Associations Between Midlife Anticholinergic Medication Use and Subsequent Cognitive Decline: A British Birth Cohort Study.

BACKGROUND: Anticholinergic medication use is associated with cognitive decline and incident dementia. Our study, a prospective birth cohort analysis, aimed to determine if repeated exposure to anticholinergic medications was associated with greater decline, and whether decline was reversed with medication reduction. METHODS: From the Medical Research Council (MRC) National Survey of Health and Development, a British birth cohort with all participants born in a single week of March 1946, we quantified anticholinergic exposure between ages 53 and 69 years using the Anticholinergic Cognitive Burden Scale (ACBS). We used multinomial regression to estimate associations with global cognition, quantified by the Addenbrooke's Cognitive Examination, 3rd Edition (ACE-III). Longitudinal associations between ACBS and cognitive test results (Verbal memory quantified by the Word Learning Test [WLT], and processing speed quantified by the Timed Letter Search Task [TLST]) at three time points (age 53, 60-64 and 69) were assessed using mixed and fixed effects linear regression models. Analyses were adjusted for sex, childhood cognition, education, chronic disease count and severity, and mental health symptoms. RESULTS: Anticholinergic exposure was associated cross-sectionally with lower ACE-III scores at age 69, with the greatest effects in those with high exposure at ages 60-64 (mean difference - 2.34, 95% confidence interval [CI] - 3.51 to - 1.17). Longitudinally, both mild-moderate and high ACBS scores were linked to lower WLT scores, again with high exposure showing larger effects (mean difference with contemporaneous exposure - 0.90, 95% CI - 1.63 to - 0.17; mean difference with lagged exposure - 1.53, 95% CI - 2.43 to - 0.64). Associations remained in fixed effects models (mean difference with contemporaneous exposure -1.78, 95% CI -2.85 to - 0.71; mean difference with lagged exposure - 2.23, 95% CI - 3.33 to - 1.13). Associations with TLST were noted only in isolated contemporaneous exposure (mean difference - 13.14, 95% CI - 19.04 to - 7.23; p < 0.01). CONCLUSIONS: Anticholinergic exposure throughout mid and later life was associated with lower cognitive function. Reduced processing speed was associated only with contemporaneous anticholinergic medication use, and not historical use. Associations with lower verbal recall were evident with both historical and contemporaneous use of anticholinergic medication, and associations with historical use persisted in individuals even when their anticholinergic medication use decreased over the course of the study.

Extremes of baseline cognitive function determine the severity of delirium: a population study.

Although delirium is a significant clinical and public health problem, little is understood about how specific vulnerabilities underlie the severity of its presentation. Our objective was to quantify the relationship between baseline cognition and subsequent delirium severity. We prospectively investigated a population-representative sample of 1510 individuals aged ≥70 years, of whom 209 (13.6%) were hospitalized across 371 episodes (1999 person-days assessment). Baseline cognitive function was assessed using the modified Telephone Interview for Cognitive Status, supplemented by verbal fluency measures. We estimated the relationship between baseline cognition and delirium severity [Memorial Delirium Assessment Scale (MDAS)] and abnormal arousal (Observational Scale of Level of Arousal), adjusted by age, sex, frailty and illness severity. We conducted further analyses examining presentations to specific hospital settings and common precipitating aetiologies. The median time from baseline cognitive assessment to admission was 289 days (interquartile range 130 to 47 days). In admitted patients, delirium was present on at least 1 day in 45% of admission episodes. The average number of days with delirium (consecutively positive assessments) was 3.9 days. Elective admissions accounted for 88 bed days (4.4%). In emergency (but not elective) admissions, we found a non-linear U-shaped relationship between baseline global cognition and delirium severity using restricted cubic splines. Participants with baseline cognition 2 standard deviations below average (z-score = -2) had a mean MDAS score of 14 points (95% CI 10 to 19). Similarly, those with baseline cognition z-score = + 2 had a mean MDAS score of 7.9 points (95% CI 4.9 to 11). Individuals with average baseline cognition had the lowest MDAS scores. The association between baseline cognition and abnormal arousal followed a comparable pattern. C-reactive protein ≥20 mg/l and serum sodium <125 mM/l were associated with more severe delirium. Baseline cognition is a critical determinant of the severity of delirium and associated changes in arousal. Emergency admissions with lowest and highest baseline cognition who develop delirium should receive enhanced clinical attention.

Anticholinergic Burden Does Not Influence Delirium Subtype or the Delirium-Mortality Association in Hospitalized Older Adults: Results from a Prospective Cohort Study.

