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BackgroundPerivascular spaces (PVS) on brain MRI are surrogates for small parenchymal blood vessels and their perivascular compartment, and may relate to brain health. However, it is unknown whether PVS can predict dementia risk and brain atrophy trajectories in participants without dementia, as longitudinal studies on PVS are scarce and current methods for PVS assessment lack robustness and inter-scanner reproducibility.MethodsWe developed a robust algorithm to automatically assess PVS count and size on clinical MRI, and investigated 1) their relationship with dementia risk and brain atrophy in participants without dementia, 2) their longitudinal evolution, and 3) their potential use as a screening tool in simulated clinical trials. We analysed 46,478 clinical measurements of cognitive functioning and 20,845 brain MRI scans from 10,004 participants (71.1 ± 9.7 years-old, 56.6% women) from three publicly available observational studies on ageing and dementia (the Alzheimer's Disease Neuroimaging Initiative, the National Alzheimer's Coordinating Centre database, and the Open Access Series of Imaging Studies). Clinical and MRI data collected between 2004 and 2022 were analysed with consistent methods, controlling for confounding factors, and combined using mixed-effects models.FindingsOur fully-automated method for PVS assessment showed excellent inter-scanner reproducibility (intraclass correlation coefficients >0.8). Fewer PVS and larger PVS diameter at baseline predicted higher dementia risk and accelerated brain atrophy. Longitudinal trajectories of PVS markers differed significantly in participants without dementia who converted to dementia compared with non-converters. In simulated placebo-controlled trials for treatments targeting cognitive decline, screening out participants at low risk of dementia based on our PVS markers enhanced the power of the trial independently of Alzheimer's disease biomarkers.InterpretationThese robust cerebrovascular markers predict dementia risk and brain atrophy and may improve risk-stratification of patients, potentially reducing cost and increasing throughput of clinical trials to combat dementia.FundingUS National Institutes of Health.

BACKGROUND: Family and unpaid caregivers play a crucial role in supporting people living with dementia; yet, they are not systematically identified and documented by health systems. OBJECTIVE: The aims of the study are to determine the extent to which caregivers are currently identified and documented in the electronic health record (EHR) and to elicit the perspectives of caregivers and clinical staff on how to best identify, engage, and support caregivers of people living with dementia through the EHR. METHODS: People with dementia were identified based on International Classification of Diseases, Tenth Revision (ICD-10) codes or dementia medications in the EHR. A chart review of people with dementia characterized how caregiver information was documented and whether caregivers had shared access to the patient portal. Caregivers of eligible people with dementia were then recruited through mailed letters and follow-up calls to the homes of people with dementia. We conducted semistructured interviews with caregivers, clinicians, and staff involved in the care of people with dementia within 2 health systems in Maryland and Colorado. Transcripts were analyzed using a mixed inductive and deductive approach. RESULTS: Caregivers of people with dementia (N=22) were usually identified in the contact information or patient contacts tab (n=20, 91%) by their name and relation to the people with dementia; this tab did not specify the caregivers role. Caregivers were also mentioned, and their roles were described to a varying degree in clinical notes (n=21, 96%). Of the 22 caregivers interviewed, the majority (n=17, 77%) reported that the people with dementia had additional caregivers. The presence of multiple caregivers could be gleaned from most charts (n=16, 73%); however, this information was not captured systematically, and caregivers individual contributions were not explicitly recorded. Interviews with 22 caregivers and 16 clinical staff revealed two major themes: (1) caregiving arrangements are complex and not systematically captured or easy to locate in the EHR and (2) health systems should develop standardized processes to obtain and document caregiver information in the EHR. CONCLUSIONS: This exploratory chart review and qualitative interview study found that people with dementia frequently have multiple caregivers, whose roles and needs are captured inconsistently in the EHR. To address this concern, caregivers and clinical staff suggested that health systems should develop and test workflows to identify caregivers, assess their needs at multiple touchpoints, and record their information in extractable EHR fields.

White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables us to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (i) LNM-informed markers surpass WMH volumes in predicting cognitive performance; and (ii) WMH contributing to cognitive impairment map to specific brain networks. We analysed cross-sectional data of 3485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in four cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based grey and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in grey and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

PURPOSE: There is a lack of systematic solutions to manage supportive care issues in racial/ethnic minorities (REM) receiving treatment for cancer. We developed and implemented an electronic patient-reported outcome (ePRO)-driven symptom management tool led by oncology pharmacists in a majority-minority cancer center located in Southern California. This study was designed to evaluate the implementation outcomes of our multilevel intervention. METHODS: This was a prospective, pragmatic, implementation study conducted between July 2021 and June 2023. Newly diagnosed adult patients with cancer receiving intravenous anticancer therapies completed symptom screening using ePRO that consists of the Patient-Reported Outcomes Measurement Information System measures at each infusion visit during the study. ePRO results were presented to an oncologist pharmacist for personalized symptom management and treatment counseling. The RE-AIM framework was used to guide implementation outcomes. Differences in symptom trajectories and clinical outcomes between groups were tested using generalized estimating equations. RESULTS: We screened 388 patients of whom 250 were enrolled (acceptance rate: 64.4%), with 564 assessments being completed. The sample consisted of non-Hispanic White (NHW, 42.4%), Hispanic/Latinx (H/L, 30.8%), and non-Hispanic Asian (20.4%), with one (21.6%) of five participants preferring speaking Spanish. Compared with NHW, H/L participants had greater odds of reporting mild to severe pain interference (odds ratio [OR], 1.91 [95% CI, 1.18 to 3.08]; P = .008) and nausea and vomiting (OR, 2.08 [95% CI, 1.21 to 3.58]; P = .008), and higher rates of urgent care utilization (OR, 1.92 [95% CI, 1.04 to 3.61]; P = .04) within 30 days. Nausea and vomiting (n = 131, 23.2%), pain (n = 91, 16.1%), and fatigue (n = 72, 12.8%) were most likely to be intervened, with 90% of the participants expressing satisfaction across all visits. CONCLUSION: Our multilevel ePRO-driven intervention led by oncology pharmacists helps facilitate symptom assessments and management and potentially reduce health disparities among REM.

