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Contains fulltext : 291966.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Vestibular schwannoma (VS) growth of ≥2 mm during serial MRI observation, irrespective of size, is the benchmark for treatment initiation in almost all centers. Although the probability of less optimal outcomes significantly increases in VS closer to the brainstem, early intervention does not improve long-term quality of life. Moving beyond the recommendation of definitive treatment for all VS after detected growth, we subclassified Koos 2 tumors based on extrameatal extension and relation to the brainstem. The aim of the current study was to evaluate the Koos 2 subclassification's validity and the inter-and intra-rater reliability of the entire Koos classification. METHODS: Six experts, including neurosurgeons, otorhinolaryngologists and radiologists from two tertiary referral centers, classified 43 VS MRI scans. Validity of the Koos 2 subclassification was evaluated by the percentage agreement against the multidisciplinary skull base tumor board management advice. Inter- and intra-rater reliability were calculated using the intraclass correlation coefficient (ICC). RESULTS: Validity was almost perfect in Koos 2a VSs with a 100% agreement and 87.5% agreement for Koos 2b. Inter-rater reliability for all Koos grades was significantly excellent (ICC 0.91; 95%CI 0.866 to 0.944, p= 0.90; p=

In 2011, a syndrome entitled ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants; Shoenfeld's syndrome) was first described. ASIA aimed to organize under a single umbrella, the existing evidence regarding certain environmental factors which possess immune stimulatory properties, in order to shed light on a common pathway of autoimmune pathogenesis. Such environmental immune stimulators, or adjuvants, include among others: aluminum salts as in vaccines, various medical implants, as well as various infectious agents. After the launch of the ASIA syndrome, the expansion and recognition of this syndrome by different researchers from different countries began. During the past decades, evidence had been accumulating that (auto)immune symptoms can be triggered by exposure to environmental immune stimulatory factors that act as an adjuvant in genetically susceptible individuals. A panoply of unexplained subjective and autonomic-related symptoms has been reported in patients with ASIA syndrome. The current review summarizes and updates accumulated knowledge from the past decades, describing new adjuvants- (e.g. polypropylene meshes) and vaccine- (e.g. HPV and COVID vaccines) induced ASIA. Furthermore, a direct association between inflammatory/autoimmune diseases with ASIA syndrome, will be discussed. Recent cases will strengthen some of the criteria depicted in ASIA syndrome such as clear improvement of symptoms by the removal of adjuvants (e.g. silicone breast implants) from the body of patients. Finally, we will introduce additional factors to be included in the criteria for ASIA syndrome such as: (1) dysregulated non-classical autoantibodies directed against G-protein coupled receptors (GPCRs) of the autonomic nervous system and (2)) small fiber neuropathy (SFN), both of which might explain, at least in part, the development of 'dysautonomia' reported in many ASIA patients.

Contains fulltext : 293770.pdf (Publisher’s version ) (Open Access) INTRODUCTION/AIMS: There is clear evidence for brain involvement in childhood myotonic dystrophy type 1 (DM1) from imaging studies and the prevalence of intellectual impairment and neurodevelopmental disorders. The cognitive profile of children with DM1 however is poorly understood. The aim of this study was to assess the cognitive profile of children with DM1. METHODS: Neuropsychological examination reports of 45 children aged 2-17 y were analyzed. All cognitive subtests used in this cohort were pooled in 10 cognitive domains. For every patient a composite z-score was calculated for every assessed domain. Composite scores were classified as average (z > -1), mild cognitive impairment (-1 ≥ z > -2), or major cognitive impairment (z ≤ -2). RESULTS: The nature and extent of neuropsychological examinations differed between centers and patients. The domains with the highest frequency of major cognitive impairment were social cognition (4/9 children tested; 44%), attention (13/32; 41%), and fine motor skills (3/10; 30%). Combining mild and major cognitive impairment, working memory (20/28; 71%), attention (21/32; 66%), and visuospatial functions (16/28; 57%) were the most frequently affected domains. Long-term memory was least affected, with mild impairment only in 5/29 (17%). DISCUSSION: Children with DM1 may have specific cognitive deficits, most frequently affecting working memory, attention, and visuospatial functions, in addition to the previously described global intellectual impairments. We recommend including a standardized neuropsychological examination in the standards of care for DM1 children. Early recognition of cognitive deficits and behavioral disorders in children with DM1 can improve their management. 01 juli 2023

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.

The brain is a highly energetic organ. Although the brain can consume metabolic substrates, such as lactate, glycogen, and ketone bodies, the energy metabolism in a healthy adult brain mainly relies on glucose provided via blood. The cerebral metabolism of glucose produces energy and a wide variety of intermediate metabolites. Since cerebral metabolic alterations have been repeatedly implicated in several brain disorders, understanding changes in metabolite levels and corresponding cell-specific neurotransmitter fluxes through different substrate utilization may highlight the underlying mechanisms that can be exploited to diagnose or treat various brain disorders. Magnetic resonance spectroscopy (MRS) is a noninvasive tool to measure tissue metabolism in vivo. 1H-MRS is widely applied in research at clinical field strengths (≤3T) to measure mostly high abundant metabolites. In addition, X-nuclei MRS including, 13C, 2H, 17O, and 31P, are also very promising. Exploiting the higher sensitivity at ultra-high-field (>4T; UHF) strengths enables obtaining unique insights into different aspects of the substrate metabolism towards measuring cell-specific metabolic fluxes in vivo. This review provides an overview about the potential role of multinuclear MRS (1H, 13C, 2H, 17O, and 31P) at UHF to assess the cerebral metabolism and the metabolic insights obtained by applying these techniques in both healthy and diseased states.

Background: After stroke, many patients experience problems with participation in daily activities. Improving participation is the main goal in stroke rehabilitation. However, the longitudinal relationship between participation and health-related quality of life (HRQoL) remains unclear.Objectives: This study aimed to examine (1) the predictive value of participation at two months on long-term HRQoL and (2) the longitudinal relationship between participation and HRQoL.Methods: In this multicenter, prospective cohort study, patients were assessed at two and 12 months after stroke. Participation was measured with the Restriction subscale of the Utrecht Scale for Evaluation of Rehabilitation - Participation. HRQoL was assessed with the three-level version of the EuroQoL five dimensions questionnaire index score.Results: This study included 291 patients. Mean age was 66.6 +/- 12.4 years, 64.3% were male and mean National Institutes of Health Stroke Scale (NIHSS) was 2.5 +/- 2.9. Multivariable linear regression, adjusted for demographic characteristics, stroke characteristics, physical and cognitive impairment, showed that a higher level of participation at two months correlated with a higher HRQoL at one year (B = .004; 95% CI =.002-.005). Patients whose participation improved had a greater increase in HRQoL, compared to patients without improvement (0.080 +/- .21 versus -.054 +/- .21; p < .001).Conclusions: The level of participation at two months post-stroke predicts HRQoL at one year. Improvement in participation during the first year after stroke is associated with improvement in HRQoL. We recommend including the assessment of participation in daily activities at follow-up visits.

Autopsy data indicate that the locus coeruleus (LC) is one of the first sites in the brain to accumulate hyperphosphorylated tau pathology, with the rostral part possibly being more vulnerable in the earlier stages of the disease. Taking advantage of recent developments in ultra-high field (7 T) imaging, we investigated whether imaging measures of the LC also reveal a specific anatomic correlation with tau using novel plasma biomarkers of different species of hyperphosphorylated tau, how early in adulthood these associations can be detected and if are associated with worse cognitive performance. To validate the anatomic correlations, we tested if a rostro-caudal gradient in tau pathology is also detected at autopsy in data from the Rush Memory and Aging Project (MAP). We found that higher plasma measures of phosphorylated tau, in particular ptau231, correlated negatively with dorso-rostral LC integrity, whereas correlations for neurodegenerative plasma markers (neurofilament light, total tau) were scattered throughout the LC including middle to caudal sections. In contrast, the plasma Aβ42/40 ratio, associated with brain amyloidosis, did not correlate with LC integrity. These findings were specific to the rostral LC and not observed when using the entire LC or the hippocampus. Furthermore, in the MAP data, we observed higher rostral than caudal tangle density in the LC, independent of the disease stage. The in vivo LC-phosphorylated tau correlations became significant from midlife, with the earliest effect for ptau231, starting at about age 55. Finally, interactions between lower rostral LC integrity and higher ptau231 concentrations predicted lower cognitive performance. Together, these findings demonstrate a specific rostral vulnerability to early phosphorylated tau species that can be detected with dedicated magnetic resonance imaging measures, highlighting the promise of LC imaging as an early marker of AD-related processes.

