The Association Between Early-life Written Language Skills and Late-life Cognitive Resilience to Alzheimer's Disease

As the population ages, projections suggest that the number of individuals living with age-related diseases such as Alzheimer’s disease will increase. Prevention of Alzheimer’s disease is a major priority since there is currently no cure for the disease. Cognitive resilience is a hypothetical construct designed to explain why some individuals manage to avoid cognitive changes despite the presence of Alzheimer neuropathology. Educational attainment is one of the well-documented examples of building cognitive resilience since high levels of educational attainment have been associated with delayed onset of cognitive impairment. Written language skills developed in early life may reflect the development of early intellect and are essential to educational attainment. Weak early-life written language skills (i.e., low idea density and low grammatical complexity) have been associated with poor cognitive function in later life. However, there is limited understanding of the influence of written language skills and their potential contribution to cognitive resilience. This research aimed to assess the association between written language skills and cognitive resilience using data from the Nun Study. The Nun Study is a longitudinal study of aging in religious sisters who were a minimum of 75 years of age at baseline. Idea density and grammatical complexity were determined using coded autobiographies. Autobiographies were obtained from archival records and were written at a mean age of 22 years. Cognitive resilience was operationalized based on whether individuals met the clinical diagnosis of dementia at last assessment prior to death according to DSM-IV criteria while fulfilling Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropathologic criteria (“definite” or “probable”) or National Institute on Aging and Reagan Institute (NIA-RI) neuropathologic criteria (“definite”, “intermediate” or “high” likelihood) for Alzheimer’s disease. Analyses included descriptive analyses (univariate and bivariate) as well as logistic regression models. The purpose of this project was to strengthen current knowledge on the potential association between early-life written language skills and late-life resilience to cognitive impairment. This study also aimed to better understand the implications of indicators of cognitive and brain reserve on this potential relationship. Based on descriptive and multivariable analyses, a relationship between written language skills (idea density and grammatical complexity) was found particularly in the CERAD sample where cognitive resilience was defined using CERAD criteria for Alzheimer neuropathology. In logistic regression models adjusting for standard covariates (age and APOE), low idea density was associated with decreased likelihood of cognitive resilience (Odds Ratio (OR): 0.15, 95% Confidence Interval (CI): 0.02-0.72). These findings meant that higher idea density (vs. low) was associated with six times greater odds of cognitive resilience. Similarly, low grammatical complexity was significantly associated with cognitive resilience in adjusted models for age and APOE (OR: 0.13, 95% CI: 0.03-0.50). That is, the odds of cognitive resilience in later life increased seven-fold among those with higher grammatical complexity compared to those with low grammatical complexity. Further analyses also suggested that grammatical complexity remained a significant predictor of cognitive resilience in the presence of indicators of cognitive (education) and brain (cerebral infarcts and cortical atrophy) reserve. In comparison, idea density was significant when separately adjusted for presence or number of infarcts along with standard covariates. However, idea density was not significant in a few full models (e.g., including adjustments for standard covariates (age and APOE), cortical atrophy and presence of infarcts, or standard covariates and education). These findings suggested the strong influences of both education and structural brain changes on the relationship between idea density and cognitive resilience. Future studies should aim to assess whether other forms of writing from early life (e.g., written language in social media) can also be associated with cognition in later life. Findings from this research contribute to the understanding of cognitive resilience and provide the foundation for further exploration into the influence of written language on the prevention of Alzheimer’s disease

Examining the Connection: Traumatic Life Events, Substance Use, and Service Utilization Among Persons Admitted to Inpatient Psychiatry in Ontario

