White matter, cognition and psychotic-like experiences in UK Biobank.

BACKGROUND: Psychotic-like experiences (PLEs) are risk factors for the development of psychiatric conditions like schizophrenia, particularly if associated with distress. As PLEs have been related to alterations in both white matter and cognition, we investigated whether cognition (g-factor and processing speed) mediates the relationship between white matter and PLEs. METHODS: We investigated two independent samples (6170 and 19 891) from the UK Biobank, through path analysis. For both samples, measures of whole-brain fractional anisotropy (gFA) and mean diffusivity (gMD), as indications of white matter microstructure, were derived from probabilistic tractography. For the smaller sample, variables whole-brain white matter network efficiency and microstructure were also derived from structural connectome data. RESULTS: The mediation of cognition on the relationships between white matter properties and PLEs was non-significant. However, lower gFA was associated with having PLEs in combination with distress in the full available sample (standardized ß = -0.053, p = 0.011). Additionally, lower gFA/higher gMD was associated with lower g-factor (standardized ß = 0.049, p < 0.001; standardized ß = -0.027, p = 0.003), and partially mediated by processing speed with a proportion mediated of 7% (p = < 0.001) for gFA and 11% (p < 0.001) for gMD. CONCLUSIONS: We show that lower global white matter microstructure is associated with having PLEs in combination with distress, which suggests a direction of future research that could help clarify how and why individuals progress from subclinical to clinical psychotic symptoms. Furthermore, we replicated that processing speed mediates the relationship between white matter microstructure and g-factor.

Three major dimensions of human brain cortical ageing in relation to cognitive decline across the eighth decade of life.

Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. However, cross-sectional brain data conflate information on ageing with patterns that are present throughout life. We characterised brain cortical ageing across the eighth decade of life in a longitudinal ageing cohort, at ages ~73, ~76, and ~79 years, with a total of 1376 MRI scans. Volumetric changes among cortical regions of interest (ROIs) were more strongly correlated (average r = 0.805, SD = 0.252) than were cross-sectional volumes of the same ROIs (average r = 0.350, SD = 0.178). We identified a broad, cortex-wide, dimension of atrophy that explained 66% of the variance in longitudinal changes across the cortex. Our modelling also discovered more specific fronto-temporal and occipito-parietal dimensions that were orthogonal to the general factor and together explained an additional 20% of the variance. The general factor was associated with declines in general cognitive ability (r = 0.431, p < 0.001) and in the domains of visuospatial ability (r = 0.415, p = 0.002), processing speed (r = 0.383, p < 0.001) and memory (r = 0.372, p < 0.001). Individual differences in brain cortical atrophy with ageing are manifest across three broad dimensions of the cerebral cortex, the most general of which is linked with cognitive declines across domains. Longitudinal approaches are invaluable for distinguishing lifelong patterns of brain-behaviour associations from patterns that are specific to aging.

Genetic contributions to Trail Making Test performance in UK Biobank.

The Trail Making Test (TMT) is a widely used test of executive function and has been thought to be strongly associated with general cognitive function. We examined the genetic architecture of the TMT and its shared genetic aetiology with other tests of cognitive function in 23 821 participants from UK Biobank. The single-nucleotide polymorphism-based heritability estimates for trail-making measures were 7.9% (part A), 22.4% (part B) and 17.6% (part B-part A). Significant genetic correlations were identified between trail-making measures and verbal-numerical reasoning (rg>0.6), general cognitive function (rg>0.6), processing speed (rg>0.7) and memory (rg>0.3). Polygenic profile analysis indicated considerable shared genetic aetiology between trail making, general cognitive function, processing speed and memory (standardized ß between 0.03 and 0.08). These results suggest that trail making is both phenotypically and genetically strongly associated with general cognitive function and processing speed.

Brain age predicts mortality.