INTRODUCTIONWe investigated the link between locus coeruleus (LC) pathology and cerebral microangiopathy in two large neuropathology datasets. METHODSWe included data from the National Alzheimer's Coordinating Center (NACC) database (n = 2197) and Religious Orders Study and Rush Memory and Aging Project (ROSMAP; n = 1637). Generalized estimating equations and logistic regression were used to examine associations between LC hypopigmentation and presence of cerebral amyloid angiopathy (CAA) or arteriolosclerosis, correcting for age at death, sex, cortical Alzheimer's disease (AD) pathology, ante mortem cognitive status, and presence of vascular and genetic risk factors. RESULTSLC hypopigmentation was associated with higher odds of overall CAA in the NACC dataset, leptomeningeal CAA in the ROSMAP dataset, and arteriolosclerosis in both datasets. DISCUSSIONLC pathology is associated with cerebral microangiopathy, independent of cortical AD pathology. LC degeneration could potentially contribute to the pathways relating vascular pathology to AD. Future studies of the LC-norepinephrine system on cerebrovascular health are warranted. HighlightsWe associated locus coeruleus (LC) pathology and cerebral microangiopathy in two large autopsy datasets.LC hypopigmentation was consistently related to arteriolosclerosis in both datasets.LC hypopigmentation was related to cerebral amyloid angiopathy (CAA) presence in the National Alzheimer's Coordinating Center dataset.LC hypopigmentation was related to leptomeningeal CAA in the Religious Orders Study and Rush Memory and Aging Project dataset.LC degeneration may play a role in the pathways relating vascular pathology to Alzheimer's disease.

Background: Hypertension alters the structure and function of cerebral blood vessels, and is an important risk factor for stroke and cerebral small vessel disease (cSVD). However, the pathophysiological process is not yet well understood. This study aimed to investigate the relationship between the pulsatility measures in small perforating arteries and hypertension, since hypertension-induced arterial stiffening may lead to a higher blood flow pulsatility and lower damping. Methods: We examined 28 patients with essential hypertension and 25 age- and sex-matched healthy controls (mean age: 63.4, range: 43–81 years, 26 males). Blood flow velocity waveforms were acquired in the lenticulostriate arteries (LSAs) and the middle cerebral artery using phase-contrast MRI at 7 Tesla. Several cSVD markers were scored. The velocity and pulsatility measures were compared between the hypertensives and controls. Results: A higher pulsatility index (PI) in the LSAs and a lower damping factor (DF) was found in the hypertensive compared to the normotensive group ( P =0.015, P =0.015, respectively), but no association was found for the PI in the middle cerebral artery. Higher systolic and mean arterial pressures were associated with higher PI in the LSA and DF. For diastolic blood pressure, only an association with a lower DF was found. Adjusting for cSVD score did not alter these relationships. Conclusions: This study shows a higher PI in the LSAs and a lower DF in subjects with hypertension, independent of cSVD presence. This supports the hypothesis that hypertension-induced arterial remodeling may alter the intracerebral blood flow velocity profiles, which could eventually contribute to cerebral tissue damage. Registration: URL: https://trialsearch.who.int/ ; Unique identifier: NL7537 and NL8798

IntroductionAlzheimer's disease and related dementias (ADRD) are among the most feared conditions. However, research around ADRD-specific fear and avoidance behaviors is lacking. Here, we validated a novel measure of fear and avoidance specific to memory loss, the Fear and Avoidance of Memory Loss (FAM) scale, and examined associations between fear avoidance and psychosocial functioning in older adults. MethodsWe assessed FAM Scale internal reliability and concurrent validity, and candidate subscales across two samples (total N = 813). We then examined associations between fear avoidance and memory performance, anxiety, depressive symptoms, sleep, social functioning, and quality of life. ResultsWe identified two subscales: fear and avoidance, which yielded strong psychometric validity. Higher fear was associated with memory failures and sleep disturbance. Higher avoidance was associated with memory failures, poorer verbal memory, reduced social functioning, and quality of life. DiscussionWe present the first measure of fear avoidance specific to memory loss. We propose that targeting fear avoidance can promote ADRD risk reduction and resiliency.

BackgroundInternational consensus on IgM +/- anti-MAG +/- PNP (IgM PNP) is lacking. Despite increasing interest in clinical trials, validated disease-specific measures are needed to adequately capture limitations and changes over time. The IMAGiNe (IgM +/- anti-myelin associated glycoprotein [MAG] peripheral neuropathy) study surges as an international collaboration to create a standardized registry of patients with IgM +/- anti-MAG PNP. The consortium, which currently consists of 11 institutions from 7 countries, presents here the IMAGiNe study design and protocol. AimsFunctional outcome measures will be constructed at the level of impairment, as well as activity and participation. We aim to describe the natural history of the cohort, the role of anti-MAG antibodies, the presence of clinical subtypes, and potential biomarkers. MethodsThe IMAGiNe study is a prospective, observational cohort study with a 3-year follow-up. At each assessment, researchers collect clinical data and subjects complete a list of preselected outcome measures. Among these, the "Pre-Rasch-built Overall Disability Scale (Pre-RODS)" questionnaire will be submitted to Rasch analysis to assess classic and modern clinimetric requirements. ResultsThe final measures will include the IgM-PNP-specific RODS and Ataxia Rating Scale (IgM-PNP-ARS). Descriptions of the disease course, clinical heterogeneity, treatment regimes, variations in laboratory values, and antibody titers will help reach consensus on diagnosis and follow-up strategies. ConclusionThe constructed interval scales will be cross-culturally valid and suitable for use in future clinical trials and daily practice. The ultimate goals are to improve functional individualized assessment, reach international consensus, and lay the foundations for successful designs in future studies.

Background Microvascular dysfunction (MVD) is an important contributor to major clinical disease such as stroke, dementia, depression, retinopathy, and chronic kidney disease. Alcohol consumption may be a determinant of MVD. Objective Main objectives were (1) to study whether alcohol consumption was associated with MVD as assessed in the brain, retina, skin, kidney and in the blood; and (2) to investigate whether associations differed by history of cardiovascular disease or sex. Design We used cross-sectional data from The Maastricht Study (N = 3,120 participants, 50.9% men, mean age 60 years, and 27.5% with type 2 diabetes [the latter oversampled by design]). We used regression analyses to study the association between total alcohol (per unit and in the categories, i.e. none, light, moderate, high) and MVD, where all measures of MVD were combined into a total MVD composite score (expressed in SD). We adjusted all associations for potential confounders; and tested for interaction by sex, and history of cardiovascular disease. Additionally we tested for interaction with glucose metabolism status. Results The association between total alcohol consumption and MVD was non-linear, i.e. J-shaped. Moderate versus light total alcohol consumption was significantly associated with less MVD, after full adjustment (beta [95% confidence interval], -0.10 [-0.19; -0.01]). The shape of the curve differed with sex (Pinteraction = 0.03), history of cardiovascular disease (Pinteraction interaction = 0.02). Conclusions The present cross-sectional, population-based study found evidence that alcohol consumption may have an effect on MVD. Hence, although increasing alcohol consumption cannot be recommended as a policy, this study suggests that prevention of MVD may be possible through dietary interventions.

