Cross-Regional Data Initiative for the Assessment and Development of Treatment for Neurological and Mental Disorders.

Purpose: To describe and categorize detailed components of databases in the Neurological and Mental Health Global Epidemiology Network (NeuroGEN). Methods: An online 132-item questionnaire was sent to key researchers and data custodians of NeuroGEN in North America, Europe, Asia and Oceania. From the responses, we assessed data characteristics including population coverage, data follow-up, clinical information, validity of diagnoses, medication use and data latency. We also evaluated the possibility of conversion into a common data model (CDM) to implement a federated network approach. Moreover, we used radar charts to visualize the data capacity assessments, based on different perspectives. Results: The results indicated that the 15 databases covered approximately 320 million individuals, included in 7 nationwide claims databases from Australia, Finland, South Korea, Taiwan and the US, 6 population-based electronic health record databases from Hong Kong, Scotland, Taiwan, the Netherlands and the UK, and 2 biomedical databases from Taiwan and the UK. Conclusion: The 15 databases showed good potential for a federated network approach using a common data model. Our study provided publicly accessible information on these databases for those seeking to employ real-world data to facilitate current assessment and future development of treatments for neurological and mental disorders.

Risk of cardiovascular events after an exacerbation of chronic obstructive pulmonary disease: results from the EXACOS-CV cohort study using the PHARMO Data Network in the Netherlands.

BACKGROUND: People living with chronic obstructive pulmonary disease (COPD) have an increased risk of experiencing cardiovascular (CV) events, particularly after an exacerbation. Such CV burden is not yet known for incident COPD patients. We examined the risk of severe CV events in incident COPD patients in periods following either moderate and/or severe exacerbations. METHODS: Persons aged ≥ 40 years with an incident COPD diagnosis from the PHARMO Data Network were included. Exposed time periods included 1-7, 8-14, 15-30, 31-180 and 181-365 days following an exacerbation. Moderate exacerbations were defined as those managed in outpatient settings; severe exacerbations as those requiring hospitalisation. The outcome was a composite of time to first severe CV event (acute coronary syndrome, heart failure decompensation, cerebral ischaemia, or arrhythmia) or death. Hazard ratios (HR) were estimated for association between each exposed period and outcome. RESULTS: 8020 patients with newly diagnosed COPD were identified. 2234 patients (28%) had ≥ 1 exacerbation, 631 patients (8%) had a non-fatal CV event, and 461 patients (5%) died during a median follow-up of 36 months. The risk of experiencing the composite outcome was increased following a moderate/severe exacerbation as compared to time periods of stable disease [range of HR: from 15.3 (95% confidence interval 11.8-20.0) in days 1-7 to 1.3 (1.0-1.8) in days 181-365]. After a moderate exacerbation, the risk was increased over the first 180 days [HR 2.5 (1.3-4.8) in days 1-7 to 1.6 (1.3-2.1) in days 31-180]. After a severe exacerbation, the risk increased substantially and remained higher over the year following the exacerbation [HR 48.6 (36.9-64.0) in days 1-7 down to 1.6 (1.0-2.6) in days 181-365]. Increase in risk concerned all categories of severe CV events. CONCLUSIONS: Among incident COPD patients, we observed a substantial risk increase of severe CV events or all-cause death following either a moderate or severe exacerbation of COPD. Increase in risk was highest in the initial period following an exacerbation. These findings highlight the significant cardiopulmonary burden among people living with COPD even with a new diagnosis.

Non-steroidal anti-inflammatory drugs and risk of myocardial infarction adjusting for use of proton pump-inhibitors in patients with no major risk factors: a nested case-control study in the UK Clinical Practice Research Datalink.

AIMS: Studies have found an increased risk of myocardial infarction (MI) in association with some non-steroidal anti-inflammatory drugs (NSAIDs). We evaluated this association in patients without major cardiovascular risk factors and assessed potential reverse causality bias. METHODS AND RESULTS: In this nested case-control study of patients aged 40-79 in Clinical Practice Research Datalink GOLD who received at least one NSAID prescription between 2006 and 2019, we found 8639 MI cases and 34 556 matched controls. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for MI comparing NSAID users to non-exposed according to the number and timing of NSAID prescriptions and proton-pump inhibitor (PPI) use. Current diclofenac use was associated with a two-fold increased risk of MI regardless of duration of use (adjusted OR, 2.08; 95% CI, 1.82-2.38). ORs ranged from 3 to 5 among current and recent diclofenac users newly exposed to PPIs. There was no spike in risk in new current diclofenac users not exposed to PPIs, but ORs rose with increasing prescriptions. The risk of MI in ibuprofen users was concentrated in new PPI users. There was no material increased risk in naproxen users, nor in past users of most NSAIDs in the absence of PPIs. CONCLUSION: The risk of MI was elevated in current diclofenac users, particularly in new concomitant PPI users. ORs increased in new users of ibuprofen and PPIs but declined with extended use and were lower in non-PPI users. This suggests that some of the findings may be explained by reverse causality bias.

Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study.

BACKGROUND: While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis. METHODS AND FINDINGS: We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001-0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males.Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings. CONCLUSIONS: We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.