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Schizophrenia (SCZ) is associated with structural brain changes, with considerable variation in the extent to which these cortical regions are influenced. We present a novel metric that summarises individual structural variation across the brain, while considering prior effect sizes, established via meta-analysis. We determine individual participant deviation from a within-sample-norm across structural MRI regions of interest (ROIs). For each participant, we weight the normalised deviation of each ROI by the effect size (Cohen’s d) of the difference between SCZ/control for the corresponding ROI from the SCZ Enhancing Neuroimaging Genomics through Meta-Analysis working group. We generate a morphometric risk score (MRS) representing the average of these weighted deviations. We investigate if SCZ-MRS is elevated in a SCZ case/control sample (NCASE = 50; NCONTROL = 125), a replication sample (NCASE = 23; NCONTROL = 20) and a sample of asymptomatic young adults with extreme SCZ polygenic risk (NHIGH-SCZ-PRS = 95; NLOW-SCZ-PRS = 94). SCZ cases had higher SCZ-MRS than healthy controls in both samples (Study 1: β = 0.62, P < 0.001; Study 2: β = 0.81, P = 0.018). The high liability SCZ-PRS group also had a higher SCZ-MRS (Study 3: β = 0.29, P = 0.044). Furthermore, the SCZ-MRS was uniquely associated with SCZ status, but not attention-deficit hyperactivity disorder (ADHD), whereas an ADHD-MRS was linked to ADHD status, but not SCZ. This approach provides a promising solution when considering individual heterogeneity in SCZ-related brain alterations by identifying individual’s patterns of structural brain-wide alterations.

This study determines the relationship between patient and investigator reported outcome measures (PROMs versus IROMs) on oropharyngeal dysphagia (OD) in Parkinson’s disease (PD). The PROMs used are the MD Anderson Dysphagia Inventory (MDADI) and the Dysphagia Severity Scale (DSS). The IROMs used are fiberoptic endoscopic evaluation of swallowing (FEES) and videofluoroscopy of swallowing (VFS). Ninety dysphagic PD patients were included. Multilayer perceptron (MLP) neural network analysis was used to investigate the relationship between PROMs and IROMs on OD in PD. MLP neural network analysis showed a moderate agreement between PROMs and IROMs, with an area under the curve between 0.6 and 0.7. Two-step cluster analysis revealed several clusters of patients with similar scores on FEES and/or VFS variables, but with significant different scores on MDADI and DSS variables. This study highlights that there are PD patients with similar FEES and/or VFS findings that cannot be lumped together under the same pathophysiological umbrella due to their differences in PROMs. Since the exact origin of these differences is not fully understood, it seems appropriate for the time being to take into account the different dimensions of OD during the swallowing assessment so that they can be included in a patient-tailored treatment plan.

Intensive care medicine 47(10), 1115-1129 (2021). doi:10.1007/s00134-021-06484-1, Published by Springer, Berlin

Background: Low-grade inflammation (LGI) and endothelial dysfunction (ED) might play a key role in the development of depression. We investigated the associations and mediation of LGI and ED with four-year incidence and course of depressive symptoms (remitted, recurrent or persistent). Design, setting, participants, measurements: In this prospective cohort study (mean age 59.6 +/- 8.2 years, 48.9% women, 26.6% diabetes by design), Cox and multinomial regression analyses, adjusted for age, sex, educational level and diabetes status were used to investigate the associations of LGI and ED with onset and course of depressive symptoms as assessed by the PHQ-9 questionnaire. Results: During 10,847 person-years of follow-up, 264 participants developed incident depression. Higher levels of LGI (OR [95%CI] per SD 1.32[1.16-1.49], p < 0.001) and ED (1.26[1.11-1.43], p < 0.001) were associated with incident depressive symptoms. In mediation analysis, 60% of the total effect of ED with incident depressive symptoms could be attributed to LGI. 76 out of 2637 participants had a persistent course of depressive symptoms. Higher levels of LGI (1.75[1.40-2.19], p < 0.001) and ED (1.33[1.04-1.71], p = 0.021) were associated with a persistent course of depressive symptoms. Higher ED was more strongly associated with persistent depressive symptoms (1.33[1.04-1.71], p = 0.021), while LGI was associated with remission of depression symptoms. Conclusions: LGI and ED were both associated with incident depressive symptoms, where the latter association was substantially mediated by LGI. ED was further associated with a persistent course of depressive symptoms, while LGI was not. These results suggest a temporal, vascular contribution of both LGI and ED to the etiology and chronicity of depressive symptoms.

Background and ObjectivesObservational research has shown that a substantial proportion of all dementia cases worldwide are attributable to modifiable risk factors. Dementia risk scores might be useful to identify high-risk individuals and monitor treatment adherence. The objective of this study was to investigate whether a dementia risk score, the Lifestyle for Brain Health (LIBRA) index, is associated with MRI markers and cognitive functioning/impairment in the general population.MethodsCross-sectional data were used from the observational population-based cohort of The Maastricht Study. The weighted compound score of LIBRA (including 12 dementia risk and protective factors, e.g., hypertension, physical inactivity) was calculated, with higher scores indicating higher dementia risk. Standardized volumes of white matter, gray matter, and CSF (as proxy for general brain atrophy), white matter hyperintensities, and presence of cerebral small vessel disease were derived from 3T MRI. Cognitive functioning was tested in 3 domains: memory, information processing speed, and executive function and attention. Values ≤1.5 SDs below the average were defined as cognitive impairment. Multiple regression analyses and structural equation modeling were used, adjusted for age, sex, education, intracranial volume, and type 2 diabetes.ResultsParticipants (n = 4,164; mean age 59 years; 49.7% men) with higher LIBRA scores (mean 1.19, range −2.7 to 9.2), denoting higher dementia risk, had higher volumes of white matter hyperintensities (β = 0.051,p= 0.002) and lower scores on information processing speed (β = −0.067,p= 0.001) and executive function and attention (β = −0.065,p= 0.004). Only in men, associations between LIBRA score and volumes of gray matter (β = −0.093,p< 0.001) and CSF (β = 0.104,p< 0.001) and memory (β = −0.054,p= 0.026) were found. White matter hyperintensities and CSF volume partly mediated the association between LIBRA score and cognition.DiscussionHigher health- and lifestyle-based dementia risk is associated with markers of general brain atrophy, cerebrovascular pathology, and worse cognition, suggesting that LIBRA meaningfully summarizes individual lifestyle-related brain health. Improving LIBRA factors on an individual level might improve population brain health. Sex differences in lifestyle-related pathology and cognition need to be further explored.Classification of EvidenceThis study provides Class II evidence that higher LIBRA scores are significantly associated with lower scores in some cognitive domains and a higher risk of cognitive impairment.

