Longitudinal Patterns of Cognitive State Changes and their Predictors in Older Adults

Older adults experience diverse patterns of cognitive state changes, including progression to dementia, that depend on genetic and non-genetic factors. With population aging, the global prevalence of dementia is rising. Given limited treatment success, research focusing on patterns of cognitive state changes and their predictors provides information for older adults and opens windows to develop interventions for preventing or delaying the onset of dementia. This dissertation is based on analyzing secondary data from the Nun Study, a longitudinal study of aging and cognition. The first aim of this dissertation was to identify patterns of changes over time in cognitive states among older adults using a clinically-driven approach and a statistical modeling method, and to compare the patterns identified using these two methods. The second aim was to test and quantify how academic achievement—educational attainment and academic performance in high school—is associated with cognitive state changes and contributes to cognitive reserve. The third aim was to test the potential antagonistic pleiotropy effect of the gene apolipoprotein E (APOE) on cognition. To identify the patterns of cognitive state changes (Aim 1), homogeneous trajectories were grouped together using two different approaches: 1) a clinically-driven approach, and 2) a statistical modeling approach, latent class mixed-effects modeling (lcmm). Using the clinically-driven approach, seven patterns were identified based on whether individuals experienced stable or non-stable trajectories and among non-stable trajectories, whether they experienced a reverse transition to an improved cognitive state, whether they developed dementia or both. These seven trajectories ranged from stable normal cognition to stable dementia. These patterns were preferred to the four classes identified using latent class mixed-effects modeling. This preference was based on the higher level of detail in trajectories captured by the clinically-driven approach compared to the latent classes identified using the lcmm approach. These details include distinguishing between trajectories with and without cognitive improvement, and with and without progression to dementia. The patterns of cognitive state changes based on the clinically-driven approach were then used as the cognitive outcomes to address the two additional aims, with stable dementia used as the reference category. Using multinomial logistic bias reduction regression, the potential presence of cognitive reserve among individuals with higher academic achievement was tested (Aim 2). Adjusting for age and APOE, higher educational attainment (i.e., a graduate degree) was associated with higher odds of experiencing three healthier patterns of cognitive state changes. Higher overall academic performance was significantly associated with experiencing stable cognitive impairment or cognitive impairment without dementia; this effect was mostly due to higher performance in algebra rather than performance in English, Latin, or geometry courses. Higher academic achievement, as evidenced by educational attainment or performance in high school courses, was thus associated with cognitive reserve through experiencing healthier patterns of cognitive trajectories versus experiencing stable dementia. To test the potential antagonistic pleiotropy effect of APOE on cognition, the effect of APOE-ε4 on both early- and late-life cognition was investigated (Aim 3). In addition, the potential modifying effect of higher education among APOE-ε4 carriers was tested. APOE-ε4 was not significantly associated with an early-life measure of cognition (educational attainment); however, among individuals with lower education, APOE-ε4 was associated with experiencing the most impaired cognitive pattern (stable dementia) in late life. This research did not support the antagonistic pleiotropy hypothesis for APOE; however, it did support the scaffolding theory of aging and cognition. Higher educational attainment among APOE-ε4 carriers compensated for the detrimental effects of APOE-ε4 on late-life cognition to the extent that APOE-ε4 carriers with high educational attainment (a graduate degree) showed cognitive aging patterns similar to APOE-ε4 non-carriers. This modifying effect of higher education on the association between APOE-ε4 and late-life cognition suggests that higher education is associated with cognitive reserve even among APOE-ε4 carriers. This dissertation provides information on patterns of cognitive state changes and their predictors in older adults that will benefit older adults, their families, and the healthcare system. Patterns of cognitive trajectories among older adults are diverse, complex, and difficult to identify. Advanced statistical approaches and their software applications are developed for modeling complex longitudinal cognitive trajectories; however, integrating clinically-driven approaches in identifying distinct patterns of cognitive state changes is beneficial. The results of this dissertation show that higher academic achievement may increase the odds of cognitive reserve by leading to healthier cognitive trajectories. While APOE-ε4 and older age are non-modifiable risk factors for dementia, it may be possible to compensate for their detrimental effects through a modifiable factor, such as graduate-level education. Therefore, investing in higher education is an important potential intervention that may prevent or delay dementia even among individuals carrying a genetic risk factor. Furthermore, it may be worthwhile for researchers targeting APOE to develop interventions that consider non-genetic factors that may modify the effect of APOE on cognition

