Potentially Modifiable Risk Factors for Dementia and Mild Cognitive Impairment: An Umbrella Review and Meta-Analysis.

INTRODUCTION: The prevalence of mild and major neurocognitive disorders (NCDs), also referred to as mild cognitive impairment and dementia, is rising globally. The prevention of NCDs is a major global public health interest. We sought to synthesize the literature on potentially modifiable risk factors for NCDs. METHODS: We conducted an umbrella review using a systematic search across multiple databases to identify relevant systematic reviews and meta-analyses. Eligible reviews examined potentially modifiable risk factors for mild or major NCDs. We used a random-effects multi-level meta-analytic approach to synthesize risk ratios for each risk factor while accounting for overlap in the reviews. We further examined risk factors for major NCD due to two common etiologies: Alzheimer's disease and vascular dementia. RESULTS: A total of 45 reviews with 212 meta-analyses were synthesized. We identified fourteen broadly defined modifiable risk factors that were significantly associated with these disorders: alcohol consumption, body weight, depression, diabetes mellitus, diet, hypertension, less education, physical inactivity, sensory loss, sleep disturbance, smoking, social isolation, traumatic brain injury, and vitamin D deficiency. All 14 factors were associated with the risk of major NCD, and five were associated with mild NCD. We found considerably less research for vascular dementia and mild NCD. CONCLUSION: Our review quantifies the risk associated with 14 potentially modifiable risk factors for mild and major NCDs, including several factors infrequently included in dementia action plans. Prevention strategies should consider approaches that reduce the incidence and severity of these risk factors through health promotion, identification, and early management.

The Effects of Cognitive Ability, Mental Health, and Self-Quarantining on Functional Ability of Older Adults During the COVID-19 Pandemic: Results From the Canadian Longitudinal Study on Aging.

OBJECTIVES: Determine whether levels of anxiety and depression, cognitive ability, and self-quarantining during and prior to the pandemic predict decreases in perceived functional ability. DESIGN AND SETTING: Longitudinal data collected from the Canadian Longitudinal Study on Aging (CLSA) COVID-19 Questionnaire Study (2020) and core CLSA study (Follow-Up 1; 2014-2018). PARTICIPANTS: 17 541 CLSA participants. MEASUREMENTS: Self-quarantining behaviours from questionnaires administered at Baseline (April 2020), Monthly, and Exit (December 2020) time points of the CLSA COVID-19 Questionnaire Study, levels of anxiety and depression at Baseline, perceived change in functional ability at Exit, and performance on neuropsychological tests (Rey Auditory Verbal Learning Task, Mental Alternation Task, Animal Fluency Test) and functional ability (Older Americans Resources and Services [OARS] Multidimensional Assessment Questionnaire) from the core CLSA study. RESULTS: Greater cognitive ability pre-pandemic (B = -.003, P < .01), higher levels of anxiety (B = -.024, P < .01) and depressive symptoms (B = -.110, P < .01) at Baseline, and higher frequency of engaging in self-quarantining throughout the COVID-19 survey period (B = -.098, P < .01) were associated with perceived loss in functional ability at Exit. Self-quarantining behaviour was associated with perceived loss in functional ability only at average and high levels of depressive symptoms (B = -.013, P < .01). CONCLUSIONS: Older adults with higher cognitive and lower functional ability prior to the pandemic were at greater risk of decreased perceived functional ability during the first year of the pandemic, as were those who experienced greater levels of anxiety and depressive symptoms during the pandemic. Strategies/interventions to preserve functional ability in older adults with cognitive independence prior to future pandemics are warranted.

Influenza vaccine coverage and factors associated with non-vaccination among caregiving and care-receiving adults in the Canadian Longitudinal Study on Aging (CLSA).

