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Pleiotropy occurs when a genetic variant influences more than one trait. This is a key property of the genomic architecture of psychiatric disorders and has been observed for rare and common genomic variants. It is reasonable to hypothesize that the microscale genetic overlap (pleiotropy) across psychiatric conditions and cognitive traits may lead to similar overlaps at the macroscale brain level such as large-scale brain functional networks. We took advantage of brain connectivity, measured by resting-state functional MRI to measure the effects of pleiotropy on large-scale brain networks, a putative step from genes to behaviour. We processed nine resting-state functional MRI datasets including 32 726 individuals and computed connectome-wide profiles of seven neuropsychiatric copy-number-variants, five polygenic scores, neuroticism and fluid intelligence as well as four idiopathic psychiatric conditions. Nine out of 19 pairs of conditions and traits showed significant functional connectivity correlations (rFunctional connectivity), which could be explained by previously published levels of genomic (rGenetic) and transcriptomic (rTranscriptomic) correlations with moderate to high concordance: rGenetic—rFunctional connectivity = 0.71 [0.40–0.87] and rTranscriptomic—rFunctional connectivity = 0.83 [0.52; 0.94]. Extending this analysis to functional connectivity profiles associated with rare and common genetic risk showed that 30 out of 136 pairs of connectivity profiles were correlated above chance. These similarities between genetic risks and psychiatric disorders at the connectivity level were mainly driven by the overconnectivity of the thalamus and the somatomotor networks. Our findings suggest a substantial genetic component for shared connectivity profiles across conditions and traits, opening avenues to delineate general mechanisms—amenable to intervention—across psychiatric conditions and genetic risks.

Background and hypothesis Recovery from psychosis is a complex phenomenon determined by an array of variables mutually impacting each other in a manner that is not fully understood. The aim of this study is to perform an approximated replication of a previous network analysis study investigating how different clinical aspects—covering psychopathology, cognition, personal resources, functional capacity, and real-life functioning—are interrelated in the context of schizophrenia-spectrum disorders. Study design A sample of 843 subjects from a multisite cohort study, with the diagnosis of a schizophrenia-spectrum disorder, was used to estimate a network comprising 27 variables. The connectivity and relative importance of the variables was examined through network analysis. We used a quantitative and qualitative approach to infer replication quality. Study results Functional capacity and real-life functioning were central and bridged different domains of the network, in line with the replicated study. Neurocognition, interpersonal relationships, and avolition were also key elements of the network, in close relation to aspects of functioning. Despite significant methodological differences, the current study could substantially replicate previous findings. Conclusions Results solidify the network analysis approach in the context of mental disorders and further inform future studies about key variables in the context of recovery from psychotic disorders.

BACKGROUND: Diet, in particular the Mediterranean diet, has been associated with better cognitive function and less cognitive decline in older populations.OBJECTIVES: To quantify associations of a healthy diet, defined by adherence to either the Mediterranean diet, the WHO guidelines, or Dutch Health Council dietary guidelines, with cognitive function and cognitive decline from middle age into old age.METHODS: From the Doetinchem Cohort Study, a large population-based longitudinal study, 3644 participants (51% females) aged 45-75 y at baseline, were included. Global cognitive function, memory, processing speed, and cognitive flexibility were assessed at 5-y time intervals up to 20-y follow-up. Adherence to the Mediterranean diet was measured with the modified Mediterranean Diet Score (mMDS), adherence to the WHO dietary guidelines with the Healthy Diet Indicator (HDI), and adherence to the Dutch Health Council dietary guidelines 2015 with the modified Dutch Healthy Diet 2015 index (mDHD15-index). The scores on the dietary indices were classified in tertiles (low, medium, high adherence). Linear mixed models were used to model level and change in cognitive function by adherence to healthy diets.RESULTS: The highest tertiles of the mMDS, HDI, and mDHD15-index were associated with better cognitive function compared with the lowest tertiles (P values CONCLUSIONS: Healthier dietary habits, determined by higher adherence to dietary guidelines, are associated with better cognitive function and slower cognitive decline with aging from middle age onwards.

