SCD ( n = 18) but without psychiatric disorders and healthy controls ( n = 31). In SCD, memory complaints were not associated with memory performance but with sub-clinical depression and executive functions. SCD-associated memory complaints correlated with higher amygdala and parahippocampal gyrus (specifically subiculum) gray matter density. In controls, but not in SCD, mesiotemporal gray matter density and superior frontal gyrus functional connectivity predicted memory performance. In contrast, in SCD, only a trend toward a correlation between memory performance and gray matter density in the parietooccipital lobes was observed. In our memory-clinic sample of SCD, we did not observe incipient neurodegeneration (limited to structural and functional MRI) but rather sub-clinical depression underlying subjective cognitive complaints. (c) 2021 Elsevier Inc. All rights reserved.

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Over the last years, the amount, variety, and complexity of neuroimaging data acquired in patients with brain tumors for routine clinical purposes and the resulting number of imaging parameters have substantially increased. Consequently, a timely and cost-effective evaluation of imaging data is hardly feasible without the support of methods from the field of artificial intelligence (AI). AI can facilitate and shorten various timeconsuming steps in the image processing workflow, e.g., tumor segmentation, thereby optimizing productivity. Besides, the automated and computer-based analysis of imaging data may help to increase data comparability as it is independent of the experience level of the evaluating clinician. Importantly, AI offers the potential to extract new features from the routinely acquired neuroimages of brain tumor patients. In combination with patient data such as survival, molecular markers, or genomics, mathematical models can be generated that allow, for example, the prediction of treatment response or prognosis, as well as the noninvasive assessment of molecular markers. The subdiscipline of AI dealing with the computation, identification, and extraction of image features, as well as the generation of prognostic or predictive mathematical models, is termed radiomics. This review article summarizes the basics, the current workflow, and methods used in radiomics with a focus on feature-based radiomics in neuro-oncology and provides selected examples of its clinical application.

Objective: Public health recommendations promote social engagement to reduce risk of cognitive decline and dementia. The objective of this study was to evaluate the longitudinal associations of social engagement and cognition in cognitively normal older adults with varying levels of neocortical amyloid-beta, the Alzheimer's disease (AD) pathologic marker. Methods: Two hundred seventeen men and women, age 63-89 underwent assessments for social engagement and cognitive performance at baseline and 3 years later using the Community Healthy Activities Model Program for Seniors questionnaire and the Preclinical Alzheimer Cognitive Composite (PACC). Amyloid-beta was measured using Pittsburgh compound B-PET. Multivariable regression models estimated main and interactive effects of baseline social engagement and amyloid-beta on cognitive change. Reciprocal models estimated main and interactive effects of baseline cognitive performance and amyloid-beta on change in social engagement. Results: Baseline social engagement was associated with PACC change as a modifier but not as a main effect. Lower baseline social engagement was associated with greater amyloid-beta-related PACC decline, while higher baseline social engagement was associated with relative preservation of PACC scores (beta = 0.05, p = 0.03). Reciprocally, lower baseline PACC score was associated with decline in social engagement score (beta = 1.1, p = 0.02). This association was not modified by amyloid-beta, and there was no direct association of amyloid-beta with change in social engagement. Conclusions: Low social engagement may be a marker of neurocognitive vulnerability in older adults who are cognitively normal but have evidence of AD pathophysiologic change. Understanding changes in social engagement in older adults may lead to earlier diagnosis of AD and advances in evidence-based prevention and treatment.