BACKGROUND: Influenza vaccination is recommended for those at increased risk of influenza complications and their household contacts to help reduce influenza exposure. Adults who require care often experience health issues that could increase the risk of severe influenza and have close contact with caregivers. Assessing influenza vaccination prevalence in caregivers and care recipients can provide important information about uptake. OBJECTIVES: We aimed to (1) estimate influenza non-vaccination prevalence and (2) assess factors associated with non-vaccination among caregivers aged ≥ 45 years and among care recipients aged ≥ 65 years. METHODS: We conducted an analysis of cross-sectional data from the Canadian Longitudinal Study on Aging collected 2015-2018. We estimated non-vaccination prevalence and reported adjusted odds ratios with 95% confidence intervals from logistic regression models to identify factors associated with non-vaccination among caregivers and care recipients. RESULTS: Of the 23,500 CLSA participants who reported providing care, 41.4% (95% CI: 40.8%, 42.0%) reported not receiving influenza vaccine in the previous 12 months. Among the 5,559 participants who reported receiving professional or non-professional care, 24.8% (95% CI: 23.7%, 26.0%) reported not receiving influenza vaccine during the same period. For both groups, the odds of non-vaccination were higher for those who had not visited a family doctor in the past year, were daily smokers, and those who identified as non-white. DISCUSSION: Identifying groups at high risk of severe influenza and their close contacts can inform public health efforts to reduce the risk of influenza. Our results suggest sub-optimal influenza vaccination uptake among caregivers and care recipients. Efforts are needed to increase influenza vaccination and highlight the direct and indirect benefits for caregiver-care recipient pairs. CONCLUSION: The proportions of both caregivers and care recipients who had not been vaccinated for influenza was high, despite the benefits of vaccination. Influenza vaccination campaigns could target undervaccinated, high-risk groups to increase coverage.

Obesity and adverse childhood experiences in relation to stress during the COVID-19 pandemic: an analysis of the Canadian Longitudinal Study on Aging.

BACKGROUND: People with obesity are at increased risk of chronic stress, and this may have been exacerbated during the COVID-19 pandemic. Adverse childhood experiences (ACE) are also associated with both obesity and stress, and may modify risk of stress among people with obesity. The objectives of this study were to evaluate the associations between obesity, ACEs, and stress during the pandemic, and to determine if the association between obesity and stress was modified by ACEs. METHODS: A longitudinal study was conducted among adults aged 50-96 years (n = 23,972) from the Canadian Longitudinal Study on Aging (CLSA) COVID-19 Study. Obesity and ACEs were collected pre-pandemic (2015-2018), and stress was measured at COVID-19 Exit Survey (Sept-Dec 2020). We used logistic, Poisson, and negative binomial regression to estimate relative risks (RRs) and 95% confidence intervals (CIs) for the associations between obesity, ACEs, and stress outcomes during the pandemic. Interaction by ACEs was evaluated on the additive and multiplicative scales. RESULTS: People with obesity were more likely to experience an increase in overall stressors (class III obesity vs. healthy weight RR = 1.19; 95% CI: 1.12-1.27) as well as increased health related stressors (class III obesity vs. healthy weight RR: 1.25; 95% CI: 1.12-1.39) but did not perceive the consequences of the pandemic as negative. ACEs were also associated an increase in overall stressors (4-8 ACEs vs. none RR = 1.38; 95% CI: 1.33-1.44) and being more likely to perceive the pandemic as negative (4-8 ACEs vs. none RR = 1.32; 95% CI: 1.19-1.47). The association between obesity and stress was not modified by ACEs. CONCLUSIONS: Increased stress during the first year of the COVID-19 pandemic was observed among people with obesity or ACEs. The long-term outcomes of stress during the pandemic need to be determined.

A national case-control study investigating demographic and environmental factors associated with NMOSD.