BACKGROUND: Although cognitive problems can recover over time, a subgroup of hematopoietic stem cell transplantation (HCT) survivors experiences persistent cognitive problems in the long-term. Despite these implications, studies assessing cognitive functioning in HCT survivors are limited. OBJECTIVES: The aim of the present study was (1) to quantify the prevalence of cognitive impairment in patients treated with HCT who survived at least 2 years, and to compare these with a matched reference group representing the general population; (2) to identify potential determinants of cognitive functioning within the HCT survivor group. STUDY DESIGN: Within the single-centre Maastricht Observational study of late effects after Stem cell trAnsplantation (MOSA) cognitive performance was assessed by a neuropsychological test battery divided into three cognitive domains respectively memory, information processing speed, and executive function & attention. An overall cognition score was calculated as the average of the domain scores. A total of 115 HCT survivors were group-matched on a 1:4 ratio to the reference group by age, sex, and level of education. Regression analyses adjusted for different sets of covariates including demographic, health- and lifestyle-related factors were used to test for differences in cognition between HCT survivors and the reference group resembling the general population. A limited set of clinical characteristics (diagnosis, type of transplant, time since treatment, conditioning regimen with TBI and age at time of transplant) were assessed as potential determinants of neurocognitive dysfunction among HCT survivors. Cognitive impairment was defined as scores in the cognitive domains < -1.5 SD from what can be expected based on someone's age, sex, and education. RESULTS: The mean age at time of transplant was 50.2 (SD 11.2) years, and the mean number of years after transplant was 8.7 (SD 5.7) years. The majority of HCT survivors were treated with autologous HCT (N = 73; 64%). The prevalence of cognitive dysfunction in HCT survivors was 34.8%, and 21.3% in the reference group (p = .002.) When adjusted for age, sex, and level of education HCT survivors had a worse overall cognition score (b=-.35, 95%CI=-.55, -.16, p

The survival and well-being of humans require solving the patch-switching problem: we must decide when to stop collecting rewards in a current patch and travel somewhere else where gains may be higher. Previous studies suggested that frontal regions are underpinned by several processes in the context of foraging decisions such as tracking task difficulty, and/or the value of exploring the environment. To dissociate between these processes, participants completed an fMRI patch-switching learning task inspired by behavioral ecology. By analyzing >11,000 trials collected across 21 participants, we found that the activation in the cingulate cortex was closely related to several patch-switching-related variables including the decision to leave the current patch, the encounter of a new patch, the harvest value, and the relative forage value. Learning-induced changes in the patch-switching threshold were tracked by activity within frontoparietal regions including the superior frontal gyrus and angular gyrus. Our findings suggest that frontoparietal regions shape patch-switching learning apart from encoding classical non-learning foraging processes. These findings provide a novel neurobiological understanding of how learning emerges neurocomputationally shaping patch-switching behavior with implications in real-life choices such as job selection and pave the way for future studies to probe the causal role of these neurobiological mechanisms.

The blood–brain barrier (BBB) is a functional interface that provides selective permeability, protection from toxic substances, transport of nutrients, and clearance of brain metabolites. Additionally, BBB disruption has been shown to play a role in many neurodegenerative conditions and diseases. Therefore, the aim of this study was to establish a functional, convenient, and efficient in vitro co-cultured BBB model that can be used for several physiological conditions related to BBB disruption. Mouse brain-derived endothelial (bEnd.3) and astrocyte (C8-D1A) cells were co-cultured on transwell membranes to establish an intact and functional in vitro model. The co-cultured model and its effects on different neurological diseases and stress conditions, including Alzheimer’s disease (AD), neuroinflammation, and obesity, have been examined by transendothelial electrical resistance (TEER), fluorescein isothiocyanate (FITC) dextran, and tight junction protein analyses. Scanning electron microscope images showed evidence of astrocyte end-feet processes passing through the membrane of the transwell. Moreover, the co-cultured model showed effective barrier properties in the TEER, FITC, and solvent persistence and leakage tests when compared to the mono-cultured model. Additionally, the immunoblot results showed that the expression of tight junction proteins such as zonula occludens-1 (ZO-1), claudin-5, and occludin-1 was enhanced in the co-culture. Lastly, under disease conditions, the BBB structural and functional integrity was decreased. The present study demonstrated that the co-cultured in vitro model mimicked the BBB’s structural and functional integrity and, under disease conditions, the co-cultured model showed similar BBB damages. Therefore, the present in vitro BBB model can be used as a convenient and efficient experimental tool to investigate a wide range of BBB-related pathological and physiological studies.

Purpose: Cognitive Adaptation Training (CAT) is a psychosocial intervention with demonstrated effectiveness. However, no validated fidelity instrument is available. In this study, a CAT Fidelity Scale was developed and its psychometric properties, including interrater reliability and internal consistency, were evaluated. Methods: The fidelity scale was developed in a multidisciplinary collaboration between international research groups using the Delphi method. Four Delphi rounds were organized to reach consensus for the items included in the scale. To examine the psychometric properties of the scale, data from a large cluster randomized controlled trial evaluating the implementation of CAT in clinical practice was used. Fidelity assessors conducted 73 fidelity reviews at four mental health institutions in the Netherlands. Results: After three Delphi rounds, consensus was reached on a 44-item CAT Fidelity Scale. After administration of the scale, 24 items were removed in round four resulting in a 20-item fidelity scale. Psychometric properties of the 20-item CAT Fidelity Scale shows a fair interrater reliability and an excellent internal consistency. Conclusions: The CAT fidelity scale in its current form is useful for both research purposes as well as for individual health professionals to monitor their own adherence to the protocol. Future research needs to focus on improvement of items and formulating qualitative anchor point to the items to increase generalizability and psychometric properties of the scale. The described suggestions for improvement provide a good starting point for further development.

Hematopoietic stem cell transplantation is an important treatment for many malignant hematological and non-hematological diseases. Survivors of hematopoietic stem cell transplantation (HCT) are at risk of long-term health problems and reduced quality of life related to previous treatments. Many studies about these long-term effects have been conducted over the last decades. However, selection bias is a concern in long-term follow-up studies and little is known about the non-participating group. As part of the Maastricht Observational study of late effects after Stem cell trAnsplantation (MOSA), investigating long-term health effects by extensively phenotyping HCT survivors, we conducted a survey to characterise the non-participating group. This survey mostly focused on quality of life and physical complaints. The survey responders were generally older than the MOSA group, had more history of relapsed disease, and described their general health as bad or mediocre significantly more often than the MOSA group. Also, more deaths occurred in the group of non-participants between the start of study inclusion in 2015 and analysis of the survey results in 2021. This study suggests that a selection of higher functioning HCT survivors with a relatively better quality of life participated in this long-term follow-up study of stem cell transplantation survivors. These results could also impact the results of other long-term follow-up studies in cancer survivors, knowing that possibly an unhealthier population is missed in these studies and some long-term negative effects of treatments might be underestimated.Trial registration number: NL-48599.

Perinatal brain injury following hypoxia-ischemia (HI) is characterized by high mortality rates and long-term disabilities. Previously, we demonstrated that depletion of Annexin A1, an essential mediator in BBB integrity, was associated with a temporal loss of blood-brain barrier (BBB) integrity after HI. Since the molecular and cellular mechanisms mediating the impact of HI are not fully scrutinized, we aimed to gain mechanistic insight into the dynamics of essential BBB structures following global HI in relation to ANXA1 expression. Global HI was induced in instrumented preterm ovine fetuses by transient umbilical cord occlusion (UCO) or sham occlusion (control). BBB structures were assessed at 1, 3, or 7 days post-UCO by immunohistochemical analyses of ANXA1, laminin, collagen type IV, and PDGFRβ for pericytes. Our study revealed that within 24 h after HI, cerebrovascular ANXA1 was depleted, which was followed by depletion of laminin and collagen type IV 3 days after HI. Seven days post-HI, increased pericyte coverage, laminin and collagen type IV expression were detected, indicating vascular remodeling. Our data demonstrate novel mechanistic insights into the loss of BBB integrity after HI, and effective strategies to restore BBB integrity should potentially be applied within 48 h after HI. ANXA1 has great therapeutic potential to target HI-driven brain injury.