Introduction: We investigated relations between amyloid-beta (A beta) status, apolipoprotein E (APOE) e4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau).Methods: We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with A beta status (Ab beta- vs. A beta+), clinical diagnosis APOE epsilon 4 carriership, baseline cognition, and change in cognition.Results: Ng and T-tau distinguished between A beta+ from A beta- individuals in each clinical group, whereas NFL and YKL-40 were associated with A beta+ in nondemented individuals only. APOE epsilon 4 carriership did not influence NFL, Ng, and YKL-40 in A beta+ individuals. NFL was the best predictor of cognitive decline in A beta+ individuals across the cognitive spectrum.Discussion: Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Childhood and adolescence represent sensitive developmental periods for brain networks implicated in a range of complex skills, including executive functions (EF; inhibitory control, working memory, and cognitive flexibility). As a consequence, these skills may be particularly vulnerable to injuries sustained during these sensitive developmental periods. The present study investigated 1) whether age at injury differentially affects EF 6 months and 2 years after TBI in children aged 5-15 years, and 2) whether the association between brain lesions and EF depend on age at injury. Children with TBI (n = 105) were categorized into four age-at-injury groups based on previous studies and proposed timing of cerebral maturational spurts: early childhood (5-6 years, n = 14), middle childhood (7-9 years, n = 24), late childhood (10-12 years, n = 52), and adolescence (13-15 years, n = 15). EF were assessed with performance-based tasks and a parent-report of everyday EF. TBI patients' EF scores 6 months and 2 years post-injury were compared to those of typically developing (TD) controls (n = 42). Brain lesions were identified using susceptibility weighted imaging (SWI). Results indicated that inhibitory control performance 2 years post-injury was differentially affected by the impact of TBI depending on age at injury. Follow-up analyses did not reveal significant differences within the age groups, preventing drawing strong conclusions regarding the contribution of age at injury to EF outcome after TBI. Tentatively, large effect sizes suggest that vulnerability is most apparent in early childhood and adolescence. Everyday inhibitory control behaviour was worse for children with TBI than TD children across childhood and adolescence at the 2-year assessment. There was no evidence for impairment in working memory or cognitive flexibility after TBI at the group level. Given small group sizes, findings from analyses into correlations between EF and SWI lesions should be interpreted with caution. Extent, number and volume of brain lesions correlated with adolescent everyday EF behaviour 6 months post-injury. Taken together, the results emphasize the need for long-term follow-up after paediatric TBI during sensitive developmental periods given negative outcomes 2-year post injury. Inhibitory control seems to be particular vulnerable to the impact of TBI. Findings of associations between EF and SWI lesions need to be replicated with larger samples.

It is often difficult to predict seizure recurrence in subjects who have suffered a first-ever epileptic seizure. In this study, the predictive value of physiological signals measured using Electroencephalography (EEG) and functional MRI (fMRI) is assessed. In particular those patients developing epilepsy (i.e. a second unprovoked seizure) that were initially evaluated as having a low risk of seizure recurrence are of interest.In total, 26 epilepsy patients, of which 8 were initially evaluated as having a low risk of seizure recurrence (i.e. converters), and 17 subjects with only a single seizure were included. All subjects underwent routine EEG as well as fMRI measurements. For diagnostic classification, features related to the temporal dynamics were determined for both the processed EEG and fMRI data. Subsequently, a logistic regression classifier was trained on epilepsy and first-seizure subjects. The trained model was tested using the clinically relevant converters group.The sensitivity, specificity, and AUC (mean +/- SD) of the regression model including metrics from both modalities were 74 +/- 19%, 82 +/- 18%, and 0.75 +/- 0.12, respectively. Positive and negative predictive values (mean SD) of the regression model with both EEG and fMRI features are 84 +/- 14% and 78 +/- 12%. Moreover, this EEG/fMRI model showed significant improvements compared to the clinical diagnosis, whereas the models using metrics from either EEG or fMRI do not reach significance (p > 0.05).Temporal metrics computationally derived from EEG and fMRI time signals may clinically aid and synergistically improve the predictive value in a first-seizure sample. (C) 2020 The Author(s). Published by Elsevier Inc.

Background: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults.Methods: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1-90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (epsilon) and spatial overlapping coefficient (DICE) between test and retest session.Results: Significant MRI site and vendor effects (p 0.43, p 0.80).Conclusion: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials.

Introduction: Amyloid positron emission tomography (PET) data are commonly expressed as binary measures of cortical deposition. However, not all individuals with high cortical amyloid will experience rapid cognitive decline. Motivated by postmortem data, we evaluated a three-stage PET classification: low cortical; high cortical, low striatal; and high cortical, high striatal amyloid; hypothesizing this model could better reflect Alzheimer's dementia progression than a model based only on cortical measures. Methods: We classified PET data from 1433 participants (646 normal, 574 mild cognitive impairment, and 213 AD), explored the successive involvement of cortex and striatum using 3-year follow-up PET data, and evaluated the associations between PET stages, hippocampal volumes, and cognition. Results: Follow-up data indicated that PET detects amyloid first in cortex and then in striatum. Our three-category staging including striatum better predicted hippocampal volumes and subsequent cognition than a three-category staging including only cortical amyloid. Discussion: PET can evaluate amyloid expansion from cortex to subcortex. Using striatal signal as a marker of advanced amyloidosis may increase predictive power in Alzheimer's dementia research. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.