Background Experiencing traumatic life events and the symptoms that follow have been associated with an increased risk for other mental health conditions. Among individuals who have experienced traumatic life events, comorbidities such as substance use disorder are particularly common. Individuals with co-morbid trauma and substance use may be less responsive to treatment, are prone to relapses, and increased hospitalizations. Gaps in care for individuals with co-occurring trauma and substance use reflect the growing need to understand associations between trauma experiences and substance use to identify opportunities for improving care and outcomes. Using data from persons who experienced trauma prior to admission to inpatient psychiatry, the purposes of this dissertation are to (1) identify the classifications of both trauma and substance use, (2) examine the service complexity received by persons with trauma, and (3) examine whether trauma classifications, and the presence of social relationships are associated with early leaves from inpatient care. Methods A population based retrospective cohort was developed using interRAI Mental Health (RAI-MH) assessment data from all inpatient psychiatric assessments in Ontario, Canada between January 1, 2015, to December 31, 2019. The RAI-MH is a comprehensive assessment tool completed by clinical staff overseeing the care of the person. Completion of the assessment draws on multiple sources of information such as a review of the patient’s clinical records, interviews and observations, consultation with other clinical staff, family, and first responders (CIHI, 2023). The cohort included all persons in non-forensic and non-geriatric beds who were over the age of 18, and who had experienced a traumatic life event at some point prior to admission. Modelling and analyses were all conducted using SAS 9.4. Study 1: Data were included for individuals with an index admission stay of 72 hours or longer during the observational window. Patients were excluded if they were admitted from another psychiatric hospital or if their first episode was not an admission assessment. Patients were included if they triggered the Traumatic Life events CAP of the RAI-MH (N=10,125). Latent class analysis was used to determine underlying subgroups of patients based on their patterns of traumatic life events and substance use behaviour. An 8-class solution was selected based on comparisons of Akaike information criteria, Bayesian information criteria, adjusted Bayesian criteria, and entropy values. Study 2: Data from the Ontario Mental Health Reporting System were included for patients who triggered the Traumatic Life events CAP with no recent psychiatric assessments (i.e., no admissions within the last two years) (N=7,871). A service complexity variable was created based on length of stay (from date of admission to date of discharge, measured in days), the frequency of non-nursing formal care use, and nursing interventions in the prior 7 days. Descriptive statistics and bivariate associations between all demographic characteristics and level of service complexity were conducted. Logistic regression modelling was then used to assess the association between latent classes and the outcome (i.e., service complexity: low/moderate versus high service complexity). Odds ratios (unadjusted and adjusted), and 95% confidence intervals were reported for the initial and final models. Study 3: All records for individuals who triggered the Traumatic Life events CAP with an index admission over 72 hours between January 1, 2015 and December 31, 2019 were included (N=11,043). Early leaves were defined based on discharge status. The variable was coded into three different levels including unplanned leaves (patients who were discharged due to an absence without an approved leave, and persons discharged against medical advice), early leave (patients with short length of stays), and no early leave. Chi-squared tests were used to understand associations between demographic and clinical characteristics, and early leaves from inpatient stays. Multinomial logistic regression modelling was then used to assess the association between latent classifications of trauma and substance use, Clinical Assessment Protocols, demographic and clinical characteristics, the multi-level outcome of early leaves (i.e., unplanned, or short length of stay), and those who did not discharge prematurely. Results Study 1: Using latent class analysis, eight classifications of trauma and substance use were identified, ranging from low (i.e., Class 1: Interpersonal Issues, Without Substance use) to high (i.e., Class 8: Widespread Trauma, Alcohol & Cannabis Addiction) complexity patterns of traumatic life events and substance use indicators. Classes with similar profiles of trauma were differentiated by variations in substances use patterns. Furthermore, substance use patterns ranged from use of specific substances to widespread use and show variation in the presence of indicators of problematic use. Multinomial logistic regression models highlighted additional factors associated with class membership such as homelessness, where those who were homeless were estimated to be 1.71-3.02 more likely to be in Class 3: Safety & Relationship Issues, Alcohol & Cannabis use, and 2.09-4.02 times more likely to be in Class 6: Widespread Trauma & Substance Addiction. Study 2: Service