BACKGROUND: Risk factors for aquaporin-4 (AQP4+) antibody neuromyelitis optica spectrum disorder (NMOSD) are not well-established. OBJECTIVE: To investigate demographic and environmental factors associated with NMOSD using a validated questionnaire and case-control design. METHODS: We enrolled patients with AQP4 + NMOSD through six Canadian Multiple Sclerosis Clinics. Participants completed the validated Environmental Risk Factors in Multiple Sclerosis Study (EnvIMS) questionnaire. Their responses were compared to those of 956 unaffected controls from the Canadian arm of EnvIMS. We calculated odds ratios (ORs) for the association between each variable and NMOSD using logistic regression and Firth's procedure for rare events. RESULTS: In 122 participants (87.7% female) with NMOSD, odds of NMOSD in East Asian and Black participants were ⩾8 times that observed in White participants. Birthplace outside Canada was associated with an increased risk of NMOSD (OR = 5.5, 95% confidence interval (CI) = 3.6-8.3) as were concomitant autoimmune diseases (OR = 2.7, 95% CI = 1.4-5.0). No association was observed with reproductive history or age at menarche. CONCLUSION: In this case-control study, risk of NMOSD in East Asian and Black versus White individuals was greater than that observed in many previous studies. Despite the preponderance of affected women, we did not observe any association with hormonal factors such as reproductive history or age at menarche.

Increased prevalence of loneliness and associated risk factors during the COVID-19 pandemic: findings from the Canadian Longitudinal Study on Aging (CLSA).

BACKGROUND: Older adults have been disproportionately impacted by COVID-19 and related preventative measures undertaken during the pandemic. Given clear evidence of the relationship between loneliness and health outcomes, it is imperative to better understand if, and how, loneliness has changed for older adults during the COVID-19 pandemic, and whom it has impacted most. METHOD: We used "pre-pandemic" data collected between 2015-2018 (n = 44,817) and "during pandemic" data collected between Sept 29-Dec 29, 2020 (n = 24,114) from community-living older adults participating in the Canadian Longitudinal Study on Aging. Loneliness was measured using the 3-item UCLA Loneliness Scale. Weighted generalized estimating equations estimated the prevalence of loneliness pre-pandemic and during the pandemic. Lagged logistic regression models examined individual-level factors associated with loneliness during the pandemic. RESULTS: We found the adjusted prevalence of loneliness increased to 50.5% (95% CI: 48.0%-53.1%) during the pandemic compared to 30.75% (95% CI: 28.72%-32.85%) pre-pandemic. Loneliness increased more for women (22.3% vs. 17.0%), those in urban areas (20.8% vs. 14.6%), and less for those 75 years and older (16.1% vs. 19.8% or more in all other age groups). Loneliness during the pandemic was strongly associated with pre-pandemic loneliness (aOR 4.87; 95% CI 4.49-5.28) and individual level sociodemographic factors [age < 55 vs. 75 + (aOR 1.41; CI 1.23-1.63), women (aOR 1.34; CI 1.25-1.43), and no post-secondary education vs. post-secondary education (aOR 0.73; CI 0.61-0.86)], living conditions [living alone (aOR 1.39; CI 1.27-1.52) and urban living (aOR 1.18; CI 1.07-1.30)], health status [depression (aOR 2.08; CI 1.88-2.30) and having two, or ≥ three chronic conditions (aOR 1.16; CI 1.03-1.31 and aOR 1.34; CI 1.20-1.50)], health behaviours [regular drinker vs. non-drinker (aOR 1.15; CI 1.04-1.28)], and pandemic-related factors [essential worker (aOR 0.77; CI 0.69-0.87), and spending less time alone than usual on weekdays (aOR 1.32; CI 1.19-1.46) and weekends (aOR 1.27; CI 1.14-1.41) compared to spending the same amount of time alone]. CONCLUSIONS: As has been noted for various other outcomes, the pandemic did not impact all subgroups of the population in the same way with respect to loneliness. Our results suggest that public health measures aimed at reducing loneliness during a pandemic should incorporate multifactor interventions fostering positive health behaviours and consider targeting those at high risk for loneliness.

Measuring physical performance in later life: reliability of protocol variations for common performance-based mobility tests.