Background Anxiety disorders occur in up to 35% of patients with Parkinson's disease (PD) and have a negative effect on motor symptoms and quality of life. To date, no clinical trials specifically targeting anxiety in PD patients have been published. Objective To describe the rationale and methodology of a randomised controlled trial (RCT) that aims to study the clinical effectiveness, alterations in brain circuitry, and cost-effectiveness of cognitive behavioural therapy (CBT) for anxiety in PD. Methods This study is a prospective, two-centre RCT in which sixty PD patients with anxiety will be randomised to CBT treatment and clinical monitoring (intervention group) or to clinical monitoring only (control group). The CBT module used in this study was specifically developed to address symptoms of anxiety in PD patients. Participants will undergo standardised clinical, cognitive and behavioural assessment at baseline and at 2 follow-up measurements, as well as resting-state fMRI and DTI scanning before and after the intervention. The primary outcome measure is changes in severity of anxiety symptoms. Secondary outcome measures involve long-term changes in anxiety symptoms, changes in functional and structural connectivity between limbic and frontal cortices, and cost-effectiveness of the treatment. The study is registered at the ClinicalTrials.gov database under registration number NCT02648737 . Conclusion This study is the first that evaluates both the clinical effectiveness, cost-effectiveness, as well as the biological impact of CBT for anxiety in PD patients that, if proven effective, will hopefully contribute to a better and evidence-based approach for these non-motor symptoms.

Large studies investigating the psychosocial effects of lifestyle interventions in patients with a severe mental illness (SMI) are scarce, especially in residential patients. This large, randomized controlled, multicentre pragmatic trial assessed the psychosocial effects of a combined diet-and-exercise lifestyle intervention targeting the obesogenic environment of SMI residential patients. Twenty-nine sheltered and clinical care teams were randomized into intervention (n = 15) or control (n = 14) arm. Team tailored diet-and-exercise lifestyle plans were set up to change the obesogenic environment into a healthier setting, and team members were trained in supporting patients to make healthier choices. The control group received care-as-usual. The Calgary Depression Scale for Schizophrenia (CDSS), Positive and Negative Syndrome Scale (PANSS), Health of the Nation Outcome Scales (HoNOS) and the Manchester Short Assessment of Quality of Life (MANSA) were assessed at baseline and after three and twelve months. Data were available for 384 intervention and 386 control patients (48.6 +/- 12.5 years old, 62.7% males, 73.7% psychotic disorder). Linear mixed model analysis showed no psychosocial improvements in the intervention group compared to care-as-usual; the intervention group showed a slightly reduced quality of life (overall) and a small increase in depressive symptoms (clinical care facilities) and psychotic symptoms (sheltered facilities). This may be due to difficulties with implementation, the intervention not being specifically designed for improvements in mental well-being, or the small change approach, which may take longer to reach an effect. Further research might elucidate what type of lifestyle intervention under what circumstances positively affects psychosocial outcomes in this population. (c) 2018 Elsevier B.V. All rights reserved.

Objective To examine the influence of vascular cognitive impairment (VCI) on the course of poststroke depression (PSD) and poststroke apathy (PSA). Methods Included were 250 stroke patients who underwent neuropsychological and neuropsychiatric assessment 3 months after stroke (baseline) and at a 6- and 12-month follow-up after baseline. Linear mixed models tested the influence of VCI in at least one cognitive domain (any VCI) or multidomain VCI (VCI in multiple cognitive domains) at baseline and domain-specific VCI at baseline on levels of depression and apathy over time, with random effects for intercept and slope. Results Almost half of the patients showed any VCI at baseline, and any VCI was associated with increasing apathy levels from baseline to the 12-month follow-up. Patients with multidomain VCI had higher apathy scores at the 6- and 12-month follow-up compared with patients with VCI in a single cognitive domain. Domain-specific analyses showed that impaired executive function and slowed information processing speed went together with increasing apathy levels from baseline to 6- and 12-month follow-up. None of the cognitive variables predicted the course of depressive symptoms. Conclusion Baseline VCI is associated with increasing apathy levels from baseline to the chronic stroke phase, whereas no association was found between baseline VCI and the course of depressive symptoms. Health professionals should be aware that apathy might be absent early after stroke but may evolve over time in patients with VCI.