The pathogenesis of Alzheimer's disease (AD) depends on environmental and heritable factors, with its molecular etiology still unclear. Here we present a spatial transcriptomic (ST) and single-nucleus transcriptomic survey of late-onset sporadic AD and AD in Down syndrome (DSAD). Studying DSAD provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. We identified transcriptomic changes that may underlie cortical layer-preferential pathology accumulation. Spatial co-expression network analyses revealed transient and regionally restricted disease processes, including a glial inflammatory program dysregulated in upper cortical layers and implicated in AD genetic risk and amyloid-associated processes. Cell-cell communication analysis further contextualized this gene program in dysregulated signaling networks. Finally, we generated ST data from an amyloid AD mouse model to identify cross-species amyloid-proximal transcriptomic changes with conformational context.

BackgroundThe cumulative, health system-wide survival benefit of immune checkpoint inhibitors (ICIs) is unclear, particularly among real-world patients with limited life expectancies and among subgroups poorly represented on clinical trials. We sought to determine the health system-wide survival impact of ICIs.MethodsWe identified all patients receiving PD-1/PD-L1 or CTLA-4 inhibitors from 2010 to 2023 in the national Veterans Health Administration (VHA) system (ICI cohort) and all patients who received non-ICI systemic therapy in the years before ICI approval (historical control). ICI and historical control cohorts were matched on multiple cancer-related prognostic factors, comorbidities, and demographics. The effect of ICI on overall survival was quantified with Cox regression incorporating matching weights. Cumulative life-years gained system-wide were calculated from the difference in adjusted 5-year restricted mean survival times.ResultsThere were 27,322 patients in the ICI cohort and 69,801 patients in the historical control cohort. Among ICI patients, the most common cancer types were NSCLC (46%) and melanoma (10%). ICI demonstrated a large OS benefit in most cancer types with heterogeneity across cancer types (NSCLC: adjusted HR [aHR] 0.56, 95% confidence interval [CI] 0.54-0.58, p

Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons.

Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.

Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but positive and negative FTD demonstrated a dissociation: negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD also showed associations with microglial cell types. These results provide an important step towards linking FTD to brain structural changes and their cellular underpinnings, providing an avenue for a better mechanistic understanding of this syndrome.

BACKGROUND: Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification of the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day. METHODS: Mouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given to hypoxia-exposed pups. Myelination was assessed at age P14 and 10 weeks to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment. RESULTS: Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed Cmax 44.0 ng/mL, t1/2 4.6 h, and AUC24 280.1 ng*hr/mL. CONCLUSIONS: Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI. IMPACT: Preterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates. Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment. The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials. We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates.

Motivation in general, and social motivation in particular are important for interpersonal functioning in individuals with schizophrenia. Still, their roles after accounting for social cognition, are not well understood. The sample consisted of 147 patients with schizophrenia. General motivation was measured using the Behavioral inhibition/activation scale (BIS/BAS). Social motivation was measured by Passive social withdrawal and Active social avoidance items from PANSS. Interpersonal functioning was evaluated with Birchwoods Social Functioning Scale (SFS). We used Exploratory Graph Analysis for network estimation and community detection. Active social avoidance, passive social withdrawal, and social withdrawal/engagement (from SFS) were the most important nodes. In addition, three distinct communities were identified: Social cognition, Social motivation, and Interpersonal functioning. Notably, the BIS and BAS measures of general motivation were not part of any community. BAS showed stronger links to functioning than BIS. Passive social withdrawal was more strongly linked to interpersonal functioning than social cognitive abilities. Results suggest that social motivation, especially social approach, is more closely related to interpersonal functioning in schizophrenia than general motivation. In contrast, we found that general motivation was largely unrelated to social motivation. This pattern highlights the importance of type of motivation for understanding variability in interpersonal difficulties in schizophrenia.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Nucleocapsid antibody assays can be used to estimate SARS-CoV-2 infection prevalence in regions implementing spike-based COVID-19 vaccines. However, poor sensitivity of nucleocapsid antibody assays in detecting infection after vaccination has been reported. We derived a lower cutoff for identifying previous infections in a large blood donor cohort (N = 142,599) by using the Ortho VITROS Anti-SARS-CoV-2 Total-N Antibody assay, improving sensitivity while maintaining specificity >98%. We validated sensitivity in samples donated after self-reported swab-confirmed infections diagnoses. Sensitivity for first infections in unvaccinated donors was 98.1% (95% CI 98.0-98.2) and for infection after vaccination was 95.6% (95% CI 95.6-95.7) based on the standard cutoff. Regression analysis showed sensitivity was reduced in the Delta compared with Omicron period, in older donors, in asymptomatic infections,

Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal trajectory of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

People with schizophrenia (SCZ) and bipolar disorder (BD) have impairments in processing social information, including faces. The neural correlates of face processing are widely studied with the N170 ERP component. However, it is unclear whether N170 deficits reflect neural abnormalities associated with these clinical conditions or differences in social environments. The goal of this study was to determine whether N170 deficits would still be present in SCZ and BD when compared with socially isolated community members. Participants included 66 people with SCZ, 37 with BD, and 125 community members (76 Community-Isolated; 49 Community-Connected). Electroencephalography was recorded during a face processing task in which participants identified the gender of a face, the emotion of a face (angry, happy, neutral), or the number of stories in a building. We examined group differences in the N170 face effect (greater amplitudes for faces vs buildings) and the N170 emotion effect (greater amplitudes for emotional vs neutral expressions). Groups significantly differed in levels of social isolation (Community-Isolated > SCZ > BD = Community-Connected). SCZ participants had significantly reduced N170 amplitudes to faces compared with both community groups, which did not differ from each other. The BD group was intermediate and did not differ from any group. There were no significant group differences in the processing of specific emotional facial expressions. The N170 is abnormal in SCZ even when compared to socially isolated community members. Hence, the N170 seems to reflect a social processing impairment in SCZ that is separate from level of social isolation.

