Associations Between Depression Symptom Burden and Delirium Risk: A Prospective Cohort Study.

Background and Objectives: Delirium and depression are prevalent in aging. There is considerable clinical overlap, including shared symptoms and comorbid conditions, including Alzheimer's disease, functional decline, and mortality. Despite this, the long-term relationship between depression and delirium remains unclear. This study assessed the associations of depression symptom burden and its trajectory with delirium risk in a 12-year prospective study of older hospitalized individuals. Research Design and Methods: A total of 319 141 UK Biobank participants between 2006 and 2010 (mean age 58 years [range 37-74, SD = 8], 54% women) reported frequency (0-3) of 4 depressive symptoms (mood, disinterest, tenseness, or lethargy) in the preceding 2 weeks prior to initial assessment visit and aggregated into a depressive symptom burden score (0-12). New-onset delirium was obtained from hospitalization records during 12 years of median follow-up. 40 451 (mean age 57 ±â€…8; range 40-74 years) had repeat assessment on average 8 years after their first visit. Cox proportional hazard models examined whether depression symptom burden and trajectory predicted incident delirium. Results: A total of 5 753 (15 per 1 000) newly developed delirium during follow-up. Increased risk for delirium was seen for mild (aggregated scores 1-2, hazards ratio, HR = 1.16, [95% confidence interval (CI): 1.08-1.25], p < .001), modest (scores 3-5, 1.30 [CI: 1.19-1.43], p < .001), and severe (scores ≥ 5, 1.38 [CI: 1.24-1.55], p < .001) depressive symptoms, versus none in the fully adjusted model. These findings were independent of the number of hospitalizations and consistent across settings (eg, surgical, medical, or critical care) and specialty (eg, neuropsychiatric, cardiorespiratory, or other). Worsening depression symptoms (≥1 point increase), compared to no change/improved score, were associated with an additional 39% increased risk (1.39 [1.03-1.88], p = .03) independent of baseline depression burden. The association was strongest in those over 65 years at baseline (p for interaction <.001). Discussion and Implications: Depression symptom burden and worsening trajectory predicted delirium risk during hospitalization. Increased awareness of subclinical depression symptoms may aid delirium prevention.

Associations between depression symptom burden and delirium risk: a prospective cohort study.

BACKGROUND AND OBJECTIVES: Delirium and depression are increasingly common in aging. There is considerable clinical overlap, including shared symptoms and comorbid conditions, including Alzheimer's disease (AD), functional decline, and mortality. Despite this, the long-term relationship between depression and delirium remains unclear. This study assessed the associations of depression symptom burden and its trajectory with delirium risk in a 12-year prospective study of older individuals during hospitalization. RESEARCH DESIGN AND METHODS: 319,141 UK biobank participants between 2006-2010 (mean 58y [range 37-74, SD=8], 54% female) reported frequency (0-3) of four depressive symptoms (mood, disinterest, tenseness, or lethargy) in the preceding 2 weeks, and aggregated into a depressive symptom burden score (0-12). New-onset delirium was obtained from hospitalization records during 12y median follow-up. 40,451 (mean age 57±8; range 40-74y) had repeat assessment on average 8y after their first. Cox proportional hazard models examined whether depression symptom burden and trajectory predicted incident delirium during hospitalization. RESULTS: 5,753 (15 per 1000) newly developed delirium during follow-up. Increased risk for delirium was seen for mild (aggregated scores 1-2, hazards ratio, HR=1.16, [95% confidence interval 1.08-1.25], p<0.001), modest (scores 3-5, 1.30 [1.19-1.43], p<0.001) and severe (scores ≥ 5, 1.38 [1.24-1.55], p<0.001) depressive symptoms, versus none in the fully adjusted model. These findings were independent of the number of hospitalizations and consistent across hospitalization settings (e.g., surgical, medical, or critical care) and specialty (e.g., neuropsychiatric, cardiorespiratory or other). Worsening depression symptoms (≥1 point increase), compared to no change/improved score, were associated with an additional 39% increased risk (1.39 [1.03-1.88], p=0.03) independent of baseline depression burden. The association was strongest in those over 65y at baseline (p for interaction <0.001). DISCUSSION AND IMPLICATIONS: Depression symptom burden and worsening trajectory predicted delirium risk during hospitalization. Increased awareness of subclinical depression symptoms may be warranted for delirium prevention.

Heart rate response and recovery during exercise predict future delirium risk-A prospective cohort study in middle- to older-aged adults.