BACKGROUND AND AIMS: Performance-based tests of mobility or physical function such as the Timed Up and Go (TUG), gait speed, chair-rise, and single-leg stance (SLS) are often administered using different protocols in aging populations, however, the reliability of their assessment protocols is not often considered. The purpose of this study was to examine the reliabilities of frequently used assessment protocols for the TUG, gait speed, chair-rise, and SLS in different age groups. METHODS: We administered the following assessment protocols in an age-stratified (50-64, 65-74, 75+ years) sample of participants (N = 147) from the Canadian Longitudinal Study on Aging (CLSA): TUG fast pace and TUG normal pace: TUG-cognitive counting backwards by ones and counting back by threes, gait speed with 3-m and 4-m course, chair-rise with arms crossed and allowing the use of arms, and SLS using preferred leg or both legs-on two occasions within 1 week. We assessed the relative (intra-class correlation) and absolute reliability (standard error of measurement, SEM and minimal detectable change, MDC) for each protocol variation and provided recommendations based on relative reliability. RESULTS: For participants aged 50-64 years, our results suggest better reliability for TUG fast-pace compared with normal-pace (ICC and 95% CI 0.70; 0.41-0.85 versus 0.38; 0.12-0.59). The reliability values for 3-m gait speed were potentially higher than for 4-m gait speed (ICC 0.75; 0.67-0.82 versus 0.64; 0.54-0.73) and values for chair-rise suggested better reliability allowing participants to use their arms than with arms crossed (ICC 0.79; 0.66-0.86 versus 0.64; 0.45-0.77) for participants overall. For participants aged 75+ years, ICCs for SLS with the preferred leg showed better reliability than for both legs (ICC = 0.62-0.79 versus 0.30-0.39). CONCLUSIONS AND DISCUSSION: These reliability data and the recommendations can help guide the selection of the most appropriate performance-based test protocols for measuring mobility in middle-aged and older community-dwelling adults.

Factors Associated With Willingness to Receive a COVID-19 Vaccine Among 23,819 Adults Aged 50 Years or Older: An Analysis of the Canadian Longitudinal Study on Aging.

Identifying persons who are least willing to receive a coronavirus disease 2019 (COVID-19) vaccine is critical for increasing uptake via targeted outreach. We conducted a survey of 23,819 Canadian Longitudinal Study on Aging participants from September 29 to December 29, 2020, to assess factors associated with COVID-19 vaccination willingness and reasons for willingness or lack thereof. Among adults aged 50-96 years, 84.1% (95% confidence interval (CI): 83.7, 84.6) were very or somewhat willing to receive a COVID-19 vaccine; 15.9% (95% CI: 15.4, 16.3) were uncertain or very or somewhat unwilling. Based on logistic regression, those who were younger, female, had lower education and income, were non-White, and lived in a rural area were less willing to receive a COVID-19 vaccine. After controlling for these factors, recent receipt of influenza vaccine (adjusted odds ratio = 14.3, 95% CI: 12.5, 16.2) or planning to receive influenza vaccine (adjusted odds ratio = 10.5, 95% CI: 9.5, 11.6), as compared with no receipt or planning, was most strongly associated with COVID-19 vaccination willingness. Willingness was also associated with believing one had never been infected with severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) and experiencing negative pandemic consequences. Safety concerns were most common among those unwilling. Our comprehensive assessment of COVID-19 vaccination willingness among older adults in Canada, a prioritized group for vaccination due to their risk of severe COVID-19 outcomes, provides a road map for conducting outreach to increase uptake, which is urgently needed.

Bacillus Calmette-Guerin vaccination and multiple sclerosis: A population-based birth cohort study in Quebec, Canada.