Purpose The objective of this study was determine the prevalence of low health literacy (HL) and low reading ability among patients with chronic lung disease referred for pulmonary rehabilitation (PR) in the Netherlands and their loved ones; and to understand whether low HL or low reading ability influence PR outcomes. Methods Health literacy was measured using the Health Literacy Survey-Europe Q16 (HLS-EU-Q16). Reading ability and cognitive functioning were measured using the Rapid Estimate of Adult Literacy in Medicine-Dutch (REALM-D) and the Montreal Cognitive Assessment. Exercise capacity, health status, and symptoms of anxiety and depression were assessed. Results Patients (n = 120) entering PR and loved ones (n = 41) participated. Of all patients, 51% had low HL and 29% had low reading ability. Also, 39% of all loved ones had low HL. PR outcomes were comparable between patients with low or adequate HL. Patients with adequate reading ability showed greater improvement in symptoms of depression than patients with low reading ability (P = .047). Conclusion Low HL and low reading ability are common among patients entering PR and their loved ones. For patients with low or adequate HL, PR is an effective treatment. Whether considering low HL and low reading ability by offering tailored education during treatment could augment the benefits of PR warrants further study.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MRI (DCE-MRI) can be employed to assess the blood-brain barrier (BBB) integrity. Detection of BBB leakage at lower field strengths (≤3T) is cumbersome as the signal is noisy, while leakage can be subtle. Utilizing the increased signal-to-noise ratio at higher field strengths, we explored the application of 7T DCE-MRI for assessing BBB leakage.METHODS: A dual-time resolution DCE-MRI method was implemented at 7T and a slow injection rate (0.3 ml/s) and low dose (3 mmol) served to obtain signal changes linearly related to the gadolinium concentration, that is, minimized for T2 * degradation effects. With the Patlak graphical approach, the leakage rate (Ki ) and blood plasma volume fraction (vp ) were calculated. The method was evaluated in 10 controls, an ischemic stroke patient, and a patient with a transient ischemic attack.RESULTS: Ki and vp were significantly higher in gray matter compared to white matter of all participants. These Ki values were higher in both patients compared to the control subjects. Finally, for the lesion identified in the ischemic stroke patient, higher leakage values were observed compared to normal-appearing tissue.CONCLUSION: We demonstrate how a dual-time resolution DCE-MRI protocol at 7T, with administration of half the clinically used contrast agent dose, can be used for assessing subtle BBB leakage. Although the feasibility of DCE-MRI for assessing the BBB integrity at 3T is well known, we showed that a continuous sampling DCE-MRI method tailored for 7T is also capable of assessing leakage with a high sensitivity over a range of Ki values.

Background The pathological hallmarks of Parkinson's disease include intraneuronal Lewy bodies, neuronal loss, and gliosis. We aim to correlate Parkinson's disease neuropsychiatric symptoms, (e.g., depression, psychosis, and anxiety) with the severity of neuropathology in the substantia nigra and locus coeruleus. Methods The brains of 175 participants with a primary pathologic diagnosis of Parkinson's disease were analyzed semi-quantitatively to ascertain the burden of neuronal loss and gliosis and Lewy body pathology within the locus coeruleus and substantia nigra. Participants’ history of anxiety, depression, and psychosis were determined using a chart-extracted medical history or record of formal psychiatric evaluation. Results Of the sample, 56% (n = 98), 50% (n = 88), and 31.25% (n = 55) of subjects had a diagnosis of psychosis, depression, and anxiety, respectively. Psychosis (χ2 = 7.1, p = 0.008, df = 1) and depression (χ2 = 7.2, p = 0.007, df = 1) were associated with severe neuronal loss and gliosis in the substantia nigra but not in the locus coeruleus. No association was observed between anxiety and neuronal loss and gliosis in either region. No neuropsychiatric symptoms were associated with Lewy body score. After controlling for disease duration and dementia, psychosis (odds ratio [OR]: 3.1, 95% confidence interval [CI]: 1.5–6.4, χ2 = 9.4, p = 0.012, df = 1) and depression (OR: 2.6, 95% CI: 1.3–5.0, χ2 = 7.9, p = 0.005, df = 1) remained associated with severe neuronal loss and gliosis in the substantia nigra. Conclusion These results suggest that psychosis and depression in Parkinson's disease are associated with the underlying neurodegenerative process and demonstrate that cell loss and gliosis may be a better marker of neuropsychiatric symptoms than Lewy body pathology.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, This work was supported by the Medical Research Council (G0901310) and the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z). This study was supported by the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London and by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust at King’s College London. Further support to EB: Mental Health Research UK’s John Grace QC award, BMA Margaret Temple grants 2016 and 2006, MRC—Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation’s NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship, the NIHR Biomedical Research Centre at UCLH, and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London. Further support to co-authors: The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to CI). The BMA Margaret Temple grant 2016 to JT. A 2014 European Research Council Marie Curie award to A Díez-Revuelta. HI has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 747429. A Medical Research Council doctoral studentship to JH-S, IA-Z and AB. A Mental Health Research UK studentship to RM. VB is supported by a Wellcome Trust Seed Award in Science (200589/Z/16/Z). FWO Senior Clinical Fellowship to RvW. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organisations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Centre and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Groningen: University Medical Centre Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical centre The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en De Kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Centre Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta). The Santander cohort was supported by Instituto de Salud Carlos III (PI020499, PI050427, PI060507), SENY Fundació (CI 2005-0308007), Fundacion Ramón Areces and Fundacion Marqués de Valdecilla (API07/011, API10/13). We thank Valdecilla Biobank for providing the biological PAFIP samples and associated data included in this study and for its help in the technical execution of this work; we also thank IDIVAL Neuroimaging Unit for its help in the acquisition and processing of imaging PAFIP data.

Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated A delta and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several poreforming voltage-gated sodium channel alpha subunits (Na-v) in a subset of patients with SFN, but the auxiliary sodium channel beta-subunits have been less implicated in the development of the disease. beta subunits modulate Na-v trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the beta 2 subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel beta subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly identified Y69H variant of the beta(2) subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the beta(2)-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of beta(2) subunits in SFN and strengthens the link between sodium channel beta subunits and the development of neuropathic pain in humans.NEW & NOTEWORTHY Small fiber neuropathy (SFN) often has no discernible cause, although mutations in the voltage-gated sodium channel alpha subunits have been implicated in some cases. We identify a patient suffering from SFN with a mutation in the auxiliary beta 2 subunit and no other discernible causes for SFN. Functional assessment confirms this mutation renders dorsal root ganglion neurons hyperexcitable and upregulates tetrodotoxin-sensitive sodium currents. This study strengthens a newly emerging link between sodium channel beta 2 subunit mutations and human pain disorders.

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.

Background Cerebral small vessel disease (CSVD) and neurodegeneration may be involved in the development and persistence of late-life depressive symptoms, but longitudinal evidence is scarce. We investigated the longitudinal associations of markers of CSVD and brain atrophy with incident depressive symptoms and the course of depressive symptoms, above and below 60 years of age. Methods White matter hyperintensity volumes (WMH), presence of lacunar infarcts and cerebral microbleeds, and white matter, grey matter, and cerebral spinal fluid volumes were assessed at baseline by 3T MRI in The Maastricht Study (mean age 59.5±8.5 years, 49.6% women, n=4,347; 16,535 person-years of follow-up). Clinically relevant depressive symptoms (9-item Patient Health Questionnaire≥10) were assessed at baseline and annually over seven years. We used Cox regression and multinomial logistic regression analyses adjusted for demographic, cardiovascular, and lifestyle risk factors. Results Above 60 years of age, larger WMH volumes were associated with an increased risk for incident depressive symptoms (HR[95%CI]:1.24[1.04;1.48] per SD) and a persistent course of depressive symptoms (OR:1.44[1.04;2.00] per SD). Total CSVD burden was associated with persistent depressive symptoms irrespective of age (adjusted OR:1.58[1.03;2.43]), while no associations were found for general markers of brain atrophy. Limitationss Our findings need replication in other large-scale population-based studies. Conclusions Our findings may suggest a temporal association of larger WMH volume with the incidence and persistence of late-life depression in the general population and may provide a potential target for the prevention of chronic late-life depression.