The LipiDiDiet randomized clinical trial is evaluating the long term effects of a multinutrient intervention (Fortasyn Connect) compared with control in participants with prodromal AD. In this post-hoc analysis we used the Alzheimer's Disease Composite Score (ADCOMS) as a measure of cognition and global function, together with a global statistical test (GST) and Bayesian hierarchical modelling (BHM) to evaluate the totality of evidence for an effect of the intervention over 36 months. The analysis includes 67 participants (39 active, 28 control) with change from baseline data after 36 months intervention. All outcome measures showed a statistically significant effect for the intervention: ADCOMS (P =0.045), GST (P

Contains fulltext : 291863.pdf (Publisher’s version ) (Open Access) Cine-MRI for adhesion detection is a promising novel modality that can help the large group of patients developing pain after abdominal surgery. Few studies into its diagnostic accuracy are available, and none address observer variability. This retrospective study explores the inter- and intra-observer variability, diagnostic accuracy, and the effect of experience. A total of 15 observers with a variety of experience reviewed 61 sagittal cine-MRI slices, placing box annotations with a confidence score at locations suspect for adhesions. Five observers reviewed the slices again one year later. Inter- and intra-observer variability are quantified using Fleiss’ (inter) and Cohen’s (intra) κ and percentage agreement. Diagnostic accuracy is quantified with receiver operating characteristic (ROC) analysis based on a consensus standard. Inter-observer Fleiss’ κ values range from 0.04 to 0.34, showing poor to fair agreement. High general and cine-MRI experience led to significantly (p < 0.001) better agreement among observers. The intra-observer results show Cohen’s κ values between 0.37 and 0.53 for all observers, except one with a low κ of −0.11. Group AUC scores lie between 0.66 and 0.72, with individual observers reaching 0.78. This study confirms that cine-MRI can diagnose adhesions, with respect to a radiologist consensus panel and shows that experience improves reading cine-MRI. Observers without specific experience adapt to this modality quickly after a short online tutorial. Observer agreement is fair at best and area under the receiver operating characteristic curve (AUC) scores leave room for improvement. Consistently interpreting this novel modality needs further research, for instance, by developing reporting guidelines or artificial intelligence-based methods.

BACKGROUND: A set of enduring conditions have been reported in the literature involving persistent sexual dysfunction after discontinuation of serotonin reuptake inhibiting antidepressants, 5 alpha-reductase inhibitors and isotretinoin.OBJECTIVE: To develop diagnostic criteria for post-SSRI sexual dysfunction (PSSD), persistent genital arousal disorder (PGAD) following serotonin reuptake inhibitors, post-finasteride syndrome (PFS) and post-retinoid sexual dysfunction (PRSD).METHODS: The original draft was designed using data from two published case series (Hogan et al., 2014 and Healy et al., 2018), which represent the largest public collections of data on these enduring conditions. It was further developed with the involvement of a multidisciplinary panel of experts.RESULTS: A set of criteria were agreed upon for each of the above conditions. Features of PSSD, PFS and PRSD commonly include decreased genital and orgasmic sensation, decreased sexual desire and erectile dysfunction. Ancillary non-sexual symptoms vary depending on the specific condition but can include emotional blunting and cognitive impairment. PGAD presents with an almost mirror image of unwanted sensations of genital arousal or irritability in the absence of sexual desire. A new term, post-SSRI asexuality, is introduced to describe a dampening of sexual interest and pleasure resulting from a pre-natal or pre-teen exposure to a serotonin reuptake inhibitor.CONCLUSIONS: These criteria will help in both clinical and research settings. As with all criteria, they will likely need modification in the light of developments.

BackgroundEarly neurological deterioration (END) after endovascular treatment (EVT) in patients with anterior circulation acute ischemic stroke (AIS) is associated with poor outcome. END may remain unexplained by parenchymal hemorrhage (UnEND). We aim to analyze the risk factors of UnEND in the medical management (MM) and EVT arms of the HERMES study.MethodsWe conducted a post-hoc analysis of anterior AIS patients who underwent EVT for proximal anterior occlusions. Risk factors of UnEND, defined as a worsening of ≥4 points between baseline National Institutes of Health Stroke Scale (NIHSS) and NIHSS at 24 hours without hemorrhage, were compared between both arms using mixed logistic regression models adjusted for baseline characteristics. An interaction analysis between the EVT and MM arms for risk factors of UnEND was conducted.ResultsAmong 1723 patients assessable for UnEND, 160 patients experienced an UnEND (9.3%), including 9.1% (78/854) in the EVT arm and 9.4% (82/869) in the MM arm. There was no significant difference in the incidence of UnEND between the two study arms. In the EVT population, independent risk factors of UnEND were lower baseline NIHSS, higher baseline glucose, and lower collateral grade. In the MM population, the only independent predictor of UnEND was higher baseline glucose. However, we did not demonstrate an interaction between EVT and MM for baseline factors as risk factors of UnEND. UnEND was, similarly in both treatment groups, a significant predictor of unfavorable outcome in both the EVT (pConclusionsUnEND is not an uncommon event, with a similar rate which ever treatment arm is considered. In the clinical scenario of AIS due to large vessel occlusion, no patient-related factor seems to increase the risk for UnEND when treated by EVT compared with MM.

Contains fulltext : 249066.pdf (Publisher’s version ) (Open Access) BACKGROUND: Frontotemporal dementia (FTD) has a profound impact on the spouse and other family caregivers involved. While caregivers have a need for support, it is difficult for healthcare providers to respond to their specific needs. This qualitative study explores the lived experiences and needs of caregivers of persons with FTD to facilitate the development of support. METHODS: Three focus group discussions were organized to explore the lived experiences of Dutch FTD caregivers. The included caregivers (n = 24) were aged 16 years or older and were involved in the care of a relative with FTD. Two researchers independently performed an inductive content analysis using open and axial coding. RESULTS: The main category emerging from the data was a lack of recognition, acknowledgment, and understanding experienced by caregivers. This was linked to caregivers' experiences with (1) complex emotional and behavioral symptoms in the person with FTD, (2) the trivializing responses of family and friends, (3) a perceived lack of knowledge and support from healthcare professionals, and (4) the bureaucratic procedures that accompany caregiving. As a result, caregivers felt lonely and solely responsible for the caregiving role. CONCLUSION: Caregivers of persons with FTD experience a lack of understanding in caring for their relative with FTD, which contributes to feelings of loneliness. A specialized support approach is needed to address the specific needs of caregivers of persons with FTD. Support should address strategies that caregivers can use to inform and involve family and friends in the caregiving situation to prevent loneliness in FTD caregivers.

Purpose Resveratrol has shown promising anti-inflammatory effects in in vitro and animal studies. We aimed to investigate this effect on arterial inflammation in vivo. Methods This was an additional analysis of a double-blind randomized crossover trial which included eight male subjects with decreased insulin sensitivity who underwent an 18F-fluoroxyglucose (18F-FDG) PET/CT after 34 days of placebo and resveratrol treatment (150 mg/day). 18F-FDG uptake was analyzed in the carotid arteries and the aorta, adipose tissue regions, spleen, and bone marrow as measures for arterial and systemic inflammation. Maximum target-to-background ratios (TBRmax) were compared between resveratrol and placebo treatment with the non-parametric Wilcoxon signed-rank test. Median values are shown with their interquartile range. Results Arterial 18F-FDG uptake was non-significantly higher after resveratrol treatment (TBRmax all vessels 1.7 (1.6–1.7)) in comparison to placebo treatment (1.5 (1.4–1.6); p=0.050). Only in visceral adipose tissue, the increase in 18F-FDG uptake after resveratrol reached statistical significance (p=0.024). Furthermore, CRP-levels were not significantly affected by resveratrol treatment (p=0.091). Conclusions Resveratrol failed to attenuate arterial or systemic inflammation as measured with 18F-FDG PET in subjects at risk of developing type 2 diabetes. However, validation of these findings in larger human studies is needed.