BACKGROUND: Anticholinergic burden (ACB) is associated with an increased risk of delirium in the older population outside of the acute hospital setting. In acute settings, delirium is associated with increased mortality, and this association is greater with full syndromal delirium (FSD) than with subsyndromal delirium (SSD). Little is known about the impact of ACB on delirium prevalence or subtype in hospitalized older adults or the impact on mortality in this population. OBJECTIVES: Our objectives were to determine whether ACB moderates associations between the subtype of delirium experienced by hospitalized older adults and to explore factors (including ACB) that might moderate consequent associations between delirium and mortality in hospital inpatients. METHODS: We conducted a retrospective analysis of a cohort of 784 older adults with unplanned admission to a North London acute medical unit between June and December 2007. Univariate regression analyses were performed to explore associations between ACB, as represented by the Anticholinergic Burden Scale (ACBS), delirium subtype (FSD vs. SSD), and mortality. RESULTS: The mean age of the sample was 83 ± standard deviation (SD) 7.4 years, and the majority of patients were female (59%), lived in their own homes (71%), were without dementia (75%), and died between hospital admission and the end of the 2-year follow-up period (59%). Mean length of admission was 13.2 ± 14.4 days. Prescription data revealed an ACBS score of 1 in 26% of the cohort, of 2 in 12%, and of ≥ 3 in 16%. The mean total ACBS score for the cohort was 1.1 ± 1.4 (range 0-9). Patients with high ACB on admission were more likely to have severe dementia, to have multiple comorbidities, and to live in residential care. Higher ACB was not associated with delirium of either subtype in hospitalized older adults. Delirium itself was associated with increased mortality, and greater associations were seen in FSD (hazard ratio [HR] 2.27; 95% confidence interval [CI] 1.70-3.01) than in SSD (HR 1.58; 95% CI 1.2-2.09); however, ACB had no impact on this relationship. CONCLUSIONS: ACB was not found to be associated with increased delirium of either subtype or to have a demonstrable impact on mortality in delirium. Prior suggestions of links between ACB and mortality in similar populations may be mediated by higher levels of functional dependence, greater levels of residential home residence, or an increased prevalence of dementia in this population.

Atypical presentations of COVID-19 in care home residents presenting to secondary care: A UK single centre study.

BACKGROUND: Atypical presentations of COVID-19 pose difficulties for early isolation and treatment, particularly in institutional care settings. We aimed to characterize the presenting symptoms and associated mortality of COVID-19 in older adults, focusing on care home residents admitted to secondary care. METHODS: A retrospective cohort study of 134 consecutive inpatients over 80 years old hospitalized with PCR confirmed COVID-19 in the United Kingdom. Symptoms at presentation and frailty were analysed. Differences between community dwelling and care home residents, and associations with mortality, were assessed using between-group comparisons and logistic regression. RESULTS: Care home residents were less likely to experience cough (46.9% vs 72.9%, P = .002) but more likely to present with delirium (51.6% vs 31.4%, P = .018), particularly hypoactive delirium (40.6% vs 24.3%, P = .043). Mortality was more likely with increasing frailty (OR 1.25, 95% CI 1.00, 1.58, P = .049) and those presenting with anorexia (OR 3.20, 95% CI 1.21, 10.09, P = .028). There were no differences in mortality or length of stay based on residential status. CONCLUSION: COVID-19 in older adults often presents with atypical symptoms, particularly in those admitted from institutional care. These individuals have a reduced incidence of cough and increased hypoactive delirium. Individuals presenting atypically, especially with anorexia, have higher mortality.

Beta-Blockers for the Secondary Prevention of Myocardial Infarction in People with Dementia: A Systematic Review.

BACKGROUND: Cardiovascular disease remains the most common cause of death in industrialized countries. The use of beta-blockers is well established as a secondary prevention of myocardial infarction. However, little is known about the benefits of beta-blockers for people living with dementia. OBJECTIVE: To evaluate the use of beta-blockers in people with dementia who have had a myocardial infarction, in order to identify associations between medication use, mortality, re-infarction and functional decline. METHODS: We searched for all studies (randomized trials, observational cohorts) reporting beta-blocker use in populations with both dementia and previous myocardial infarction. Relevant keywords were used in Medline, Embase, and Web of Science up to October 2018. Titles and abstracts were independently screened by two reviewers. Quality of eligible studies was assessed using the Newcastle-Ottawa Scale. PRISMA recommendations were followed throughout. RESULTS: Two observational studies were included, representing 10,992 individuals in a community setting and 129,092 individuals from a hospital record-linkage study. One showed use of beta-blockers reduced all-cause mortality (HR 0.74 (95% CI 0.64- 0.86) alongside evidence for an increased rate of functional decline in individuals aged≥65 with moderate to severe cognitive impairment (OR 1.34 (95% CI 1.11- 1.61)). The second study did not find an association between beta-blocker use and mortality in the population living with dementia. CONCLUSION: There is insufficient evidence to support use of beta-blockers to persons living with dementia. A single study provides limited evidence that beta-blockers improve survival rates but with associated detrimental effects on functional status in nursing home residents with cognitive impairment. Decisions to continue beta-blockers in persons living with dementia should be made on an individual basis.