BACKGROUND: Delirium is a neurocognitive disorder characterized by an abrupt decline in attention, awareness, and cognition after surgical/illness-induced stressors on the brain. There is now an increasing focus on how cardiovascular health interacts with neurocognitive disorders given their overlapping risk factors and links to subsequent dementia and mortality. One common indicator for cardiovascular health is the heart rate response/recovery (HRR) to exercise, but how this relates to future delirium is unknown. METHODS: Electrocardiogram data were examined in 38,740 middle- to older-aged UK Biobank participants (mean age = 58.1 years, range: 40-72 years; 47.3% males) who completed a standardized submaximal exercise stress test (15-s baseline, 6-min exercise, and 1-min recovery) and required hospitalization during follow-up. An HRR index was derived as the product of the heart rate (HR) responses during exercise (peak/resting HRs) and recovery (peak/recovery HRs) and categorized into low/average/high groups as the bottom quartile/middle 2 quartiles/top quartile, respectively. Associations between 3 HRR groups and new-onset delirium were investigated using Cox proportional hazards models and a 2-year landmark analysis to minimize reverse causation. Sociodemographic factors, lifestyle factors/physical activity, cardiovascular risk, comorbidities, cognition, and maximal workload achieved were included as covariates. RESULTS: During a median follow-up period of 11 years, 348 participants (9/1000) newly developed delirium. Compared with the high HRR group (16/1000), the risk for delirium was almost doubled in those with low HRR (hazard ratio = 1.90, 95% confidence interval (95%CI): 1.30-2.79, p = 0.001) and average HRR (hazard ratio = 1.54, 95%CI: 1.07-2.22, p = 0.020)). Low HRR was equivalent to being 6 years older, a current smoker, or ≥3 additional cardiovascular disease risks. Results were robust in sensitivity analysis, but the risk appeared larger in those with better cognition and when only postoperative delirium was considered (n = 147; hazard ratio = 2.66, 95%CI: 1.46-4.85, p = 0.001). CONCLUSION: HRR during submaximal exercise is associated with future risk for delirium. Given that HRR is potentially modifiable, it may prove useful for neurological risk stratification alongside traditional cardiovascular risk factors.

Daytime napping and Alzheimer's dementia: A potential bidirectional relationship.

INTRODUCTION: Daytime napping is frequently seen in older adults. The longitudinal relationship between daytime napping and cognitive aging is unknown. METHODS: Using data from 1401 participants of the Rush Memory and Aging Project, we examined the longitudinal change of daytime napping inferred objectively by actigraphy, and the association with incident Alzheimer's dementia during up to 14-year follow-up. RESULTS: Older adults tended to nap longer and more frequently with aging, while the progression of Alzheimer's dementia accelerates this change by more than doubling the annual increases in nap duration/frequency. Longer and more frequent daytime naps were associated with higher risk of Alzheimer's dementia. Interestingly, more excessive (longer or more frequent) daytime napping was correlated with worse cognition a year later, and conversely, worse cognition was correlated with more excessive naps a year later. DISCUSSION: Excessive daytime napping and Alzheimer's dementia may possess a bidirectional relationship or share common pathophysiological mechanisms.

Association of Poor Sleep Burden in Middle Age and Older Adults With Risk for Delirium During Hospitalization.

BACKGROUND: Delirium is a distressing neurocognitive disorder recently linked to sleep disturbances. However, the longitudinal relationship between sleep and delirium remains unclear. This study assessed the associations of poor sleep burden, and its trajectory, with delirium risk during hospitalization. METHODS: About 321 818 participants from the UK Biobank (mean age 58 ± 8 years [SD]; range 37-74 years) reported (2006-2010) sleep traits (sleep duration, excessive daytime sleepiness, insomnia-type complaints, napping, and chronotype-a closely related circadian measure for sleep timing), aggregated into a sleep burden score (0-9). New-onset delirium (n = 4 775) was obtained from hospitalization records during a 12-year median follow-up. About 42 291 (mean age 64 ± 8 years; range 44-83 years) had repeat sleep assessment on average 8 years after their first. RESULTS: In the baseline cohort, Cox proportional hazards models showed that moderate (aggregate scores = 4-5) and severe (scores = 6-9) poor sleep burden groups were 18% (hazard ratio = 1.18 [95% confidence interval: 1.08-1.28], p < .001) and 57% (1.57 [1.38-1.80], p < .001), more likely to develop delirium, respectively. The latter risk magnitude is equivalent to 2 additional cardiovascular risks. These findings appeared robust when restricted to postoperative delirium and after exclusion of underlying dementia. Higher sleep burden was also associated with delirium in the follow-up cohort. Worsening sleep burden (score increase ≥2 vs no change) further increased the risk for delirium (1.79 [1.23-2.62], p = .002) independent of their baseline sleep score and time lag. The risk was highest in those younger than 65 years at baseline (p for interaction <.001). CONCLUSION: Poor sleep burden and worsening trajectory were associated with increased risk for delirium; promotion of sleep health may be important for those at higher risk.

Fractal motor activity regulation and sex differences in preclinical Alzheimer's disease pathology.