BACKGROUND AND PURPOSE: The bacillus Calmette-Guerin (BCG) vaccine could reduce the incidence of multiple sclerosis (MS) through immunomodulation. Previous studies, presenting some limitations, reported no association. We re-examined this association in a large cohort focusing on relapsing-remitting MS (RRMS). METHODS: The cohort included 400,563 individuals, and was linked with the Quebec provincial BCG vaccination registry and administrative health data. Individuals were followed up from 1983 to 2014 and then within Period 1 (1983-1996) and Period 2 (1997-2014), for the occurrence of MS. Incident MS cases were defined as those with ≥3 hospital or physician claims for MS. Subjects with ≥1 drug reimbursement for MS disease-modifying therapies were classified as RRMS. Cox proportional hazards regression was used to estimate hazard ratios (HRs) over the follow-ups, adjusting for potential confounders. Possible effect modification due to sex was assessed. RESULTS: A total of 178,335 (46%) individuals were BCG vaccinated. There were 274 (0.06%) incident MS cases identified in 1983-1996, and 1433 (0.4%) in 1997-2014. No association was found with RRMS, either in Period 1 (adjusted HR [HRadj ] = 0.96, 95% confidence interval [CI] = 0.63-1.45; 96 cases) or in Period 2 (HRadj  = 1.02, 95% CI = 0.85-1.23; 480 cases). The remaining MS cases, for whom the phenotype was unknown, were positively associated with BCG over the entire follow-up (HRadj  = 1.25, 95% CI = 1.10-1.41; 1131 cases) and in Period 2 (HRadj  = 1.33, 95% CI = 1.17-1.52; 953 cases). No interaction with sex was found. CONCLUSIONS: Findings suggest that BCG vaccination does not decrease the risk of RRMS, and that future studies should consider phenotypes of MS.

Symptoms of depression and anxiety, and unmet healthcare needs in adults during the COVID-19 pandemic: a cross-sectional study from the Canadian Longitudinal Study on Aging.

BACKGROUND: The COVID-19 pandemic disrupted access to healthcare services in Canada. Research prior to the pandemic has found that depression and anxiety symptoms were associated with increased unmet healthcare needs. The primary objective of this study was to examine if mental health was associated with perceived access to healthcare during the pandemic METHODS: A cross-sectional study was conducted using data from 23,972 participants (aged 50-96) in the Canadian Longitudinal Study on Aging COVID-19 Exit Survey (Sept-Dec 2020). We used logistic regression to estimate how the presence of depression and anxiety symptoms, defined using scores of ≥10 on the Center for Epidemiologic Studies Depression Scale and ≥10 on the Generalized Anxiety Disorder Scale, were associated with the odds of reporting: 1) challenges accessing healthcare, 2) not going to a hospital or seeing a doctor when needed, 3) experiencing barriers to COVID-19 testing. Models were adjusted for sex, age, region, urban/rural residence, racial background, immigrant status, income, marital status, work status, chronic conditions, and pre-pandemic unmet needs. RESULTS: The presence of depressive (aOR=1.96; 95% CI=1.82, 2.11) and anxiety symptoms (aOR=2.33; 95% CI=2.04, 2.66) compared to the absence of these symptoms were independently associated with higher odds of challenges accessing healthcare. A statistically significant interaction with sex suggested stronger associations in females with anxiety. Symptoms of depression (aOR=2.88; 95% CI=2.58, 3.21) and anxiety (aOR=3.05; 95% CI=2.58, 3.60) were also associated with increased odds of not going to a hospital or seeing a doctor when needed. Lastly, depressive (aOR=1.99; 95% CI=1.71, 2.31) and anxiety symptoms (aOR=2.01; 95% CI=1.58, 2.56) were associated with higher odds of reporting barriers to COVID-19 testing. There was no significantly significant interaction with sex for the latter two outcomes. CONCLUSION: The presence of depression and anxiety symptoms were strongly associated with perceived unmet healthcare needs during the COVID-19 pandemic. Interventions to improve healthcare access for adults with depression and anxiety during the pandemic may be necessary.

Appraising clinical applicability of studies: mapping and synthesis of current frameworks, and proposal of the FrACAS framework and VICORT checklist.