Identifying the lifetime cognitive and socioeconomic antecedents of cognitive state: seven decades of follow-up in a British birth cohort study.

OBJECTIVES: The life course determinants of midlife and later life cognitive function have been studied using longitudinal population-based cohort data, but far less is known about whether the pattern of these pathways is similar or distinct for clinically relevant cognitive state. We investigated this for Addenbrooke's Cognitive Examination third edition (ACE-III), used in clinical settings to screen for cognitive impairment and dementia. DESIGN: Longitudinal birth cohort study. SETTING: Residential addresses in England, Wales and Scotland. PARTICIPANTS: 1762 community-dwelling men and women of European heritage, enrolled since birth in the Medical Research Council (MRC) National Survey of Health and Development (the British 1946 birth cohort). PRIMARY OUTCOME: ACE-III. RESULTS: Path modelling estimated direct and indirect associations between apolipoprotein E (APOE) status, father's social class, childhood cognition, education, midlife occupational complexity, midlife verbal ability (National Adult Reading Test; NART), and the total ACE-III score. Controlling for sex, there was a direct negative association between APOE ε4 and the ACE-III score (ß=-0.04 [-0.08 to -0.002], p=0.04), but not between APOE ε4 and childhood cognition (ß=0.03 [-0.006 to 0.069], p=0.10) or the NART (ß=0.0005 [-0.03 to 0.03], p=0.97). The strongest influences on the ACE-III were from childhood cognition (ß=0.20 [0.14 to 0.26], p<0.001) and the NART (ß=0.35 [0.29 to 0.41], p<0.001); educational attainment and occupational complexity were modestly and independently associated with the ACE-III (ß=0.08 [0.03 to 0.14], p=0.002 and ß=0.05 [0.01 to 0.10], p=0.02, respectively). CONCLUSIONS: The ACE-III in the general population shows a pattern of life course antecedents that is similar to neuropsychological measures of cognitive function, and may be used to represent normal cognitive ageing as well as a screen for cognitive impairment and dementia.

The prevalence and determinants of polypharmacy at age 69: a British birth cohort study.

BACKGROUND: To describe the development of polypharmacy and its components in a British birth cohort in its seventh decade and to investigate socioeconomic and gender differences independent of disease burden. METHODS: Data from the MRC National Survey for Health and Development were analysed to determine the prevalence and composition of polypharmacy at age 69 and changes since ages 60 to 64. Multinomial regression was used to test associations between gender, education and occupational social class and total, cardiological and non-cardiological polypharmacy controlling for disease burden. RESULTS: At age 69, 22.8% of individuals were taking more than 5 medications. There was an increase in the use of 5 to 8 medications (+ 2.3%) and over 9 medications (+ 0.8%) between ages 60-64 and 69. The greatest increases were found for cardiovascular (+ 13.4%) and gastrointestinal medications (+ 7.3%). Men experienced greater cardiological polypharmacy, women greater non-cardiological polypharmacy. Higher levels of education were associated with lower polypharmacy independent of disease burden, with strongest effects seen for over five cardiological medications (RRR 0.3, 95% CI 0.2-0.5 p < 0.001 for advanced secondary qualifications compared with no qualification); there was no additional effect of social class. CONCLUSIONS: Polypharmacy increased over the seventh decade. Those with lower levels of education had more polypharmacy (total, cardiological and non-cardiological), even allowing for disease burden. Further analysis of future outcomes resulting from polypharmacy should take into account educational and gender differences, in an effort to identify at-risk populations who could benefit from medication reviews.

Associations Between Polypharmacy and Cognitive and Physical Capability: A British Birth Cohort Study.