Improving research capacity is key to better understand dementia globally (Gonzalez et al., 2014) and it depends on the investment made on the career development of the early- and mid-career resear...

No abstract applicable.

Contains fulltext : 290747.pdf (Publisher’s version ) (Open Access) INTRODUCTION/AIMS: Although the extent of muscle weakness and organ complications has not been well studied in patients with late-onset myotonic dystrophy type 1 (DM1), adult-onset DM1 is associated with severe muscle involvement and possible life-threatening cardiac and respiratory complications. In this study we aimed to compare the clinical phenotype of adult-onset vs late-onset DM1, focusing on the prevalence of cardiac, respiratory, and muscular involvement. METHODS: Data were prospectively collected in the Dutch DM1 registry. RESULTS: Two hundred seventy-five adult-onset and 66 late-onset DM1 patients were included. Conduction delay on electrocardiogram was present in 123 of 275 (45%) adult-onset patients, compared with 24 of 66 (36%) late-onset patients (P = .218). DM1 subtype did not predict presence of conduction delay (odds ratio [OR] 0.706; confidence interval [CI] 0.405 to 1.230, P = .219). Subtype did predict indication for noninvasive ventilation (NIV) (late onset vs adult onset: OR, 0.254; CI, 0.104 to 0.617; P = .002) and 17% of late-onset patients required NIV compared with 40% of adult-onset patients. Muscular Impairment Rating Scale (MIRS) scores were significantly different between subtypes (MIRS 1 to 3 in 66% of adult onset vs 100% of late onset [P

Biomarker discovery, development, and validation are reliant on large-scale analyses of high-quality samples and data. Currently, significant quantities of data and samples have been generated by European studies on Alzheimer's disease (AD) and other neurodegenerative diseases (NDD), representing a valuable resource for developing biomarkers to support early detection of disease, treatment monitoring, and patient stratification. However, discovery of, access to, and sharing of data and samples from AD and NDD research are hindered both by silos that limit collaboration, and by the array of complex requirements for secure, legal, and ethical sharing. In this Perspective article, we examine key challenges currently hampering large-scale biomarker research, and outline how the European Platform for Neurodegenerative Diseases (EPND) plans to address them. The first such challenge is a fragmented landscape filled with technical barriers that make it difficult to discover and access high-quality samples and data in one location. A second challenge is related to the complex array of legal and ethical requirements that must be navigated by researchers when sharing data and samples, to ensure compliance with data protection regulations and research ethics. Another challenge is the lack of broad-scale collaboration and opportunities to facilitate partnerships between data and sample contributors and researchers, in addition to a lack of regulatory engagement early in the research process to enable validation of potential biomarkers. A further challenge facing projects is the need to remain sustainable beyond initial funding periods, ensuring data and samples are shared and reused, thereby driving further research and innovation. In addressing these challenges, EPND will enable an environment of faster and more disruptive research on diagnostics and disease-modifying therapies for Alzheimer's disease and other neurodegenerative diseases.

Background: Anecdotally, cystic vestibular schwannomas (cVSs) are regarded to have unpredictable biologic activity with poorer clinical results and most studies showed a less favorable prognosis following surgery. While stereotactic radiosurgery (SRS) is a well-established therapeutic option for small to medium-sized VSs, cVSs are often larger, thus making upfront SRS more complicated. The purpose of this retrospective study was to assess the efficacy and safety of upfront SRS for large cVSs. Methods: The authors reviewed the data of 54 patients who received upfront, single-session GKRS with a diagnosis of large cVS (>4 cm3). Patients with neurofibromatosis type 2, multiple VSs, or recurrent VSs and < 24 months of clinical and neuroimaging follow-up were excluded.Results: Hearing loss (48.1%) was the primary presenting symptom. The majority of cVSs were KOOS grade IV (66.7%), and the most prevalent cyst pattern was “mixed pattern of small and big cysts” (46.3%). The median time between diagnosis and GKRS was 12 months (range, 1-147 months). At GKRS, the median cVS volume was 6.95 cm3 (range, 4.1–22 cm3). The median marginal dose was 12 Gy (range, 10-12 Gy). The mean radiological and clinical follow-up periods were 62.2 ± 34.04 months (range, 24-169 months) and 94.9 ± 45.41 months (range, 24-175 months), respectively. At 2, 6, and 12 years, the tumor control rates were 100%, 95.7%, and 85.0%, respectively. Tumor shrinkage occurred in 92.6% of patients (n=50), tumor volume remained stable in 5.6% of patients (n=3), and tumor growth occurred in 1.9 percent of patients (n=1). At a median follow-up of 53.5 months, the pre-GKRS tumor volume significantly decreased to 2.35 cm3 (pConclusions: Contrary to what was believed, our findings suggest that upfront GKRS seems to be a safe and effective treatment option for large cVSs.

Introduction Behaviour change interventions represent key means for supporting healthy ageing and reducing dementia risk yet brief, scalable behaviour change interventions targeting dementia risk reduction in older adults is currently lacking. Here we describe the aims and design of the three-month Brain Bootcamp initiative that seeks to target multiple dementia risk and protective factors (healthy eating, physical, social and cognitive inactivity), through the use of multiple behaviour change techniques, including goal-setting for behaviour, information about health consequences and physical prompts to change behaviours that reduce dementia risk among older adults. Our secondary aim is to understand participants’ views of dementia prevention and explore the acceptability and integration of this campaign into daily life. Methods Brain Bootcamp is a pre-post feasibility trial conducted in Sydney, Australia beginning in January 2021 until late August. Participants aged ≥65 years living independently in the community (n = 252), recruited through social media and flyers, will provide information about their demographics, medical history, alcohol consumption, smoking habits, mental health, physical activity, cognitive activity, and diet to generate a dementia risk profile at baseline and assess change therein at three-month follow-up. During the intervention, participants will receive a resource pack containing their individual risk profile, educational booklet on dementia risk factors and four physical items designed to prompt physical, social and mental activity, and better nutrition. Outcome measures include change in dementia risk scores, dementia awareness and motivation. A qualitative process evaluation will interview a sample of participants on the acceptability and feasibility of the intervention. Discussion This will be the first short-term multi-domain intervention targeting dementia risk reduction in older adults. Findings will generate a new evidence base on how to best support efforts targeting lifestyle changes and to identify ways to optimise acceptability and effectiveness towards brain health for older adults. Trial registration number ACTRN 381046 (registered 17/02/2021); Pre-results.