Age-associated disease and disability are placing a growing burden on society. However, ageing does not affect people uniformly. Hence, markers of the underlying biological ageing process are needed to help identify people at increased risk of age-associated physical and cognitive impairments and ultimately, death. Here, we present such a biomarker, 'brain-predicted age', derived using structural neuroimaging. Brain-predicted age was calculated using machine-learning analysis, trained on neuroimaging data from a large healthy reference sample (N=2001), then tested in the Lothian Birth Cohort 1936 (N=669), to determine relationships with age-associated functional measures and mortality. Having a brain-predicted age indicative of an older-appearing brain was associated with: weaker grip strength, poorer lung function, slower walking speed, lower fluid intelligence, higher allostatic load and increased mortality risk. Furthermore, while combining brain-predicted age with grey matter and cerebrospinal fluid volumes (themselves strong predictors) not did improve mortality risk prediction, the combination of brain-predicted age and DNA-methylation-predicted age did. This indicates that neuroimaging and epigenetics measures of ageing can provide complementary data regarding health outcomes. Our study introduces a clinically-relevant neuroimaging ageing biomarker and demonstrates that combining distinct measurements of biological ageing further helps to determine risk of age-related deterioration and death.

Structural brain imaging correlates of general intelligence in UK Biobank.

The associations between indices of brain structure and measured intelligence are unclear. This is partly because the evidence to-date comes from mostly small and heterogeneous studies. Here, we report brain structure-intelligence associations on a large sample from the UK Biobank study. The overall N = 29,004, with N = 18,426 participants providing both brain MRI and at least one cognitive test, and a complete four-test battery with MRI data available in a minimum N = 7201, depending upon the MRI measure. Participants' age range was 44-81 years (M = 63.13, SD = 7.48). A general factor of intelligence (g) was derived from four varied cognitive tests, accounting for one third of the variance in the cognitive test scores. The association between (age- and sex- corrected) total brain volume and a latent factor of general intelligence is r = 0.276, 95% C.I. = [0.252, 0.300]. A model that incorporated multiple global measures of grey and white matter macro- and microstructure accounted for more than double the g variance in older participants compared to those in middle-age (13.6% and 5. 4%, respectively). There were no sex differences in the magnitude of associations between g and total brain volume or other global aspects of brain structure. The largest brain regional correlates of g were volumes of the insula, frontal, anterior/superior and medial temporal, posterior and paracingulate, lateral occipital cortices, thalamic volume, and the white matter microstructure of thalamic and association fibres, and of the forceps minor. Many of these regions exhibited unique contributions to intelligence, and showed highly stable out of sample prediction.

Polygenic risk score for schizophrenia and structural brain connectivity in older age: A longitudinal connectome and tractography study.

Higher polygenic risk score for schizophrenia (szPGRS) has been associated with lower cognitive function and might be a predictor of decline in brain structure in apparently healthy populations. Age-related declines in structural brain connectivity-measured using white matter diffusion MRI -are evident from cross-sectional data. Yet, it remains unclear how graph theoretical metrics of the structural connectome change over time, and whether szPGRS is associated with differences in ageing-related changes in human brain connectivity. Here, we studied a large, relatively healthy, same-year-of-birth, older age cohort over a period of 3 years (age ∼ 73 years, N = 731; age ∼76 years, N = 488). From their brain scans we derived tract-averaged fractional anisotropy (FA) and mean diffusivity (MD), and network topology properties. We investigated the cross-sectional and longitudinal associations between these structural brain variables and szPGRS. Higher szPGRS showed significant associations with longitudinal increases in MD in the splenium (ß = 0.132, pFDR = 0.040), arcuate (ß = 0.291, pFDR = 0.040), anterior thalamic radiations (ß = 0.215, pFDR = 0.040) and cingulum (ß = 0.165, pFDR = 0.040). Significant declines over time were observed in graph theory metrics for FA-weighted networks, such as mean edge weight (ß = -0.039, pFDR = 0.048) and strength (ß = -0.027, pFDR = 0.048). No significant associations were found between szPGRS and graph theory metrics. These results are consistent with the hypothesis that szPGRS confers risk for ageing-related degradation of some aspects of structural connectivity.

Healthy cognitive ageing in the Lothian Birth Cohort studies: marginal gains not magic bullet.

