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Objectives To determine the frequency, accrual, attribution and outcome of neuropsychiatric (NP) events and impact on quality of life over 3 years in a large inception cohort of patients with systemic lupus erythematosus (SLE). Methods The study was conducted by the Systemic Lupus International Collaborating Clinics. Patients were enrolled within 15 months of SLE diagnosis. NP events were identified using the American College of Rheumatology case definitions, and decision rules were derived to determine the proportion of NP disease attributable to SLE. The outcome of NP events was recorded and patient-perceived impact determined by the SF-36. Results 1206 patients (89.6% female) with a mean (±SD) age of 34.5±13.2 years were included in the study. The mean disease duration at enrolment was 5.4±4.2 months. Over a mean follow-up of 1.9±1.2 years, 486/1206 (40.3%) patients had ≥1 NP events, which were attributed to SLE in 13.0–23.6% of patients using two a priori decision rules. The frequency of individual NP events varied from 47.1% (headache) to 0% (myasthenia gravis). The outcome was significantly better for those NP events attributed to SLE, especially if they occurred within 1.5 years of the diagnosis of SLE. Patients with NP events, regardless of attribution, had significantly lower summary scores for both mental and physical health over the study. Conclusions NP events in patients with SLE are of variable frequency, most commonly present early in the disease course and adversely impact patients' quality of life over time. Events attributed to non-SLE causes are more common than those due to SLE, although the latter have a more favourable outcome. [ABSTRACT FROM PUBLISHER]

Background: Increasing evidence for cardiovascular mortality among patients with psoriasis and psoriatic arthritis (PsA) has accumulated, together with evidence for increased prevalence of risk factors for cardiovascular disease (CVD). Objectives: To describe cardiovascular morbidity in PsA, determine its prevalence and identify risk factors for its development. Methods: At the University of Toronto, patients were followed up prospectively according to a standard protocol, including disease-related features and comorbidities. Patients with CVD, including myocardial infarction (MI), angina, hypertension and cerebrovascular accident (CVA), were identified. The prevalence of CVD morbidities in these patients was compared with data from the Canadian Community Health Survey through standardised prevalence ratios (SPRs). Cox relative risk regression analysis was used to analyse risk factors. Results: At the time of analysis, 648 patients were registered in the database. After clinic entry, 122 developed hypertension, 38 had an MI and 5, 21 and 11 had CVA, angina and congestive heart failure (CHF), respectively. 155 patients had at least one of these conditions. The SPRs for MI (2.57; 95% CI 1.73 to 3.80), angina (1.97; 95% CI 1.24 to 3.12) and hypertension (1.90; 95% CI 1.59 to 2.27) were statistically significant, whereas the SPRs for CHF (1.19; 95% CI 0.50 to 2.86) and CVA (0.91; 95% CI 0.34 to 2.43) were not. Factors associated with CVD included diabetes, hyperlipidaemia and high Psoriasis Area and Severity Index scores. Conclusion: Patients with PsA are at increased risk of cardiovascular morbidities compared with the general population. In addition to known risk factors for CVD, severe psoriasis is an important predictor in patients with PsA. [ABSTRACT FROM PUBLISHER]

Background: Endothelial injury is an important prognostic factor in acute respiratory distress syndrome (ARDS). Vascular endothelial growth factor (VEGF) plays a critical role in endothelial destruction and angiogenesis. Genetic variations of the VEGF gene have been associated with VEGF production. A study was undertaken to investigate the impact of VEGF gene polymorphisms on the clinical outcomes of ARDS.Methods: Three VEGF polymorphisms (-460C/T, +405C/G and +936C/T) were determined in 1253 patients in an intensive care unit with risk factors for ARDS, 394 of whom developed ARDS. Patients were followed for assessment of 60 day survival. Plasma VEGF levels were measured in 71 patients with ARDS.Results: The +936TT (OR 4.29, 95% CI 1.12 to 16.40, p = 0.03) and +936CT+TT (OR 1.98, 95% CI 1.14 to 3.42, p = 0.01) genotypes were significantly associated with increased mortality from ARDS. Plasma VEGF levels in patients with ARDS with the +936CT+TT genotype were significantly lower than in subjects with the +936CC genotype (median 49 (IQR 16-98) pg/ml vs 112 (IQR 47-162) pg/ml, p = 0.02). At the haplotype level, haplotype TCT (-460T+405C+936T) was significantly associated with a higher rate of mortality (OR 2.89, 95% CI 1.30 to 6.43, p = 0.009) and haplotype CGT (-460C+405G+936T) was associated less strongly with increased mortality (OR 1.90, 95% CI 0.94 to 3.83, p = 0.07) in patients with ARDS. Lower plasma VEGF levels were correlated with the probability of haplotype CGT (coefficient = -0.26, p<0.05), but the same trend of correlation was not significant to haplotype TCT.Conclusions: VEGF polymorphisms may contribute to the prognosis and inter-individual variations in circulating VEGF levels in patients with ARDS. [ABSTRACT FROM AUTHOR]