BACKGROUND: Research using latent variable models demonstrates that pre-attentive measures of early auditory processing (EAP) and cognition may initiate a cascading effect on daily functioning in schizophrenia. However, such models fail to account for relationships among individual measures of cognition and EAP, thereby limiting their utility. Hence, EAP and cognition may function as complementary and interacting measures of brain function rather than independent stages of information processing. Here, we apply a data-driven approach to identifying directional relationships among neurophysiologic and cognitive variables. METHODS: Using data from the Consortium on the Genetics of Schizophrenia 2, we estimated Gaussian Graphical Models and Bayesian networks to examine undirected and directed connections between measures of EAP, including mismatch negativity and P3a, and cognition in 663 outpatients with schizophrenia and 630 control participants. RESULTS: Chain structures emerged among EAP and attention/vigilance measures in schizophrenia and control groups. Concerning differences between the groups, object memory was an influential variable in schizophrenia upon which other cognitive domains depended, and working memory was an influential variable in controls. CONCLUSIONS: Measures of EAP and attention/vigilance are conditionally independent of other cognitive domains that were used in this study. Findings also revealed additional causal assumptions among measures of cognition that could help guide statistical control and ultimately help identify early-stage targets or surrogate endpoints in schizophrenia.

BACKGROUND: People with schizophrenia on average are more socially isolated, lonelier, have more social cognitive impairment, and are less socially motivated than healthy individuals. People with bipolar disorder also have social isolation, though typically less than that seen in schizophrenia. We aimed to disentangle whether the social cognitive and social motivation impairments observed in schizophrenia are a specific feature of the clinical condition v. social isolation generally. METHODS: We compared four groups (clinically stable patients with schizophrenia or bipolar disorder, individuals drawn from the community with self-described social isolation, and a socially connected community control group) on loneliness, social cognition, and approach and avoidance social motivation. RESULTS: Individuals with schizophrenia (n = 72) showed intermediate levels of social isolation, loneliness, and social approach motivation between the isolated (n = 96) and connected control (n = 55) groups. However, they showed significant deficits in social cognition compared to both community groups. Individuals with bipolar disorder (n = 48) were intermediate between isolated and control groups for loneliness and social approach. They did not show deficits on social cognition tasks. Both clinical groups had higher social avoidance than both community groups. CONCLUSIONS: The results suggest that social cognitive deficits in schizophrenia, and high social avoidance motivation in both schizophrenia and bipolar disorder, are distinct features of the clinical conditions and not byproducts of social isolation. In contrast, differences between clinical and control groups on levels of loneliness and social approach motivation were congruent with the groups degree of social isolation.

IntroductionEmerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome.MethodsWe used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAβ-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD).ResultsEighteen-month female (but not male) hAβ-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAβ-KI mice microbiomes were distinguishable from 3xTg-AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups.DiscussionThese findings highlight a sex-dependent variation in the microbiomes of hAβ-KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD.HighlightsMicrobial diversity and the abundance of several species differed in human amyloid beta knock-in (hAβ-KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAβ-KI mice were distinct from 3xTg-AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenias alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

The African claw-toed frog, Xenopus laevis, is a well-established laboratory model for the biology of vertebrate oogenesis, fertilisation, and development at embryonic, larval, and metamorphic stages. For ovulation, X. laevis females are usually injected with chorionic gonadotropin, whereupon they lay typically hundreds to thousands of eggs in a day. After being rested for a minimum of three months, animals are re-used. The literature suggests that adult females can lay much larger numbers of eggs in a short period. Here, we compared the standard single ovulation protocol with a double ovulation protocol, in which females were ovulated, then re-ovulated after seven days and then rested for three months before re-use. We quantified egg number, fertilisation rate (development to cleavage stage), and corticosterone secretion rate as a measure of stress response for the two protocol groups over seven 3-month cycles. We found no differences in egg number-per-ovulation or egg quality between the groups and no long-term changes in any measures over the 21-month trial period. Corticosterone secretion was elevated by ovulation, similarly for the single ovulation as for the first ovulation in the double-ovulation protocol, but more highly for the second ovulation (to a level comparable to that seen following shipment) in the latter. However, both groups exhibited the same baseline secretion rates by the time of the subsequent cycle. Double ovulation is thus transiently more stressful/demanding than single ovulation but within the levels routinely experienced by laboratory X. laevis. Noting that stress hormone corticosterone/cortisol secretion is linked to physiological processes, such as ovulation, that are not necessarily harmful to the individual, we suggest that the benefits of a doubling in egg yield-per-cycle per animal without loss of egg quality or signs of acute or long-term harm may outweigh the relatively modest and transient corticosterone elevation we observed. The double ovulation protocol therefore represents a potential new standard practice for promoting the 3Rs (animal use reduction, refinement and replacement) mission for Xenopus research.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Converging evidence implicates disrupted brain connectivity in autism spectrum disorder (ASD); however, the mechanisms linking altered connectivity early in development to the emergence of ASD symptomatology remain poorly understood. Here we examined whether atypicalities in the Salience Network - an early-emerging neural network involved in orienting attention to the most salient aspects of ones internal and external environment - may predict the development of ASD symptoms such as reduced social attention and atypical sensory processing. Six-week-old infants at high likelihood of developing ASD based on family history exhibited stronger Salience Network connectivity with sensorimotor regions; infants at typical likelihood of developing ASD demonstrated stronger Salience Network connectivity with prefrontal regions involved in social attention. Infants with higher connectivity with sensorimotor regions had lower connectivity with prefrontal regions, suggesting a direct tradeoff between attention to basic sensory versus socially-relevant information. Early alterations in Salience Network connectivity predicted subsequent ASD symptomatology, providing a plausible mechanistic account for the unfolding of atypical developmental trajectories associated with vulnerability to ASD.