BACKGROUND: The objective of the ZMILE study was to compare the effectiveness of a multicomponent self-management intervention (MCI) with care as usual (CAU) in adult patients with epilepsy (PWE) over a six-month period.METHODS: Participants (PWE & relative) were randomized into intervention or CAU groups. Self-report questionnaires were used to measure disease-specific self-efficacy as the primary outcome measure and general self-efficacy, adherence, seizure severity, emotional functioning, quality of life, proactive coping, and side-effects of antiepileptic drugs (AED) as secondary outcome measures. Instruments used at baseline and during a six-month follow-up period were the following: disease-specific self-efficacy (Epilepsy Self-Efficacy Scale [ESES], General Self-Efficacy Scale [GSES]); adherence (Medication Adherence Scale [MARS] and Medication Event Monitoring System [MEMS]); seizure severity (National Hospital Seizure Severity Scale [NHS3]); emotional well-being (Hospital Anxiety and Depression Scale [HADS]); quality of life (Quality of Life in Epilepsy [QOLIE-31P]); proactive coping (Utrecht Proactive Coping Competence [UPCC]); and side-effects of antiepileptic drugs [SIDAED]. Multilevel analyses were performed, and baseline differences were corrected by inclusion of covariates in the analyses.RESULTS: In total, 102 PWE were included in the study, 52 of whom were in the intervention group. On the SIDAED and on three of the quality of life subscales QOLIE-31P, a significant difference was found (pSIGNIFICANCE: Although we found no statistically significant difference in the primary outcome measure, disease-specific self-efficacy, this MCI could prove promising, since we found improvement in some domains of quality of life in epilepsy scale and a decrease in AED side-effects in the MCI group compared with the CAU group.

Chronic fatigue complaints are frequently reported in the general population and fatigue ranks among the most commonly reported symptoms in chronic disease. In contrast to its high prevalence and impact on quality of life, relatively little is understood about the etiology of chronic fatigue. We present a cognitive-behavioral framework, the 'ALT+F' model, that conceptualizes fatigue from an associative learning perspective, and we will evaluate the current evidence for this position. Central to this framework is the notion that interoceptive and exteroceptive stimuli can become associated with the fatigue experience. Consequently, these stimuli may acquire the capacity to elicit fatigue as well as anticipatory fear-related avoidance behavior. We will argue that associative learning processes may contribute to the development of chronic fatigue, fear of fatigue, avoidance of fatigue and activity, and eventually, functional disability. The extent to which associative learning processes give rise to chronic fatigue and fear-related avoidance behavior may depend on a number of risk factors, including perceptual-cognitive biases, sensitization, fatigue catastrophizing, and excessive generalization. The presented framework offers a new window on treatment and intervention options for chronic fatigue.

Aims: Type 2 diabetes, hyperinsulinemia, and insulin resistance are associated with cognitive impairment. Experimental studies indicate that insulin signaling in the brain is related to cognitive performance. Here we evaluated whether insulin-related variables contribute to the variance in cognitive performance among individuals with type 2 diabetes. Methods: A total of 806 individuals with type 2 diabetes (mean age 62 +/- 8 years, HbAlc 6.9 +/- 1.1%) completed a neuropsychological test battery. Insulin-related variables evaluated were: fasting plasma insulin, C-peptide, and the Homeostasis Model Assessment (HOMA2-IR; in individuals without insulin treatment; n = 641). The unadjusted coefficient of determination (R-2), obtained from multiple linear regression analyses, was used to estimate the proportion of variance in cognition explained by insulin-related variables. Results: Sex, age, and educational level together explained 18.0% (R-2) of the variance in memory function, 26.5% in information processing speed, and 22.8% in executive function and attention. Fasting insulin, C-peptide, or HOMA2-IR did not increase the explained variance (maximum Delta R-2 0.3%, P >= 0.14). Similar results were obtained when insulin-related variables were added to models that additionally included glycemic control, cardiovascular risk factors, and depression. Conclusions: Our results show that measures of peripheral insulin resistance are unrelated to cognitive performance among individuals with adequately controlled type 2 diabetes.