INTRODUCTION: Degradation in fractal motor activity regulation (FMAR), a measure of multiscale self-similarity of motor control, occurs in aging and accelerates with clinical progression to Alzheimer's disease (AD). Whether FMAR changes occur during the pre-symptomatic phase of the disease in women and men remains unknown. METHODS: FMAR was assessed in cognitively normal participants (n = 178) who underwent 7 to 14 days of home actigraphy. Preclinical AD pathology was determined by amyloid imaging-Pittsburgh compound B (PiB) and cerebrospinal fluid (CSF) phosphorylated-tau181 (p-tau) to amyloid beta 42 (Aß42) ratio. RESULTS: Degradation in daytime FMAR was overall significantly associated with preclinical amyloid plaque pathology via PiB+ imaging (beta coefficient ß = 0.217, standard error [SE] = 0.101, P = .034) and increasing CSF tau181-Aß42 ratio (ß = 0.220, SE = 0.084, P = .009). In subset analysis by sex, the effect sizes were significant in women for PiB+ (ß = 0.279, SE = 0.112, P = .015) and CSF (ß = 0.245, SE = 0.094, P = .011) but not in men (both Ps > .05). These associations remained after inclusion of daily activity level, apolipoprotein E ε4 carrier status, and rest/activity patterns. DISCUSSION: Changes in daytime FMAR from actigraphy appear to be present in women early in preclinical AD. This may be a combination of earlier pathology changes in females reflected in daytime FMAR, and a relatively underpowered male group. Further studies are warranted to test FMAR as an early noncognitive physiological biomarker that precedes the onset of cognitive symptoms.

Objective Assessment of Daytime Napping and Incident Heart Failure in 1140 Community-Dwelling Older Adults: A Prospective, Observational Cohort Study.

Background Disrupted nighttime sleep has been associated with heart failure (HF). However, the relationship between daytime napping, an important aspect of sleep behavior commonly seen in older adults, and HF remains unclear. We sought to investigate the association of objectively assessed daytime napping and risk of incident HF during follow-up. Methods and Results We studied 1140 older adults (age, 80.7±7.4 [SD] years; female sex, 867 [76.1%]) in the Rush Memory and Aging Project who had no HF at baseline and were followed annually for up to 14 years. Motor activity (ie, actigraphy) was recorded for ≈10 days at baseline. We assessed daytime napping episodes between 9 am and 7 pm objectively from actigraphy using a previously published algorithm for sleep detection. Cox proportional hazards models examined associations of daily napping duration and frequency with incident HF. Eighty-six participants developed incident HF, and the mean onset time was 5.7 years (SD, 3.4; range, 1-14). Participants who napped longer than 44.4 minutes (ie, the median daily napping duration) showed a 1.73-fold higher risk of developing incident HF than participants who napped <44.4 minutes. Consistently, participants who napped >1.7 times/day (ie, the median daily napping frequency) showed a 2.20-fold increase compared with participants who napped <1.7 times/day. These associations persisted after adjustment for covariates, including nighttime sleep, comorbidities, and cardiovascular disease/risk factors. Conclusions Longer and more frequent objective napping predicted elevated future risk of developing incident HF. Future studies are needed to establish underlying mechanisms.

Resting Heartbeat Complexity Predicts All-Cause and Cardiorespiratory Mortality in Middle- to Older-Aged Adults From the UK Biobank.

Background Spontaneous heart rate fluctuations contain rich information related to health and illness in terms of physiological complexity, an accepted indicator of plasticity and adaptability. However, it is challenging to make inferences on complexity from shorter, more practical epochs of data. Distribution entropy (DistEn) is a recently introduced complexity measure that is designed specifically for shorter duration heartbeat recordings. We hypothesized that reduced DistEn predicted increased mortality in a large population cohort. Method and Results The prognostic value of DistEn was examined in 7631 middle-older-aged UK Biobank participants who had 2-minute resting ECGs conducted (mean age, 59.5 years; 60.4% women). During a median follow-up period of 7.8 years, 451 (5.9%) participants died. In Cox proportional hazards models with adjustment for demographics, lifestyle factors, physical activity, cardiovascular risks, and comorbidities, for each 1-SD decrease in DistEn, the risk increased by 36%, 56%, and 73% for all-cause, cardiovascular, and respiratory disease-related mortality, respectively. These effect sizes were equivalent to the risk of death from being >5 years older, having been a former smoker, or having diabetes mellitus. Lower DistEn was most predictive of death in those <55 years with a prior myocardial infarction, representing an additional 56% risk for mortality compared with older participants without prior myocardial infarction. These observations remained after controlling for traditional mortality predictors, resting heart rate, and heart rate variability. Conclusions Resting heartbeat complexity from short, resting ECGs was independently associated with mortality in middle- to older-aged adults. These risks appear most pronounced in middle-aged participants with prior MI, and may uniquely contribute to mortality risk screening.