BACKGROUND: Not all research findings are translated to clinical practice. Reasons for lack of applicability are varied, and multiple frameworks and criteria exist to appraise the general applicability of epidemiological and clinical research. In this two-part study, we identify, map, and synthesize frameworks and criteria; we develop a framework to assist clinicians to appraise applicability specifically from a clinical perspective. METHODS: We conducted a literature search in PubMed and Embase to identify frameworks appraising applicability of study results. Conceptual thematic analysis was used to synthesize frameworks and criteria. We carried out a framework development process integrating contemporary debates in epidemiology, findings from the literature search and synthesis, iterative pilot-testing, and brainstorming and consensus discussions to propose a concise framework to appraise clinical applicability. RESULTS: Of the 4622 references retrieved, we identified 26 unique frameworks featuring 21 criteria. Frameworks and criteria varied by scope and level of aggregation of the evidence appraised, target user, and specific area of applicability (internal validity, clinical applicability, external validity, and system applicability). Our proposed Framework Appraising the Clinical Applicability of Studies (FrACAS) classifies studies in three domains (research, practice informing, and practice changing) by examining six criteria sequentially: Validity, Indication-informativeness, Clinical relevance, Originality, Risk-benefit comprehensiveness, and Transposability (VICORT checklist). CONCLUSIONS: Existing frameworks to applicability vary by scope, target user, and area of applicability. We introduce FrACAS to specifically assess applicability from a clinical perspective. Our framework can be used as a tool for the design, appraisal, and interpretation of epidemiological and clinical studies.

Revisiting the hypothesis of syndromic frailty: a cross-sectional study of the structural validity of the frailty phenotype.

BACKGROUND: Fried's Phenotype Model of Frailty (PMF) postulates that frailty is a syndrome. Features of a syndrome are a heterogeneous population that can be split into at least two classes, those presenting and those not presenting the syndrome. Syndromes are characterized by a specific mixture of signs and symptoms which increase in prevalence, from less to more severe classes. So far, the null hypothesis of homogeneity - signs and symptoms of frailty cannot identify at least two classes - has been tested using Latent Class Analysis (LCA) on the five dichotomized components of PMF (unintentional weight loss, exhaustion, weakness, slowness, and low physical activity). The aim of this study is to investigate further the construct validity of frailty as a syndrome using the extension offered by Factor Mixture Models (FMM). METHODS: LCA on dichotomized scores and FMM on continuous scores were conducted to test homogeneity on the five PMF components in a sample of 1643 community-dwelling older adults living in Québec, Canada (FRéLE). RESULTS: With dichotomized LCA, three frailty classes were found: robust, prefrail and frail, and the hypothesis of homogeneity was rejected. However, in FMM, frailty was better represented as a continuous variable than as latent heterogeneous classes. Thus, the PMF measurement model of frailty did not meet the features of a syndrome in this study. CONCLUSION: Using the FRéLE cohort, the PMF measurement model validity is questioned. Valid measurement of a syndrome depends on an understanding of its etiological factors and pathophysiological processes, and on a modelling of how the measured components are linked to these processes. Without these features, assessing frailty in a clinical setting may not improve patient health. Research on frailty should address these issues before promoting its use in clinical settings.

A framework for measurement and harmonization of pediatric multiple sclerosis etiologic research studies: The Pediatric MS Tool-Kit.

BACKGROUND: While studying the etiology of multiple sclerosis (MS) in children has several methodological advantages over studying etiology in adults, studies are limited by small sample sizes. OBJECTIVE: Using a rigorous methodological process, we developed the Pediatric MS Tool-Kit, a measurement framework that includes a minimal set of core variables to assess etiological risk factors. METHODS: We solicited input from the International Pediatric MS Study Group to select three risk factors: environmental tobacco smoke (ETS) exposure, sun exposure, and vitamin D intake. To develop the Tool-Kit, we used a Delphi study involving a working group of epidemiologists, neurologists, and content experts from North America and Europe. RESULTS: The Tool-Kit includes six core variables to measure ETS, six to measure sun exposure, and six to measure vitamin D intake. The Tool-Kit can be accessed online ( www.maelstrom-research.org/mica/network/tool-kit ). CONCLUSION: The goals of the Tool-Kit are to enhance exposure measurement in newly designed pediatric MS studies and comparability of results across studies, and in the longer term to facilitate harmonization of studies, a methodological approach that can be used to circumvent issues of small sample sizes. We believe the Tool-Kit will prove to be a valuable resource to guide pediatric MS researchers in developing study-specific questionnaire.