Localized sources of morphogens, called signalling centres, play a fundamental role in coordinating tissue growth and cell fate specification during organogenesis. However, how these signalling centres are established in tissues during embryonic development is still unclear. Here we show that the main signalling centre orchestrating development of rodent incisors, the enamel knot (EK), is specified by a cell proliferation-driven buildup in compressive stresses (mechanical pressure) in the tissue. Direct mechanical measurements indicate that the stresses generated by cell proliferation are resisted by the surrounding tissue, creating a circular pattern of mechanical anisotropy with a region of high compressive stress at its centre that becomes the EK. Pharmacological inhibition of proliferation reduces stresses and suppresses EK formation, and application of external pressure in proliferation-inhibited conditions rescues the formation of the EK. Mechanical information is relayed intracellularly through YAP protein localization, which is cytoplasmic in the region of compressive stress that establishes the EK and nuclear in the stretched anisotropic cells that resist the pressure buildup around the EK. Together, our data identify a new role for proliferation-driven mechanical compression in the specification of a model signalling centre during mammalian organ development.

IntroductionAlzheimer's disease (AD) is a neurodegenerative disorder with multifactorial etiology, including genetic factors that play a significant role in disease risk and resilience. However, the role of genetic diversity in preclinical AD studies has received limited attention.MethodsWe crossed five Collaborative Cross strains with 5xFAD C57BL/6J female mice to generate F1 mice with and without the 5xFAD transgene. Amyloid plaque pathology, microglial and astrocytic responses, neurofilament light chain levels, and gene expression were assessed at various ages.ResultsGenetic diversity significantly impacts AD-related pathology. Hybrid strains showed resistance to amyloid plaque formation and neuronal damage. Transcriptome diversity was maintained across ages and sexes, with observable strain-specific variations in AD-related phenotypes. Comparative gene expression analysis indicated correlations between mouse strains and human AD.DiscussionIncreasing genetic diversity promotes resilience to AD-related pathogenesis, relative to an inbred C57BL/6J background, reinforcing the importance of genetic diversity in uncovering resilience in the development of AD.HighlightsGenetic diversity's impact on AD in mice was explored. Diverse F1 mouse strains were used for AD study, via the Collaborative Cross. Strain-specific variations in AD pathology, glia, and transcription were found. Strains resilient to plaque formation and plasma neurofilament light chain (NfL) increases were identified. Correlations with human AD transcriptomics were observed.

BACKGROUND: DATATOP was a study of early Parkinsons disease (PD) conducted in the 1980 s, before mandatory folic acid fortification in the United States. Our analysis of its baseline serum samples revealed a geometric mean vitamin B12 of 369 pg/mL and homocysteine (tHcy) of 9.5μmol/l. We also found that low B12 predicted greater worsening of ambulatory capacity (AC) and elevated tHcy (>15μmol/L) predicted greater declines in cognitive function. OBJECTIVE: We sought to measure B12 and tHcy in contemporary trial participants with early PD who had not started dopaminergic treatment and to determine whether these analytes were associated with clinical progression. METHODS: We measured B12 and tHcy from baseline and end-of-study blood samples from three recent clinical trials. RESULTS: Baseline geometric mean B12 levels for these studies ranged from 484- 618 pg/ml and for tHcy ranged from 7.4- 10μmol/L. Use of B12-containing supplements ranged from 41- 61%, and those taking supplements had higher B12 and lower tHcy. Those who began levodopa, but were not taking B12-supplements, had greater end-of-study tHcy. There was no association of baseline tHcy > 15μmol/L with annualized change in Montreal Cognitive Assessment and no association of baseline B12 tertiles with change in AC. CONCLUSIONS: In these longitudinal trials, B12 levels were higher than for DATATOP, due in large part to increased B12-supplement intake, while tHcy levels were similar. Initiation of levodopa was associated with increases of tHcy in those not taking a B12-containing supplement. These smaller studies did not replicate prior findings of low B12 and elevated tHcy with features of progression, possibly due to higher baseline B12.

Few evidence-based interventions exist to improve person-centred maternity care in low-resource settings. This study aimed to understand whether a quality improvement (QI) intervention could improve person-centred maternity care (PCMC) experiences for women delivering in public health facilities in Kenya. A pre-post design was used to examine changes in PCMC scores across three intervention and matched control facilities at baseline (n = 491) and endline (n = 677). A QI intervention, using the Model for Improvement, was implemented in three public health facilities in Nairobi and Kiambu Counties in Kenya. Difference-in-difference analyses using models that included main effects of both treatment group and survey round was conducted to understand the impact of the intervention on PCMC scores. Findings suggest that intervention facilities' average total PCMC score decreased by 5.3 points post-intervention compared to baseline (95% CI: -8.8, -1.9) and relative to control facilities, holding socio-demographic and facility variables constant. Additionally, the intervention was significantly associated with a 1.8-point decrease in clinical quality index pre-post-intervention (95% CI: -2.9, -0.7), decreased odds of provider visits, and less likelihood to plan to use postpartum family planning. While improving the quality of women's experiences during childbirth is a critical component to ensure comprehensive, high-quality maternity care experiences and outcomes, further research is required to understand which intervention methods may be most appropriate to improve PCMC in resource-constrained settings.

INTRODUCTION: Screening for opioid misuse and treatment for opioid use disorder are critical for reducing morbidity and mortality. We sought to understand the extent of self-reported past 30-day buprenorphine use in various settings among women of reproductive age with self-reported nonmedical prescription opioid use being assessed for substance use problems. METHODS: The study collected data from individuals being assessed for substance use problems using the Addiction Severity Index-Multimedia Version in 2018-2020. We stratified the sample of 10,196 women ages 12-55 self-reporting past 30-day nonmedical prescription opioid use by buprenorphine use and setting type. We categorized setting types as: buprenorphine in specialty addiction treatment, buprenorphine in office-based opioid treatment, and diverted buprenorphine. We included each womans first intake assessment during the study period. The study assessed number of buprenorphine products, reasons for using buprenorphine, and sources of buprenorphine procurement. The study calculated frequency of reasons for using buprenorphine to treat opioid use disorder outside of a doctor-managed treatment, overall and by race/ethnicity. RESULTS: Overall, 25.5 % of the sample used buprenorphine in specialty addiction treatment, 6.1 % used buprenorphine prescribed in office-based treatment, 21.7 % used diverted buprenorphine, and 46.7 % reported no buprenorphine use during the past 30 days. Among women who reported using buprenorphine to treat opioid use disorder, but not as part of a doctor-managed treatment, 72.3 % could not find a provider or get into a treatment program, 21.8 % did not want to be part of a program or see a provider, and 6.0 % reported both; a higher proportion of American Indian/Alaska Native women (92.1 %) reported that they could not find a provider or get into a treatment program versus non-Hispanic White (78.0 %), non-Hispanic Black (76.0 %), and Hispanic (75.0 %) women. CONCLUSIONS: Appropriate screening for nonmedical prescription opioid use to assess need for treatment with medication for opioid use disorder is important for all women of reproductive age. Our data highlight opportunities to improve treatment program accessibility and availability and support the need to increase equitable access for all women.

