New opportunities for antioxidants in amelioration of neurodegenerative diseases.

This comprehensive review elucidates the critical role of antioxidants to mitigate oxidative stress, a common denominator in an array of neurodegenerative disorders. Oxidative stress-induced damage has been linked to the development of diseases such as Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis. This article examines a wide range of scientific literature and methodically delineates the several methods by which antioxidants exercise their neuroprotective benefits. It also explores into the complex relationship between oxidative stress and neuroinflammation, focusing on how antioxidants can alter signaling pathways and transcription factors to slow neurodegenerative processes. Key antioxidants, such as vitamins C and E, glutathione, and polyphenolic compounds, are tested for their ability to combat reactive oxygen and nitrogen species. The dual character of antioxidants, which operate as both direct free radical scavengers and regulators of cellular redox homeostasis, is investigated in terms of therapeutic potential. Furthermore, the study focuses on new antioxidant-based therapy techniques and their mechanisms including Nrf-2, PCG1α, Thioredoxin etc., which range from dietary interventions to targeted antioxidant molecules. Insights into ongoing clinical studies evaluating antioxidant therapies in neurodegenerative illnesses offer an insight into the translational potential of antioxidant research. Finally, this review summarizes our present understanding of antioxidant processes in neurodegenerative illnesses, providing important possibilities for future study and treatment development.

Social health and subsequent cognitive functioning in people aged 50 years and older: examining the mediating roles of depressive symptoms and inflammatory biomarkers in two European longitudinal studies.

BACKGROUND: Social health markers, including marital status, contact frequency, network size, and social support, have been shown to be associated with cognition. However, the mechanisms underlying these associations remain poorly understood. We investigated whether depressive symptoms and inflammation mediated associations between social health and subsequent cognition. METHODS: In the English Longitudinal Study of Ageing (ELSA), a nationally representative longitudinal study in England, UK, we sampled 7136 individuals aged 50 years or older living in private households without dementia at baseline or at the intermediate mediator assessment timepoint, who had recorded information on at least one social health marker and potential mediator. We used four-way decomposition to examine to what extent depressive symptoms, C-reactive protein, and fibrinogen mediated associations between social health and subsequent standardised cognition (verbal fluency and delayed and immediate recall), including cognitive change, with slopes derived from multilevel models (12-year slope). We examined whether findings were replicated in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a population-based longitudinal study in Sweden, in a sample of 2604 individuals aged 60 years or older living at home or in institutions in Kungsholmen (central Stockholm) without dementia at baseline or at the intermediate mediator assessment timepoint (6-year slope). Social health exposures were assessed at baseline, potential mediators were assessed at an intermediate timepoint (wave 2 in ELSA and 6-year follow-up in SNAC-K); cognitive outcomes were assessed at a single timepoint (wave 3 in ELSA and 12-year follow-up in SNAC-K), and cognitive change (between waves 3 and 9 in ELSA and between 6-year and 12-year follow-ups in SNAC-K). FINDINGS: The study sample included 7136 participants from ELSA, of whom 3962 (55·5%) were women and 6934 (97·2%) were White; the mean baseline age was 63·8 years (SD 9·4). Replication analyses included 2604 participants from SNAC-K, of whom 1604 (61·6%) were women (SNAC-K did not collect ethnicity data); the mean baseline age was 72·3 years (SD 10·1). In ELSA, we found indirect effects via depressive symptoms of network size, positive support, and less negative support on subsequent verbal fluency, and of positive support on subsequent immediate recall (pure indirect effect [PIE] 0·002 [95% CI 0·001-0·003]). Depressive symptoms also partially mediated associations between less negative support and slower decline in immediate recall (PIE 0·001 [0·000-0·002]) and in delayed recall (PIE 0·001 [0·000-0·002]), and between positive support and slower decline in immediate recall (PIE 0·001 [0·000-0·001]). We did not observe mediation by inflammatory biomarkers. Findings of mediation by depressive symptoms in the association between positive support and verbal fluency and between positive support and change in immediate recall were replicated in SNAC-K. INTERPRETATION: The findings of this study provide new insights into mechanisms linking social health with cognition, suggesting that associations between interactional aspects of social health, especially social support, and cognition are partly underpinned by depressive symptoms. FUNDING: EU Joint Programme-Neurodegenerative Disease Research (JPND) and Alzheimer's Society. TRANSLATION: For the Swedish translation of the abstract see Supplementary Materials section.

Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia.

Importance: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. Objective: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases. Design, Setting, and Participants: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022. Exposures: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations. Main Outcomes and Measures: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses. Results: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke. Conclusions: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.

Evolution of Clinical Simulation Training and Pandemic-Led Acceleration: The International Medical University (IMU), Malaysia Journey.

In many universities, simulation-based learning has finally been inducted as a member of 'the accepted teaching modality community'. This paper is to share the challenges and successes in the journey towards the inclusion of simulation-based learning in the medical curriculum at the authors' university which saw a steep surge during the COVID-19 pandemic. Our teaching and learning that was heavily traditional based went through a dramatic change to adapt to the new norm when the actual environment and patients became out of reach. We followed five factors (5 Fs) that significantly influenced the successful change: fast, force, fellowship, flexibility, and favourable reception.

Racial and Socioeconomic Differences and Surgical Outcomes in Pancreaticoduodenectomy Patients: A Systematic Review of High- Versus Low-Volume Hospitals in the United States.

BACKGROUND: Pancreaticoduodenectomy (PD) is associated with better outcomes in high-volume hospitals. However, it is unknown whether and to what extent the improved performance of high-volume hospitals may be associated with racial and socioeconomic factors, which have been shown to impact operative and postoperative outcomes in major surgeries. This review aims to identify the differences in racial and socioeconomic characteristics of patients who underwent PD surgery in high- and low-volume hospitals. METHODS: PubMed, Cochrane, and Web of Science were systematically searched between May 1, 2023 and May 7, 2023 without any time restriction on publication date. Studies that were conducted in the United States and had a direct comparison between high- and low-volume hospitals were included. RESULTS: A total of 30 observational studies were included. When racial proportions were compared by hospital volume, thirteen studies reported that compared to high-volume hospitals, a higher percentage of racial minorities underwent PD in low-volume hospitals. Disparities in traveling distance, education levels, and median income at baseline between high- and low-volume hospitals were reported by four, three, and two studies, respectively. CONCLUSION: A racial difference at baseline between high- and low-volume hospitals was observed. Socioeconomic factors were less frequently included in existing literature. Future studies are needed to understand the socioeconomic differences between patients receiving PD surgery in high- and low-volume hospitals.

Bone mineral density and the risk of incident dementia: A meta-analysis.

BACKGROUND: It is not known whether bone mineral density (BMD) measured at baseline or as the rate of decline prior to baseline (prior bone loss) is a stronger predictor of incident dementia or Alzheimer's disease (AD). METHODS: We performed a meta-analysis of three longitudinal studies, the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Rush Memory and Aging Project (MAP), modeling the time to diagnosis of dementia as a function of BMD measures accounting for covariates. We included individuals with one or two BMD assessments, aged ≥60 years, and free of dementia at baseline with follow-up available. BMD was measured at the hip femoral neck using dual-energy X-ray absorptiometry (DXA), or at the heel calcaneus using quantitative ultrasound to calculate estimated BMD (eBMD). BMD at study baseline ("baseline BMD") and annualized percentage change in BMD prior to baseline ("prior bone loss") were included as continuous measures. The primary outcome was incident dementia diagnosis within 10 years of baseline, and incident AD was a secondary outcome. Baseline covariates included age, sex, body mass index, ApoE4 genotype, and education. RESULTS: The combined sample size across all three studies was 4431 with 606 incident dementia diagnoses, 498 of which were AD. A meta-analysis of baseline BMD across three studies showed higher BMD to have a significant protective association with incident dementia with a hazard ratio of 0.47 (95% CI: 0.23-0.96; p = 0.038) per increase in g/cm2 , or 0.91 (95% CI: 0.84-0.995) per standard deviation increase. We observed a significant association between prior bone loss and incident dementia with a hazard ratio of 1.30 (95% CI: 1.12-1.51; p < 0.001) per percent increase in prior bone loss only in the FHS cohort. CONCLUSIONS: Baseline BMD but not prior bone loss was associated with incident dementia in a meta-analysis across three studies.