Physical activity is associated with a decreased multiple sclerosis risk: The EnvIMS study.

BACKGROUND: The lifestyle factors smoking and obesity have been associated with the risk of multiple sclerosis (MS). Physical activity (PA) may also be of importance. OBJECTIVE: To examine the association between PA and MS risk in Italy, Norway, and Sweden and to evaluate the possible influence by established risk factors. METHODS: In this case-control study, 1904 cases and 3694 controls were asked to report their average weekly amounts of light and vigorous PA during adolescence on a scale ranging from none to more than 3 hours activity. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and adjusted for potential confounders. RESULTS: Vigorous PA was inversely associated with MS risk in the pooled analysis ( p-trend < 0.001) with an age- and sex-adjusted OR of 0.74 (95% CI: 0.63-0.87) when comparing the highest and lowest levels. Adjusting for outdoor activity, infectious mononucleosis, body size, and smoking yielded similar results. The association was present in all countries and was not affected by exclusion of patients with early disease onset. Light PA was not associated with the risk of MS. CONCLUSION: Our findings suggest that vigorous PA can modify the risk of developing MS independent of established risk factors.

The relation between DNA methylation patterns and serum cytokine levels in community-dwelling adults: a preliminary study.

BACKGROUND: The levels of circulating cytokines fluctuate with age, acute illness, and chronic disease, and are predictive of mortality; this is also true for patterns of DNA (CpG) methylation. Given that immune cells are particularly sensitive to changes in the concentration of cytokines in their microenvironment, we hypothesized that serum levels of TNF, IL-6, IL-8 and IL-10 would correlate with genome-wide alterations in the DNA methylation levels of blood leukocytes. To test this, we evaluated community-dwelling adults (n = 14; 48-78 years old) recruited to a pilot study for the Canadian Longitudinal Study on Aging (CLSA), examining DNA methylation patterns in peripheral blood mononuclear cells using the Illumina HumanMethylation 450 K BeadChip. RESULTS: We show that, apart from age, serum IL-10 levels exhibited the most substantial association to DNA methylation patterns, followed by TNF, IL-6 and IL-8. Furthermore, while the levels of these cytokines were higher in elderly adults, no associations with epigenetic accelerated aging, derived using the epigenetic clock, were observed. CONCLUSIONS: As a preliminary study with a small sample size, the conclusions drawn from this work must be viewed with caution; however, our observations are encouraging and certainly warrant more suitably powered studies of this relationship.

Negative interaction between smoking and EBV in the risk of multiple sclerosis: The EnvIMS study.

BACKGROUND: Results from previous studies on a possible interaction between smoking and Epstein-Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting. OBJECTIVES: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS. METHODS: Within the case-control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale. RESULTS: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis ( p = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66-1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): -0.98, 95% CI: -2.05-0.15, p = 0.09). CONCLUSION: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.

Comparison of Standardization Methods for the Harmonization of Phenotype Data: An Application to Cognitive Measures.

Standardization procedures are commonly used to combine phenotype data that were measured using different instruments, but there is little information on how the choice of standardization method influences pooled estimates and heterogeneity. Heterogeneity is of key importance in meta-analyses of observational studies because it affects the statistical models used and the decision of whether or not it is appropriate to calculate a pooled estimate of effect. Using 2-stage individual participant data analyses, we compared 2 common methods of standardization, T-scores and category-centered scores, to create combinable memory scores using cross-sectional data from 3 Canadian population-based studies (the Canadian Study on Health and Aging (1991-1992), the Canadian Community Health Survey on Healthy Aging (2008-2009), and the Quebec Longitudinal Study on Nutrition and Aging (2004-2005)). A simulation was then conducted to assess the influence of varying the following items across population-based studies: 1) effect size, 2) distribution of confounders, and 3) the relationship between confounders and the outcome. We found that pooled estimates based on the unadjusted category-centered scores tended to be larger than those based on the T-scores, although the differences were negligible when adjusted scores were used, and that most individual participant data meta-analyses identified significant heterogeneity. The results of the simulation suggested that in terms of heterogeneity, the method of standardization played a smaller role than did different effect sizes across populations and differential confounding of the outcome measure across studies. Although there was general consistency between the 2 types of standardization methods, the simulations identified a number of sources of heterogeneity, some of which are not the usual sources considered by researchers.