Acquired Brain Injury (ABI) can have lifelong consequences and accordingly, persons with ABI often receive various types of healthcare. Facilities have their own preferences towards measurement instruments used to evaluate patients, impeding data comparison across healthcare settings. In this cross-sectional study, we used the previously developed minimal dataset for persons with ABI (MDS-ABI) to uniformly document and compare characteristics and outcomes of ABI patients in three healthcare settings: (1) residential care (n = 21), (2) non-residential care (n = 80), and (3) no ABI-related care (n = 22). Overall, patients of residential care settings had the lowest functional outcome compared with patients in the remaining groups. Nonetheless, all groups showed substantial disabilities within numerous life domains, indicating that the consequences of ABI are widespread among patients within and outside of healthcare facilities. These results demonstrate the need for a broad measurement of the potential consequences of ABI. The MDS-ABI covers twelve life domains most frequently affected by ABI and therefore helps to better recognize the consequences of ABI. In research contexts, implementation of the MDS-ABI allows for direct comparison of research findings. Future directions should be aimed at further implementation of the MDS-ABI to guide clinical decision-making and assist in identifying treatment goals specific to each healthcare setting.

Background Identifying momentary risk and protective mechanisms may enhance our understanding and treatment of mental disorders. Affective stress reactivity is one mechanism that has been reported to be altered in individuals with early and later stages of mental disorder. Additionally, initial evidence suggests individuals with early and enduring psychosis may have an extended recovery period of negative affect in response to daily stressors (ie, a longer duration until affect reaches baseline levels after stress), but evidence on positive affective recovery as a putative protective mechanism remains limited. Objective This study aimed to investigate trajectories of positive affect in response to stress across the continuum of mental disorder in a transdiagnostic sample. Methods Using the Experience Sampling Method, minor activity-, event-, and overall stress and positive affect were assessed 10 times a day, with time points approximately 90 minutes apart on six consecutive days in a pooled data set including 367 individuals with a mental disorder, 217 individuals at risk for a severe mental disorder, and 227 controls. Multilevel analysis and linear contrasts were used to investigate trajectories of positive affect within and between groups. Results Baseline positive affect differed across groups, and we observed stress reactivity in positive affect within each group. We found evidence for positive affective recovery after reporting activity- or overall stress within each group. While controls recovered to baseline positive affect about 90 minutes after stress, patients and at-risk individuals required about 180 minutes to recover. However, between-group differences in the affective recovery period fell short of significance (all P>.05). Conclusions The results provide first evidence that positive affective recovery may be relevant within transdiagnostic subclinical and clinical stages of mental disorder, suggesting that it may be a potential target for mobile health interventions fostering resilience in daily life.

Neuropathic pain is a characteristic feature of small fiber neuropathy (SFN), which in 18% of the cases is caused by genetic variants in voltage-gated sodium ion channels. In this study, we assessed the role of fifteen other ion channels in neuropathic pain. Patients with SFN (n = 414) were analyzed for ANO1, ANO3, HCN1, KCNA2, KCNA4, KCNK18, KCNN1, KCNQ3, KCNQ5, KCNS1, TRPA1, TRPM8, TRPV1, TRPV3 and TRPV4 variants by single-molecule molecular inversion probes–next-generation sequencing. These patients did not have genetic variants in SCN3A, SCN7A-SCN11A and SCN1B-SCN4B. In twenty patients (20/414, 4.8%), a potentially pathogenic heterozygous variant was identified in an ion-channel gene (ICG). Variants were present in seven genes, for two patients (0.5%) in ANO3, one (0.2%) in KCNK18, two (0.5%) in KCNQ3, seven (1.7%) in TRPA1, three (0.7%) in TRPM8, three (0.7%) in TRPV1 and two (0.5%) in TRPV3. Variants in the TRP genes were the most frequent (n = 15, 3.6%), partly in patients with high mean maximal pain scores VAS = 9.65 ± 0.7 (n = 4). Patients with ICG variants reported more severe pain compared to patients without such variants (VAS = 9.36 ± 0.72 vs. VAS = 7.47 ± 2.37). This cohort study identified ICG variants in neuropathic pain in SFN, complementing previous findings of ICG variants in diabetic neuropathy. These data show that ICG variants are central in neuropathic pain of different etiologies and provides promising gene candidates for future research.

BACKGROUND: Telemedicine (TM) contributes to bridge the gap between healthcare facilities and patients' homes with neuromuscular disease (NMD) because of mobility issues. However, its deployment is limited due to difficulties evaluating subtle neurological signs such as mild weakness or sensory deficits. The COVID-19 pandemic has disrupted healthcare delivery worldwide, necessitating rapid measures implementation by health care providers (HCPs) to protect patients from acquiring SARS-CoV-2 while maintaining the best care and treatment.OBJECTIVES: Given the challenges faced by remote healthcare assistance of NMD patients, we aim to evaluate the use of TM in NMD during the COVID-19 pandemic.METHODS: Based on the Model for Assessment-of-Telemedicine-Applications (MAST), we conducted a survey amongst clinicians of the ERN EURO NMD (European-Reference-Network-for-Rare-Neuromuscular-Diseases).RESULTS: Based on 42 responses over 76 expected ones, our results show that the COVID-19 pandemic significantly increased the number of HCPs using TM (from 60% to 100%). The TM types most used during the COVID-19 period are teleconsultation and consultation by phone, particularly in the context of symptoms worsening in NMD patients with COVID-19 infection. Most European HCPs were satisfied when using TM but as a complementary option to physical consultations. Many responses addressed the issue of technical aspects needing improvement, particularly for elderly patients who need caregivers' assistance for accessing the TM platform.CONCLUSIONS: TM has been essential during COVID-19, but its use still presents some limitations for NMD patients with cognitive deficits or for first-time diagnosis. Thus, TM should be used as complement to, rather than substitute, for face-to-face consultations.

Objective Small fiber neuropathy (SFN) is characterized by chronic neuropathic pain and autonomic dysfunction. Currently, symptomatic pharmacological treatment is often insufficient and frequently causes side effects. SFN patients have a reduced quality of life. However, little is known regarding whether psycho-social variables influence the development and maintenance of SFN-related disability and complaints. Additional knowledge may have consequences for the treatment of SFN. For example, factors such as thinking, feeling, and behavior are known to play roles in other chronic pain conditions. The aim of this study was to obtain further in-depth information about the experience of living with SFN and related chronic pain. Methods Fifteen participants with idiopathic SFN participated in a prospective, semi-structured, qualitative, focus group interview study. The focus groups were audio-recorded, transcribed, and analyzed cyclically after each interview. Results The following main themes were identified: “pain appraisal”, “coping”, “social, work, and health environment”, and “change in identity”. Catastrophic thoughts and negative emotions were observed. Living with SFN resulted in daily limitations and reduced quality of life. Conclusions Given the results, it can be concluded that an optimal treatment should include biological, psychological, and social components.