OBJECTIVES: The recommendation of induced hypertension for delayed cerebral ischemia treatment after aneurysmal subarachnoid hemorrhage has been challenged recently and ideal pressure targets are missing. A new concept advocates an individual cerebral perfusion pressure where cerebral autoregulation functions best to ensure optimal global perfusion. We characterized optimal cerebral perfusion pressure at time of delayed cerebral ischemia and tested the conformity of induced hypertension with this target value. DESIGN: Retrospective analysis of prospectively collected data. SETTING: University hospital neurocritical care unit. PATIENTS: Thirty-nine aneurysmal subarachnoid hemorrhage patients with invasive neuromonitoring (20 with delayed cerebral ischemia, 19 without delayed cerebral ischemia). INTERVENTIONS: Induced hypertension greater than 180 mm Hg systolic blood pressure. MEASUREMENTS AND MAIN RESULTS: Changepoint analysis was used to calculate significant changes in cerebral perfusion pressure, optimal cerebral perfusion pressure, and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure 48 hours before delayed cerebral ischemia diagnosis. Optimal cerebral perfusion pressure increased 30 hours before the onset of delayed cerebral ischemia from 82.8 +/- 12.5 to 86.3 +/- 11.4 mm Hg (p < 0.05). Three hours before delayed cerebral ischemia, a changepoint was also found in the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure (decrease from -0.2 +/- 11.2 to -7.7 +/- 7.6 mm Hg; p < 0.05) with a corresponding increase in pressure reactivity index (0.09 +/- 0.33 to 0.19 +/- 0.37; p < 0.05). Cerebral perfusion pressure at time of delayed cerebral ischemia was lower than in patients without delayed cerebral ischemia in a comparable time frame (cerebral perfusion pressure delayed cerebral ischemia 81.4 +/- 8.3 mm Hg, no delayed cerebral ischemia 90.4 +/- 10.5 mm Hg; p < 0.05). Inducing hypertension resulted in a cerebral perfusion pressure above optimal cerebral perfusion pressure (+12.4 +/- 8.3 mm Hg; p < 0.0001). Treatment response (improvement of delayed cerebral ischemia: induced hypertension(+) [n = 15] or progression of delayed cerebral ischemia: induced hypertension(-) [n = 5]) did not correlate to either absolute values of cerebral perfusion pressure or optimal cerebral perfusion pressure, nor the resulting difference (cerebral perfusion pressure [p = 0.69]; optimal cerebral perfusion pressure [p = 0.97]; and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure [p = 0.51]). CONCLUSIONS: At the time of delayed cerebral ischemia occurrence, there is a significant discrepancy between cerebral perfusion pressure and optimal cerebral perfusion pressure with worsening of autoregulation, implying inadequate but identifiable individual perfusion. Standardized induction of hypertension resulted in cerebral perfusion pressures that exceeded individual optimal cerebral perfusion pressure in delayed cerebral ischemia patients. The potential benefit of individual blood pressure management guided by autoregulation-based optimal cerebral perfusion pressure should be explored in future intervention studies.

Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+ channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by leukoencephalopathy leading to cognitive impairment. Subtle cognitive deficits can be observed early in the course of the disease, before the occurrence of the first stroke. Therefore, markers that can predict disease progression at this early stage, when interventions are likely to alter disease course, are needed. We aimed to examine the biological cascade of microstructural and macrostructural white matter (WM) abnormalities underlying cognitive deficits in CADASIL. Methods: We examined 20 nondemented CADASIL mutation carriers and 23 noncarriers who underwent neuropsychological evaluation and magnetic resonance imaging. Using probabilistic tractography of key WM tracts, we examined group differences in diffusivity measures and WM hyperintensity volume. Successive mediation models examined whether tract-specific WM abnormalities mediated subtle cognitive differences between CADASIL mutation carriers and noncarriers. Results: The largest effect size differentiating the two groups was observed for left superior longitudinal fasciculus–temporal (SLFt) diffusivity (Cohen's f = 0.49). No group differences were observed with a global diffusion measure. These specific microstructural differences in the SLFt were associated with higher WM hyperintensities burden, and subtle executive deficits in CADASIL mutation carriers. Discussion: Worse diffusivity in the left SLFt is related to greater severity of small vessel disease and worse executive functioning in the asymptomatic stage of the disease. Worse diffusivity of the left SLFt may potentially hold promise as an indicator of disease progression. IMPACT STATEMENT: Diffusion tensor imaging outperforms conventional imaging of subcortical small vessel disease as a potential marker of future disease progression. Here we identified the left superior longitudinal temporal fasciculus as a critical white matter fiber bundle, of which worse diffusivity can link presence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy mutations to greater severity of small vessel disease and worse executive functioning in asymptomatic stages of the disease. This tract may hold promise and deserves further examination as an early indicator of disease progression.

Purpose Detecting malignant peripheral nerve sheath tumors (MPNSTs) remains difficult. 18F-FDG PET-CT has been shown helpful, but ideal threshold values of semi-quantitative markers remain unclear, partially because of variation among scanners. Using EU-certified scanners diagnostic accuracy of ideal and commonly used 18F-FDG PET-CT thresholds were investigated and differences between adult and pediatric lesions were evaluated. Methods A retrospective cohort study was performed including patients from two hospitals with a clinical or radiological suspicion of MPNST between 2013 and 2019. Several markers were studied for ideal threshold values and differences among adults and children. A diagnostic algorithm was subsequently developed. Results Sixty patients were included (10 MPNSTs). Ideal threshold values were 5.8 for SUVmax (sensitivity 0.70, specificity 0.92), 5.0 for SUVpeak (sensitivity 0.70, specificity 0.97), 1.7 for TLmax (sensitivity 0.90, specificity 0.86), and 2.3 for TLmean (sensitivity 0.90, specificity 0.79). The standard TLmean threshold value of 2.0 yielded a sensitivity of 0.90 and specificity of 0.74, while the standard SUVmax threshold value of 3.5 yielded a sensitivity of 0.80 and specificity of 0.63. SUVmax and adjusted SUV for lean body mass (SUL) were lower in children, but tumor-to-liver ratios were similar in adult and pediatric lesions. Using TLmean > 2.0 or TLmean 3.5, a sensitivity and specificity of 1.00 and 0.63 can be achieved. Conclusion 18F-FDG PET-CT offers adequate accuracy to detect MPNSTs. SUV values in pediatric MPNSTs may be lower, but tumor-to-liver ratios are not. By combining TLmean and SUVmax values, a 100% sensitivity can be achieved with acceptable specificity.

Evidence suggests that self-esteem is an important mechanism in pathways to psychosis. However, whether low or high self-esteem is associated with psychotic experiences remains unclear. Besides, a limited number of studies has investigated fluctuations in state self-esteem in psychotic patients. This study investigated cross-sectional and temporal associations of momentary self-esteem and fluctuations in self-esteem with psychotic symptoms in three groups with different levels of (familial) liability to psychotic disorder. Using the Experience Sampling Method (ESM), momentary self-esteem, fluctuations in self-esteem (i.e., variability and instability), and psychotic experiences, paranoia, negative symptoms (i.e., event anhedonia and social anhedonia), intensity of negative affect and altered affective experiences (instability and variability in negative affect) were assessed in 147 psychotic patients, 131 of their siblings and 113 controls. Lower levels of momentary self-esteem were associated with an increased intensity of psychotic experiences, paranoia and negative affect, with the magnitude of the associations for momentary self-esteem being greatest in patients, followed by relatives. Variability in self-esteem was associated with psychotic and paranoid experiences, the magnitudes were greatest in relatives. Furthermore, we found reciprocal effects between momentary self-esteem and psychotic experiences, paranoia, negative affect, and instability in negative affect. These findings suggest that individuals with familial liability to psychosis (patients and their first-degree relatives) might benefit from targeting momentary self-esteem and variability in self-esteem to decrease the intensity of psychotic experiences, paranoia, and negative affect in daily life.General Scientific SummaryThis study provides evidence on cross-sectional and temporal associations of self-esteem and fluctuations in self-esteem, on the one hand, and intensity of psychotic experiences, paranoia, negative symptoms (social anhedonia and event anhedonia), intensity of negative affect, and altered affective experiences, on the other, in daily life, outside the research lab or clinics, in patients with psychotic disorder, their first-degree relatives, and controls. The results tentatively suggest that patients and their relatives may benefit from targeting (variability in) self-esteem in order to decrease the intensity of their psychotic experiences, paranoia, and negative affect in daily life.

