Latent profiles of modifiable dementia risk factors in later midlife: relationships with incident dementia, cognition, and neuroimaging outcomes.

In 2020, the Lancet Commission identified 12 modifiable factors that increase population-level dementia risk. It is unclear if these risk factors co-occur among individuals in a clinically meaningful way. Using latent class analysis, we identified profiles of modifiable dementia risk factors in dementia-free adults aged 60-64 years from the UK Biobank. We then estimated associations between these profiles with incident dementia, cognition, and neuroimaging outcomes, and explored the differences across profiles in the effects of a polygenic risk score for Alzheimer's disease on outcomes. In 55,333 males and 63,063 females, three sex-specific latent profiles were identified: cardiometabolic risk, substance use-related risk, and low risk. The cardiometabolic risk profile in both males and females was associated with greater incidence of all-cause dementia (male: OR [95% CI] = 2.33 [2.03, 2.66]; female: OR [95% CI] = 1.44 [1.24, 1.68]), poorer cognitive performance, greater brain atrophy, and greater white matter hyperintensity volume compared to the low risk profile. The substance use-related risk profile in males was associated with poorer cognitive performance and greater white matter hyperintensities compared to the low risk profile, but no difference in all-cause dementia incidence was observed (OR [95% CI] = 1.00 [0.95, 1.06]). In females, the substance use-related risk profile demonstrated increased dementia incidence (OR [95% CI] = 1.58 [1.57, 1.58]) and greater brain atrophy but smaller white matter hyperintensity volume compared to the low risk profile. The polygenic risk score had larger effects among females, and differentially influenced outcomes across profiles; for instance, there were larger effects of the polygenic risk score on atrophy in the cardiometabolic profile vs. the low risk profile among males, and larger effects of the polygenic risk score on loss of white matter integrity in the cardiometabolic profile vs. the low risk profile among females. These results reveal three modifiable dementia risk profiles, their unique cognitive/neuroimaging outcomes, and their interactions with genetic risk for Alzheimer's disease. These differences highlight the need to consider population heterogeneity in risk prediction tools and in planning personalized prevention strategies.

No association between metformin initiation and incident dementia in older adults newly diagnosed with diabetes.

BACKGROUND: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity. OBJECTIVES: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias. METHODS: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models. RESULTS: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years). CONCLUSION: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.

Cardiovascular phenotypes in type 2 diabetes: Latent class analysis of the CANVAS Program and CREDENCE trial.

AIM: To identify unique clinical phenotypes in type 2 diabetes (T2D) and investigate their treatment response to canagliflozin using latent class analysis. METHODS: This was a pooled latent class analysis of the individuals in the CANVAS Program and CREDENCE trial. The co-primary endpoints were hospitalization for heart failure (HHF) and the composite of cardiovascular death (CVD) or HHF. Secondary endpoints included three-point major adverse CV events, its individual components, and all-cause mortality. We completed Cox proportional hazards models to evaluate the effect of canagliflozin across phenotypes. RESULTS: Four distinct phenotypes were identified: Phenotype 1 (n = 966, 6.6%), with the lowest prevalence of heart failure, kidney dysfunction and hypertension; Phenotype 2 (n = 4169, 28.7%), primarily comprising females with a high prevalence of atherosclerotic vascular disease (ASCVD); Phenotype 3 (n = 7108, 48.9%), predominately males with a high prevalence of ASCVD; and Phenotype 4 (n = 2300, 15.8%), possessing the highest prevalences of HF and renal dysfunction. A hierarchical increase in the risk of the primary endpoint was observed across the phenotypes, with the highest CV risk observed for Phenotype 4 (hazard ratio for HHF: 7.57 [95% CI: 4.19-13.69]). Canagliflozin significantly reduced HHF and the composite CVD or HHF across phenotypes (all P values for interaction > .05). CONCLUSION: We identified four clinically distinct T2D phenotypes with differential CV risks. Canagliflozin reduced the risk of CV events, irrespective of the phenotype, emphasizing its broad therapeutic acceptability.