The clozapine conundrum: Navigating neutropenia and the pursuit of effective care in treatment-resistant schizophrenia.

Background: This case explores the challenges encountered in managing treatment-resistant paranoid schizophrenia, focusing on the limitations of using Clozapine due to the risk of neutropenia. The United Kingdom Clozapine Patient Monitoring Service (UK CPMS) and its eligibility criteria are discussed, highlighting the potential benefits of expanding access to Clozapine for patients who could potentially benefit from this medication. The integration of Clozapine genetic testing as a personalised approach is explored, emphasising the importance of identifying patients with a favourable genetic profile for Clozapine response. Study Sample: The case presentation of Mr. X exemplifies the difficulties faced in managing treatment-resistant schizophrenia when access to Clozapine is restricted, leading to persistent negative symptoms. Conclusion: The article underscores the importance of innovative solutions and personalized care to enhance the treatment outcomes for patients with treatment-resistant paranoid schizophrenia. It acknowledges that certain restrictions can limit the effectiveness of treatment for individuals in this context.

The association between polypharmacy and health-related quality of life among non-dialysis chronic kidney disease patients.

BACKGROUND AND OBJECTIVE: The United States government spends over $85 billion annually on treating non-dialysis chronic kidney disease (CKD). Patients with CKD are prescribed a multitude of medications to manage numerous comorbidities associated with CKD. Thus, this study aims to investigate the association between polypharmacy and health-related quality of life (HRQoL) in non-dialysis CKD patients. METHODS: This cross-sectional study utilized data from the Medical Expenditure Panel Survey (MEPS) from 2010 through 2019. We classified polypharmacy into three groups based on the number of medication classes: ≤ 4 (minor polypharmacy), 5 through 9 (major polypharmacy), and ≥ 10 (hyperpolypharmacy). To measure HRQoL, a Physical Component Summary (PCS) and a Mental Component Summary (MCS) were obtained from the 12-item Short-Form Health Survey version 2 and Veteran's Rand 12 item. We applied multivariable ordinary least squares regression to assess the association between polypharmacy and HRQoL in non-dialysis CKD patients. RESULTS: A total of 649 CKD patients (weighted n = 667,989) were included. Patients with minor polypharmacy, major polypharmacy, and hyperpolypharmacy were 22.27%, 48.24%, and 29.48%, respectively. Major polypharmacy and hyperpolypharmacy were significantly and negatively associated with lower PCS scores when compared with minor polypharmacy [Beta = -3.12 (95% CI: -3.62, -2.62), p-value<0.001; Beta = -4.13 (95CI: -4.74, -3.52), p-value<0.001]. Similarly, major polypharmacy and hyperpolypharmacy were significantly and negatively associated with lower MCS scores when compared to minor polypharmacy [Beta = -0.38 (95% CI: -0.55, -0.20), p-value<0.001; Beta = -1.70 (95% CI: -2.01, -1.40), p-value<0.001]. The top 5 classes of medications used by CKD patients were antihyperlipidemic (56.31%), beta-adrenergic blockers (49.71%), antidiabetics (42.14%), analgesics (42.17%), and diuretics (39.65%). CONCLUSION: Our study found that both major polypharmacy and hyperpolypharmacy were associated with lower HRQoL among non-dialysis CKD patients. This study highlights the need for further evaluation of the combination of medications taken by non-dialysis CKD patients to minimize unnecessary and inappropriate medication use.

Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.

Importance: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear. Objective: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia. Design Setting and Participants: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022. Exposures: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke. Main outcomes and measures: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (ADmeta, n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses. Results: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of ADmeta (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and ADmeta, with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke. Conclusion: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.