BACKGROUND AND PURPOSE: Intraplaque hemorrhage contributes to lipid core enlargement and plaque progression, leading to plaque destabilization and stroke. The mechanisms that contribute to the development of intraplaque hemorrhage are not completely understood. A higher incidence of intraplaque hemorrhage and thin/ruptured fibrous cap (upstream of the maximum stenosis in patients with severe [?70%] carotid stenosis) has been reported. We aimed to noninvasively study the distribution of intraplaque hemorrhage and a thin/ruptured fibrous cap in patients with mild-to-moderate carotid stenosis. MATERIALS AND METHODS: Eighty-eight symptomatic patients with stroke (

Purpose Over the last 2 years, the artificial intelligence (AI) community has presented several automatic screening tools for coronavirus disease 2019 (COVID-19) based on chest radiography (CXR), with reported accuracies often well over 90%. However, it has been noted that many of these studies have likely suffered from dataset bias, leading to overly optimistic results. The purpose of this study was to thoroughly investigate to what extent biases have influenced the performance of a range of previously proposed and promising convolutional neural networks (CNNs), and to determine what performance can be expected with current CNNs on a realistic and unbiased dataset. Methods Five CNNs for COVID-19 positive/negative classification were implemented for evaluation, namely VGG19, ResNet50, InceptionV3, DenseNet201, and COVID-Net. To perform both internal and cross-dataset evaluations, four datasets were created. The first dataset Valencian Region Medical Image Bank (BIMCV) followed strict reverse transcriptase-polymerase chain reaction (RT-PCR) test criteria and was created from a single reliable open access databank, while the second dataset (COVIDxB8) was created through a combination of six online CXR repositories. The third and fourth datasets were created by combining the opposing classes from the BIMCV and COVIDxB8 datasets. To decrease inter-dataset variability, a pre-processing workflow of resizing, normalization, and histogram equalization were applied to all datasets. Classification performance was evaluated on unseen test sets using precision and recall. A qualitative sanity check was performed by evaluating saliency maps displaying the top 5%, 10%, and 20% most salient segments in the input CXRs, to evaluate whether the CNNs were using relevant information for decision making. In an additional experiment and to further investigate the origin of potential dataset bias, all pixel values outside the lungs were set to zero through automatic lung segmentation before training and testing. Results When trained and evaluated on the single online source dataset (BIMCV), the performance of all CNNs is relatively low (precision: 0.65-0.72, recall: 0.59-0.71), but remains relatively consistent during external evaluation (precision: 0.58-0.82, recall: 0.57-0.72). On the contrary, when trained and internally evaluated on the combinatory datasets, all CNNs performed well across all metrics (precision: 0.94-1.00, recall: 0.77-1.00). However, when subsequently evaluated cross-dataset, results dropped substantially (precision: 0.10-0.61, recall: 0.04-0.80). For all datasets, saliency maps revealed the CNNs rarely focus on areas inside the lungs for their decision-making. However, even when setting all pixel values outside the lungs to zero, classification performance does not change and dataset bias remains. Conclusions Results in this study confirm that when trained on a combinatory dataset, CNNs tend to learn the origin of the CXRs rather than the presence or absence of disease, a behavior known as short-cut learning. The bias is shown to originate from differences in overall pixel values rather than embedded text or symbols, despite consistent image pre-processing. When trained on a reliable, and realistic single-source dataset in which non-lung pixels have been masked, CNNs currently show limited sensitivity (

Background Cerebral small vessel disease (cSVD) is a late consequence of cerebral microvascular dysfunction (MVD). MVD is hard to measure in the brain due to its limited accessibility. Extracerebral MVD (eMVD) measures can give insights in the etiology of cerebral MVD, as MVD may be a systemic process. We aim to investigate whether a compound score consisting of several eMVD measures is associated with structural cSVD MRI markers. Methods Cross-sectional data of the population-based Maastricht Study was used (n = 1872, mean age 59 ± 8 years, 49% women). Measures of eMVD included flicker light-induced retinal arteriolar and venular dilation response (retina), albuminuria and glomerular filtration rate (kidney), heat-induced skin hyperemia (skin), and plasma biomarkers of endothelial dysfunction (sICAM-1, sVCAM-1, sE-selectin, and von Willebrand factor). These measures were standardized into z scores and summarized into a compound score. Linear and logistic regression analyses were used to investigate the associations between the compound score and white matter hyperintensity (WMH) volume, and the presence of lacunes and microbleeds, as measured by brain MRI. Results The eMVD compound score was associated with WMH volume independent of age, sex, and cardiovascular risk factors (St β 0.057 [95% CI 0.010–0.081], p value 0.01), but not with the presence of lacunes (OR 1.011 [95% CI 0.803–1.273], p value 0.92) or microbleeds (OR 1.055 [95% CI 0.896–1.242], p value 0.52). Conclusion A compound score of eMVD is associated with WMH volume. Further research is needed to expand the knowledge about the role of systemic MVD in the pathophysiology of cSVD.

Linked Comment: E. Epstein. Br J Dermatol 2022; 186:203. Plain language summary available online

Tau accumulation starts during the preclinical phase of Alzheimer’s disease and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated with tau accumulation and spread. Studying genetically identical twin-pairs may give insight into genetic and environmental contributions to tau pathology, as similarities in identical twin-pairs largely result from genetic factors, while differences in identical twin-pairs can largely be attributed to non-shared, environmental factors. This study aimed to examine similarities and dissimilarities in a cohort of genetically identical older twin-pairs in (i) tau load; and (ii) spatial distribution of tau, measured with 18F-flortaucipir PET. We selected 78 genetically identical twins (39 pairs; average age 73 ± 6 years), enriched for amyloid-β pathology and APOE ε4 carriership, who underwent dynamic 18F-flortaucipir PET. We extracted binding potentials (BPND) in entorhinal, temporal, widespread neocortical and global regions, and examined within-pair similarities in BPND using age and sex corrected intra-class correlations. Furthermore, we tested whether twin-pairs showed a more similar spatial 18F-flortaucipir distribution compared to non-twin pairs, and whether the participant’s co-twin could be identified solely based on the spatial 18F-flortaucipir distribution. Last, we explored whether environmental (e.g. physical activity, obesity) factors could explain observed differences in twins of a pair in 18F-flortaucipir BPND. On visual inspection, Alzheimer’s disease-like 18F-flortaucipir PET patterns were observed, and although we mainly identified similarities in twin-pairs, some pairs showed strong dissimilarities. 18F-flortaucipir BPND was correlated in twins in the entorhinal (r = 0.40; P = 0.01), neocortical (r = 0.59; P < 0.01) and global (r = 0.56; P < 0.01) regions, but not in the temporal region (r = 0.20; P = 0.10). The 18F-flortaucipir distribution pattern was significantly more similar between twins of the same pair [mean r = 0.27; standard deviation (SD) = 0.09] than between non-twin pairings of participants (mean r = 0.01; SD = 0.10) (P < 0.01), also after correcting for proxies of off-target binding. Based on the spatial 18F-flortaucipir distribution, we could identify with an accuracy of 86% which twins belonged to the same pair. Finally, within-pair differences in 18F-flortaucipir BPND were associated with within-pair differences in depressive symptoms (0.37 < β < 0.56), physical activity (−0.41 < β < −0.42) and social activity (−0.32 < β < −0.36) (all P < 0.05). Overall, identical twin-pairs were comparable in tau load and spatial distribution, highlighting the important role of genetic factors in the accumulation and spreading of tau pathology. Considering also the presence of dissimilarities in tau pathology in identical twin-pairs, our results additionally support a role for (potentially modifiable) environmental factors in the onset of Alzheimer’s disease pathological processes, which may be of interest for future prevention strategies.

Purpose Resective epilepsy surgery is a well-established, evidence-based treatment option in patients with drug-resistant focal epilepsy. A major predictive factor of good surgical outcome is visualization and delineation of a potential epileptogenic lesion by MRI. However, frequently, these lesions are subtle and may escape detection by conventional MRI (≤ 3 T). Methods We present the EpiUltraStudy protocol to address the hypothesis that application of ultra-high field (UHF) MRI increases the rate of detection of structural lesions and functional brain aberrances in patients with drug-resistant focal epilepsy who are candidates for resective epilepsy surgery. Additionally, therapeutic gain will be addressed, testing whether increased lesion detection and tailored resections result in higher rates of seizure freedom 1 year after epilepsy surgery. Sixty patients enroll the study according to the following inclusion criteria: aged ≥ 12 years, diagnosed with drug-resistant focal epilepsy with a suspected epileptogenic focus, negative conventional 3 T MRI during pre-surgical work-up. Results All patients will be evaluated by 7 T MRI; ten patients will undergo an additional 9.4 T MRI exam. Images will be evaluated independently by two neuroradiologists and a neurologist or neurosurgeon. Clinical and UHF MRI will be discussed in the multidisciplinary epilepsy surgery conference. Demographic and epilepsy characteristics, along with postoperative seizure outcome and histopathological evaluation, will be recorded. Conclusion This protocol was reviewed and approved by the local Institutional Review Board and complies with the Declaration of Helsinki and principles of Good Clinical Practice. Results will be submitted to international peer-reviewed journals and presented at international conferences. Trial registration number www.trialregister.nl: NTR7536.