Purpose: While levetiracetam (LEV) usage is a known risk factor for psychosis in epilepsy, the modulating effect of certain patient and treatment characteristics on the risk of psychosis has yet to be fully elucidated.Methods: In our tertiary epilepsy center, 84 patients with psychotic symptoms during LEV usage and 100 controls without psychotic symptoms during LEV usage were selected. Patient records were reviewed including demographics, medical history, antiepileptic drug use, and cognitive abilities. Univariate comparisons were performed, and variables with p Results: The total incidence of psychosis during LEV therapy in our population was 3.7%. The timing of psychotic symptoms was classified as postictal in 20 (19.8%), interictal in 14 (15.4%), postepilepsy surgery in 1 (1.1%), and unknown in 18 cases (19.8%). In 31 cases (34.1%), psychotic symptoms were classified as an antiepileptic druginduced psychotic disorder (AIPD) as a result of LEV. In 7 cases (7.7%), AIPD occurred as a result of a different antiepileptic drug. A significant association was found between the experience of psychotic symptoms and status epilepticus (p = 0.002), a history of psychotic symptoms (p Conclusion: Our retrospective study found that psychotic symptoms during LEV therapy were significantly associated with status epilepticus, a history of psychotic symptoms, a history of psychiatric illness other than psychosis, and concomitant PHT usage, whereas concomitant LTG usage was protective. Psychotic symptoms specifically as an adverse drug reaction to LEV were significantly associated with female gender, intellectual disability, status epilepticus, and a history of psychotic symptoms. (C) 2019 Elsevier Inc. All rights reserved.

Item does not contain fulltext BACKGROUND: Because anxiety is postulated as a risk factor for dementia, we performed a systematic review and meta-analysis to investigate whether anxiety predicts cognitive decline and/or dementia, taking the stage of cognitive decline as well as setting into account. METHODS: A systematic literature search up to January 2015 was performed to identify all longitudinal studies on the association between anxiety and cognition. Data extraction and methodological quality assessment were conducted independently by two authors. Where possible, pooled relative risks were calculated to examine anxiety as a possible risk factor for cognitive decline cognitive impairment and dementia in community studies (objective 1), as well as for conversion to dementia patients referred to memory clinics (objective 2). RESULTS: Twenty studies met inclusion criteria. Data on cognitive decline were too heterogeneous for meta-analysis. Anxiety predicted incident cognitive impairment (4 studies, relative risk [RR]: 1.77, 95% confidence interval [CI]: 1.38-2.26, z = 4.50, p < 0.001) and dementia (6 studies, RR: 1.57, 95% CI: 1.02-2.42, z = 2.05, p = 0.040) in the community, the latter driven by studies with a mean age of 80 years or above. Among clinical mild cognitive impairment samples, anxiety did not predict conversion to dementia (RR: 1.21, 95% CI: 0.90-1.63, z = 1.28, p = 0.200). CONCLUSIONS: Anxiety is associated with an increased risk for cognitive impairment and dementia in the community. Stronger associations were driven by higher age, suggesting that it is a prodromal symptom. Causal biological pathways have also been described, which could explain the risk for incident cognitive impairment in the community. Future studies should include mediating mechanism when studying anxiety as a predictor for cognitive decline and/or dementia.

Objective: Young-onset dementia (YOD) is defined as dementia that develops before the age of 65. Neuropsychiatric symptoms (NPS) have important clinical consequences for patients and their family members. To date, knowledge about the prevalence and correlates of NPS in YOD is limited, but essential to establish specific tailored care for patients with YOD. The aim of this study was to explore the prevalence and correlates of NPS in nursing home residents with YOD.Design/Setting: Cross-sectional cohort study in Dutch long-term care facilities providing specialized care for YOD.Participants: Participants included 230 institutionalized patients with YOD.Measurements: NPS were assessed using the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory-Nursing Home version (NPI-NH). The influence of gender, dementia severity, type of dementia, and disease awareness on clusters of relevant NPS was investigated using multivariate logistic regression analysis and subsequently corrected for the possible confounders of age, duration of institutionalization, and psychoactive medication use.Results: Ninety percent of the nursing home residents with YOD showed 1 or more neuropsychiatric symptoms, 88% showed significant agitation, and 56% showed relevant apathy. No gender differences were found. Although physically aggressive behavior, non-physically aggressive behavior, and apathy were more common in patients with (very) severe cognitive decline (Global Deterioration Scale [GDS] stage 6-7), verbally agitated behavior was common in patients in all except the most severe stages of dementia (GDS 2-6). Apathy was more prevalent in alcohol-related dementia. Low levels of awareness were associated with more physically aggressive behavior and aberrant motor behavior.Conclusion: The prevalence of NPS was high and was associated with the severity and type of dementia and disease awareness. Agitation and apathy are the most important symptoms to focus on in YOD. The high prevalence of NPS supports the idea of care delivery in special care units. Further research is needed on potentially influencing environmental correlates of NPS in YOD. (C) 2016 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