Breast cancer brain metastasis (BCBM) is a lethal disease with no effective treatments. Prior work has shown that brain cancers and metastases are densely infiltrated with anti-inflammatory, protumourigenic tumour-associated macrophages, but the role of brain-resident microglia remains controversial because they are challenging to discriminate from other tumour-associated macrophages. Using single-cell RNA sequencing, genetic and humanized mouse models, we specifically identify microglia and find that they play a distinct pro-inflammatory and tumour-suppressive role in BCBM. Animals lacking microglia show increased metastasis, decreased survival and reduced natural killer and T cell responses, showing that microglia are critical to promote anti-tumour immunity to suppress BCBM. We find that the pro-inflammatory response is conserved in human microglia, and markers of their response are associated with better prognosis in patients with BCBM. These findings establish an important role for microglia in anti-tumour immunity and highlight them as a potential immunotherapy target for brain metastasis.

Anemia is a multifactorial condition; approaches to address it must recognize that the causal factors represent an ecology consisting of internal (biology, genetics, and health) and external (social/behavioral/demographic and physical) environments. In this paper, we present an approach for selecting interventions, followed by a description of key issues related to the multiple available interventions for prevention and reduction of anemia. We address interventions for anemia using the following 2 main categories: 1) those that address nutrients alone, and, 2) those that address nonnutritional causes of anemia. The emphasis will be on interventions of public health relevance, but we also consider the clinical context. We also focus on interventions at different stages of the life course, with a particular focus on women of reproductive age and preschool-age children, and present evidence on various factors to consider when selecting an intervention-inflammation, genetic mutations, nutrient delivery, bioavailability, and safety. Each section on an intervention domain concludes with a brief discussion of key research areas.

Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention.

OBJECTIVE: To phenotype SLE based on symptom burden (disease damage, system involvement and patient reported outcomes), with a specific focus on objective and subjective cognitive function. METHODS: SLE patients ages 18-65 years underwent objective cognitive assessment using the ACR Neuropsychological Battery (ACR-NB) and data were collected on demographic and clinical variables, disease burden/activity, health-related quality of life (HRQoL), depression, anxiety, fatigue and perceived cognitive deficits. Similarity network fusion (SNF) was used to identify patient subtypes. Differences between the subtypes were evaluated using Kruskal-Wallis and χ2 tests. RESULTS: Of the 238 patients, 90% were female, with a mean age of 41 years (s.d. 12) and a disease duration of 14 years (s.d. 10) at the study visit. The SNF analysis defined two subtypes (A and B) with distinct patterns in objective and subjective cognitive function, disease burden/damage, HRQoL, anxiety and depression. Subtype A performed worst on all significantly different tests of objective cognitive function (P

BACKGROUND: Studies that examined sex differences in first-episode patients consistently show that males compared to females have poor premorbid adjustment, earlier age of onset, worse clinical characteristics, and poorer outcomes. However, little is known about potential mediators that could explain these sex differences. METHODS: Our sample consisted of 137 individuals with first episode schizophrenia (males, n = 105; 77%) with a mean age of 22.1(s.d. = 4.1) years and mean education of 12.5(s.d. = 1.7) years. At entry, patients were within 2 years of their first psychotic episode onset. Baseline assessments were conducted for premorbid adjustment, symptoms, cognitive functioning, insight, and at 6-months for role and social functioning. RESULTS: Males as compared to females had poorer premorbid adjustment across several key developmental periods (p < 0.01), an earlier age of onset [M = 20.3(3.3) v. 22.8(5.6), p = 0.002], more negative symptoms (p = 0.044), poorer insight (p = 0.031), and poorer baseline and 6-month role (p = 0.002) and social functioning (p = 0.034). Several of these variables in which males showed impairment were significant predictors of 6-month role and social functioning. Premorbid adjustment and insight mediated the relationship between sex and role and social functioning at 6-months, but not negative symptoms. DISCUSSION: Males compared to females were at lower levels across several key premorbid and clinical domains which are strongly associated with functional outcome supporting the hypothesis that males might have a more disabling form of schizophrenia. The relationship between sex with role and social functioning was mediated through premorbid adjustment and insight suggesting pathways for understanding why females might have a less disabling form of schizophrenia.

Pityrosporum folliculitis (PF) is a fungal acneiform disease of the hair follicles that often presents with pruritic papules and pustules on the upper body and face. This condition is commonly mistaken for acne vulgaris and can be distinguished from bacterial acne by the presence of fungal spores in the follicular lumen. Although studies have been performed to describe PF in cohorts, little work has been done to aggregate these data. Thus, the goal of this review is to describe the clinical characteristics and treatment outcomes of PF in immunocompetent patients. PubMed, Web of Science, and Embase were searched using the terms "Pityrosporum folliculitis" or "Malassezia folliculitis." All cohorts reporting PF characteristics in patients classified as immunocompetent were reviewed. A total of 15 studies were included. Majority of patients were male (64%) with the average age of presentation of 24.26 years. The most common locations of lesions were the chest (70%) and back/shoulders (69.2%). Pruritus was reported by the majority of patients (71.7%). Additionally, 40.5% of patients reported a history of unsuccessful treatment regimens. Treatment was most successful with an oral antifungal (92%), followed by a topical antifungal (81.6%). In conclusion, majority of patients with PF were younger males. Many patients were primarily treated incorrectly, suggesting the importance of proper diagnosis. PF may be distinguishable from acne vulgaris by the presence of pruritus or suggested when a new acneiform eruption develops following antibiotic therapy or immunosuppression. When properly diagnosed, majority of cases of PF achieve complete response with oral or topical antifungals.