Assessing cardiovascular disease risk in women with a history of hypertensive disorders of pregnancy: A guidance paper for studies using administrative data.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are a major cause of maternal morbidity and mortality, and their association with increased cardiovascular disease (CVD) risk represents a major public health concern. However, assessing CVD risk in women with a history of these conditions presents unique challenges, especially when studies are carried out using routinely collected data. OBJECTIVES: To summarise and describe key challenges related to the design and conduct of administrative studies assessing CVD risk in women with a history of HDP and provide concrete recommendations for addressing them in future research. METHODS: This is a methodological guidance paper. RESULTS: Several conceptual and methodological factors related to the data-generating mechanism and study conceptualisation, design/data management and analysis, as well as the interpretation and reporting of study findings should be considered and addressed when designing and carrying out administrative studies on this topic. Researchers should develop an a priori conceptual framework within which the research question is articulated, important study variables are identified and their interrelationships are carefully considered. CONCLUSIONS: To advance our understanding of CVD risk in women with a history of HDP, future studies should carefully consider and address the conceptual and methodological considerations outlined in this guidance paper. In highlighting these challenges, and providing specific recommendations for how to address them, our goal is to improve the quality of research carried out on this topic.

Maternal Health Outcomes After Pregnancy-Associated Stroke: A Population-Based Study With 19 Years of Follow-Up.

BACKGROUND: Pregnancy-associated stroke carries high short-term morbidity and mortality, but data on subsequent maternal outcomes are limited. We evaluated long-term maternal health outcomes after pregnancy-associated stroke. METHODS: In this retrospective cohort study, we used administrative data to identify pregnant adults aged ≤49 years with stroke between 2002-2020 in Ontario, Canada and 2 comparison groups: (1) non-pregnant female patients with stroke and (2) pregnant patients without stroke. Patients who survived the index admission were followed until 2021. After propensity score matching, we used Cox regression with a robust variance estimator to compare pregnant patients with stroke and the 2 comparison groups for the composite outcome of death and all-cause non-pregnancy readmission. Where proportional hazard assumption was not met, we reported time-varying hazard ratios (HR) with 95% CIs by modeling the log-hazard ratio as a function of time using restricted cubic splines. RESULTS: We identified 217 pregnant patients with stroke, 7604 non-pregnant patients with stroke, and 1 496 256 pregnant patients without stroke. Of the 202 pregnant patients with stroke who survived the index stroke admission, 41.6% (6.8 per 100 person-years) subsequently died or were readmitted during follow-up. Median follow-up times were 5 years (pregnancy-associated stroke), 3 years (non-pregnant stroke), and 8 years (pregnant without stroke). Pregnant patients with stroke had a lower hazard of death and all-cause readmission compared with non-pregnant patients with stroke at 1-year follow-up (HR, 0.64 [95% CI, 0.44-0.94]), but this association did not persist during longer-term follow-up. Conversely, pregnant patients with stroke had higher hazard of death and readmission compared with pregnant patients without stroke at 1-year follow-up (HR, 5.70 [95% CI, 3.04-10.66]), and this association persisted for a decade. CONCLUSIONS: Stroke during pregnancy is associated with long-term health consequences. It is essential to transition care postpartum to primary or specialty care to optimize vascular health.

Dynamic relationships between depressive symptoms and insulin resistance over 20 years of adulthood.

BACKGROUND: Bidirectional longitudinal relationships between depression and diabetes have been observed, but the dominant direction of their temporal relationships remains controversial. METHODS: The random-intercept cross-lagged panel model decomposes observed variables into a latent intercept representing the traits, and occasion-specific latent 'state' variables. This permits correlations to be assessed between the traits, while longitudinal 'cross-lagged' associations and cross-sectional correlations can be assessed between occasion-specific latent variables. We examined dynamic relationships between depressive symptoms and insulin resistance across five visits over 20 years of adulthood in the population-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Possible differences based on population group (Black v. White participants), sex and years of education were tested. Depressive symptoms and insulin resistance were quantified using the Center for Epidemiologic Studies Depression (CES-D) scale and the homeostatic model assessment for insulin resistance (HOMA-IR), respectively. RESULTS: Among 4044 participants (baseline mean age 34.9 ± 3.7 years, 53% women, 51% Black participants), HOMA-IR and CES-D traits were weakly correlated (r = 0.081, p = 0.002). Some occasion-specific correlations, but no cross-lagged associations were observed overall. Longitudinal dynamics of these relationships differed by population groups such that HOMA-IR at age 50 was associated with CES-D score at age 55 (ß = 0.076, p = 0.038) in White participants only. Longitudinal dynamics were consistent between sexes and based on education. CONCLUSIONS: The relationship between depressive symptoms and insulin resistance was best characterized by weak correlations between occasion-specific states and enduring traits, with weak evidence that insulin resistance might be temporally associated with subsequent depressive symptoms among White participants later in adulthood.