Study Objectives The ability to generate slow waves (SW) during non-rapid eye movement (NREM) sleep decreases as early as the 5th decade of life, predominantly over frontal regions. This decrease may concern prominently SW characterized by a fast switch from hyperpolarized to depolarized, or down-to-up, state. Yet, the relationship between these fast and slow switcher SW and cerebral microstructure in ageing is not established. Methods We recorded habitual sleep under EEG in 99 healthy late midlife individuals (mean age = 59.3 ± 5.3 years; 68 women) and extracted SW parameters (density, amplitude, frequency) for all SW as well as according to their switcher type (slow vs. fast). We further used neurite orientation dispersion and density imaging (NODDI) to assess microstructural integrity over a frontal grey matter region of interest (ROI). Results In statistical models adjusted for age, sex, and sleep duration, we found that a lower SW density, particularly for fast switcher SW, was associated with a reduced orientation dispersion of neurites in the frontal ROI (p = 0.018, R2β* = 0.06). In addition, overall SW frequency was positively associated with neurite density (p = 0.03, R2β* = 0.05). By contrast, we found no significant relationships between SW amplitude and NODDI metrics. Conclusions Our findings suggest that the complexity of neurite organization contributes specifically to the rate of fast switcher SW occurrence in healthy middle-aged individuals, corroborating slow and fast switcher SW as distinct types of SW. They further suggest that the density of frontal neurites plays a key role for neural synchronization during sleep. Trial registration number EudraCT 2016-001436-35.

Background Evidence on potentially modifiable risk factors for dementia is accumulating rapidly, including e.g. physical inactivity, hypertension, or diabetes. It is unclear to what extent these risk factors are known among the general population in Germany. We investigated knowledge on risk and protective factors for dementia and openness to eHealth interventions for brain health in the older general population in Germany. Methods A population-based telephone survey among randomly selected community-dwelling adults aged ≥ 60 years was conducted. We assessed sociodemographic factors, knowledge on risk and protective factors for dementia, openness towards eHealth and psychosocial outcomes (health literacy, resilience). Factors associated with interest in information on brain health and openness towards eHealth interventions were assessed using multivariable logistic regression. Results Of n = 500 respondents (mean age: 74.8 years, % female: 62.8), 67.9% believed that dementia risk is modifiable. Participants mostly endorsed physical and cognitive activity as protective factors and social isolation as a risk factor. Knowledge on cardiovascular risk factors was low to moderate. 38.0% were interested in information on dementia risk reduction. Better knowledge of risk factors for dementia and higher age were linked to interest in information on brain health. Being widowed and higher levels of health literacy were associated with lower interest in information. Openness to eHealth interventions was moderate (46.2%). Younger age, better knowledge of risk and protective factors were linked to openness towards eHealth tools, as was knowing someone with dementia and interest in information on brain health. Conclusion Belief in preventability of dementia was higher in our sample than previously reported. However, knowledge on cardiovascular risk factors for disease was insufficient and more information and intervention approaches targeted at older adults are needed. Interest in information on dementia risk reduction and eHealth approaches was moderate, and further studies are warranted to assess needs and concerns of older adults regarding dementia prevention.

Cognitive impairment is a debilitating symptom in Parkinson’s disease (PD). We aimed to establish an accurate multivariate machine learning (ML) model to predict cognitive outcome in newly diagnosed PD cases from the Parkinson’s Progression Markers Initiative (PPMI). Annual cognitive assessments over an eight-year time span were used to define two cognitive outcomes of i) cognitive impairment, and ii) dementia conversion. Selected baseline variables were organized into three subsets of clinical, biofluid and genetic/epigenetic measures and tested using four different ML algorithms. Irrespective of the ML algorithm used, the models consisting of the clinical variables performed best and showed better prediction of cognitive impairment outcome over dementia conversion. We observed a marginal improvement in the prediction performance when clinical, biofluid, and epigenetic/genetic variables were all included in one model. Several cerebrospinal fluid measures and an epigenetic marker showed high predictive weighting in multiple models when included alongside clinical variables.

Purpose Sulfur amino acids (SAAs) have been associated with obesity and obesity-related metabolic diseases. We investigated whether plasma SAAs (methionine, total cysteine (tCys), total homocysteine, cystathionine and total glutathione) are related to specific fat depots. Methods We examined cross-sectional subsets from the CODAM cohort (n = 470, 61.3% men, median [IQR]: 67 [61, 71] years) and The Maastricht Study (DMS; n = 371, 53.4% men, 63 [55, 68] years), enriched with (pre)diabetic individuals. SAAs were measured in fasting EDTA plasma with LC–MS/MS. Outcomes comprised BMI, skinfolds, waist circumference (WC), dual-energy X-ray absorptiometry (DXA, DMS), body composition, abdominal subcutaneous and visceral adipose tissues (CODAM: ultrasound, DMS: MRI) and liver fat (estimated, in CODAM, or MRI-derived, in DMS, liver fat percentage and fatty liver disease). Associations were examined with linear or logistic regressions adjusted for relevant confounders with z-standardized primary exposures and outcomes. Results Methionine was associated with all measures of liver fat, e.g., fatty liver disease [CODAM: OR = 1.49 (95% CI 1.19, 1.88); DMS: OR = 1.51 (1.09, 2.14)], but not with other fat depots. tCys was associated with overall obesity, e.g., BMI [CODAM: β = 0.19 (0.09, 0.28); DMS: β = 0.24 (0.14, 0.34)]; peripheral adiposity, e.g., biceps and triceps skinfolds [CODAM: β = 0.15 (0.08, 0.23); DMS: β = 0.20 (0.12, 0.29)]; and central adiposity, e.g., WC [CODAM: β = 0.16 (0.08, 0.25); DMS: β = 0.17 (0.08, 0.27)]. Associations of tCys with VAT and liver fat were inconsistent. Other SAAs were not associated with body fat. Conclusion Plasma concentrations of methionine and tCys showed distinct associations with different fat depots, with similar strengths in the two cohorts.

Depression is more common in neurodegenerative diseases such as Huntington’s disease than the general population. Antidepressant efficacy is well-established for depression within the general population: a recent meta-analysis showed serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants and mirtazapine outperformed other antidepressants. Despite the severe morbidity, antidepressant choice in Huntington’s disease is based on Class IV evidence. We used complementary approaches to determine treatment choice for depression in Huntington’s disease: propensity score analyses of antidepressant treatment outcome using the ENROLL-HD data set, and a dissection of the cognitive mechanisms underlying depression in Huntington’s disease using a cognitive battery based on the Research Domain Criteria for Depression. Study 1 included ENROLL-HD 5486 gene-positive adult patients started on an antidepressant medication for depression. Our outcome measures were depression (Hospital Anxiety and Depression Scale or Problem Behaviours Assessment ‘Depressed Mood’ item) at first follow-up (primary outcome) and all follow-ups (secondary outcome). The intervention was antidepressant class. We used Svyglm&Twang in R to perform propensity scoring, using known variables (disease progression, medical comorbidity, psychiatric morbidity, sedatives, number of antidepressants, demographics and antidepressant contraindications) to determine the probability of receiving different antidepressants (propensity score) and then included the propensity score in a model of treatment efficacy. Study 2 recruited 51 gene-positive adult patients and 26 controls from the South Wales Huntington’s Disease Management Service. Participants completed a motor assessment, in addition to measures of depression and apathy, followed by tasks measuring consummatory anhedonia, motivational anhedonia, learning from reward and punishment and reaction to negative outcome. We used generalised linear models to determine the association between task performance and depression scores. Study 1 showed selective serotonin reuptake inhibitors outperformed serotonin norepinephrine reuptake inhibitors on the primary outcome (P = 0.048), whilst both selective serotonin reuptake inhibitors (P = 0.00069) and bupropion (P = 0.0045) were superior to serotonin norepinephrine reuptake inhibitors on the secondary outcome. Study 2 demonstrated an association between depression score and effort for reward that was not explained by apathy. No other mechanisms were associated with depression score. We found that selective serotonin reuptake inhibitors and bupropion outperform serotonin norepinephrine reuptake inhibitors at alleviating depression in Huntington’s disease. Moreover, motivational anhedonia appears the most significant mechanism underlying depression in Huntington’s disease. Bupropion is improves motivational anhedonia and has a synergistic effect with selective serotonin reuptake inhibitors. This work provides the first large-scale, objective evidence to determine treatment choice for depression in Huntington’s disease, and provides a model for determining antidepressant efficacy in other neurodegenerative diseases.