OBJECTIVES: Social and nonsocial cognition are defined as distinct yet related constructs. However, the relative independence of individual variables-and whether specific tasks directly depend on performance in other tasks-is still unclear. The current study aimed to answer this question by using a Bayesian network approach to explore directional dependencies among social and nonsocial cognitive domains. STUDY DESIGN: The study sample comprised 173 participants with schizophrenia (71.7% male; 28.3% female). Participants completed 5 social cognitive tasks and the MATRICS Consensus Cognitive Battery. We estimated Bayesian networks using directed acyclic graph structures to examine directional dependencies among the variables. STUDY RESULTS: After accounting for negative symptoms and demographic variables, including age and sex, all nonsocial cognitive variables depended on processing speed. More specifically, attention, verbal memory, and reasoning and problem solving solely depended on processing speed, while a causal chain emerged between processing speed and visual memory (processing speed → attention → working memory → visual memory). Social processing variables within social cognition, including emotion in biological motion and empathic accuracy, depended on facial affect identification. CONCLUSIONS: These results suggest that processing speed and facial affect identification are fundamental domains of nonsocial and social cognition, respectively. We outline how these findings could potentially help guide specific interventions that aim to improve social and nonsocial cognition in people with schizophrenia.

Lesbian, gay, bisexual, transgender, and queer (LGBTQ) youth of color experience high rates of mental health disorders, yet they experience challenges to accessing mental health services. Community health worker (CHW) models of care have potential to promote equitable mental health services among LGBTQ youth. Our aim was to understand how CHW models could be adapted to better support LGBTQ youth of color in accessing mental health services. Semi-structured qualitative interviews were conducted with LGBTQ youth of color (n = 16), caregivers of LGBTQ youth (n = 11), and CHWs (n = 15) in Massachusetts and California. Interviews were coded by 8 members of the research team. A Rapid Qualitative Analysis was conducted to identify themes. Caregivers, youth, and CHWs all endorsed the value of CHW models for this population. They also almost universally suggested multiple adaptations are needed for the model to be effective. Four main categories of themes emerged related to intervention adaptations: (1) Why adaptations are needed for LGBTQ youth, (2) Who should serve as CHWs providing care, (3) How CHWs should be trained, and (4) What content needs to be included in the intervention. Broadly, findings suggest the relevance of having CHW models for LGBTQ youth of color to address stigma and discrimination experienced, access to culturally and linguistically relevant services, and the need for caregiver support of LGBTQ youth. CHWs need increased training in these areas.

Background and aimsTo investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19).MethodsWe conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd 2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU) admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL.ResultsWe identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0 years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with a higher likelihood of ICU admission, need of MV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need of MV and ICU admission, respectively.ConclusionsBlood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

ObjectiveIn gout, hyperuricemia promotes urate crystal deposition, which stimulates the NLRP3 inflammasome and interleukin-1β (IL-1β)-mediated arthritis. Incident gout without background hyperuricemia is rarely reported. To identify hyperuricemia-independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis in a young female patient with normouricemia diagnosed as having sufficient and weighted classification criteria for gout according to the American College of Rheumatology (ACR)/EULAR gout classification criteria (the proband).MethodsWe conducted whole-genome sequencing, quantitative proteomics, whole-blood RNA-sequencing analysis using serum samples from the proband. We used a mouse model of IL-1β-induced knee synovitis to characterize proband candidate genes, biomarkers, and pathogenic mechanisms of gout.ResultsLubricin level was attenuated in human proband serum and associated with elevated acute-phase reactants and inflammatory whole-blood transcripts and transcriptional pathways. The proband had predicted damaging gene variants of NLRP3 and of inter-α trypsin inhibitor heavy chain 3, an inhibitor of lubricin-degrading cathepsin G. Changes in the proband's serum protein interactome network supported enhanced lubricin degradation, with cathepsin G activity increased relative to its inhibitors, SERPINB6 and thrombospondin 1. Activation of Toll-like receptor 2 (TLR-2) suppressed levels of lubricin mRNA and lubricin release in cultured human synovial fibroblasts (P

Background and objectivesWith the increasing use of visually evoked potentials (VEPs) as quantitative outcome parameters for myelin in clinical trials, an in-depth understanding of longitudinal VEP latency changes and their prognostic potential for subsequent neuronal loss will be required. In this longitudinal multicenter study, we evaluated the association and prognostic potential of VEP latency for retinal neurodegeneration, measured by optical coherence tomography (OCT), in relapsing-remitting MS (RRMS).MethodsWe included 293 eyes of 147 patients with RRMS (age [years, median ± SD] 36 ± 10, male sex 35%, F/U [years, median {IQR} 2.1 {1.5-3.9}]): 41 eyes had a history of optic neuritis (ON) ≥6 months before baseline (CHRONIC-ON), and 252 eyes had no history of ON (CHRONIC-NON). P100 latency (VEP), macular combined ganglion cell and inner plexiform layer volume (GCIPL), and peripapillary retinal nerve fiber layer thickness (pRNFL) (OCT) were quantified.ResultsP100 latency change over the first year predicted subsequent GCIPL loss (36 months) across the entire chronic cohort (p = 0.001) and in (and driven by) the CHRONIC-NON subset (p = 0.019) but not in the CHRONIC-ON subset (p = 0.680). P100 latency and pRNFL were correlated at baseline (CHRONIC-NON p = 0.004, CHRONIC-ON p < 0.001), but change in P100 latency and pRNFL were not correlated. P100 latency did not differ longitudinally between protocols or centers.DiscussionVEP in non-ON eyes seems to be a promising marker of demyelination in RRMS and of potential prognostic value for subsequent retinal ganglion cell loss. This study also provides evidence that VEP may be a useful and reliable biomarker for multicenter studies.