Discriminative Utility of Transcranial Magnetic Stimulation-Derived Markers of Cortical Excitability for Transient Ischemic Attack.

BACKGROUND: Several guidelines currently recommend acute diffusion weighted imaging (DWI) for the detection of ischemia in transient ischemic attack (TIA). However, DWI hyperintensities resolve early and only 30%-50% with clinically defined TIA show acute DWI positivity. A recent meta-analysis reported an unexplained 7-fold variation in DWI positivity in TIA across studies, concluding that DWI does not provide a consistent basis for defining ischemia. Intracortical excitability, measured using transcranial magnetic stimulation (TMS), has previously been shown to be altered after TIA and associated with ABCD2 scores; however, whether altered cortical excitability is associated with clinical and DWI-based definitions of TIA remains unclear. METHODS: Individuals with TIA symptoms (N = 23; mean age = 61 ± 12) were prospectively recruited and underwent DWI and paired-pulse TMS. Multivariate linear regression was used to estimate associations between TMS-derived excitability thresholds, and clinical TIA diagnosis, and imaging-based evidence of cerebral ischemia (DWI positivity). Area under the curve (AUC) analyses was used to compare the discriminability of TMS-derived thresholds and clinical TIA diagnoses. RESULTS: Thresholds for intracortical inhibition in the TIA-unaffected hemisphere were significantly associated with the clinical diagnosis of TIA. No associations between TMS-derived thresholds and DWI positivity were observed. TMS thresholds showed low-moderate discriminability and values differed by age (65+) and sex. CONCLUSIONS: In this small sample, TMS-derived markers of intracortical excitability were associated with clinical TIA diagnoses but not DWI positivity. Our results provide preliminary evidence for the potential discriminative utility of TMS for the diagnosis of TIA and highlight the need for future work in larger cohorts.

The new frontline: exploring the links between moral distress, moral resilience and mental health in healthcare workers during the COVID-19 pandemic.

BACKGROUND: Global health crises, such as the COVID-19 pandemic, confront healthcare workers (HCW) with increased exposure to potentially morally distressing events. The pandemic has provided an opportunity to explore the links between moral distress, moral resilience, and emergence of mental health symptoms in HCWs. METHODS: A total of 962 Canadian healthcare workers (88.4% female, 44.6 + 12.8 years old) completed an online survey during the first COVID-19 wave in Canada (between April 3rd and September 3rd, 2020). Respondents completed a series of validated scales assessing moral distress, perceived stress, anxiety, and depression symptoms, and moral resilience. Respondents were grouped based on exposure to patients who tested positive for COVID-19. In addition to descriptive statistics and analyses of covariance, multiple linear regression was used to evaluate if moral resilience moderates the association between exposure to morally distressing events and moral distress. Factors associated with moral resilience were also assessed. FINDINGS: Respondents working with patients with COVID-19 showed significantly more severe moral distress, anxiety, and depression symptoms (F > 5.5, p < .020), and a higher proportion screened positive for mental disorders (Chi-squared > 9.1, p = .002), compared to healthcare workers who were not. Moral resilience moderated the relationship between exposure to potentially morally distressing events and moral distress (p < .001); compared to those with higher moral resilience, the subgroup with the lowest moral resilience had a steeper cross-sectional worsening in moral distress as the frequency of potentially morally distressing events increased. Moral resilience also correlated with lower stress, anxiety, and depression symptoms (r > .27, p < .001). Factors independently associated with stronger moral resilience included: being male, older age, no mental disorder diagnosis, sleeping more, and higher support from employers and colleagues (B [0.02, |-0.26|]. INTERPRETATION: Elevated moral distress and mental health symptoms in healthcare workers facing a global crisis such as the COVID-19 pandemic call for the development of interventions promoting moral resilience as a protective measure against moral adversities.