Background A frequent post stroke disorder in lateralized attention is visuospatial neglect (VSN). As VSN has a strong negative impact on recovery in general and independence during daily life, optimal treatment is deemed urgent. Next to traditional stroke treatment, non-invasive brain stimulation offers the potential to facilitate stroke recovery as a complementary approach. In the present study, visual scanning training (VST; the current conventional treatment) will be combined with transcranial alternating current stimulation (tACS) to evaluate the additive effects of repeated sessions of tACS in combination with six-weeks VST rehabilitation. Methods In this double-blind randomized placebo-controlled intervention study (RCT), we will compare the effects of active tACS plus VST to sham (placebo) tACS plus VST, both encompassing 18 VST training sessions, 40 minutes each, during 6 weeks. Chronic stroke patients with VSN (> 6 months post-stroke onset) are considered eligible for study participation. In total 22 patients are needed for the study. The primary outcome is change in performance on a cancellation task. Secondary outcomes are changes in performance on a visual detection task, two line bisection tasks, and three measures to assess changes in activities of daily living. Assessment is at baseline, directly after the first and ninth training session, after the last training session (post training), and 1 week and 3 months after termination of the training (follow-up). Discussion If effective, a tACS-VST rehabilitation program could be implemented as a treatment option for VSN. Trial registration ClinicalTrials.gov; registration number: NCT05466487; registration date: July 18, 2022 retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT05466487

BackgroundIndividuals with depression often experience widespread and persistent cognitive deficits, which might be due to brain atrophy and cerebral small vessel disease (CSVD). We therefore studied the associations between depression, markers of brain atrophy and CSVD, and cognitive functioning.MethodsWe used cross-sectional data from the population-based Maastricht study (n = 4734; mean age 59.1 ± 8.6 years, 50.2% women), which focuses on type 2 diabetes. A current episode of major depressive disorder (MDD, n = 151) was assessed by the Mini-International Neuropsychiatric Interview. Volumes of cerebral spinal fluid, white matter, gray matter and white matter hyperintensities, presence of lacunar infarcts and cerebral microbleeds, and total CSVD burden were assessed by 3 T magnetic resonance imaging. Multiple linear and logistic regression analyses tested the associations between MDD, brain markers and cognitive functioning in memory, information processing speed, and executive functioning & attention, and presence of cognitive impairment. Structural equation modeling was used to test mediation.ResultsIn fully adjusted models, MDD was associated with lower scores in information processing speed [mean difference = −0.18(−0.28;−0.08)], executive functioning & attention [mean difference = −0.13(−0.25;−0.02)], and with higher odds of cognitive impairment [odds ratio (OR) = 1.60(1.06;2.40)]. MDD was associated with CSVD in participants without type 2 diabetes [OR = 1.65(1.06;2.56)], but CSVD or other markers of brain atrophy or CSVD did not mediate the association with cognitive functioning.ConclusionsMDD is associated with more impaired information processing speed and executive functioning & attention, and overall cognitive impairment. Furthermore, MDD was associated with CSVD in participants without type 2 diabetes, but this association did not explain an impaired cognitive profile.

PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP.METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay.RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants.CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

BackgroundIntracranial hemorrhage (ICH) is a frequent complication after endovascular stroke treatment.ObjectiveTo assess the association of the occurrence and type of ICH after endovascular treatment (EVT) with functional outcome.MethodsWe analyzed data from the MR CLEAN-NO IV and MR CLEAN-MED trials. Both trials included adult patients with ischemic stroke with a large vessel occlusion in the anterior circulation, who were eligible for EVT. ICH was classified (1) as asymptomatic or symptomatic (concomitant neurological deterioration of ≥4 points on the NIHSS, or ≥2 points on 1 NIHSS item), and (2) according to the Heidelberg Bleeding Classification. We used multivariable ordinal logistic regression analyses to assess the association of the occurrence and type of ICH with the modified Rankin Scale score at 90 days.ResultsOf 1017 included patients, 331 (33%) had an asymptomatic ICH, and 90 (9%) had a symptomatic ICH. Compared with no ICH, both asymptomatic (adjusted common OR (acOR)=0.76; 95% CI 0.58 to 0.98) and symptomatic (acOR=0.07; 95% CI 0.04 to 0.14) ICH were associated with worse functional outcome. In particular, isolated parenchymal hematoma type 2 (acOR=0.37; 95% CI 0.14 to 0.95), combined parenchymal hematoma with hemorrhage outside infarcted brain tissue (acOR=0.17; 95% CI 0.10 to 0.30), and combined hemorrhages outside infarcted brain tissue (acOR=0.14; 95% CI 0.03 to 0.74) were associated with worse functional outcome than no ICH.Strength of the association of ICH with functional outcome depends on the type of ICH. Although the association is stronger for symptomatic ICH, asymptomatic ICH after EVT is also associated with worse functional outcome.

PURPOSE: Cerebral palsy (CP) is a major cause of childhood disability. Children with CP often lack motor skills to effectively perform activities of daily living. The aim is to assess the effectiveness of a functional intensive therapy program focused on improving individual goals in the domain of mobility and self-care in children and adolescents with CP. MATERIAL AND METHODS: Thirty-five CP patients, aged 11-19 years, GMFCS I-IV, received daily 6-7 h of functional therapy for 15 days. Outcomes were assessed at baseline, immediately after the program and at three months follow-up. RESULTS: Significant post-intervention improvement was seen on all primary and secondary outcome measures; personal goals (GAS score; COPM performance and COPM satisfaction), daily activities (ACTIVLIM), hand function (ABILHAND-Kids), mobility (ABILOCO-Kids; GMFM-66-IS score). There was no loss to follow up during the program and after three months. At follow-up, improvements were retained except for ABILOCO and GMFM-66-IS. CONCLUSIONS: Functional intensive therapy appears feasible and seems to be effective in improving treatment goals focused on mobility and self-care, even in older and more severely affected children and adolescents with CP. After three months, these possible effects were still present.Implications for rehabilitationShort intensive functional training is feasible and showing no loss to follow up in the older and more severely affected children and adolescents with cerebral palsy (CP).Short intensive functional training appears effective in improving individual goals in children and adolescents with CP and improvements endorse three months.Short intensive functional training seems to be effective on both mobility and self-care domains of the ICF-CY.

Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association remain to be determined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a genetic disorder linked with neurodevelopmental disorders and associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA and leads to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Significantly, the EHMT1-regulated miRNA gene set not only controls NRSF/REST but is enriched for association for Intellectual Disability (ID) and schizophrenia. This reveals a broad molecular interaction between H3K9 demethylation, NSRF/REST regulation and risk for ID and Schizophrenia.