In the face of shifting demographics and an increase in human longevity, it is important to examine carefully what is known about cognitive ageing, and to identify and promote possibly malleable lifestyle and health-related factors that might mitigate age-associated cognitive decline. The Lothian Birth Cohorts of 1921 (LBC1921, n = 550) and 1936 (LBC1936, n = 1091) are longitudinal studies of cognitive and brain ageing based in Scotland. Childhood IQ data are available for these participants, who were recruited in later life and then followed up regularly. This overview summarises some of the main LBC findings to date, illustrating the possible genetic and environmental contributions to cognitive function (level and change) and brain imaging biomarkers in later life. Key associations include genetic variation, health and fitness, psychosocial and lifestyle factors, and aspects of the brain's structure. It addresses some key methodological issues such as confounding by early-life intelligence and social factors and emphasises areas requiring further investigation. Overall, the findings that have emerged from the LBC studies highlight that there are multiple correlates of cognitive ability level in later life, many of which have small effects, that there are as yet few reliable predictors of cognitive change, and that not all of the correlates have independent additive associations. The concept of marginal gains, whereby there might be a cumulative effect of small incremental improvements across a wide range of lifestyle and health-related factors, may offer a useful way to think about and promote a multivariate recipe for healthy cognitive and brain ageing.

Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151).

People's differences in cognitive functions are partly heritable and are associated with important life outcomes. Previous genome-wide association (GWA) studies of cognitive functions have found evidence for polygenic effects yet, to date, there are few replicated genetic associations. Here we use data from the UK Biobank sample to investigate the genetic contributions to variation in tests of three cognitive functions and in educational attainment. GWA analyses were performed for verbal-numerical reasoning (N=36 035), memory (N=112 067), reaction time (N=111 483) and for the attainment of a college or a university degree (N=111 114). We report genome-wide significant single-nucleotide polymorphism (SNP)-based associations in 20 genomic regions, and significant gene-based findings in 46 regions. These include findings in the ATXN2, CYP2DG, APBA1 and CADM2 genes. We report replication of these hits in published GWA studies of cognitive function, educational attainment and childhood intelligence. There is also replication, in UK Biobank, of SNP hits reported previously in GWA studies of educational attainment and cognitive function. GCTA-GREML analyses, using common SNPs (minor allele frequency>0.01), indicated significant SNP-based heritabilities of 31% (s.e.m.=1.8%) for verbal-numerical reasoning, 5% (s.e.m.=0.6%) for memory, 11% (s.e.m.=0.6%) for reaction time and 21% (s.e.m.=0.6%) for educational attainment. Polygenic score analyses indicate that up to 5% of the variance in cognitive test scores can be predicted in an independent cohort. The genomic regions identified include several novel loci, some of which have been associated with intracranial volume, neurodegeneration, Alzheimer's disease and schizophrenia.

A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial.

OBJECTIVE: To compare the efficacy of etanercept (ETN) and methotrexate (MTX) versus MTX monotherapy for remission induction in patients with early inflammatory arthritis. METHODS: In a 78-week multicentre randomised placebo-controlled superiority trial, 110 DMARD-naïve patients with early clinical synovitis (≥1 tender and swollen joint, and within 3 months of diagnosis) and either rheumatoid factor, anticitrullinated protein antibodies or shared epitope positive were randomised 1:1 to receive MTX+ETN or MTX+placebo (PBO) for 52 weeks. Injections (ETN or PBO) were stopped in all patients at week 52. In those with no tender or swollen joints (NTSJ) for >26 weeks, injections were stopped early. If patients had NTSJ >12 weeks after stopping the injections, MTX was weaned. The primary endpoint was NTSJ at week 52. RESULTS: No statistically significant difference was seen for the primary endpoint (NTSJ at week 52 (32.5% vs 28.1% [adjusted OR 1.32 (0.56 to 3.09), p=0.522]) in the MTX+ETN and MTX+PBO groups, respectively). The secondary endpoints did not differ between groups at week 52 or 78. Exploratory analyses showed a higher proportions of patients with DAS28-CRP<2.6 in the MTX+ETN group at week 2 (38.5% vs 9.2%, adjusted OR 8.87 (2.53 to 31.17), p=0.001) and week 12 (65.1% vs 43.8%, adjusted OR 2.49 (1.12 to 5.54), p=0.026). CONCLUSIONS: In this group of patients with early inflammatory arthritis, almost a third had no tender, swollen joints after 1 year. MTX+ETN was not superior to MTX monotherapy in achieving this outcome. Clinical responses, however, including DAS28-CRP<2.6, were achieved earlier with MTX+ETN combination therapy. TRIAL REGISTRATION NUMBER: The EMPIRE trial is registered on the following trial registries: Eudract-2005-005467-29; ISRCTN 55428162 (http://www.controlled-trials.com/ISRCTN55428162/EMPIRE). The full trial protocol can be obtained from the corresponding author.