Research studies based on tractography have revealed a prominent reduction of asymmetry in some key white-matter tracts in schizophrenia (SCZ). However, we know little about the influence of common genetic risk factors for SCZ on the efficiency of routing on structural brain networks (SBNs). Here, we use a novel recall-by-genotype approach, where we sample young adults from a population-based cohort (ALSPAC:N genotyped = 8,365) based on their burden of common SCZ risk alleles as defined by polygenic risk score (PRS). We compared 181 individuals at extremes of low (N = 91) or high (N = 90) SCZ-PRS under a robust diffusion MRI-based graph theoretical SBN framework. We applied a semi-metric analysis revealing higher SMR values for the high SCZ-PRS group compared with the low SCZ-PRS group in the left hemisphere. Furthermore, a hemispheric asymmetry index showed a higher leftward preponderance of indirect connections for the high SCZ-PRS group compared with the low SCZ-PRS group (PFDR

Brain lesions are a rare cause of tic disorders. However, they can provide uniquely causal insights into tic pathophysiology and can also inform on possible neuromodulatory therapeutic targets. Based on a systematic literature review, we identified 22 cases of tics causally attributed to brain lesions and employed ‘lesion network mapping’ to interrogate whether tic-inducing lesions would be associated with a common network in the average human brain. We probed this using a normative functional connectome acquired in 1000 healthy participants. We then examined the specificity of the identified network by contrasting tic-lesion connectivity maps to those seeding from 717 lesions associated with a wide array of neurological and/or psychiatric symptoms within the Harvard Lesion Repository. Finally, we determined the predictive utility of the tic-inducing lesion network as a therapeutic target for neuromodulation. Specifically, we collected retrospective data of 30 individuals with Tourette disorder, who underwent either thalamic (n = 15; centromedian/ventrooralis internus) or pallidal (n = 15; anterior segment of globus pallidus internus) deep brain stimulation and calculated whether connectivity between deep brain stimulation sites and the lesion network map could predict clinical improvements. Despite spatial heterogeneity, tic-inducing lesions mapped to a common network map, which comprised the insular cortices, cingulate gyrus, striatum, globus pallidus internus, thalami and cerebellum. Connectivity to a region within the anterior striatum (putamen) was specific to tic-inducing lesions when compared with control lesions. Connectivity between deep brain stimulation electrodes and the lesion network map was predictive of tic improvement, regardless of the deep brain stimulation target. Taken together, our results reveal a common brain network involved in tic generation, which shows potential as a therapeutic target for neuromodulation.

Background Feasible and effective interventions to improve daily functioning in people with a severe mental illness (SMI), such as schizophrenia, in need of longer-term rehabilitation are scarce. Aims We assessed the effectiveness of Cognitive Adaptation Training (CAT), a compensatory intervention to improve daily functioning, modified into a nursing intervention. Method In this cluster randomized controlled trial, 12 nursing teams were randomized to CAT in addition to treatment as usual (CAT; n = 42) or TAU (n = 47). Daily functioning (primary outcome) was assessed every 3 months for 1 year. Additional follow-up assessments were performed for the CAT group in the second year. Secondary outcomes were assessed every 6 months. Data were analyzed using multilevel modeling. Results CAT participants improved significantly on daily functioning, executive functioning, and visual attention after 12 months compared to TAU. Improvements were maintained after 24 months. Improved executive functioning was related to improved daily functioning. Other secondary outcomes (quality of life, empowerment, negative symptoms) showed no significant effects. Conclusions As a nursing intervention, CAT leads to maintained improvements in daily functioning, and may improve executive functioning and visual attention in people with SMI in need of longer-term intensive psychiatric care. Given the paucity of evidence-based interventions in this population, CAT can become a valuable addition to recovery-oriented care.

The prevalence of brain pathologies increases with age and cognitive and physical functions worsen over the lifetime. It is unclear whether these processes show a similar increase with age. We studied the association of markers for brain pathology cognitive and physical functions with age in 288 cognitively normal individuals aged 60–102 years selected from the cross-sectional EMIF-AD PreclinAD and 90+ Study at the Amsterdam UMC. An abnormal score was consistent with a score below the 5th percentile in the 60- to 70-year-old individuals. Prevalence of abnormal scores was estimated using Generalized Estimating Equations (GEE) models. The prevalence of abnormal handgrip strength, the Digit Symbol Substitution Test, and hippocampal volume showed the fastest increase with age and abnormal MMSE score, muscle mass, and amyloid aggregation the lowest. The increase in prevalence of abnormal markers was partly dependent on sex, level of education, and amyloid aggregation. We did not find a consistent pattern in which markers of brain pathology cognitive and physical processes became abnormal with age.