This study aims to investigate distractibility quantified by recording and analyzing eye movements during task-irrelevant distraction in children with and without ADHD and in children with and without neurological disorders. Gaze behavior data and press latencies of 141 participants aged 6–17 that were collected during a computerized distraction paradigm with task-irrelevant stimuli (IDistrack) were analyzed. Children using attention-regulating medication were excluded from participation. Data were analyzed for subgroups that were formed based on the presence of neurological disorders and the presence of ADHD separately. Participants with ADHD and participants with neurological disorders spent less time fixating on the target stimuli compared to their peers without ADHD (p = 0.025) or their peers without neurological disorders (p < 0.001). Participants with and without ADHD had equal press latencies (p = 0.79). Participants with neurological disorders had a greater press latency compared to their typically developing peers (p < 0.001). Target fixation duration shows a significant association with parent-reported attention problems (r = −0.39, p < 0.001). We conclude that eye tracking during a distraction task reveals potentially valid clinical information that may contribute to the assessment of dysfunctional attentional processes. Further research on the validity and reliability of this paradigm is recommended.

The mining of personal data collected by multiple organizations remains challenging in the presence of technical barriers, privacy concerns, and legal and/or organizational restrictions. While a number of privacy-preserving and data mining frameworks have recently emerged, much remains to show their practical utility. In this study, we implement and utilize a secure infrastructure using data from Statistics Netherlands and the Maastricht Study to learn the association between Type 2 Diabetes Mellitus (T2DM) and healthcare expenses considering the impact of lifestyle, physical activities, and complications of T2DM. Through experiments using real-world distributed personal data, we present the feasibility and effectiveness of the secure infrastructure for practical use cases of linking and analyzing vertically partitioned data across multiple organizations. We discovered that individuals diagnosed with T2DM had significantly higher expenses than those with prediabetes, while participants with prediabetes spent more than those without T2DM in all the included healthcare categories to different degrees. We further discuss a joint effort from technical, ethical-legal, and domain-specific experts that is highly valued for applying such a secure infrastructure to real-life use cases to protect data privacy.

Background Certain cases of superior semicircular canal dehiscence or benign paroxysmal positional vertigo can be treated by plugging of the affected semicircular canal. However, the extent of the impact on vestibular function and hearing during postoperative follow-up is not known. Objective To evaluate the evolution of vestibular function and hearing after plugging of a semicircular canal. Methods Six patients underwent testing before and 1 week, 2 months, and 6 months after plugging of the superior or posterior semicircular canal. Testing included caloric irrigation test, video Head Impulse Test (vHIT), cervical and ocular Vestibular Evoked Myogenic Potentials (VEMPs) and audiometry. Results Initially, ipsilateral caloric response decreased in all patients and vHIT vestibulo-ocular reflex (VOR) gain of each ipsilateral semicircular canal decreased in 4/6 patients. In 4/6 patients, postoperative caloric response recovered to > 60% of the preoperative value. In 5/6 patients, vHIT VOR gain was restored to > 85% of the preoperative value for both ipsilateral non-plugged semicircular canals. In the plugged semicircular canal, this gain decreased in 4/5 patients and recovered to > 50% of the preoperative value. Four patients preserved cervical and ocular VEMP responses. Bone conduction hearing deteriorated in 3/6 patients, but recovered within 6 months postoperatively, although one patient had a persistent loss of 15 dB at 8 kHz. Conclusion Plugging of a semicircular canal can affect both vestibular function and hearing. After initial deterioration, most patients show recovery during follow-up. However, a vestibular function loss or high-frequency hearing loss can persist. This stresses the importance of adequate counseling of patients considering plugging of a semicircular canal.

Pre-eclampsia is a vascular complication of pregnancy, associated with a long-term risk of cerebrovascular and mental disorders. We explored whether formerly pre-eclamptic women exhibit differences in functional brain organization, especially in regions that may explain the commonly reported emotional symptoms and cognitive complaints even years after the pregnancy.Formerly pre-eclamptic women and control women with a history of normotensive pregnancy underwent structural and functional 7-Tesla magnetic resonance imaging scans. Using graph theoretical analysis, the efficiency and clustering coefficient of the functional brain network were investigated. The study included local analysis focusing on particular brain structures, such as the limbic system and the prefrontal cortex, and global analysis of the whole cerebrum. Univariable and multivariable linear regression was used to investigate the relationship between brain network-related graph measures and the group (formerly pre-eclamptic or control).A total of 17 control parous women and 55 women with a history of pre-eclampsia were recruited. The time intervals between the index pregnancy and recruitment were 8.0 and 5.6 years for the two groups, respectively. Compared with control women, formerly pre-eclamptic women had higher local efficiency in the prefrontal cortex (P = 0.048) and anterior cingulate cortex (P = 0.03) but lower local efficiency and local clustering coefficient in the amygdala (P = 0.004 and P = 0.02, respectively) and parahippocampal cortex (P = 0.007 and P = 0.008, respectively). No differences were found in the global functional brain organization.Compared to controls with a history of normotensive pregnancy, formerly pre-eclamptic women displayed a different local functional brain organization. These differences in functional connectivity, especially in the limbic regions and the prefrontal cortex, are in line with the psychological and cognitive complaints reported commonly by women with a history of pre-eclampsia. © 2022 The Authors. Ultrasound in Obstetricsamp; Gynecology published by John Wileyamp; Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

BACKGROUND: Voltage-gated sodium channels are essential for the generation and conduction of electrical impulses in excitable cells. Sodium channel Nav 1.7, encoded by the SCN9A-gene, has been of special interest in the last decades because missense gain-of-function mutations have been linked to a spectrum of neuropathic pain conditions, including inherited erythermalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN).METHODS: In this case report, we present a 61-year-old woman who was referred to our tertiary referral center in a standard day care setting with suspicion of SFN. We performed additional investigations: skin biopsy to determine the intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST), and blood examination (including DNA analysis) for possible underlying conditions.RESULTS: The patient showed a clinical picture that fulfilled the criteria of IEM, PEPD, and SFN. DNA analysis revealed the heterozygous variant c.554G > A in the SCN9A-gene (OMIM 603415). This variant has already been described in all three human pain conditions separately, but never in one patient having symptoms of all three conditions. Because its pathogenicity has never been functionally confirmed, the variant is classified as a variance of unknown significance (VUS)/risk factor. This suggests that another genetic and/or environmental substrate plays a role in the development of neuropathic conditions like described.CONCLUSION: We have described this as the SCN9A-pain triangle phenomenon. Treatment should focus on pain management, genetic counseling, and improving/maintaining quality of life by treating symptoms and, if indicated, starting a rehabilitation program.