Profiles of sleep changes during the COVID-19 pandemic: Demographic, behavioural and psychological factors.

This study aimed to evaluate changes in sleep during the COVID-19 outbreak, and used data-driven approaches to identify distinct profiles of changes in sleep-related behaviours. Demographic, behavioural and psychological factors associated with sleep changes were also investigated. An online population survey assessing sleep and mental health was distributed between 3 April and 24 June 2020. Retrospective questions were used to estimate temporal changes from before to during the outbreak. In 5,525 Canadian respondents (67.1% females, 16-95 years old: Mean ± SD = 55.6 ± 16.3 years), wake-up times were significantly delayed relative to pre-outbreak estimates (p < .001, ηp2  = 0.04). Occurrences of clinically meaningful sleep difficulties significantly increased from 36.0% before the outbreak to 50.5% during the outbreak (all p < .001, g ≥ 0.27). Three subgroups with distinct profiles of changes in sleep behaviours were identified: "Reduced Time in Bed", "Delayed Sleep" and "Extended Time in Bed". The "Reduced Time in Bed" and "Delayed Sleep" subgroups had more adverse sleep outcomes and psychological changes during the outbreak. The emergence of new sleep difficulties was independently associated with female sex, chronic illnesses, being employed, family responsibilities, earlier wake-up times, higher stress levels, as well as heavier alcohol use and television exposure. The heterogeneity of sleep changes in response to the pandemic highlights the need for tailored interventions to address sleep problems.

Emerging New Psychiatric Symptoms and the Worsening of Pre-existing Mental Disorders during the COVID-19 Pandemic: A Canadian Multisite Study: Nouveaux symptômes psychiatriques émergents et détérioration des troubles mentaux préexistants durant la pandémie de la COVID-19: une étude canadienne multisite.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has caused global disruptions with serious psychological impacts. This study investigated the emergence of new psychiatric symptoms and the worsening of pre-existing mental disorders during the COVID-19 pandemic, identified factors associated with psychological worsening, and assessed changes in mental health service use. METHODS: An online survey was circulated between April 3 and June 23, 2020. Respondents were asked to complete mental health questionnaires based on 2 time referents: currently (i.e., during the outbreak) and in the month preceding the outbreak. A total of 4,294 Canadians between 16 and 99 years of age were subdivided based on the presence of self-reported psychiatric diagnoses. RESULTS: The proportion of respondents without prior psychiatric history who screened positive for generalized anxiety disorder and depression increased by 12% and 29%, respectively, during the outbreak. Occurrences of clinically important worsening in anxiety, depression, and suicidal ideation symptoms relative to pre-outbreak estimates were significantly higher in those with psychiatric diagnoses. Furthermore, 15% to 19% of respondents reported increased alcohol or cannabis use. Worse psychological changes relative to pre-outbreak estimate were associated with female sex, younger age, lower income, poorer coping skills, multiple psychiatric comorbidities, previous trauma exposure, deteriorating physical health, poorer family relationships, and lower exercising. Reductions in mental health care were associated with increased suicidal ideation. CONCLUSION: The worsening in mental health symptoms and the decline in access to care call for the urgent development of adapted interventions targeting both new mental disorders and pre-existing psychiatric conditions affected by the COVID-19 pandemic.

Depression and Diabetes Mellitus Multimorbidity Is Associated With Loss of Independence and Dementia Poststroke.