Neuromodulation is a field of science, medicine, and bioengineering that encompasses implantable and non-implantable technologies for the purpose of improving quality of life and functioning of humans. Brain neuromodulation involves different neurostimulation techniques: transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), which are being used both to study their effects on cognitive brain functions and to treat neuropsychiatric disorders. The mechanisms of action of neurostimulation remain incompletely understood. Insight into the technical basis of neurostimulation might be a first step towards a more profound understanding of these mechanisms, which might lead to improved clinical outcome and therapeutic potential. This review provides an overview of the technical basis of neurostimulation focusing on the equipment, the present understanding of induced electric fields, and the stimulation protocols. The review is written from a technical perspective aimed at supporting the use of neurostimulation in clinical practice.

Electrical carotid baroreflex activation therapy is an emerging device-based treatment for patients with resistant hypertension. Its blood pressure lowering effect has been demonstrated in several animal and human studies, with prolonged effect over the long-term. The main mechanism of the blood pressure reduction during this therapy is by inhibition of the sympathetic outflow. Yet the question arises whether the inhibition of central sympathetic activity is sufficient to be the sole mechanism behind the sustained reduction in blood pressure. The major focus of this review is to elucidate the mechanisms of action that account for the effects of continuous carotid baroreflex activation on blood pressure in humans. Recent results of baroreflex activation therapy as a treatment for heart failure will also be discussed.

IntroductionDuring transition to adult medical care, the adolescent with epilepsy is especially prone to emotional, mental, physical, and social developmental difficulties, leading to stigma and poor psychosocial and socioeconomic outcome in the long term.ObjectivesThe aim of this review is twofold: to describe the psychosocial and medical transition from adolescence to adulthood and to evaluate the most effective model for transitional services in adolescents with epilepsy.MethodsWe searched PubMed for quantitative and qualitative data about transition from adolescence to adulthood in patients with epilepsy.ResultsA total of 49 articles were retrieved. We reviewed personal, psychosocial, and medical issues during transition and their long-term individual and societal consequences. Identifying risk factors for poor transition can lead to appropriate interventions for patients and their family. Although the concept of multidisciplinary transition care for adolescents with epilepsy is widely recognized, only a few transition clinics have been established. There is lack of evidence for their quality and cost-effectiveness.ConclusionIn addition to medical problems, more attention should be paid to the risk of psychosocial problems during transition from pediatric to adult care. The implementation of transition care for adolescents with epilepsy is considered beneficial; however, its effectiveness should be further investigated.

VNS therapy was delivered to patients for the first time in 1988. After 25 years, insight in the antiepileptic and antidepressant mechanism of action of VNS has grown steadily. The effects on cognition and especially memory remain controversial. This review provides an elaborate overview of studies addressing cognition and describes potential underlying mechanisms for the reported effects. Short-term VNS has an effect on verbal memory recognition when administered at the correct timing and dosage. Chronic VNS resulted into a positive effect on the cognitive status in an Alzheimer population. Positive effect of chronic VNS in epilepsy or depression patients on global cognitive functioning are less convincing. Neither do the results reveal a negative effect which has major implications for chronic treatment of neurology patients. A cascade of neurochemical processes put in motion by changes in NE concentrations in reaction to stimulation of the vagal nerve may underlie the VNS-induced effects on cognition and memory. In Alzheimer pathology, NE may act as an anti-inflammatory agent on brainstem nuclei.