Vitamin B12 is an essential nutrient that is not made by plants; consequently, unfortified plant-based foods are not a reliable supply. Recent estimates suggest high rates of vitamin B12 deficiency among the vegetarian and vegan populations, particularly in pregnant women or women of child-bearing age who, for ethical and health reasons, are shifting towards higher consumption of plant-based foods in ever-increasing numbers. Vitamin B12 plays crucial metabolic roles across the life-course and in particular during pregnancy and in early development (first 1000 days of life). Evidence now implicates vitamin B12 deficiency with increased risk to a range of neuro, vascular, immune, and inflammatory disorders. However, the current UK recommended nutrient intake for vitamin B12 does not adequately consider the vitamin B12 deficit for those choosing a plant-based diet, including vegetarianism and in particular veganism, representing a hidden hunger. We provide a cautionary note on the importance of preventing vitamin B12 deficits for those individuals choosing a plant-based diet and the health professionals advising them.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membrane-permeant ligands, such as the anti-smoking drug varenicline (Chantix), distribute in brain. Ligands, like varenicline, with high pKa and high affinity for α4β2-type nicotinic receptors (α4β2Rs) are trapped in intracellular acidic vesicles containing α4β2Rs in vitro Nicotine, with lower pKa and α4β2R affinity, is not trapped. Here, we extend our results by imaging nicotinic PET ligands in vivo in male and female mouse brain and identifying the trapping brain organelle in vitro as Golgi satellites (GSats). Two PET 18F-labeled imaging ligands were chosen: [18F]2-FA85380 (2-FA) with varenicline-like pKa and affinity and [18F]Nifene with nicotine-like pKa and affinity. [18F]2-FA PET-imaging kinetics were very slow consistent with 2-FA trapping in α4β2R-containing GSats. In contrast, [18F]Nifene kinetics were rapid, consistent with its binding to α4β2Rs but no trapping. Specific [18F]2-FA and [18F]Nifene signals were eliminated in β2 subunit knock-out (KO) mice or by acute nicotine (AN) injections demonstrating binding to sites on β2-containing receptors. Chloroquine (CQ), which dissipates GSat pH gradients, reduced [18F]2-FA distributions while having little effect on [18F]Nifene distributions in vivo consistent with only [18F]2-FA trapping in GSats. These results are further supported by in vitro findings where dissipation of GSat pH gradients blocks 2-FA trapping in GSats without affecting Nifene. By combining in vitro and in vivo imaging, we mapped both the brain-wide and subcellular distributions of weak-base nicotinic receptor ligands. We conclude that ligands, such as varenicline, are trapped in neurons in α4β2R-containing GSats, which results in very slow release long after nicotine is gone after smoking.SIGNIFICANCE STATEMENT Mechanisms of nicotine addiction remain poorly understood. An earlier study using in vitro methods found that the anti-smoking nicotinic ligand, varenicline (Chantix) was trapped in α4β2R-containing acidic vesicles. Using a fluorescent-labeled high-affinity nicotinic ligand, this study provided evidence that these intracellular acidic vesicles were α4β2R-containing Golgi satellites (GSats). In vivo PET imaging with F-18-labeled nicotinic ligands provided additional evidence that differences in PET ligand trapping in acidic vesicles were the cause of differences in PET ligand kinetics and subcellular distributions. These findings combining in vitro and in vivo imaging revealed new mechanistic insights into the kinetics of weak base PET imaging ligands and the subcellular mechanisms underlying nicotine addiction.

Previous reports have provided evidence that insufficient or excessive maternal folic acid (FA) intake during pregnancy can alter neurodevelopment of the offspring by modulating prenatal neurogenesis. Furthermore, our earlier work in a mouse model confirmed long-term structural changes at the cellular level of either deficient or excessive FA supply by comparably reducing dendritic arborization of cortical projection neurons. Here, we report that excessive amounts of FA decrease arborization of deep layer projection neurons, but not upper layer neurons and that reduced complexity of deep layer neurons is not observed when folic acid is replaced by folinic acid, a stable reduced form of folate. In addition, deficiency of B12, a vitamin that critically regulates folate metabolism, causes even more marked decreases in neuronal arborization in both deep and upper layer neurons and particularly in combination with FA excess. Furthermore, both FA excess and B12 deficiency affect synaptic density and morphology. Our findings point to neurodevelopmental risks associated with insufficient amounts of prenatal B12, particularly in association with high levels of FA intake, suggesting that the neurodevelopmental program is sensitive to an imbalance in the status of these interacting micronutrients.

BackgroundWe report on community-based participatory research (CBPR) initiated by women firefighters in order to share successful elements that can be instructive for other community-engaged research. This CBPR initiative, known as the Women Worker Biomonitoring Collaborative (WWBC) is the first we are aware of to investigate links between occupational exposures and health outcomes, including breast cancer, for a cohort of exclusively women firefighters.MethodsIn order to be reflective of the experiences and knowledge of those most intimately involved, this article is co-authored by leaders of the research initiative. We collected leaders' input via recorded meeting sessions, emails, and a shared online document. We also conducted interviews (N = 10) with key research participants and community leaders to include additional perspectives.ResultsFactors contributing to the initiative's success in enacting broadscale social change and advancing scientific knowledge include (1) forming a diverse coalition of impacted community leaders, labor unions, scientists, and advocacy organizations, (2) focusing on impacts at multiple scales of action and nurturing different, yet mutually supportive, goals among partners, (3) adopting innovative communication strategies for study participants, research partners, and the broader community, (4) cultivating a prevention-based ethos in the scientific research, including taking early action to reduce community exposures based on existing evidence of harm, and (5) emphasizing co-learning through all the study stages. Furthermore, we discuss external factors that contribute to success, including funding programs that elevate scientist-community-advocacy partnerships and allow flexibility to respond to emerging science-policy opportunities, as well as institutional structures responsive to worker concerns.ConclusionsWhile WWBC shares characteristics with other successful CBPR partnerships, it also advances approaches that increase the ability for CBPR to translate into change at multiple levels. This includes incorporating partners with particular skills and resources beyond the traditional researcher-community partnerships that are the focus of much CBPR practice and scholarly attention, and designing studies so they support community action in the initial stages of research. Moreover, we emphasize external structural factors that can be critical for CBPR success. This demonstrates the importance of critically examining and advocating for institutional factors that better support this research.