BACKGROUND AND PURPOSE: Many patients with ischemic stroke present with multiple comorbidities that threaten survival and recovery. This study sought to determine the risks of adverse long-term stroke outcomes associated with multimorbid diabetes mellitus and depression. METHODS: Retrospective analysis of prospectively collected data on consecutive patients without premorbid dementia admitted from the community for a first-ever acute ischemic stroke to comprehensive stroke centers across Ontario, Canada (2003-2013). Premorbid histories of diabetes mellitus and depression were ascertained within 5 years before stroke admission. Adjusted hazard ratios (aHR [95% CI]) of admission to long-term care, incident dementia, readmission for stroke or transient ischemic attack and all-cause mortality, over time among those discharged back into the community poststroke. RESULTS: Among 23 579 stroke admissions, n=20 201 were discharged back into the community. Diabetes mellitus and depression were associated with synergistic hazards of admission to long-term care (X2=5.4; P=0.02) over a median follow-up of 5.6 years. This interaction was observed among women specifically; depression multimorbidity showed particularly high hazards of admission to long-term care (aHRDepression=1.57 [1.24-1.98]) and incident dementia (aHRDepression=1.85 [1.40-2.44]) among women with diabetes mellitus. In the whole cohort, diabetes mellitus and depression were associated individually with long-term care admission (aHRDiabetes=1.20 [1.12-1.29]; aHRDepression=1.19 [1.04-1.37]), incident dementia (aHRDiabetes=1.14 [1.06-1.23]; aHRDepression=1.27 [1.08-1.49]), stroke/transient ischemic attack readmission (aHRDiabetes=1.18 [1.10-1.26]; aHRDepression=1.24 [1.07-1.42]), and all-cause mortality (aHRDiabetes=1.29 [1.23-1.36]; aHRDepression=1.16 [1.05-1.29]). CONCLUSIONS: The risks of dementia and needing long-term care in the years after surviving a stroke were particularly elevated among women when premorbid diabetes mellitus and depression occurred together. Long-term stroke recovery strategies might target high-risk patients with mood and metabolic multimorbidity.

Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer's disease, and the role APOE carrier status.

INTRODUCTION: Few studies have examined memory decline among patients with type 2 diabetes using different oral hypoglycemic drugs. METHODS: Participants with normal cognition (NC) or Alzheimer's disease (AD) dementia using a hypoglycemic medication (2005 to 2019) were identified from the National Alzheimer's Coordinating Center database. Delayed memory was assessed using the Wechsler Memory Scale Revised-Logical Memory test. Associations between oral drug classes and memory over time were examined using mixed-effects models with inverse probability treatment weights. RESULTS: In NC (n = 1192), metformin use was associated with better memory performance over time, whereas in AD (n = 807), dipeptidyl peptidase-4 (DPP4) inhibitor use was associated with a slower rate of memory decline. Interaction effects suggested greater benefit associated with DPP4 inhibitor use among APOE ε4 carriers. DISCUSSION: Associations between different oral hypoglycemic drugs and memory change were not consistent between cognitively normal elderly and those with AD dementia. APOE ε4 genotype modified some relationships.

Changes to white matter microstructure in transient ischemic attack: A longitudinal diffusion tensor imaging study.

Transient ischemic attack (TIA) is associated with localized ischemic changes, identifiable by diffusion-weighted imaging. Past research has not considered whether TIA is also associated with diffuse changes to white matter microstructure; further past work has not tracked changes longitudinally. Here we examine whole-brain changes in fractional anisotropy (FA) in individuals with TIA presenting with sensorimotor symptoms. Twenty individuals with a recent (within 30 days) TIA and 12 healthy older adults were recruited. Participants underwent 3.0 T diffusion MRI at baseline; scans were repeated for the TIA group 90 days post-TIA. Track-based spatial statistics (TBSS) was used to conduct a voxel-wise analysis of FA between groups. FA was significantly lower in the TIA group relative to healthy controls, primarily in anterior white matter tracts including: forceps minor, anterior thalamic radiations, cingulum, inferior fronto-occipital fasciculus, and corticospinal tract. TBSS results informed an ROI-based longitudinal examination of FA in the TIA group. There were no changes to TBSS-identified clusters, forceps minor, or the corticospinal tract over time. There was lower FA in the anterior thalamic radiations in the TIA-affected hemisphere at baseline, but no difference between hemispheres at 90 days. In summary, individuals with TIA presenting with sensorimotor symptoms have decreased FA in tracts that are also implicated in sensorimotor function, which outlast the clinical symptoms associated with TIA. This suggests a more profound type of brain damage associated with TIA than has been typically described in past work. Diffusion tensor imaging may have utility as a marker of TIA-associated changes to white matter pathways. Hum Brain Mapp 38:5795-5803, 2017. © 2017 Wiley Periodicals, Inc.