Objectives: Endotoxin exposure induces airway inflammation, hyper-responsiveness and higher expression of tumour necrosis factor (TNF). This study was conducted to investigate whether TNF polymorphisms modify the effect of endotoxin exposure on chronic declines in lung function.Methods: Associations between TNF and LTA polymorphisms, endotoxin exposure and lung function were analysed in 263 cotton workers and 230 silk workers as a reference group, who were prospectively followed for 20 years. Multiple linear regression models were used to assess the association, with adjustment for smoking and other covariates.Results: Endotoxin exposure was associated with faster lung function decline among genotypes associated with higher TNF expression levels, with estimates of annual FEV1 change in relation to endotoxin exposure of -2.9 ml and -6.8 ml in the G/G and G/A+AA genotypes, respectively, for the TNF polymorphism; and -2.0 ml, -4.0 ml and -3.6 ml in A/A, A/G and G/G genotypes, respectively, for the LTA polymorphism. When joint effects of endotoxin exposure and smoking were considered, the effect modification of TNF and LTA polymorphisms was prominent in never smokers.Conclusions: TNF and LTA polymorphisms may modify the association between occupational endotoxin exposure and longitudinal lung function decline, which was more clearly observed in never smokers. [ABSTRACT FROM AUTHOR]

Background: Hyperbilirubinaemia is a common complication of sepsis. Elevated bilirubin may induce inflammation and apoptosis. It was hypothesised that increased serum bilirubin on Intensive Care Unit (ICU) admission contributes to sepsis-related acute respiratory distress syndrome (ARDS). Methods: Serum bilirubin on ICU admission was measured in 1006 patients with sepsis. Serial serum bilirubin was analysed prospectively in patients with sepsis who had ARDS for a period of 28 days. The effects of clinical factors and variants of the UGT1A1 gene on serum bilirubin levels were determined. Outcomes were ARDS risk and mortality. Results: During 60-day follow-up, 326 patients with sepsis developed ARDS, of whom 144 died from ARDS. The hyperbilirubinaemia (⩾02.0 mg/dl) rate in patients with ARDS (22.4%) was higher than in those without ARDS (14.1%, p = 0.002). For each 1.0 mg/dl increase in admission bilirubin, ARDS risk and 28- and 60-day ARDS mortalities were increased by 7% (OR = 1.07; p = 0.003), 20% (OR = 1.20; p = 0.002) and 18% (OR = 1.18; p = 0.004), respectively. Compared with subjects with bilirubin levels <2.0 mg/dl, patients with hyperbilirubinaemia had higher risks of ARDS (OR = 2.12; p = 0.0007) and 28-day (OR = 2.24; p = 0.020) and 60-day ARDS mortalities (OR = 2.09; p = 0.020). In sepsis-related ARDS, serial bilirubin levels in non-survivors were consistently higher than in survivors (p<0.0001). Clinical variables explained 29.5% of the interindividual variation in bilirubin levels, whereas genetic variants of UGT1A1 contributed 7.5%. Conclusion: In sepsis, a higher serum bilirubin level on ICU admission is associated with subsequent ARDS development and mortality. [ABSTRACT FROM AUTHOR]

Background: Although trigeminal nerve involvement is a characteristic of multiple sclerosis (MS), its prevalence across studies varies greatly due to MRI resolution and cohort selection bias. The mechanism behind the site specificity of trigeminal nerve injury is still unclear. We aim to determine the prevalence of trigeminal nerve involvement in patients with MS in a consecutive 7T brain MRI cohort., Methods: This observational cohort originates from an ongoing China National Registry of Neuro-Inflammatory Diseases. Inclusion criteria were the following: age 18 years or older, diagnosis of MS according to the 2017 McDonald criteria and no clinical relapse within the preceding 3 months. Each participant underwent 7T MAGNETOM Terra scanner (Siemens, Erlangen, Germany), using a 32-channel phased array coil at Beijing Tiantan Hospital. T1-weighted magnetisation-prepared rapid acquisition gradient echoes, fluid-attenuated inversion recovery (FLAIR) and fluid and white matter suppression images were used to identify lesions. FLAIR* and T2* weighted images were used to identify central vein sign (CVS) within the trigeminal lesions., Results: 120 patients underwent 7T MRI scans between December 2021 and May 2023. 19/120 (15.8%) patients had a total of 45 trigeminal lesions, of which 11/19 (57.9%) were bilateral. The linear lesions extended along the trigeminal nerve, from the root entry zone (REZ) (57.8%, 26/45) to the pontine-medullary nucleus (42.2%, 19/45). 