OBJECTIVES: To investigate longitudinal associations between polypharmacy and cognitive and physical capability and to determine whether these associations differ with cumulative exposure to polypharmacy. DESIGN: Prospective birth cohort study. SETTING: England, Scotland, and Wales. PARTICIPANTS: An eligible sample of men and women from the Medical Research Council National Survey of Health and Development with medication data at age 69 (N=2,122, 79%). MEASUREMENTS: Cognitive capability was assessed using a word learning test, visual search speed task, and the Addenbrooke's Cognitive Examination, Third Edition (ACE-III). Physical capability was measured using chair rise speed, standing balance time, walking speed, and grip strength. RESULTS: Polypharmacy (5-8 prescribed medications) was present in 18.2% of participants at age 69 and excessive polypharmacy (≥9 prescribed medications) in 4.7%. Both were associated with poorer cognitive and physical capability in models adjusted for sex, education, and disease burden. Stronger associations were found for excessive polypharmacy (e.g., difference in mean ACE-III scores comparing polypharmacy=-2.0, 95% CI=-2.8 to -1.1 and excessive polypharmacy=-2.9, 95% CI=-4.4 to -1.4 with no polypharmacy). Participants with polypharmacy at age 60 to 64 and at age 69 showed stronger Negative associations with cognitive and physical capability were stronger still in participants with polypharmacy at both age 60 to 64 and at age 69 (e.g. difference in mean chair rise speed, comparing polypharmacy with no polypharmacy at both ages=-3.9, 95% CI=-5.2 to -2.6 and at age 60-64 only=-2.5, 95% CI=-4.1 to -0.9). CONCLUSION: Polypharmacy at age 60 to 64 and age 69 was associated with poorer physical and cognitive capability, even after adjusting for disease burden. Stronger negative associations were seen in participants with longstanding polypharmacy, suggesting a cumulative, dose-dependent relationship (where dose is the number of prescribed medications). Future research aiming to improve cognitive and physical capability should consider interventions to reduce the duration and level of polypharmacy at younger ages, in addition to optimizing disease control with appropriate medications.

Apolipoprotein-E (Apoe) ε4 and cognitive decline over the adult life course.

We tested the association between APOE-ε4 and processing speed and memory between ages 43 and 69 in a population-based birth cohort. Analyses of processing speed (using a timed letter search task) and episodic memory (a 15-item word learning test) were conducted at ages 43, 53, 60-64 and 69 years using linear and multivariable regression, adjusting for gender and childhood cognition. Linear mixed models, with random intercepts and slopes, were conducted to test the association between APOE and the rate of decline in these cognitive scores from age 43 to 69. Model fit was assessed with the Bayesian Information Criterion. A cross-sectional association between APOE-ε4 and memory scores was detected at age 69 for both heterozygotes and homozygotes (ß = -0.68 and ß = -1.38, respectively, p = 0.03) with stronger associations in homozygotes; no associations were observed before this age. Homozygous carriers of APOE-ε4 had a faster rate of decline in memory between ages 43 and 69, when compared to non-carriers, after adjusting for gender and childhood cognition (ß = -0.05, p = 0.04). There were no cross-sectional or longitudinal associations between APOE-ε4 and processing speed. We conclude that APOE-ε4 is associated with a subtly faster rate of memory decline from midlife to early old age; this may be due to effects of APOE-ε4 becoming manifest around the latter stage of life. Continuing follow-up will determine what proportion of this increase will become clinically significant.

Factors associated with medication adherence in older patients: A systematic review.

OBJECTIVE: Medication adherence is a major challenge in the treatment of older patients; however, they are under-represented in research. We undertook a systematic review focused on older patients to assess the reasons underlying non-adherence in this population. METHODS: We searched multiple electronic databases for studies reporting reasons for non-adherence to medication regimens in patients aged 75 years and over. Our results were not limited to specific diseases, health-care settings, or geographical locations. The quality of eligible studies was assessed using the Newcastle-Ottawa Scale. A narrative synthesis of findings was performed. RESULTS: A total of 25 publications were included, all of which were in community settings. Frequent medication review and knowledge regarding the purpose of the medication were positively associated with adherence. Factors associated with poor adherence were multimorbidity, cognitive impairment, complex regimens with multiple prescribing physicians, and problems with drug storage or formulation. CONCLUSION: These findings suggest that interventions to improve adherence could focus on medication review aimed at simplifying regimens and educating patients about their treatment. Groups with poor adherence that may benefit most from such a model include patients with multiple comorbidities and cognitive impairment.

NARP Syndrome: A 20-Year Follow-Up.

One member of a pedigree with NARP syndrome (neurogenic weakness, ataxia, and retinitis pigmentosa), a mitochondrial disorder due to a point mutation at position 8993 in the mitochondrial genome ATPase 6 gene, was reevaluated some 20 years after first being reported in the medical literature. Initially assessed at age 39 years, she had retinitis pigmentosa and a mild sensory axonal neuropathy, typical features of NARP, but was otherwise clinically normal. At age 59 years, she was registered blind, had sensorineural hearing impairment, had recently been diagnosed with diabetes mellitus, and may have had some mild cognitive impairment. This case shows that the clinical phenotype of NARP due to mitochondrial dysfunction may evolve over a period of decades.