complexity ranged from 1 to 13, with the most common services being psychiatrist (84.3%), nurse practitioners or medical doctors (non-psychiatrists) (64.1%), and social workers (59.7%). High service complexity, defined as the upper quintile of formal care service use (scores of greater than or equal to 9), nursing interventions, and longer length of stay was observed in 18.1% of individuals with trauma. Compared to patients with few trauma experiences and no substance use, patients with more widespread trauma experiences and indicators of alcohol and cannabis addiction were 2.1 times (95% CI: 1.68-2.50) more likely to have high service complexity. Patients with safety and relationship traumas with alcohol and cannabis use, were less likely to have high service complexity compared to patients with interpersonal issues, without substance use (adj. OR: 0.70, 95% CI: 0.54-0.91). Characteristics such being female, having greater education, and being employed were associated with higher service complexity. Study 3: Multinomial logistic regression revealed that individuals in latent classes with patterns of substance use (e.g., Class 6: Widespread Trauma & Substance Addiction) were more likely to have unplanned early leaves compared to those without substance use (adj. OR: 4.17, 95% CI: 2.72-6.39). Individuals with interpersonal conflict (i.e., conflict in relationships and widespread interpersonal conflict) had increased odds of having early leaves that were unplanned. Persons in Class 4: Immigration with Interpersonal Issues, Alcohol & Cannabis Addiction (adj. OR: 0.68, 95% CI:0.56-0.83), and Class 8: Widespread Trauma, Alcohol & Cannabis Addiction (adj. OR:0.73, 95% CIL 0.60-0.89) were less likely to have early leaves that were short length of stays compared to all other classes. Discussion The findings highlight multi-dimensional experiences of both trauma and substance use. That is, experiences of trauma and patterns of substance use vary among patients with trauma admitted to inpatient psychiatry. Patterns of service use, and discharge status also varied. Differences identified suggest the need to consider the nuances of trauma to support patients, consider ongoing prevention of substance use, and address barriers in maintaining treatment. Study 1: When considering traumatic life events across the latent classes, experiences of trauma were diverse among inpatients: from those with a few traumatic life experiences centered around health and loss (Class 1) to those with widespread experiences that include accidents, health challenges, grief and loss, and other social circumstances (Class 8). In Ontario, there are few specialized programs in place for supporting trauma, except for several tertiary hospitals. Advances in publicly funded services outlined in provincial strategic plans may hold promise, such as the introduction of structured psychotherapy programs and specific resources to support the military and first responders (Ministry of Health, 2022). Increasingly, dual treatment options for both trauma and substance use (e.g., Concurrent Treatment of PTSD and Substance Use Disorders (COPE)) should be further explored (Persson et al., 2017). Further research should explore patterns of trauma and substance use in community mental health settings, and supporting clinician confidence in discussing traumatic life events with patients. Study 2: Nuances were observed when considering the relationship between latent classes of trauma and level of service complexity. Patients with indicators of substance addiction were more likely to have high service complexity. Findings highlight the importance of ensuring funding is allocated to public services for the continuation of care post-discharge. The RAI-MH can identify specific experiences and needs of persons with trauma that may be useful for informing further analyses on resource utilization and service planning. Given that economic costs data were not available, future research may consider the use of resource measurement and cost data to validate observed differences in service complexity. Study 3: The results of study 3 point to differences between early leaves that are unplanned versus short length of stays. Both discharge statuses reflect an important period for providing treatment and recognizing substance use. Latent classes with the highest likelihood of unplanned early leaves generally included indicators of substance use. An eagerness to return to the community to utilize substances may reflect early unplanned discharges in this study. Inpatient admissions highlight an important timeframe to intervene in ongoing substance use. Unplanned early leaves may also reflect individuals with complex trauma that would better be supported in longer-term specialized treatment programs. Other factors such as interpersonal conflict, and eating disorders were associated with early discharge status. Future studies should assess the association between social relationships, formal supports, and early leaves

Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used