Long-term morbidity and mortality in patients without early complications after stroke or transient ischemic attack.

BACKGROUND: Secondary prevention after stroke and transient ischemic attack (TIA) has focused on high early risk of recurrence, but survivors of stroke can have substantial long-term morbidity and mortality. We quantified long-term morbidity and mortality for patients who had no early complications after stroke or TIA and community-based controls. METHODS: This longitudinal case-control study included all ambulatory or hospitalized patients with stroke or TIA (discharged from regional stroke centres in Ontario from 2003 to 2013) who survived for 90 days without recurrent stroke, myocardial infarction, all-cause admission to hospital, admission to an institution or death. Cases and controls were matched on age, sex and geographic location. The primary composite outcome was death, stroke, myocardial infarction, or admission to long-term or continuing care. We calculated 1-, 3- and 5-year rates of composite and individual outcomes and used cause-specific Cox regression to estimate long-term hazards for cases versus controls and for patients with stroke versus those with TIA. RESULTS: Among patients who were initially stable after stroke or TIA (n = 26 366), the hazard of the primary outcome was more than double at 1 year (hazard ratio [HR] 2.4, 95% confidence interval [CI] 2.3-2.5), 3 years (HR 2.2, 95% CI 2.1-2.3) and 5 years (HR 2.1, 95% CI 2.1-2.2). Hazard was highest for recurrent stroke at 1 year (HR 6.8, 95% CI 6.1-7.5), continuing to 5 years (HR 5.1, 95% CI 4.8-5.5), and for admission to an institution (HR 2.1, 95% CI 1.9-2.2). Survivors of stroke had higher mortality and morbidity, but 31.5% (1789/5677) of patients with TIA experienced an adverse event within 5 years. INTERPRETATION: Patients who survive stroke or TIA without early complications are typically discharged from secondary stroke prevention services. However, these patients remain at substantial long-term risk, particularly for recurrent stroke and admission to an institution. Novel approaches to prevention, potentially embedded in community or primary care, are required for long-term management of these initially stable but high-risk patients.

Diagnostic Accuracy of Transient Ischemic Attack from Physician Claims.

BACKGROUND: Hospitalization data underestimate the occurrence of transient ischemic attack (TIA). As TIA is frequently diagnosed in primary care, methodologies for the accurate ascertainment of a TIA from physician claims data are required for surveillance and health systems planning in this population. The present study evaluated the diagnostic accuracy of multiple algorithms for TIA from a longitudinal population-based physician billing database. METHODS: Population-based administrative data from the province of British Columbia were used to identify the base population (1992-2007; N=102,492). Using discharge records for hospital admissions for acute ischemic stroke with a recent (<90 days) TIA as the reference standard, we performed receiver-operating characteristic analyses to calculate sensitivity, specificity, positive and negative predictive values and overall accuracy, and to compare area under the curve for each physician billing algorithm. To evaluate the impact of different case definitions on population-based TIA burden, we also estimated the annual TIA occurrence associated with each algorithm. RESULTS: Physician billing algorithms showed low to moderate sensitivity, with the algorithm for two consecutive physician visits within 90 days showing the highest sensitivity at 37.7% (CI 95%=37.4-38.1). All algorithms demonstrated high specificity and moderate to high overall accuracy, resulting in low positive predictive values (≤5%), low discriminability (0.53-0.57) and high false positive rates (1 - specificity). Population-based estimates of TIA occurrence were comparable to prior studies and declined over time. CONCLUSIONS: Physician billing data have insufficient sensitivity to identify TIAs but may be used in combination with hospital discharge data to improve the accuracy of estimating the population-based occurrence of TIAs.

Associations between amyloid ß and white matter hyperintensities: A systematic review.