Neuro-oncology advances : NOA 3(1), vdab044 (2021). doi:10.1093/noajnl/vdab044, Published by Oxford University Press, Oxford

Background. Depression is common in individuals with chronic kidney disease (CKD). However, data on the association of albuminuria, which together with reduced estimated glomerular filtration rate (eGFR) defines CKD, with depression are scarce and conflicting. In addition, it is not clear when in the course from normal kidney function to CKD the association with depression appears. Methods. We examined the cross-sectional associations of albuminuria and eGFR with depressive symptoms and depressive episodes in 2872 and 3083 40- to 75-year-old individuals, respectively, who completed the baseline survey of an ongoing population-based cohort study conducted in the southern part of The Netherlands between November 2013. Urinary albumin excretion (UAE) was the average UAE in two 24-h urine collections and eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration equation based on creatinine and cystatin C. Depressive symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9) and the presence of a minor or major depressive episode was assessed with the MINI-International Neuropsychiatric Interview. Results. In total, 5.4% had a minor or major depressive episode. UAE was = 30 mg/24 h in 8.6%. In a multivariable logistic regression analysis adjusted for potential confounders, and with UAE = 10). Conclusions. Albuminuria was associated with depressive symptoms and depressive episodes, even at levels of UAE that do not fulfil the CKD criteria. Future longitudinal studies should examine the direction of this association and whether albuminuria could serve as a biomarker to identify individuals at risk of depression.

Background/Objective studies on the association of dementia with specific body composition (BC) components are scarce. Our aim was to investigate associations of BC measures with different levels of cognitive function in late-life. Methods we studied 5,169 participants (mean age 76 years, 42.9% men) in the AGES-Reykjavik Study of whom 485 (9.4%) were diagnosed with mild cognitive impairment (MCI) and 307 (5.9%) with dementia. Visceral fat, abdominal and thigh subcutaneous fat, and thigh muscle were assessed by computed tomography. MCI and dementia were based on clinical assessment and a consensus meeting; those without MCI or dementia were categorised as normal. Multinomial regression models assessed the associations stratified by sex and in additional analyses by midlife body mass index (BMI). Results among women, there was a decreased likelihood of dementia per SD increase in abdominal subcutaneous fat (OR 0.72; 95% CI: 0.59-0.88), thigh subcutaneous fat (0.81; 0.67-0.98) and thigh muscle (0.63; 0.52-0.76), but not visceral fat, adjusting for demographics, vascular risk factors, stroke and depression. Inverse associations of fat with dementia were attenuated by weight change from midlife and were strongest in women with midlife BMI

Judgments of learning (JOL) pertain to introspective metamemory processes evaluating how well information is learned. Using a functional magnetic resonance imaging (fMRI) task, we investigated the neural substrates of JOL predictions in a group of 105 cognitively unimpaired older adults from the Harvard Aging Brain Study. Associations of JOL performance and its neural correlates with amyloid-β (Aβ) and tau pathology, two proteinopathies associated with Alzheimer’s disease (AD) and aging, were also examined. We found that trials judged as learned well relative to trials judged as learned less well (high JOL > low JOL) engaged the ventromedial prefrontal cortex and precuneus, among other midline regions, in addition to bilateral hippocampi. In this cohort of older adults, greater levels of entorhinal tau deposition were associated with overestimation of memory performance and with lower fMRI signal in midline regions during predicted memory success. No associations with Aβ were found. The findings suggest that tau pathology in unimpaired older adults may play a role in altered metamemory processes. We discuss our findings in light of the hypothesis that JOLs are partially dependent on a process involving attempts to retrieve a correct answer from memory, as well as implications for clinical research investigating unawareness of memory performance (i.e., anosognosia) in patients with AD dementia.

High-quality information to measure the need for, and the uptake, cost, quality and impact of care is essential in the pursuit of scaling up mental health care in low- and middle-income countries (LMIC). The aim of this study was to identify indicators for the measurement of effective coverage of mental health treatment. We conducted a two-round Delphi study (n = 93 experts from primarily LMIC countries Ethiopia, India, Nepal, Nigeria, South Africa and Uganda), in order to generate and prioritize a set of indicators. First, 52 unique indicators were generated (based on a total of 876 responses from participants). Second, the selected indicators were then scored for significance, relevance and feasibility. Mean priority scores were calculated per indicator (score range, 1-5). All 52 indicators had a weighted mean score that ranged from 3.20 for the lowest ranked to 4.27 for the highest ranked. The 15 highest ranked indicators cover the different domains of measuring effective mental health treatment coverage. This set of indicators is highly stable between the different groups of experts, as well as between the different participating countries. This study provides data on how mental health service and financial coverage can be assessed in LMIC. This is an important element in the move to scale-up mental health care.