Validation of a polygenic risk score for frailty in the Lothian Birth Cohort 1936 and English longitudinal study of ageing.

Frailty is a complex trait. Twin studies and high-powered Genome Wide Association Studies conducted in the UK Biobank have demonstrated a strong genetic basis of frailty. The present study utilized summary statistics from a Genome Wide Association Study on the Frailty Index to create and test the predictive power of frailty polygenic risk scores (PRS) in two independent samples - the Lothian Birth Cohort 1936 (LBC1936) and the English Longitudinal Study of Ageing (ELSA) aged 67-84 years. Multiple regression models were built to test the predictive power of frailty PRS at five time points. Frailty PRS significantly predicted frailty, measured via the FI, at all-time points in LBC1936 and ELSA, explaining 2.1% (ß = 0.15, 95%CI, 0.085-0.21) and 1.8% (ß = 0.14, 95%CI, 0.10-0.17) of the variance, respectively, at age ~ 68/ ~ 70 years (p < 0.001). This work demonstrates that frailty PRS can predict frailty in two independent cohorts, particularly at early ages (~ 68/ ~ 70). PRS have the potential to be valuable instruments for identifying those at risk for frailty and could be important for controlling for genetic confounders in epidemiological studies.

Multi-polygenic prediction of frailty highlights chronic pain and educational attainment as key risk and protective factors.

Frailty is a complex trait. Twin studies and recent Genome-Wide Association Studies have demonstrated a strong genetic basis of frailty but there remains a lack of genetic studies exploring genetic prediction of Frailty. Previous work has shown that a single polygenic predictor - represented by a Frailty polygenic score - predicts Frailty, measured via the frailty index, in independent samples within the United Kingdom. We extended this work, using a multi-polygenic score (MPS) approach to increase predictive power. Predictor variables - twenty-six polygenic scores (PGS) were modelled in regularised Elastic net regression models, with repeated cross-validation, to estimate joint prediction of the polygenic scores and order the predictions by their contributing strength to Frailty in two independent cohorts aged 65+ - the English Longitudinal Study of Ageing (ELSA) and Lothian Birth Cohort 1936 (LBC1936). Results showed that the MPS explained 3.6% and 4.7% of variance compared to the best single-score prediction of 2.6% and 2.2% of variance in ELSA and LBC1936 respectively. The strongest polygenic predictors of worsening frailty came from PGS for Chronic pain, Frailty and Waist circumference; whilst PGS for Parental Death, Educational attainment, and Rheumatoid Arthritis were found to be protective to frailty. Results from the predictors remaining in the final model were then validated using the longitudinal LBC1936, with equivalent PGS scores from the same GWAS summary statistics. Thus, this MPS approach provides new evidence for the genetic contributions to frailty in later life and sheds light on the complex structure of the Frailty Index measurement.

The pharmacokinetics of maropitant citrate dosed orally to dogs at 2 mg/kg and 8 mg/kg once daily for 14 days consecutive days.

The pharmacokinetics of maropitant were evaluated in beagle dogs dosed orally with Cerenia® tablets (Pfizer Animal Health) once daily for 14 consecutive days at either 2 mg/kg or 8 mg/kg bodyweight. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration data to measure the AUC(0-24) (after first and last doses), Ct (trough concentration-measured 24 h after each dose), Cmax (after first and last doses), tmax (after first and last doses), λz (terminal disposition rate constant; after last dose), t(1/2) (after last dose), and CL/F (oral clearance; after last dose). Maropitant accumulation in plasma was substantially greater after fourteen daily 8 mg/kg doses than after fourteen daily 2 mg/kg doses as reflected in the AUC(0-24) accumulation ratio of 4.81 at 8 mg/kg and 2.46 at 2 mg/kg. This is most likely due to previously identified nonlinear pharmacokinetics of maropitant in which high doses (8 mg/kg) saturate the metabolic clearance mechanisms and delay drug elimination. To determine the time to reach steady-state maropitant plasma levels, a nonlinear model was fit to the least squares (LS) means maropitant Ct values for each treatment group. Based on this model, 90% of steady-state was determined to occur at approximately four doses for daily 2 mg/kg oral dosing and eight doses for daily 8 mg/kg oral dosing.