BackgroundThis study examined the associations between accelerometer-derived sedentary time (ST), lower intensity physical activity (LPA), higher intensity physical activity (HPA) and the incidence of depressive symptoms over 4 years of follow-up.MethodsWe included 2082 participants from The Maastricht Study (mean ± s.d. age 60.1 ± 8.0 years; 51.2% men) without depressive symptoms at baseline. ST, LPA and HPA were measured with the ActivPAL3 activity monitor. Depressive symptoms were measured annually over 4 years of follow-up with the 9-item Patient Health Questionnaire (PHQ-9). Cox regression analysis was performed to examine the associations between ST, LPA, HPA and incident depressive symptoms (PHQ-9 ⩾ 10). Analyses were adjusted for total waking time per day, age, sex, education level, type 2 diabetes mellitus, body mass index, total energy intake, smoking status and alcohol use.ResultsDuring 7812.81 person-years of follow-up, 203 (9.8%) participants developed incident depressive symptoms. No significant associations [Hazard Ratio (95% confidence interval)] were found between sex-specific tertiles of ST (lowest v. highest tertile) [1.13 (0.76–1.66], or HPA (highest v. lowest tertile) [1.14 (0.78–1.69)] and incident depressive symptoms. LPA (highest v. lowest tertile) was statistically significantly associated with incident depressive symptoms in women [1.98 (1.19–3.29)], but not in men (p-interaction ConclusionsWe did not observe an association between ST or HPA and incident depressive symptoms. Lower levels of daily LPA were associated with an increased risk of incident depressive symptoms in women. Future research is needed to investigate accelerometer-derived measured physical activity and ST with incident depressive symptoms, preferably stratified by sex.

This research investigates how municipalities can become more age-friendly, and how they can learn from each other across borders. It focuses on policies that support people with dementia, people with late-life depression, and informal caregivers. To this end, over thirty Belgian, Dutch and German municipalities and nine project partners from the Meuse-Rhine Euroregion took part in the Senior Friendly Communities project. Interviews were conducted with representatives of the municipalities before and after the project. During the project, a knowledge exchange and an exchange of existing interventions, including those from over the borders took place. Such interventions were offered in translated form if needed. The research shows that the project has mainly increased awareness among the municipality officials, on the target groups but also on how the municipalities can support the target groups, and with which partner organizations they can collaborate to do so. This is the start of more inclusive policies.

Cancers 14(18), 4521 (2022). doi:10.3390/cancers14184521 special issue: "Special Issue "Imaging Biomarker in Oncology" / Special Issue Editor: Dr. Damiano Caruso, Guest Editor", Published by MDPI, Basel

Background: Quality of life (QoL) is an important outcome from the perspective of patients and their caregivers, in both dementia and pre-dementia stages.1 Yet, little is known about the long-term changes in QoL over time.2 We aimed to compare the trajectories of the QoL between amyloid-positive and amyloid-negative patients along the Alzheimer’s disease (AD) continuum of cognitively normal to dementia. Method: In this longitudinal study, we included n = 447 (age 61.6±6.6, n(40%)F, Mini Mental State Examination (MMSE) 29(27-29), 23% amyloid-positive) patients with Subjective Cognitive Decline (SCD), n = 276 (age 64.6±7.0, n(33%F), MMSE 27(25-28), 52% amyloid-positive) patients with Mild Cognitive Impairment (MCI) and n = 417 (age 64.4±7.0, n(51%F), MMSE 23 (19-25), all amyloid-positive) with AD dementia from the Amsterdam Dementia Cohort. We used linear mixed-effect models (LMM) to compare QoL trajectories of the European Quality of Life-5 Dimensions (EQ-5D-3L and EQ-5D-5L) and Visual Analogue Scale (VAS) between 1) amyloid-positive and amyloid-negative SCD or MCI patients and 2) amyloid-positive SCD, MCI, and dementia patients. The models were adjusted for age, sex, Charlson Comorbidity Index (CCI), education and EQ-5D scale (3 or 5 level). Result: In SCD, amyloid-positive participants had a higher VAS at baseline, but showed a steeper decline over time in EQ-5D and VAS than amyloid-negative participants (figure 1). Also in MCI, amyloid-positive patients had higher QoL at baseline, but subsequently showed a steeper decline in QoL over time compared to amyloid-negative patients. When we compared amyloid-positive patients along the Alzheimer continuum, we found no difference between SCD, MCI or dementia in baseline QoL, but QoL decreased at a faster rate in the dementia stage compared with the pre-dementia stages of SCD and MCI (figure 2). When we additionally adjusted for covariates in model 2, the effects remained. Conclusion: QoL decreased at a faster rate over time in amyloid-positive SCD or MCI patients than amyloid-negative patients. QoL decreases over time along the entire continuum of AD of SCD, MCI and dementia, with the strongest decrease in dementia patients.

BACKGROUND: MRI is a valuable method to assist in the diagnostic work-up of Parkinson's disease (PD). The olfactory tract (OT) has been proposed as a potential MRI biomarker for distinguishing PD patients from healthy controls.OBJECTIVE: This study aims to further investigate whether diffusion measures of the OT differ between early stage PD patients and healthy controls.METHODS: Twenty hyposmic/anosmic PD patients, 65 normosmic PD patients, and 36 normosmic healthy controls were evaluated and a 7T diffusion weighted image scan was acquired. Manual seed regions of interest were drawn in the OT region. Tractography of the OT was performed using a deterministic streamlines algorithm. Diffusion measures (fractional anisotropy and mean- radial- and axial diffusivity) of the generated streamlines were compared between groups.RESULTS: Diffusion measures did not differ between PD patients compared to healthy controls and between hyposmic/anosmic PD patients, normosmic PD patients, and normosmic healthy controls. A positive correlation was found between age and mean- and axial diffusivity within the hyposmic/anosmic PD subgroup, but not in the normosmic groups. A positive correlation was found between MDS-UPDRSIII scores and fractional anisotropy.CONCLUSION: This study showed that fiber tracking of the OT was feasible in both early stage PD and healthy controls using 7T diffusion weighted imaging data. However, 7T MRI diffusion measures of the OT are not useful as an early clinical biomarker for PD. Future work is needed to clarify the role of other OT measurements as a biomarker for PD and its different subgroups.

(1) Background: This study aimed to investigate two-year societal costs and generic health-related quality of life (QoL) using a bottom-up approach for the Restore4Stroke Cohort. (2) Methods: Adult post-stroke patients were recruited from stroke units throughout the Netherlands. The societal costs were calculated for healthcare and non-healthcare costs in the first two years after stroke. The QoL was measured using EQ-5D-3L. The differences between (sub)groups over time were investigated using a non-parametric bootstrapping method. (3) Results: A total of 344 post-stroke patients were included. The total two-year societal costs of a post-stroke were EUR 47,502 (standard deviation (SD = EUR 2628)). The healthcare costs decreased by two thirds in the second year −EUR 14,277 (95% confidence interval −EUR 17,319, −EUR 11,236). In the second year, over 50% of the total societal costs were connected to non-healthcare costs (such as informal care, paid help, and the inability to perform unpaid labor). Sensitivity analyses confirmed the importance of including non-healthcare costs for long-term follow-up. The subgroup analyses showed that patients who did not return home after discharge, and those with moderate to severe stroke symptoms, incurred significantly more costs compared to patients who went directly home and those who reported fewer symptoms. QoL was stable over time except for the stroke patients over 75 years of age, where a significant and clinically meaningful decrease in QoL over time was observed. (4) Conclusions: The non-healthcare costs have a substantial impact on the first- and second-year total societal costs post-stroke. Therefore, to obtain a complete picture of all the relevant costs related to a stroke, a societal perspective with a follow-up of at least two years is highly recommended. Additionally, more research is needed to investigate the decline in QoL found in stroke patients above the age of 75 years.