Granulomatous interstitial nephritis has been observed in

Background: polypharmacy contributes to patients' non-adherence with physicians' prescriptions. Patients' knowledge about the indications for their medicines is one of the factors influencing adherence. Objective: to identify factors associated with appropriate knowledge about the indications for drugs prescribed to older patients with polypharmacy. Methods: in a primary care setting, using home interviews and postal questionnaires, patients aged 60 and over who were taking five or more prescribed drugs simultaneously were asked about their medication. Multiple logistic regression analysis was used to evaluate the association (odds ratio, OR) between medication knowledge and explanatory variables like medication use, sex, age, living situation and educational level. Results: seven hundred and fifty-four participants (mean age 73.2 years) reported an average daily intake of nine (SD 3.0) prescribed drugs. Only 15% of the patients were able to recall the indication for each of their prescribed drugs. Variables that were negatively associated with correct reporting of all indications were taking many prescribed drugs (e.g. a parts per thousand yen10 versus a parts per thousand currency sign5: OR 0.05), age 80 years or over (versus 60-69 years: OR 0.47) and male sex (OR 0.53). Patients living with a partner were more knowledgeable than patients living alone (OR 2.11). We did not find an association with educational level. Conclusion: among older patients using five or more prescribed drugs, there was little understanding of the indications for their drugs, especially among patients taking the highest number of drugs, patients aged 80 or over, and men. Patients living independently with a partner were more knowledgeable than others.

The aetiology of painful peripheral neuropathy is often unknown. Huang et al. sequence the gene encoding sodium channel Na(v)1.9 in 393 patients with small fibre neuropathy and identify eight variants in 12 individuals. Functional analysis of two variants reveals that they confer gain-of-function attributes to Na(v)1.9, and induce nociceptor hyperexcitability.Sodium channel Na(v)1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in sodium channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral sodium channels Na(v)1.7 and Na(v)1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown. We evaluated 459 patients who were referred for possible painful peripheral neuropathy, and confirmed the diagnosis of small fibre neuropathy in a cohort of 393 patients (369 patients with pure small fibre neuropathy, and small fibre neuropathy together with large fibre involvement in an additional 24 patients). From this cohort of 393 patients with peripheral neuropathy, we sequenced SCN11A in 345 patients without mutations in SCN9A and SCN10A, and found eight variants in 12 patients. Functional profiling by electrophysiological recordings showed that these Na(v)1.9 mutations confer gain-of-function attributes to the channel, depolarize resting membrane potential of dorsal root ganglion neurons, enhance spontaneous firing, and increase evoked firing of these neurons. Our data show, for the first time, missense mutations of Na(v)1.9 in individuals with painful peripheral neuropathy. These genetic and functional observations identify missense mutations of Na(v)1.9 as a cause of painful peripheral neuropathy.

Background: Based on presumed negative social comparisons in lower socioeconomic status groups, we set out to examine whether notions of 'internalized inferiority' are more common in these groups. Methods: Dutch Studie naar Medische Informatie en Leefwijzen in Eindhoven (SMILE) data on 1323 participants, aged 58-94 in 2008, were used to estimate odds ratios (ORs) of internalized inferiority by childhood and adulthood socioeconomic indicators. Questionnaires for social inadequacy and shame were used to measure internalized inferiority. Results: Both adulthood low educational level [OR 1.58; 95% confidence interval (CI): 1.04-2.40] and low income level (OR 1.88; 95% CI: 1.23-2.88) had substantial associations with reports of social inadequacy. Recalled childhood poverty was strongly associated with reports of shame (OR 2.20; 95% CI: 1.39-3.48). Conclusions: The socioeconomic patterning of social inadequacy and shame suggests that notions of internalized inferiority in the individual, psychological makeup might be important in the generation and maintenance of socioeconomic inequalities in health.

Background: The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment. Patients and methods: A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc (c)), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20). Results: Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores. Conclusion: None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.