We investigated preserved episodic recognition memory based on incidental learning of visual associations in Alzheimer's disease (AD). In a cross-sectional design, we analyzed episodic memory score profiles of patients with amnestic mild cognitive impairment (a-MCI) (n = 42) or mild AD (n = 19) who had hippocampal atrophy, and healthy elderly controls (n = 43). The Visual Association Test-Extended served as a measure of episodic memory. Multiple-choice cued recognition was compared with paired associate recall and free recall within groups. Results showed that patients recognized learned material much better compared to when they had to recall material, resulting in large effect sizes (Cohen's d) ranging from 1.3 to 3.5. We conclude that episodic recognition memory based on incidental learning of visual associations is largely preserved when compared to recall in a-MCI and mild AD. This suggests that the episodic memory impairment in AD may be characterized as a retrieval impairment rather than a consolidation impairment, indicating that preserved recognition compared to recall may be compatible with AD being the correct diagnosis. Measuring the episodic memory impairment in AD may benefit from using tests that capture different aspects of memory processes such as incidental learning of visual associations.

This document presents the initiative of the Bárány Society to improve diagnosis and care of patients presenting with vestibular symptoms worldwide. The Vestibular Medicine (VestMed) concept embraces a wide approach to the potential causes of vestibular symptoms, acknowledging that vertigo, dizziness, and unsteadiness are non-specific symptoms that may arise from a broad spectrum of disorders, spanning from the inner ear to the brainstem, cerebellum and supratentorial cerebral networks, to many disorders beyond these structures. The Bárány Society Vestibular Medicine Curriculum (BS-VestMed-Cur) is based on the concept that VestMed is practiced by different physician specialties and non-physician allied health professionals. Each profession has its characteristic disciplinary role and profile, but all work in overlapping areas. Each discipline requires good awareness of the variety of disorders that can present with vestibular symptoms, their underlying mechanisms and etiologies, diagnostic criteria and treatment options. Similarly, all disciplines require an understanding of their own limitations, the contribution to patient care from other professionals and when to involve other members of the VestMed community. Therefore, the BS-VestMed-Cur is the same for all health professionals involved, the overlaps and differences of the various relevant professions being defined by different levels of detail and depth of knowledge and skills. The BS-VestMed-Cur defines a Basic and an Expert Level Curriculum. The Basic Level Curriculum covers the VestMed topics in less detail and depth, yet still conveys the concept of the wide net approach. It is designed for health professionals as an introduction to, and first step toward, VestMed expertise. The Expert Level Curriculum defines a Focused and Broad Expert. It covers the VestMed spectrum in high detail and requires a high level of understanding. In the Basic and Expert Level Curricula, the range of topics is the same and runs from anatomy, physiology and physics of the vestibular system, to vestibular symptoms, history taking, bedside examination, ancillary testing, the various vestibular disorders, their treatment and professional attitudes. Additionally, research topics relevant to clinical practice are included in the Expert Level Curriculum. For Focused Expert proficiency, the Basic Level Curriculum is required to ensure a broad overview and additionally requires an expansion of knowledge and skills in one or a few specific topics related to the focused expertise, e.g. inner ear surgery. Broad Expert proficiency targets professionals who deal with all sorts of patients presenting with vestibular symptoms (e.g. otorhinolaryngologists, neurologists, audiovestibular physicians, physical therapists), requiring a high level of VestMed expertise across the whole spectrum. For the Broad Expert, the Expert Level Curriculum is required in which the minimum attainment targets for all the topics go beyond the Basic Level Curriculum. The minimum requirements regarding knowledge and skills vary between Broad Experts, since they are tuned to the activity profile and underlying specialty of the expert. The BS-VestMed-Cur aims to provide a basis for current and future teaching and training programs for physicians and non-physicians. The Basic Level Curriculum could also serve as a resource for inspiration for teaching VestMed to students, postgraduate generalists such as primary care physicians and undergraduate health professionals, or anybody wishing to enter VestMed. VestMed is considered a set of competences related to an area of practice of established physician specialties and non-physician health professions rather than a separate clinical specialty. This curriculum does not aim to define a new single clinical specialty. The BS-VestMed-Cur should also integrate with, facilitate and encourage translational research in the vestibular field.

Introduction: Progressive cognitive decline is the cardinal behavioral symptom in most dementia-causing diseases such as Alzheimer’s disease. While most well-established measures for cognition might not fit tomorrow’s decentralized remote clinical trials, digital cognitive assessments will gain importance. We present the evaluation of a novel digital speech biomarker for cognition (SB-C) following the Digital Medicine Society’s V3 framework: verification, analytical validation, and clinical validation. Methods: Evaluation was done in two independent clinical samples: the Dutch DeepSpA (N = 69 subjective cognitive impairment [SCI], N = 52 mild cognitive impairment [MCI], and N = 13 dementia) and the Scottish SPeAk datasets (N = 25, healthy controls). For validation, two anchor scores were used: the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale. Results: Verification: The SB-C could be reliably extracted for both languages using an automatic speech processing pipeline. Analytical Validation: In both languages, the SB-C was strongly correlated with MMSE scores. Clinical Validation: The SB-C significantly differed between clinical groups (including MCI and dementia), was strongly correlated with the CDR, and could track the clinically meaningful decline. Conclusion: Our results suggest that the ki:e SB-C is an objective, scalable, and reliable indicator of cognitive decline, fit for purpose as a remote assessment in clinical early dementia trials.

Accessible Summary What is known on the subject? To date, the majority of the research regarding innovative psychosocial interventions in psychiatry focuses upon the development and effectiveness of the interventions. Despite the fact that these are important clinical and scientific contributions, only a small percentage of the evidence-based interventions reach clinical practice. Cognitive Adaptation Training (CAT) is an effective psychosocial intervention to increase daily functioning and cognitive functioning in people diagnosed with severe mental illness (SMI) in inpatient and outpatient psychiatric care. Despite knowledge on the intervention's effectiveness, systematic use of CAT in the daily routine of mental health nurses is insufficient. What the paper adds to existing knowledge? To date, no research is available that describes the factors associated to the implementation of CAT from a nursing perspective. This research also adds to the literature on rehabilitation in people diagnosed with SMI in an inpatient setting. The results contribute to the science of implementing interventions in long-term psychiatric care and may help future interventions in their implementation process. What are the implications for practice? This study highlights that multiple factors need to be considered when implementing an intervention in routine care and that it is a complicated process. Future implementation initiatives require ongoing training and supervision of CAT specialists, appointment of local champions to increase commitment among nursing staff and inclusion and commitment of management to overcome organizational barriers. Without acknowledging the presence of barriers to implementation and considering strategies to overcome these barriers, sustainable implementation is likely to be unsuccessful. Introduction Evidence-based interventions in psychiatry often fail to reach clinical practice. Cognitive Adaptation Training (CAT) is an evidence-based psychosocial intervention that aims to improve daily functioning of people diagnosed with a severe mental illness. Implementation of CAT remains challenging, despite demonstrated effectiveness. Aim Identifying facilitators and barriers of CAT on the intervention, nursing, and organizational levels, and investigating relationships between capability, opportunity, motivation, and appraisal using the COM-B model. Method The Measurement Instrument for Determinants of Innovations and CAT-specific questions were administered to 46 nurses. The relationship among capability, opportunity, motivation and appraisal was calculated using the Pearson's r correlation coefficient. Results Nine barriers (mostly organizational level) and 13 facilitators (mostly intervention and nursing level) were identified. Significant moderate correlations were found between capability and opportunity, capability and motivation, capability and appraisal and a strong correlation between motivation and appraisal. Discussion The results suggest that barriers at the organizational level should be removed and facilitators at intervention and nursing levels may be exploited to improve implementation. Implications for practice Future implementation initiatives require ongoing training and supervision of CAT specialists, appointment of local champions to increase commitment among nursing staff and inclusion and commitment of management to overcome organizational barriers.