Validation of a polygenic risk score for Frailty in the Lothian Birth Cohort and English Longitudinal Study of Ageing.

Frailty is a complex trait. Twin studies and a high-powered Genome Wide Association Study (GWAS) conducted in the UK Biobank have demonstrated a strong genetic basis of frailty. The present study utilized summary statistics from this GWAS to create and test the predictive power of frailty polygenic risk scores (PRS) in two independent samples - the Lothian Birth Cohort 1936 (LBC1936) and the English Longitudinal Study of Ageing (ELSA) aged 67-84 years. Multiple regression models were built to test the predictive power of frailty PRS at five time points. Frailty PRS significantly predicted frailty at all-time points in LBC1936 and ELSA, explaining 2.1% (ß = 0.15, 95%CI, 0.085-0.21) and 1.6% (ß = 0.14, 95%CI, 0.10-0.17) of the variance, respectively, at age ~68/~70 years (p < 0.001). This work demonstrates that frailty PRS can predict frailty in two independent cohorts, particularly at early ages (~68/~70). PRS have the potential to be valuable instruments for identifying those at risk for frailty and could be important for controlling for genetic confounders in epidemiological studies.

Mediterranean-Type Diet and Brain Structural Change from 73 to 79 Years in the Lothian Birth Cohort 1936.

OBJECTIVES: To test whether Mediterranean-type Diet (MeDi) at age 70 years is associated with longitudinal trajectories of total brain MRI volume over a six-year period from age 73 to 79. DESIGN: Cohort study which uses a correlational design. SETTING: Participants residing in the Lothian region of Scotland and living independently in the community. PARTICIPANTS: A relatively healthy Scottish sample drawn from the Lothian Birth Cohort 1936. MEASUREMENTS: Total brain volume measurements were available at ages 73, 76 and 79 (N ranged 332 to 563). Adherence to the MeDi was based on food frequency questionnaire data collected three years before the baseline imaging scans, and was used in growth curve models to predict the trajectory of total brain volume change. RESULTS: No association was found (p>.05) between adherence to the MeDi at age 70 and total brain volume change from 73 to 79 years in minimally-adjusted (sex) or fully adjusted models controlling for additional health confounders. CONCLUSIONS: Variation in adherence to the MeDi was not predictive of total brain atrophy over a six-year period. This suggests that previous findings of dietary associations with brain volume are not long lasting or become less important as ageing-related conditions account for greater variation in brain volume change. More frequent collection of dietary intake data is needed to clarify these findings.

Concomitant pulmonary disease is common among patients with extrapulmonary TB.

BACKGROUND: Microbiologic screening of extrapulmonary TB (EPTB) patients could inform recommendations for aerosol precautions and close contact prophylaxis. However, this is currently not routinely recommended in India. Therefore, we estimated the proportion of Indian patients with EPTB with microbiologic evidence of pulmonary TB (PTB).METHODS: We characterized baseline clinical, radiological and sputum microbiologic data of 885 adult and pediatric TB patients in Chennai and Pune, India, between March 2014 and November 2018.RESULTS: Of 277 patients with EPTB, enhanced screening led to the identification of 124 (45%) with concomitant PTB, including 53 (19%) who reported a cough >2 weeks; 158 (63%) had an abnormal CXR and 51 (19%) had a positive sputum for TB. Of 70 participants with a normal CXR and without any cough, 14 (20%) had a positive sputum for TB. Overall, the incremental yield of enhanced screening of patients with EPTB to identify concomitant PTB disease was 14% (95% CI 12-16).CONCLUSIONS: A high proportion of patients classified as EPTB in India have concomitant PTB. Our results support the need for improved symptom and CXR screening, and recommends routine sputum TB microbiology screening of all Indian patients with EPTB.