INTRODUCTION: This systematic review synthesizes current evidence for associations between cortical amyloid ß, visualized on amyloid positron emission tomography imaging, and white matter hyperintensity (WMH) burden on magnetic resonance imaging in healthy elderly adults and individuals with cognitive impairment and dementia. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) systematic review guidelines, we systematically searched MEDLINE, Embase, Cochrane, and PsycINFO databases from January 2000 to September 2015. RESULTS: Our search returned 492 articles, 34 of which met criteria for inclusion in the final selection. Most studies reported no significant relationships between amyloid ß and WMH burden across diagnostic groups. DISCUSSION: Findings of this systematic review suggest that amyloid accumulation and WMH are independent but additive processes. The limited number of independent cohorts, lack of longitudinal data, and exclusion of individuals with mixed dementia limit the generalizability of these findings. Further studies are required to elucidate the putative contributions of vascular processes to neurodegenerative pathology.

Amyloid PET is a new imaging technology that visualizes accumulations of b-amyloid. Literature suggests that amyloid pathology and WMH may be additive processes. The potential association between b-amyloid and WMH requires further study.

Trends in Long-Term Mortality and Morbidity in Patients with No Early Complications after Stroke and Transient Ischemic Attack.

BACKGROUND: Advances in acute management and secondary prevention have reduced mortality and early recurrent risk after stroke and transient ischemic attack (TIA). However, whether improved outcomes are sustained long term among those without early adverse complications is not clear. We describe trends in long-term mortality and morbidity in patients with ischemic stroke or TIA who are clinically stable at 90 days. METHODS: This is a longitudinal cohort registry study (2003-2013) of patients presenting to stroke centers in Ontario, Canada, with a stroke or TIA, with no hospitalization, stroke, myocardial infarction (MI), institutionalization, or death within 90 days (N = 26,698). Primary outcomes were 1-, 3-, and 5-year age-adjusted composite rates of death, stroke or MI, and institutionalization, and secondary analyses evaluated outcomes individually. Trend tests were used to evaluate change over time. RESULTS: One-year adjusted composite rates decreased from 9.3% in 2003 to 7.4% in 2012 (trend test P = .02). Significant decreases in 3-year (P < .001) and 5-year (P = .002) composite rates were also observed. Rates of recurrent stroke decreased at 1 and 3 years (P < .01), but not 5 years (P = .21), whereas death rates declined across follow-up times. Conversely, rates of institutionalization increased at 3 and 5 years (P < .01). CONCLUSIONS: Long-term mortality and morbidity post stroke and TIA have declined, confirming trends for improved long-term outcomes for patients clinically stable during the initial high-risk period. However, increased long-term rates of institutionalization also suggest that stroke and TIA patients are at risk of long-term functional decline, despite improved clinical outcomes. Further studies evaluating challenges for sustaining functional gains after stroke and TIA are required.

Underutilization of Ambulatory ECG Monitoring After Stroke and Transient Ischemic Attack: Missed Opportunities for Atrial Fibrillation Detection.

BACKGROUND AND PURPOSE: Detection and treatment of atrial fibrillation is a major goal in secondary stroke prevention. Guidelines recommend at least 24 hours of ECG monitoring after stroke. However, it is unclear how often this is done in routine practice. METHODS: In this longitudinal cohort study using data from the Ontario Stroke Registry, we analyzed consecutive patients presenting to designated stroke centers in Ontario, Canada (2003-2013) with a first acute ischemic stroke or transient ischemic attack (TIA) in sinus rhythm and without known atrial fibrillation. The primary outcome was the proportion of patients who received at least 24-hour Holter monitoring within 30 days after stroke/TIA. Secondary analyses assessed total duration of ECG monitoring completed within 90 days after stroke/TIA, temporal trends in monitoring use, and use of Holter monitoring relative to echocardiography. RESULTS: Among 17 398 consecutive eligible patients (mean age 68.8±14.3 years), 30.6% had at least 24 hours of Holter monitoring within 30 days after stroke/TIA. Less than 1% of patients received prolonged monitoring beyond 48 hours. The median time to start monitoring was 9 days poststroke (interquartile range 3-25). Stroke/TIA patients were nearly twice as likely to receive an echocardiogram than a Holter monitor within 90 days (odds ratio 1.8, 95% confidence interval 1.67-2.01). CONCLUSIONS: Less than one third of patients in our cohort received guideline-recommended 24-hour Holter monitoring, and <1% received prolonged ambulatory ECG monitoring. These findings highlight a modifiable evidence-practice gap that likely contributes to an overdiagnosis of strokes as cryptogenic, an underdiagnosis of atrial fibrillation, and missed anticoagulant treatment opportunities for secondary stroke prevention.