BackgroundDuring adolescence, microglia are actively involved in neocortical maturation while concomitantly undergoing profound phenotypic changes. Because the teenage years are also a time of experimentation with cannabis, we evaluated whether adolescent exposure to the drug's psychotropic constituent, Δ9-tetrahydrocannabinol (THC), might persistently alter microglia function.MethodsWe administered THC (5 mg/kg, intraperitoneal) once daily to male and female mice from postnatal day (PND) 30 to PND44 and examined the transcriptome of purified microglia in adult animals (PND70 and PND120) under baseline conditions or following either of two interventions known to recruit microglia: lipopolysaccharide injection and repeated social defeat. We used high-dimensional mass cytometry by time-of-flight to map brain immune cell populations after lipopolysaccharide challenge.ResultsAdolescent THC exposure produced in mice of both sexes a state of microglial dyshomeostasis that persisted until young adulthood (PND70) but receded with further aging (PND120). Key features of this state included broad alterations in genes involved in microglia homeostasis and innate immunity along with marked impairments in the responses to lipopolysaccharide- and repeated social defeat-induced psychosocial stress. The endocannabinoid system was also dysfunctional. The effects of THC were prevented by coadministration of either a global CB1 receptor inverse agonist or a peripheral CB1 neutral antagonist and were not replicated when THC was administered in young adulthood (PND70-84).ConclusionsDaily low-intensity CB1 receptor activation by THC during adolescence may disable critical functions served by microglia until young adulthood with potentially wide-ranging consequences for brain and mental health.

High maternal weight is associated with detrimental outcomes in offspring, including increased susceptibility to neurological disorders such as anxiety, depression and communicative disorders. Despite widespread acknowledgement of sex biases in the development of these disorders, few studies have investigated potential sex-biased mechanisms underlying disorder susceptibility. Here, we show that a maternal high-fat diet causes endotoxin accumulation in fetal tissue, and subsequent perinatal inflammation contributes to sex-specific behavioural outcomes in offspring. In male offspring exposed to a maternal high-fat diet, increased macrophage Toll-like receptor 4 signalling results in excess microglial phagocytosis of serotonin (5-HT) neurons in the developing dorsal raphe nucleus, decreasing 5-HT bioavailability in the fetal and adult brains. Bulk sequencing from a large cohort of matched first-trimester human samples reveals sex-specific transcriptome-wide changes in placental and brain tissue in response to maternal triglyceride accumulation (a proxy for dietary fat content). Further, fetal brain 5-HT levels decrease as placental triglycerides increase in male mice and male human samples. These findings uncover a microglia-dependent mechanism through which maternal diet can impact offspring susceptibility for neuropsychiatric disorder development in a sex-specific manner.

Growth in early infancy is hypothesized to affect chronic disease risk factors later in life. To date, most reports draw on European-ancestry cohorts with few repeated observations in early infancy. We investigated the association between infant growth before 6 months and lipid levels in adolescents in a Hispanic/Latino cohort. We characterized infant growth from birth to 5 months in male (n = 311) and female (n = 285) infants from the Santiago Longitudinal Study (1991-1996) using 3 metrics: weight (kg), length (cm), and weight-for-length (g/cm). Superimposition by translation and rotation (SITAR) and latent growth mixture models (LGMMs) were used to estimate the association between infant growth characteristics and lipid levels at age 17 years. We found a positive relationship between the SITAR length velocity parameter before 6 months of age and high-density lipoprotein cholesterol levels in adolescence (11.5, 95% confidence interval; 3.4, 19.5), indicating higher high-density lipoprotein cholesterol levels occurring with faster length growth. The strongest associations from the LGMMs were between higher low-density lipoprotein cholesterol and slower weight-for-length growth, following a pattern of associations between slower growth and adverse lipid profiles. Further research in this window of time can confirm the association between early infant growth as an exposure and adolescent cardiovascular disease risk factors.

There is a growing body of research focused on developing and evaluating behavioral training paradigms meant to induce enhancements in cognitive function. It has recently been proposed that one mechanism through which such performance gains could be induced involves participants expectations of improvement. However, no work to date has evaluated whether it is possible to cause changes in cognitive function in a long-term behavioral training study by manipulating expectations. In this study, positive or negative expectations about cognitive training were both explicitly and associatively induced before either a working memory training intervention or a control intervention. Consistent with previous work, a main effect of the training condition was found, with individuals trained on the working memory task showing larger gains in cognitive function than those trained on the control task. Interestingly, a main effect of expectation was also found, with individuals given positive expectations showing larger cognitive gains than those who were given negative expectations (regardless of training condition). No interaction effect between training and expectations was found. Exploratory analyses suggest that certain individual characteristics (e.g., personality, motivation) moderate the size of the expectation effect. These results highlight aspects of methodology that can inform future behavioral interventions and suggest that participant expectations could be capitalized on to maximize training outcomes.

High-molecular-weight hyaluronan (HMWH) is an agonist at cluster of differentiation (CD)44, the cognate hyaluronan receptor, on nociceptors, where it acts to induce antihyperalgesia in preclinical models of inflammatory and neuropathic pain. In the present experiments, we studied the CD44 second messengers that mediate HMWH-induced attenuation of pain associated with oxaliplatin and paclitaxel chemotherapy-induced peripheral neuropathy (CIPN). While HMWH attenuated CIPN only in male rats, after ovariectomy or intrathecal administration of an oligodeoxynucleotide (ODN) antisense to G protein-coupled estrogen receptor (GPR30) mRNA, female rats were also sensitive to HMWH. Intrathecal administration of an ODN antisense to CD44 mRNA markedly attenuated HMWH-induced antihyperalgesia in male rats with CIPN induced by oxaliplatin or paclitaxel. Intradermal administration of inhibitors of CD44 second messengers, RhoA (member of the Rho family of GTPases), phospholipase C, and phosphatidylinositol (PI) 3-kinase gamma (PI3Kγ), attenuated HMWH-induced antihyperalgesia as does intrathecal administration of an ODN antisense to PI3Kγ. Our results demonstrated that HMWH induced antihyperalgesia in CIPN, mediated by its action at CD44 and downstream signaling by RhoA, phospholipase C, and PI3Kγ.