Diagnostic challenge of Creutzfeldt-Jakob disease in a patient with multimorbidity: a case-report.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and ultimately fatal neurodegenerative condition caused by prions. The clinical symptoms of CJD vary with its subtype, and may include dementia, visual hallucinations, myoclonus, ataxia, (extra)pyramidal signs and akinetic mutism. In the early course of disease however, several clinical symptoms of CJD may mimic those of co-existing morbidities. CASE PRESENTATION: We report a male in his 60s with a history of situs inversus totalis and Churg Strauss syndrome, who presented with speech fluency disturbances, neuropsychiatric symptoms and allodynia, a few months after becoming a widower. Initially presumed a bereavement disorder along with a flare-up of Churg Strauss, his symptoms gradually worsened with apraxia, myoclonic jerks and eventually, akinetic mutism. MRI revealed hyperintensities at the caudate nucleus and thalami, while the cerebrospinal fluid was positive for the 14-3-3 protein and the real-time quick test, making the diagnosis of CJD highly probable. This case illustrates the complexities that may arise in diagnosing CJD when pre-existing multimorbidity may cloud the clinical presentation. We also discuss the potential mechanisms underlying the co-occurrence of three rare conditions (situs inversus totalis, Churg Strauss syndrome, CJD) in one patient, taking into consideration the possibility of coincidence as well as common underlying factors. CONCLUSIONS: The diagnosis of CJD may be easily missed when its clinical symptoms are obscured by those of pre-existing (rare) multimorbidity. This case highlights that when the multimorbidity has neurological manifestations, an extensive evaluation remains crucial to establish the diagnosis, minimize the risk of prion-transmission and provide appropriate guidance to patients and their caregivers.

Social Health and Change in Cognitive Capability among Older Adults: Findings from Four European Longitudinal Studies.

INTRODUCTION: In this study, we examine whether social health markers measured at baseline are associated with differences in cognitive capability and the rate of cognitive decline over an 11-to-18-year period among older adults and compare results across studies. METHODS: We applied an integrated data analysis approach to 16,858 participants (mean age 65 years; 56% female) from the National Survey for Health and Development (NSHD), the English Longitudinal Study of Aging (ELSA), the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), and the Rotterdam Study. We used multilevel models to examine social health in relation to cognitive capability and the rate of cognitive decline. RESULTS: Pooled estimates show distinct relationships between markers of social health and cognitive domains, e.g., a large network size (≥6 people vs. none) was associated with higher executive function (0.17 standard deviation [SD] [95% CI: 0.00, 0.34], I2 = 27%) but not with memory (0.08 SD [95% CI: -0.02, 0.18], I2 = 19%). We also observed pooled associations between being married or cohabiting, having a large network size, and participating in social activities with slower decline in cognitive capability. However, estimates were close to zero, e.g., 0.01 SD/year (95% CI: 0.01, 0.02) I2 = 19% for marital status and executive function. There were clear study-specific differences: results for average processing speed were the most homogenous, and results for average memory were the most heterogeneous. CONCLUSION: Overall, markers of good social health have a positive association with cognitive capability. However, we found differential associations between specific markers of social health and cognitive domains and differences between studies. These findings highlight the importance of examining between-study differences and considering the context specificity of findings in developing and deploying interventions.

Unraveling Neuro-Proteogenomic Landscape and Therapeutic Implications for Human Behaviors and Psychiatric Disorders.

Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.

Projections of costs and quality adjusted life years lost due to dementia from 2020 to 2050: A population-based microsimulation study.

INTRODUCTION: Efficient healthcare planning requires reliable projections of the future increase in costs and quality-adjusted life years (QALYs) lost due to dementia. METHODS: We used the microsimulation model MISCAN-Dementia to simulate life histories and dementia occurrence using population-based Rotterdam Study data and nationwide birth cohort demographics. We estimated costs and QALYs lost in the Netherlands from 2020 to 2050, incorporating literature estimates of cost and utility for patients and caregivers by dementia severity and care setting. RESULTS: Societal costs and QALYs lost due to dementia are estimated to double between 2020 and 2050. Costs are incurred predominantly through institutional (34%), formal home (31%), and informal home care (20%). Lost QALYs are mostly due to shortened life expectancy (67%) and, to a lesser extent, quality of life with severe dementia (14%). DISCUSSION: To limit healthcare costs and quality of life losses due to dementia, interventions are needed that slow symptom progression and reduce care dependency.

Genetic mechanisms of 184 neuro-related proteins in human plasma.

Understanding the genetic basis of neuro-related proteins is essential for dissecting the disease etiology of neuropsychiatric disorders and other complex traits and diseases. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-reiated proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-reiated traits as well as complex diseases such as hypertension, high cholesterol, immune-related disorders, and psychiatric disorders. Integrating with established drug information, we validated 13 combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets for diseases and comorbidities. This consortium effort provides a large-scale proteogenomic resource for biomedical research.