Level of education and multiple sclerosis risk after adjustment for known risk factors: The EnvIMS study.

BACKGROUND: Several recent studies have found a higher risk of multiple sclerosis (MS) among people with a low level of education. This has been suggested to reflect an effect of smoking and lower vitamin D status in the social class associated with lower levels of education. OBJECTIVE: The objective of this paper is to investigate the association between level of education and MS risk adjusting for the known risk factors smoking, infectious mononucleosis, indicators of vitamin D levels and body size. METHODS: Within the case-control study on Environmental Factors In MS (EnvIMS), 953 MS patients and 1717 healthy controls from Norway reported educational level and history of exposure to putative environmental risk factors. RESULTS: Higher level of education were associated with decreased MS risk (p trend = 0.001) with an OR of 0.53 (95% CI 0.41-0.68) when comparing those with the highest and lowest level of education. This association was only moderately reduced after adjusting for known risk factors (OR 0.61, 95% CI 0.44-0.83). The estimates remained similar when cases with disease onset before age 28 were excluded. CONCLUSION: These findings suggest that factors related to lower socioeconomic status other than established risk factors are associated with MS risk.

Age, Gender, Comorbidity, and the MDS-UPDRS: Results from a Population-Based Study.

BACKGROUND: Understanding sources of variation in International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores is essential for planning clinical trials in Parkinson's disease and interpreting studies of mild parkinsonian signs. METHODS: We describe the characteristics of the MDS-UPDRS in a population-based sample of individuals without parkinsonism. Multiple linear regression and Spearman's rank correlation coefficients were used to examine potential associations. RESULTS: Among 194 consecutive individuals without parkinsonism, the mean total MDS-UPDRS score was 12.5 (SD 9.8). Sixty-nine percent (134/193) had motor examination (Part III) scores of 2 or more, 16% (30/194) had scores of 10 or more. Female sex, arthritis or spondylosis, diabetes mellitus, and essential tremor were found to be associated with statistically significant increases in MDS-UPDRS Part III scores. For every 10-year increase in age, the Part III score was greater on average by 2.2 (1.5-2.8). CONCLUSIONS: Elevated MDS-UPDRS scores are common in the general population. The overall burden of motor signs of parkinsonism is especially high in older age groups, in women, and in those with particular comorbidities. Whether this represents evidence of a subclinical neurodegenerative process or the effect of comorbid conditions requires further examination.

General Practitioner Preferences in Managing Care of Multiple Sclerosis Patients.

BACKGROUND: Multiple sclerosis (MS) is a lifelong neurological disorder requiring care in a variety of settings. The purpose of this study is to describe preferences of general practitioners (GPs) with regards to providing care for MS patients. METHODS: A stratified sample of 900 GPs in the province of Quebec were sent a questionnaire, with 266 returning completed questionnaires. Respondents were surveyed about their preferences using four clinical scenarios describing hypothetical patients experiencing different stages of MS. Respondents were asked whether they would continue managing the patient themselves, formally refer the patient to a specialist, or seek specialist advice. RESULTS: In two scenarios representing stable courses, 40.9% and 61.6% of GPs, respectively, intended to manage the patient themselves. GPs who reported having experience with MS patients were more likely to report an intention to continue management. In one scenario, GPs operating in rural areas were less likely to consider management than those in the Montreal metropolitan area (odds ratio=0.422, 95% confidence interval 0.20-0.90). CONCLUSIONS: For MS patients with a stable disease course, an important proportion of GPs appear to be willing to manage long-term care for MS patients.