Population pharmacokinetics of mavacoxib in osteoarthritic dogs.

Mavacoxib (Trocoxil™) is an oral long-acting COX-2 inhibitor approved for the treatment of osteoarthritis in dogs. Two field trials were conducted in client-owned dogs suffering from osteoarthritis, with dosages of 4 mg/kg body weight (BW) (Study 1) or 2 mg/kg BW (Study 2). Mavacoxib plasma concentrations were determined from trough blood samples and from blood samples collected at 4-10 months after the last dose. A one-compartment linear model was fitted to the concentration data (1317 concentration records from 286 patients), and parameters for oral clearance (Cl/F), apparent volume of distribution (V(d) /F) and their between-subject variabilities (BSV) were estimated. Covariates were included in the model based on the outcomes of stepwise regression procedures. In the final model, the typical value of Cl/F was a function of BW, age and breed. German shepherds and Labrador retrievers were found to have 31% higher values of Cl/F than patients from different breeds with similar ages and BWs. The typical value of V(d) /F was found to be dependent only on BW. The two field studies appeared to differ similarly with respect to Cl/F and V(d) /F. The explanation for this difference is not known, but the difference was accounted for in the final model as a 23.9% lower bioavailability in Study 2. Mavacoxib exhibited relatively broad BSV in Cl/F and V(d) /F, with coefficients of variation of 47% and 19%, respectively. The typical value for mavacoxib's terminal elimination plasma half-life (t(1/2) ) was 44 days, but a minority of patients (approximately 5%) had empirical Bayes estimates of t(1/2) exceeding 80 days. Simulations with the model indicated that the majority of patients treated with mavacoxib 2 mg/kg will maintain trough plasma mavacoxib concentrations associated with efficacy. Results of the population pharmacokinetic analysis helped to reduce the dose from 4 to 2 mg/kg and thus increased the therapeutic index for this molecule.

Pharmacokinetics of ceftiofur crystalline-free acid sterile suspension in the equine.

Absolute bioavailability and dose proportionality studies were performed with ceftiofur in horses. In the absolute bioavailability study, thirty animals received either an intravenous dose of ceftiofur sodium at 1.0 mg/kg or an intramuscular (i.m.) dose of ceftiofur crystalline-free acid (CCFA) at 6.6 mg/kg. In the dose proportionality study, 48 animals received daily i.m. ceftiofur sodium injections at 1.0 mg/kg for ten doses or two doses of CCFA separated by 96 h, with CCFA doses of 3.3, 6.6, or 13.2 mg/kg. Noncompartmental and mixed-effect modeling procedures were used to assess pharmacokinetics (PK). CCFA was well absorbed with a bioavailability of 100%. AUC(0-∞) and C(max) increased in a dose-related manner following administration of the two doses of CCFA at 3.3, 6.6, and 13.2 mg/kg. The least-squares mean terminal half-life (t(½) ) following the tenth daily i.m. injection of ceftiofur sodium at 2.2 mg/kg was 40.8 h, but the least-squares mean t(½) following the second i.m. injection of CCFA at 6.6 mg/kg was 100 h. The time that plasma ceftiofur equivalent concentrations remain above a threshold concentration of 0.2 µg/mL has been associated with efficacy, and following administration of two 6.6 mg/kg doses of CCFA, the mean time above 0.2 µg/mL was 262 h. Simulations with the nonlinear mixed-effect PK model predicted that more than 97.5% of horses will have plasma ceftiofur equivalent concentrations >0.2 µg/mL for 96 h after the second 6.6 mg/kg dose of CCFA.

Associations between total MRI-visible small vessel disease burden and domain-specific cognitive abilities in a community-dwelling older-age cohort.