26.9% (7/26) of the lesions in REZ showed a typical central venous sign., Conclusion: In this 7T MRI cohort, the prevalence of trigeminal nerve involvement was 15.8%. Characteristic CVS was detected in 26.9% of lesions in REZ. This suggests an inflammatory demyelination mechanism of trigeminal nerve involvement in MS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This longitudinal study compared emerging plasma biomarkers for neurodegenerative disease between controls, patients with Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP)., Methods: Plasma phosphorylated tau at threonine-181 (p-tau181), amyloid beta (Αβ)42, Aβ40, neurofilament light (NfL) and glial fibrillar acidic protein (GFAP) were measured using highly sensitive single molecule immunoassays (Simoa) in a multicentre cohort of 300 participants (controls=73, amyloid positive mild cognitive impairment (MCI+) and AD dementia=63, LBD=117, FTD=28, PSP=19). LBD participants had known positron emission tomography (PET)-Aβ status., Results: P-tau181 was elevated in MCI+AD compared with all other groups. Aβ42/40 was lower in MCI+AD compared with controls and FTD. NfL was elevated in all dementias compared with controls while GFAP was elevated in MCI+AD and LBD. Plasma biomarkers could classify between MCI+AD and controls, FTD and PSP with high accuracy but showed limited ability in differentiating MCI+AD from LBD. No differences were detected in the levels of plasma biomarkers when comparing PET-Aβ positive and negative LBD. P-tau181, NfL and GFAP were associated with baseline and longitudinal cognitive decline in a disease specific pattern., Conclusion: This large study shows the role of plasma biomarkers in differentiating patients with different dementias, and at monitoring longitudinal change. We confirm that p-tau181 is elevated in MCI+AD, versus controls, FTD and PSP, but is less accurate in the classification between MCI+AD and LBD or detecting amyloid brain pathology in LBD. NfL was elevated in all dementia groups, while GFAP was elevated in MCI+AD and LBD., Competing Interests: Competing interests: Competing interests unrelated to this work, JBR serves as an associate editor to Brain and is a non-remunerated trustee of the Guarantors of Brain, Darwin College and the PSP Association (UK). He provides consultancy to Asceneuron, Biogen, UCB and has research grants from AZ-Medimmune, Janssen, Lilly as industry partners in the Dementias Platform UK. Unrelated to this work, JTOB has received honoraria for work as DSMB chair or member for TauRx, Axon, Eisai, has acted as a consultant for Roche, and has received research support from Alliance Medical and Merck. HZ has served at scientific advisory boards and/or as a consultant for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, CogRx and Red Abbey Labs, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company, enabled use of the 18F-florbetapir by providing tracer and funding scanner time, but was not involved in data analysis or interpretation., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Markers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral small vessel disease (SVD), and if it predicted future progression of SVD. We also determined its relationship to systemic inflammation, which has been additionally implicated in dementia and SVD., Methods: Cognitively healthy midlife participants were assessed at baseline (n=185) and 2-year follow-up (n=158). To assess SVD, we quantified white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds and lacunes. We derived composite scores of SVD burden, and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. Inflammation was quantified using serum C-reactive protein (CRP) and fibrinogen., Results: At baseline, higher CAIDE scores were associated with all markers of SVD and inflammation. Longitudinally, CAIDE scores predicted greater total (p<0.001), periventricular (p<0.001) and deep (p=0.012) WMH progression, and increased CRP (p=0.017). Assessment of individual CAIDE components suggested that markers were driven by different risk factors (WMH/EPVS: age/hypertension, lacunes/deep microbleeds: hypertension/obesity). Interaction analyses demonstrated that higher CAIDE scores amplified the effect of age on SVD, and the effect of WMH on poorer memory., Conclusion: Higher CAIDE scores, indicating greater risk of dementia, predicts future progression of both WMH and systemic inflammation. Findings highlight the CAIDE score's potential as both a prognostic and predictive marker in the context of cerebrovascular disease, identifying at-risk individuals who might benefit most from managing modifiable risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objective: Depression and trauma are associated with changes in brain regions implicated in Alzheimer's disease. The present study examined associations between childhood trauma, depression, adult cognitive functioning and risk of dementia., Methods: Data from 378 participants in the PREVENT Dementia Study aged 40-59 years. Linear and logistic models were used to assess associations between childhood trauma, depression, dementia risk, cognitive test scores and hippocampal volume., Results: Childhood trauma was associated with depression and