We describe a treatment alternative for intractable, startle-provoked, epileptic seizures in four children aged between 8 and 14. Three of the four children had symptomatic localization-related epilepsy. They all suffered from intractable epilepsy precipitated by sudden sounds. The fact that seizures tended to occur with high frequency – more than one seizure a day – had a clear impact on daily life. Clinical seizure pattern demonstrated asymmetric tonic posturing in all four children. Three children experienced several seizure types including focal seizure onset. All children had focal neurological signs or learning disabilities or a combination of both. Our noninvasive treatment method using psychoeducational counseling and sound generators was applied in four children, resulting in a seizure frequency reduction of ≥50% in two of them.

In the absence of disease modifying therapies for dementia, the question rises what the benefits are of an early dementia diagnosis for patients and their caregivers. This paper reviews the caregiver perspective in dementia and addresses the question what the consequences are of promoting earlier dementia diagnosis. An early diagnosis offers caregivers the opportunity to advance the process of adaptation to the caregiver role. Caregivers that are better able to adapt to the changes that characterize dementia, feel more competent to care and experience less psychological problems. However, drawbacks of an early diagnosis may outweigh the benefits if people are left with a diagnosis but little support. There is convincing evidence that multicomponent caregiver interventions in the mild to moderate dementia stages are effective to improve caregiver well-being and delay institutionalization. However, there still exist a gap between the improved possibilities to diagnose people in the predementia stage versus the scarce knowledge on intervention effects in this very early stage. This stresses the urgent need for more research on early caregiver interventions that enhance role adaptation and that include long-term follow-up and cost-effectiveness evaluation. Early interventions may help caregivers in anticipating and accepting the future care role and transitions, with the increased possibility that caregivers can still involve the patient in the decision making process. As levels of stress and burden are still low in the predementia stage it provides excellent opportunities to empower the resources of caregivers.

This review addresses the effect on language function of nocturnal epileptiform EEG discharges and nocturnal epileptic seizures in children. In clinical practice, language impairment is frequently reported in association with nocturnal epileptiform activity. Vice versa, nocturnal epileptiform EEG abnormalities are a common finding in children with specific language impairment. We suggest a spectrum that is characterized by nocturnal epileptiform activity and language impairment ranging from specific language impairment to rolandic epilepsy, nocturnal frontal lobe epilepsy, electrical status epilepticus of sleep, and Landau-Kleffner syndrome. In this spectrum, children with specific language impairment have the best outcome, and children with electrical status epilepticus of sleep or Landau-Kleffner syndrome, the worst. The exact nature of this relationship and the factors causing this spectrum are unknown. We suggest that nocturnal epileptiform EEG discharges and nocturnal epileptic seizures during development will cause or contribute to diseased neuronal networks involving language. The diseased neuronal networks are less efficient compared with normal neuronal networks. This disorganization may cause language impairments.

Purpose To compare pretreatment scans with perfusion computed tomography (pCT) vs. dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in rectal tumors. Methods and Materials Nineteen patients diagnosed with rectal cancer were included in this prospective study. All patients underwent both pCT and DCE-MRI. Imaging was performed on a dedicated 40-slice CT–positron emission tomography system and a 3-T MRI system. Dynamic contrast enhancement was measured in tumor tissue and the external iliac artery. Tumor perfusion was quantified in terms of pharmacokinetic parameters: transfer constant K trans , fractional extravascular–extracellular space v e , and fractional plasma volume v p . Pharmacokinetic parameter values and their heterogeneity (by 80% quantile value) were compared between pCT and DCE-MRI. Results Tumor K trans values correlated significantly for the voxel-by-voxel–derived median (Kendall's τ correlation, τ = 0.81, p τ = 0.54, p = 0.04), as well as for the averaged uptake ( τ = 0.58, p = 0.03). However, no significant correlations were found for v e and v p derived from the voxel-by-voxel–derived median and 80% quantile and derived from the averaged uptake curves. Conclusions T his study demonstrated for the first time that pCT provides K trans values comparable to those of DCE-MRI. However, no correlation was found for the v e and v p parameters between CT and MRI. Computed tomography can serve as an alternative modality to MRI for the in vivo evaluation of tumor angiogenesis in terms of the transfer constant K trans .

Both the patient's and the caregiver's perspectives are discussed. The guideline includes chapters on epidemiology, etiology and risk factors, and the non-pharmacological and pharmacological prevention and treatmentof delirium. Inaddition, onechapter is dedicated to the ‘organization of care’. This latter chapter was more heavily based on expert opinion than the other chapters.