Factors associated with COVID-19-related mental health among Asian Indians in the United States.

Background: In the United States, the COVID-19 pandemic has caused increased mental health symptoms and mental illness. Specific subgroups such as Asian Indians in the US have also been subject to additional stressors due to unprecedented loss of lives in their home country and increased Asian hate due to the misperception that Asians are to be blamed for the spread of the SARS-CoV-2. Objective: We examined the various factors including discrimination associated with COVID-19-related mental health symptoms among Asian Indians. Methods: We administered an online survey between May 2021 and July 2021 using convenient and snowball sampling methods to recruit Asian Indian adults (age > 18 years, N = 289). The survey included questions on mental health and the experience with unfair treatment in day-to-day life. Descriptive analysis and logistic regressions were performed. Results: Overall, 46.0% reported feeling down, depressed, or lonely and feeling nervous, tense, or worried due to the COVID-19 pandemic; 90.0% had received at least one dose of vaccination and 74.7% reported some form of discrimination. In the fully-adjusted logistic regression, age (AOR = 0.95; 95%CI- 0.92, 0.97;p < 0.01) and general health (AOR=0.84; 95%CI- 0.73, 0.97; p < 0.015) were negatively associated with mental health symptoms. Participants who experienced discrimination were more likely (AOR=1.26; 95%CI- 1.08, 1.46; p < 0.01) to report mental health symptoms. Conclusion: In this highly vaccinated group of Asian Indians discriminatory behaviors were associated with mental health symptoms suggesting the need for novel institutional level policy responses to reduce anti-Asian racism.

Subcortical brain structures and the risk of dementia in the Rotterdam Study.

INTRODUCTION: Volumetric and morphological changes in subcortical brain structures are present in persons with dementia, but it is unknown if these changes occur prior to diagnosis. METHODS: Between 2005 and 2016, 5522 Rotterdam Study participants (mean age: 64.4) underwent cerebral magnetic resonance imaging (MRI) and were followed for development of dementia until 2018. Volume and shape measures were obtained for seven subcortical structures. RESULTS: During 12 years of follow-up, 272 dementia cases occurred. Mean volumes of thalamus (hazard ratio [HR] per standard deviation [SD] decrease 1.94, 95% confidence interval [CI]: 1.55-2.43), amygdala (HR 1.66, 95% CI: 1.44-1.92), and hippocampus (HR 1.64, 95% CI: 1.43-1.88) were strongly associated with dementia risk. Associations for accumbens, pallidum, and caudate volumes were less pronounced. Shape analyses identified regional surface changes in the amygdala, limbic thalamus, and caudate. DISCUSSION: Structure of the amygdala, thalamus, hippocampus, and caudate is associated with risk of dementia in a large population-based cohort of older adults.

Genome-wide profiling of circulatory microRNAs associated with cognition and dementia.

INTRODUCTION: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Their role in the pathophysiology of dementia and potential as biomarkers remains undetermined. METHODS: We conducted a single- (one-by-one) and multi-marker (joint) analysis to identify well-expressed circulating miRNAs in plasma (total = 591) associated with general cognition and incident dementia, for 1615 participants of the population-based Rotterdam Study. RESULTS: During single-marker analysis, 47 miRNAs were nominally (P ≤ .05) associated with cognition and 18 miRNAs were nominally associated with incident dementia, after adjustment for potential confounders. Three miRNAs were common between cognition and dementia (miR-4539, miR-372-3p, and miR-566), with multi-marker analysis revealing another common miRNA (miR-7106-5p). In silico analysis of these four common miRNAs led to several putative target genes expressed in the brain, highlighting the mitogen-activated protein kinase signaling pathway. DISCUSSION: We provide population-based evidence on the relationship between circulatory miRNAs with cognition and dementia, including four common miRNAs that may elucidate downstream mechanisms. HIGHLIGHTS: MicroRNAs (miRNAs) are involved in the (dys)function of the central nervous system. Four circulating miRNAs in plasma are associated with cognition and incident dementia. Several predicted target genes of these four miRNAs are expressed in the brain. These four miRNAs may be linked to pathways underlying dementia. Although miRNAs are promising biomarkers, experimental validation remains essential.