Cerebral small vessel disease (SVD) is a leading cause of vascular cognitive impairment, however the precise nature of SVD-related cognitive deficits, and their associations with structural brain changes, remain unclear. We combined computational volumes and visually-rated MRI markers of SVD to quantify total SVD burden, using data from the Lothian Birth Cohort 1936 (n = 540; age: 72.6 ± 0.7 years). We found negative associations between total SVD burden and general cognitive ability (standardized ß: -0.363; 95%CI: [-0.49, -0.23]; p(FDR) < 0.001), processing speed (-0.371 [-0.50, -0.24]; p(FDR) < 0.001), verbal memory (-0.265; [-0.42, -0.11]; p(FDR) = 0.002), and visuospatial ability (-0.170; [-0.32, -0.02]; p(FDR) = 0.029). Only the association between SVD burden and processing speed remained after accounting for covariance with general cognitive ability (-0.325; [-0.61, -0.04]; p(FDR) = 0.029). This suggests that SVD's association with poorer processing speed is not driven by, but is independent of its association with poorer general cognitive ability. Tests of processing speed may be particularly sensitive to the cognitive impact of SVD, but all major cognitive domains should be tested to determine the full range of SVD-related cognitive characteristics.

Cerebral small vessel disease burden and longitudinal cognitive decline from age 73 to 82: the Lothian Birth Cohort 1936.

Slowed processing speed is considered a hallmark feature of cognitive decline in cerebral small vessel disease (SVD); however, it is unclear whether SVD's association with slowed processing might be due to its association with overall declining general cognitive ability. We quantified the total MRI-visible SVD burden of 540 members of the Lothian Birth Cohort 1936 (age: 72.6 ± 0.7 years; 47% female). Using latent growth curve modelling, we tested associations between total SVD burden at mean age 73 and changes in general cognitive ability, processing speed, verbal memory and visuospatial ability, measured at age 73, 76, 79 and 82. Covariates included age, sex, vascular risk and childhood cognitive ability. In the fully adjusted models, greater SVD burden was associated with greater declines in general cognitive ability (standardised ß: -0.201; 95% CI: [-0.36, -0.04]; pFDR = 0.022) and processing speed (-0.222; [-0.40, -0.04]; pFDR = 0.022). SVD burden accounted for between 4 and 5% of variance in declines of general cognitive ability and processing speed. After accounting for the covariance between tests of processing speed and general cognitive ability, only SVD's association with greater decline in general cognitive ability remained significant, prior to FDR correction (-0.222; [-0.39, -0.06]; p = 0.008; pFDR = 0.085). Our findings do not support the notion that SVD has a specific association with declining processing speed, independent of decline in general cognitive ability (which captures the variance shared across domains of cognitive ability). The association between SVD burden and declining general cognitive ability supports the notion of SVD as a diffuse, whole-brain disease and suggests that trials monitoring SVD-related cognitive changes should consider domain-specific changes in the context of overall, general cognitive decline.

Unhealthy alcohol use independently associated with unfavorable TB treatment outcomes among Indian men.

BACKGROUND: Approximately 10% of incident TB cases worldwide are attributable to alcohol. However, evidence associating alcohol with unfavorable TB treatment outcomes is weak.METHODS: We prospectively evaluated men (≥18 years) with pulmonary TB in India for up to 24 months to investigate the association between alcohol use and treatment outcomes. Unhealthy alcohol use was defined as a score of ≥4 on the Alcohol Use Disorders Identification Test-Concise (AUDIT-C) scale at entry. Unfavorable TB treatment outcomes included failure, recurrence, and all-cause mortality, analyzed as composite and independent endpoints.RESULTS: Among 751 men, we identified unhealthy alcohol use in 302 (40%). Median age was 39 years (IQR 28-50); 415 (55%) were underweight (defined as a body mass index [BMI] <18.5 kg/m²); and 198 (26%) experienced an unfavorable outcome. Unhealthy alcohol use was an independent risk factor for the composite unfavorable outcome (adjusted incidence rate ratio [aIRR] 1.47, 95% CI 1.05-2.06; P = 0.03) and death (aIRR 1.90, 95% CI 1.08-3.34; P = 0.03), specifically. We found significant interaction between AUDIT-C and BMI; underweight men with unhealthy alcohol use had increased risk of unfavorable outcomes (aIRR 2.22, 95% CI 1.44-3.44; P < 0.001) compared to men with BMI ≥18.5 kg/m² and AUDIT-C <4.CONCLUSION: Unhealthy alcohol use was independently associated with unfavorable TB treatment outcomes, highlighting the need for integrating effective alcohol interventions into TB care.