reduced hippocampal volume but not current cognitive function or dementia risk. Poorer performance on a delayed face/name recall task was associated with depression. Childhood trauma was associated with lower hippocampal volume however poorer cognitive performance was mediated by depression rather than structural brain differences., Conclusion: Depressive symptomatology may be associated with dementia risk via multiple pathways, and future studies should consider subtypes of depressive symptomatology when examining its relationship to dementia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [ 11 C]PK11195 positron emission tomography (PET) imaging., Methods: Forty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer's disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [ 11 C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [ 11 C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [ 11 C]PK11195., Results: Global [ 11 C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (β=0.63, F(1,35)=35.24, p<0.001), deep WMH (β=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [ 11 C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (β=0.66-0.76, t=3.90-5.58, FDR-corrected p (p FDR )=<0.001-0.002) and orbitofrontal cortex (β=0.51-0.57, t=3.53-4.30, p FDR =0.001-0.004)., Conclusion: Microglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Regional cerebral hypoperfusion is characteristic of Alzheimer's disease (AD). Previous studies report conflicting findings in cognitively normal individuals at high risk of AD. Understanding early preclinical perfusion alterations may improve understanding of AD pathogenesis and lead to new biomarkers and treatment targets., Methods: 3T arterial spin labelling MRI scans from 162 participants in the PREVENT-Dementia cohort were analysed (cognitively normal participants aged 40-59, stratified by future dementia risk). Cerebral perfusion was compared vertex-wise according to APOE ε4 status and family history (FH). Correlations between individual perfusion, age and cognitive scores (COGNITO battery) were explored., Results: Regional hyperperfusion was found in APOE ε4 +group (left cingulate and lateral frontal and parietal regions p<0.01, threshold-free cluster enhancement, TFCE) and in FH +group (left temporal and parietal regions p<0.01, TFCE). Perfusion did not correlate with cognitive test scores., Conclusions: Regional cerebral hyperperfusion in individuals at increased risk of AD in mid-life may be a very early marker of functional brain change related to AD. Increased perfusion may reflect a functional 'compensation' mechanism, offsetting the effects of early neural damage or may itself be risk factor for accelerating spread of degenerative pathology., Competing Interests: Competing interests: Unrelated to this work, he has received honoraria for work as DSMB chair or member for TauRx, Axon, Eisai, has acted as a consultant for Lilly and has received honorarium for talks from GE Healthcare and research support from Alliance Medical., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Increased rates of brain atrophy on serial MRI are frequently used as a surrogate marker of disease progression in Alzheimer's disease and other dementias. However, the extent to which they are associated with future risk of dementia in asymptomatic subjects is not clear. In this study, we investigated the relationship between the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) risk score and longitudinal atrophy in middle-aged subjects., Materials and Methods: A sample of 167 subjects (aged 40-59 at baseline) from the PREVENT-Dementia programme underwent MRI scans on two separate occasions (mean interval 735 days; SD 44 days). We measured longitudinal rates of brain atrophy using the FSL Siena toolbox., Results: Annual percentage rates of brain volume and ventricular volume change were greater in those with a high (>6) vs low CAIDE score-absolute brain volume percentage loss 0.17% (CI 0.07 to 0.27) and absolute ventricular enlargement 1.78% (CI 1.14 to 2.92) higher in the at risk group. Atrophy rates did not differ between subjects with and without a parental history of dementia, but were significantly correlated with age. Using linear regression, with covariates of age, sex and education, CAIDE score >6 was the only significant predictor of whole brain atrophy rates (p=0.025) while age (p=0.009), sex (p=0.002) and CAIDE>6 (p=0.017) all predicted ventricular expansion rate., Conclusion: Our results show that progressive brain atrophy is associated with increased risk of future dementia in asymptomatic middle-aged subjects, two decades before dementia onset., Competing Interests: Competing interests: JTO’B has no conflicts related to this study. Unrelated to this work, he has received honoraria for work as DSMB chair or member for TauRx, Axon, Eisai, has acted as a consultant for Lilly and has received honorarium for talks from GE Healthcare and research support from Alliance Medical., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)