Temporal Trends in the Use of Investigations After Stroke or Transient Ischemic Attack.

BACKGROUND: Guidelines recommend that patients with stroke or transient ischemic attack (TIA) undergo neuroimaging and cardiac investigations to determine etiology and guide treatment. It is not known how the use of these investigations has changed over time and whether there have been associated changes in management. OBJECTIVES: To evaluate temporal trends in the use of brain and vascular imaging, echocardiography, and antithrombotic and surgical therapy after stroke or TIA. RESEARCH DESIGN: We analyzed 42,738 patients with stroke or TIA presenting to any of the 11 regional stroke centers in Ontario, Canada between 2003 and 2012 using the Ontario Stroke Registry database. The study period was divided into 1-year intervals and we used the Cochran-Armitage test to determine trends over time. RESULTS: Between 2003/2004 and 2011/2012, the proportion of patients undergoing brain imaging increased from 96% to 99%, as did the proportion receiving ≥3 brain scans (21%-39%), magnetic resonance imaging (13%-50%), vascular imaging (62%-88%), or echocardiography (52%-70%) (P<0.0001 for all comparisons). There was an increase in the proportion receiving any antithrombotic therapy (83%-91%, P<0.0001) but no change in use of anticoagulation (25% overall and 68% in subgroup with atrial fibrillation) or carotid revascularization (1.4%-1.5%, P=0.49). CONCLUSIONS: The use of investigations after stroke has increased over time without concomitant changes in medical or surgical management. Although initial neurovascular imaging is in accordance with practice guidelines, the use of multiple imaging procedures and routine echocardiography are of uncertain clinical effectiveness.

A Bayesian model calibration framework for stochastic compartmental models with both time-varying and time-invariant parameters.

We consider state and parameter estimation for compartmental models having both time-varying and time-invariant parameters. In this manuscript, we first detail a general Bayesian computational framework as a continuation of our previous work. Subsequently, this framework is specifically tailored to the susceptible-infectious-removed (SIR) model which describes a basic mechanism for the spread of infectious diseases through a system of coupled nonlinear differential equations. The SIR model consists of three states, namely, the susceptible, infectious, and removed compartments. The coupling among these states is controlled by two parameters, the infection rate and the recovery rate. The simplicity of the SIR model and similar compartmental models make them applicable to many classes of infectious diseases. However, the combined assumption of a deterministic model and time-invariance among the model parameters are two significant impediments which critically limit their use for long-term predictions. The tendency of certain model parameters to vary in time due to seasonal trends, non-pharmaceutical interventions, and other random effects necessitates a model that structurally permits the incorporation of such time-varying effects. Complementary to this, is the need for a robust mechanism for the estimation of the parameters of the resulting model from data. To this end, we consider an augmented state vector, which appends the time-varying parameters to the original system states whereby the time evolution of the time-varying parameters are driven by an artificial noise process in a standard manner. Distinguishing between time-varying and time-invariant parameters in this fashion limits the introduction of artificial dynamics into the system, and provides a robust, fully Bayesian approach for estimating the time-invariant system parameters as well as the elements of the process noise covariance matrix. This computational framework is implemented by leveraging the robustness of the Markov chain Monte Carlo algorithm permits the estimation of time-invariant parameters while nested nonlinear filters concurrently perform the joint estimation of the system states and time-varying parameters. We demonstrate performance of the framework by first considering a series of examples using synthetic data, followed by an exposition on public health data collected in the province of Ontario.