A Linear Decomposition Approach to Explain Excess Direct Healthcare Expenditures Associated with Pain Among Adults with Osteoarthritis.

Objective: Many patients with osteoarthritis experience pain which can lead to higher healthcare expenditures. It is important to understand the factors that drive the excess expenditures associated with pain in osteoarthritis. Design: Cross-sectional. Study sample: Our study sample consisted of adults (age ⩾ 18 years) from the Medical Expenditure Panel Survey (MEPS, 2018). Methods: Adults who were alive during the calendar year and had pain status were included in this study (N = 2804 weighted N = 32.03 million). Osteoarthritis was identified from the medical conditions file and household file. We used multivariable ordinary least squares regression to identify the statistically significant association of pain with direct healthcare expenditures. The Blinder-Oaxaca post-linear decomposition on log-transformed total direct healthcare expenditures was used to estimate the extent to which differences in characteristics contribute to the excess expenditures associated with pain. Results: Adults with osteoarthritis and pain had higher average expenditures ($21 814 vs $10 827, P < .001; 9.318 vs 8.538 in logtransformed expenditures) compared to those without pain. Pooled regression weights explained 62.9% of excess expenditures differences in characteristics between the 2 groups. The 2 main drivers of excess healthcare expenditures among adults with osteoarthritis and pain were (i) comorbidities (diabetes, asthma, chronic obstructive pulmonary disease, depression, heart diseases, cancer, and non-cancer pain conditions and (ii) prescription medications (NSAIDs, opioids, and polypharmacy). Conclusion: Need factors such as comorbid conditions, and prescription treatment explained the excess healthcare expenditures among adults with osteoarthritis and pain. The study findings suggest that reducing polypharmacy and appropriate management of comorbid conditions may be a pathway to reduce excess expenditures among adults with osteoarthritis and pain.

Time spent in physical activity, sedentary behavior, and sleep: Associations with self-rated sleep quality in middle-aged and older adults.

OBJECTIVES: We examined the associations of estimated allocations of time spent in physical activity, sedentary behavior and sleep with self-rated sleep quality. METHODS: Between 2011 and 2016, 1918 participants (mean age 71 ± 9 years, 51% women) from the population-based Rotterdam Study were included. Durations of light physical activity, moderate-to-vigorous physical activity, sedentary behavior, and sleep were assessed by accelerometry, self-rated sleep quality with the Pittsburgh Sleep Quality Index. Associations were assessed with compositional isotemporal substitution analyses. RESULTS: Spending 30 minutes more in sedentary behavior (adjusted mean difference in PSQI score: 0.21, 95% confidence interval [0.15; 0.28] or in light physical activity (adjusted mean difference in PSQI score: 0.25 [0.03; 0.46], and 30 minutes less in sleep, was associated with poorer sleep quality. CONCLUSIONS: Our findings suggest reducing sedentary behavior and increasing sleep duration might be a potential intervention target to improve sleep quality in this population of middle-aged and older adults.

Metabolomic profiles predict individual multidisease outcomes.

Risk stratification is critical for the early identification of high-risk individuals and disease prevention. Here we explored the potential of nuclear magnetic resonance (NMR) spectroscopy-derived metabolomic profiles to inform on multidisease risk beyond conventional clinical predictors for the onset of 24 common conditions, including metabolic, vascular, respiratory, musculoskeletal and neurological diseases and cancers. Specifically, we trained a neural network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured in 117,981 participants with ~1.4 million person-years of follow-up from the UK Biobank and validated the model in four independent cohorts. We found metabolomic states to be associated with incident event rates in all the investigated conditions, except breast cancer. For 10-year outcome prediction for 15 endpoints, with and without established metabolic contribution, a combination of age and sex and the metabolomic state equaled or outperformed established predictors. Moreover, metabolomic state added predictive information over comprehensive clinical variables for eight common diseases, including type 2 diabetes, dementia and heart failure. Decision curve analyses showed that predictive improvements translated into clinical utility for a wide range of potential decision thresholds. Taken together, our study demonstrates both the potential and limitations of NMR-derived metabolomic profiles as a multidisease assay to inform on the risk of many common diseases simultaneously.