Recently, an intronic biallelic (AAGGG)n repeat expansion in RFC1 was shown to be a cause of CANVAS and adult-onset ataxia in multiple populations. As the prevalence of the RFC1 repeat expansion in Dutch cases was unknown, we retrospectively tested 9 putative CANVAS cases and two independent cohorts (A and B) of 395 and 222 adult-onset ataxia cases, respectively, using the previously published protocol and, for the first time optical genome mapping to determine the size of the expanded RFC1 repeat. We identified the biallelic (AAGGG)n repeat expansion in 5/9 (55%) putative CANVAS patients and in 10/617 (1.6%; cohorts A + B) adult-onset ataxia patients. In addition to the AAGGG repeat motif, we observed a putative GAAGG repeat motif in the repeat expansion with unknown significance in two adult-onset ataxia patients. All the expanded (AAGGG)n repeats identified were in the range of 800–1299 repeat units. The intronic biallelic RFC1 repeat expansion thus explains a number of the Dutch adult-onset ataxia cases that display the main clinical features of CANVAS, and particularly when ataxia is combined with neuropathy. The yield of screening for RFC1 expansions in unselected cohorts is relatively low. To increase the current diagnostic yield in ataxia patients, we suggest adding RFC1 screening to the genetic diagnostic workflow by using advanced techniques that attain long fragments.

Background Due to ageing of the population the incidence of multimorbidity and polypharmacy is rising. Polypharmacy is a risk factor for medication-related (re)admission and therefore places a significant burden on the healthcare system. The reported incidence of medication-related (re)admissions varies widely due to the lack of a clear definition. Some medications are known to increase the risk for medication-related admission and are therefore published in the triggerlist of the Dutch guideline for Polypharmacy in older patients. Different interventions to support medication optimization have been studied to reduce medication-related (re)admissions. However, the optimal template of medication optimization is still unknown, which contributes to the large heterogeneity of their effect on hospital readmissions. Therefore, we implemented a clinical decision support system (CDSS) to optimize medication lists and investigate whether continuous use of a CDSS reduces the number of hospital readmissions in older patients, who previously have had an unplanned probably medication-related hospitalization. Methods The CHECkUP study is a multicentre randomized study in older (≥60 years) patients with an unplanned hospitalization, polypharmacy (≥5 medications) and using at least two medications from the triggerlist, from Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. Patients will be randomized. The intervention consists of continuous (weekly) use of a CDSS, which generates a Medication Optimization Profile, which will be sent to the patient’s general practitioner and pharmacist. The control group will receive standard care. The primary outcome is hospital readmission within 1 year after study inclusion. Secondary outcomes are one-year mortality, number of emergency department visits, nursing home admissions, time to hospital readmissions and we will evaluate the quality of life and socio-economic status. Discussion This study is expected to add evidence on the knowledge of medication optimization and whether use of a continuous CDSS ameliorates the risk of adverse outcomes in older patients, already at an increased risk of medication-related (re)admission. To our knowledge, this is the first large study, providing one-year follow-up data and reporting not only on quality of care indicators, but also on quality-of-life. Trial registration The trial was registered in the Netherlands Trial Register on October 14, 2018, identifier: NL7449 (NTR7691). https://www.trialregister.nl/trial/7449.

The brainstem is among the first regions to accumulate Alzheimer’s disease (AD)-related hyperphosphorylated tau pathology during aging. We aimed to examine associations between brainstem volume and neocortical amyloid-β or tau pathology in 271 middle-aged clinically normal individuals of the Framingham Heart Study who underwent MRI and PET imaging. Lower volume of the medulla, pons, or midbrain was associated with greater neocortical amyloid burden. No associations were detected between brainstem volumes and tau deposition. Our results support the hypothesis that lower brainstem volumes are associated with initial AD-related processes and may signal preclinical AD pathology.

Background The "dual syndrome hypothesis" distinguished two subtypes in mild cognitive impairment (MCI) in Parkinson's disease: frontostriatal, characterized by attentional and executive deficits; and posterior cortical, characterized by visuospatial, memory, and language deficits. Objective The aim was to identify resting-state functional modifications associated with these subtypes. Methods Ninety-five nondemented patients categorized as having normal cognition (n = 31), frontostriatal (n = 14), posterior cortical (n = 20), or mixed (n = 30) cognitive subtype had a 3 T resting-state functional magnetic resonance imaging scan. Twenty-four age-matched healthy controls (HCs) were also included. A group-level independent component analysis was performed to identify resting-state networks, and the selected components were subdivided into 564 cortical regions in addition to 26 basal ganglia regions. Global intra- and inter-network connectivity along with global and local efficiencies was compared between groups. The network-based statistics approach was used to identify connections significantly different between groups. Results Patients with posterior cortical deficits had increased intra-network functional connectivity (FC) within the basal ganglia network compared with patients with frontostriatal deficits. Patients with frontostriatal deficits had reduced inter-network FC between several networks, including the visual, default-mode, sensorimotor, salience, dorsal attentional, basal ganglia, and frontoparietal networks, compared with HCs, patients with normal cognition, and patients with a posterior cortical subtype. Similar results were also found between patients with a mixed subtype and HCs. Conclusion MCI subtypes are associated with specific changes in resting-state FC. Longitudinal studies are needed to determine the predictive potential of these markers regarding the risk of developing dementia. (c) 2021 International Parkinson and Movement Disorder Society

BACKGROUND: Altered functional brain connectivity has been proposed as an intermediate phenotype between genetic risk loci and clinical expression of schizophrenia. Genetic high-risk groups of healthy subjects are particularly suited for the investigation of this proposition because they can be tested in the absence of medication or other secondary effects of schizophrenia. METHODS: Here, we applied dynamic functional connectivity analysis to functional magnetic resonance imaging data to reveal the reconfiguration of brain networks during a cognitive task. We recruited healthy carriers of common risk variants using the recall-by-genotype design. We assessed 197 individuals: 99 individuals (52 female, 47 male) with low polygenic risk scores (schizophrenia risk profile scores [SCZ-PRSs]) and 98 individuals (52 female, 46 male) with high SCZ-PRSs from both tails of the SCZ-PRS distribution from a genotyped population cohort, the Avon Longitudinal Study of Parents and Children (N = 8169). We compared groups both on conventional brain activation profiles, using the general linear model of the experiment, and on the neural flexibility index, which quantifies how frequent a brain region's community affiliation changes over experimental time. RESULTS: Behavioral performance and standard brain activation profiles did not differ significantly between groups. High SCZ-PRS was associated with reduced flexibility index and network modularity across n-back levels. The whole-brain flexibility index and that of the frontoparietal working memory network was associated with n-back performance. We identified a dynamic network phenotype related to high SCZ-PRS. CONCLUSIONS: Such neurophysiological markers can become important for the elucidation of biological mechanisms of schizophrenia and, particularly, the associated cognitive deficit.

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.

IntroductionEstimating differences in neural health across different sites within the individual cochlea potentially enables clinical applications for subjects with a cochlear implant. The electrically evoked compound action potential (ECAP) is a measure of neural excitability that possibly provides an indication of a neural condition. There are many factors, however, that affect this measure and increase the uncertainty of its interpretation. To better characterize the ECAP response, its relationship with electrode positioning, impedances, and behavioral stimulation levels was explored.MethodsA total of 14 adult subjects implanted with an Advanced Bionics cochlear electrode array were prospectively followed up from surgery to 6 months postoperative. Insertion depth, distance to the modiolus, and distance to the medial wall were assessed for each electrode by postoperative CT analysis. ECAPs were measured intraoperatively and at three visits postoperatively on all 16 electrodes using the NRI feature of clinical programming software and characterized using multiple parameters. Impedances and behavioral stimulation levels were measured at every fitting session.ResultsPatterns in ECAPs and impedances were consistent over time, but high variability existed among subjects and between different positions in the cochlea. Electrodes located closer to the apex of the cochlea and closer to the modiolus generally showed higher neural excitation and higher impedances. Maximum loudness comfort levels were correlated strongly with the level of current needed to elicit a response of 100 μV ECAP.ConclusionMultiple factors contribute to the ECAP response in subjects with a cochlear implant. Further research might address whether the ECAP parameters used in this study will benefit clinical electrode fitting or the assessment of auditory neuron integrity.