Fragmentation of Rest/Activity Patterns in Community-Based Elderly Individuals Predicts Incident Heart Failure.

STUDY OBJECTIVES: Heart failure has previously been linked to sleep disorders that are often associated with frequent disturbances to human rest/activity patterns. We tested whether fragmentation of sustained rest/activity patterns derived from actigraphic recordings at baseline predicts incident heart failure in community-based elderly individuals. METHODS: We studied 1099 community-based elderly adults participating in the Rush Memory and Aging Project who had baseline motor activity monitoring up to 11 days and were followed annually for up to 14 years. Fragmentation was assessed using previously validated indexes, derived from the probability of transitions once sustained rest or activity has been established. Heart failure was recorded via a clinical interview during the annual follow-up. Cox proportional hazards models were constructed to examine the relationship between rest fragmentation index and incident heart failure. Covariates grouped in terms of demographics, lifestyle factors and co-morbidities and cardiovascular risk factors/diseases were included. RESULTS: Increased rest fragmentation (but not activity fragmentation) was associated with higher risk for incident heart failure. Specifically, a subject with a rest fragmentation at the 90th percentile showed a 57% increased risk of developing incident heart failure compared to a subject at the 10th percentile in this cohort. This effect was equivalent to that of being over a decade older. These observations were consistent after adjusting for all covariates. CONCLUSION: Increased rest fragmentation, a potential surrogate for sleep fragmentation, is independently associated with a higher risk of developing heart failure in community-based elderly adults during up to 14 years of follow-up. Further work is required to examine the specific contributions from daytime napping versus nighttime sleep periods in the elderly, as well as the underlying autonomic and cardio-dynamic pathways that may explain the effects on heart function.

Circadian disturbances in Alzheimer's disease progression: a prospective observational cohort study of community-based older adults.

BACKGROUND: Circadian disturbances are commonly seen in people with Alzheimer's disease and have been reported in individuals without symptoms of dementia but with Alzheimer's pathology. We aimed to assess the temporal relationship between circadian disturbances and Alzheimer's progression. METHODS: We did a prospective cohort study of 1401 healthy older adults (aged >59 years) enrolled in the Rush Memory and Aging Project (Rush University Medical Center, Chicago, IL, USA) who had been followed up for up to 15 years. Participants underwent annual assessments of cognition (with a battery of 21 cognitive performance tests) and motor activities (with actigraphy). Four measures were extracted from actigraphy to quantify daily and circadian rhythmicity, which were amplitude of 24-h activity rhythm, acrophase (representing peak activity time), interdaily stability of 24-h activity rhythm, and intradaily variability for hourly fragmentation of activity rhythm. We used Cox proportional hazards models and logistic regressions to assess whether circadian disturbances predict an increased risk of incident Alzheimer's dementia and conversion of mild cognitive impairment to Alzheimer's dementia. We used linear mixed-effects models to investigate how circadian rhythms changed longitudinally and how the change integrated to Alzheimer's progression. FINDINGS: Participants had a median age of 81·8 (IQR 76·3-85·7) years. Risk of developing Alzheimer's dementia was increased with lower amplitude (1 SD decrease, hazard ratio [HR] 1·39, 95% CI 1·19-1·62) and higher intradaily variability (1 SD increase, 1·22, 1·04-1·43). In participants with mild cognitive impairment, increased risk of Alzheimer's dementia was predicted by lower amplitude (1 SD decrease, HR 1·46, 95% CI 1·24-1·72), higher intradaily variability (1 SD increase, 1·36, 1·15-1·60), and lower interdaily stability (1 SD decrease, 1·21, 1·02-1·44). A faster transition to Alzheimer's dementia in participants with mild cognitive impairment was predicted by lower amplitude (1 SD decrease, odds ratio [OR] 2·08, 95% CI 1·53-2·93), increased intradaily variability (1 SD increase, 1·97, 1·43-2·79), and decreased interdaily stability (1 SD decrease, 1·35, 1·01-1·84). Circadian amplitude, acrophase, and interdaily stability progressively decreased over time, and intradaily variability progressively increased over time. Alzheimer's progression accelerated these aging effects by doubling or more than doubling the annual changes in these measures after the diagnosis of mild cognitive impairment, and further doubled them after the diagnosis of Alzheimer's dementia. The longitudinal change of global cognition positively correlated with the longitudinal changes in amplitude and interdaily stability and negatively correlated with the longitudinal change in intradaily variability. INTERPRETATION: Our results indicate a link between circadian dysregulation and Alzheimer's progression, implying either a bidirectional relation or shared common underlying pathophysiological mechanisms. FUNDING: National Institutes of Health, and the BrightFocus Foundation.