Cognitive Reserve and Mild Cognitive Impairment

Background and Objectives Little is known about the effect of education or other indicators of cognitive reserve on the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) or the relative rate (RR) of reversion from MCI to NC vs progression from MCI to dementia. Our objectives were to (1) estimate transition rates from MCI to NC and dementia and (2) determine the effect of age, APOE, and indicators of cognitive reserve on the RR of reversion vs progression using multistate Markov modeling. Methods We estimated instantaneous transition rates between NC, MCI, and dementia after accounting for transition to death across up to 12 assessments in the Nun Study, a cohort study of religious sisters aged 75+ years. We estimated RRs of reversion vs progression for age, APOE, and potential cognitive reserve indicators: education, academic performance (high school grades), and written language skills (idea density, grammatical complexity). Results Of the 619 participants, 472 were assessed with MCI during the study period. Of these 472, 143 (30.3%) experienced at least one reverse transition to NC, and 120 of the 143 (83.9%) never developed dementia (mean follow-up = 8.6 years). In models adjusted for age group and APOE, higher levels of education more than doubled the RR ratio of reversion vs progression. Novel cognitive reserve indicators were significantly associated with a higher adjusted RR of reversion vs progression (higher vs lower levels for English grades: RR ratio = 1.83; idea density: RR ratio = 3.93; and grammatical complexity: RR ratio = 5.78). Discussion Knowledge of frequent reversion from MCI to NC may alleviate concerns of inevitable cognitive decline in those with MCI. Identification of characteristics predicting the rate of reversion from MCI to NC vs progression from MCI to dementia may guide population-level interventions targeting these characteristics to prevent or postpone MCI and dementia. Research on cognitive trajectories would benefit from incorporating predictors of reverse transitions and competing events, such as death, into statistical modeling. These results may inform the design and interpretation of MCI clinical trials, given that a substantial proportion of participants may experience improvement without intervention

Adverse outcomes of cannabis use in Canada, before and after legalisation of non-medical cannabis: cross-sectional analysis of the International Cannabis Policy Study

Objectives To date, there is little evidence on the extent to which cannabis legalisation affects the prevalence of adverse events from cannabis at the population level. The current study examined trends in the prevalence of adverse events among people who consumed cannabis before and after Canada’s legalisation of recreational cannabis.Design Data come from the first four survey waves of the International Cannabis Policy Study, which were conducted online annually immediately prior to non-medical cannabis legalisation in Canada in October 2018, and in the three following years (2019–2021).Participants The current analysis included 18 285 Canadian respondents aged 16–65 who reported cannabis use in the past 12 months.Outcome measures Primary outcomes included types of adverse events experienced from cannabis use, medical help-seeking and the types of products used. Weighted logistic regression models examined differences in help-seeking, emergency room usage and the experience of cannabinoid hyperemesis syndrome across survey years.Results Approximately one-third of people who consume cannabis reported experiencing at least one adverse event within the past 12 months, including 5% of consumers who sought medical help for an adverse event, most commonly for panic attacks, feeling faint/dizzy/passing out, heart/blood pressure problems and nausea/vomiting. The prevalence of seeking help and the types of adverse events were similar before (2018) and after legalisation (2019–2021); however, the proportion of consumers seeking help from emergency rooms increased postlegalisation (F=2.77, p=0.041). Adverse events were associated with various product types, with dried flower and oral oils accounting for the largest proportion of events. Help-seeking associated with cannabis edibles significantly decreased after legalisation (p=0.001).Conclusions Substantial proportions of people who consume cannabis report adverse events, suggesting widespread difficulty in ‘dosing’. Few changes were observed in the prevalence of adverse events reported by consumers since legalisation; however, the location of medical help-seeking and associated products used have changed postlegalisation

Boletín de Segovia: Número 29 - 1884 marzo 5

Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 200

Senior-Loken syndrome in an Iranian family

Senior-Loken syndrome is a rare entity that combines familial juvenile nephro-nophthisis with retinal dystrophy. Herein, we report Senior-Loken syndrome in six members of an Iranian family with progressive blindness and renal failure since childhood. Although, this syn-drome was reported from other parts of the world, report of six members of one family with this syndrome is rare. To the best of our knowledge, this is the first report from Iran