Background: We investigated the effect of delirium burden in mechanically ventilated patients, beginning in the ICU and continuing throughout hospitalization, on functional neurologic outcomes up to 2.5 years following critical illness. Methods: Prospective cohort study of enrolling 178 consecutive mechanically ventilated adult medical and surgical ICU patients between October 2013 and May 2016. Altogether, patients were assessed daily for delirium 2941days using the Confusion Assessment Method for the ICU (CAM-ICU). Hospitalization delirium burden (DB) was quantified as number of hospital days with delirium divided by total days at risk. Survival status up to 2.5 years and neurologic outcomes using the Glasgow Outcome Scale were recorded at discharge 3, 6, and 12 months post-discharge. Results: Of 178 patients, 19 (10.7%) were excluded from outcome analyses due to persistent coma. Among the remaining 159, 123 (77.4%) experienced delirium. DB was independently associated with >4-fold increased mortality at 2.5 years following ICU admission (adjusted hazard ratio [aHR], 4.77; 95% CI, 2.10–10.83; P < .001), and worse neurologic outcome at discharge (adjusted odds ratio [aOR], 0.02; 0.01–0.09; P < .001), 3 (aOR, 0.11; 0.04–0.31; P < .001), 6 (aOR, 0.10; 0.04–0.29; P < .001), and 12 months (aOR, 0.19; 0.07–0.52; P = .001). DB in the ICU alone was not associated with mortality (HR, 1.79; 0.93–3.44; P = .082) and predicted neurologic outcome less strongly than entire hospital stay DB. Similarly, the number of delirium days in the ICU and for whole hospitalization were not associated with mortality (HR, 1.00; 0.93–1.08; P = .917 and HR, 0.98; 0.94–1.03, P = .535) nor with neurological outcomes, except for the association between ICU delirium days and neurological outcome at discharge (OR, 0.90; 0.81–0.99, P = .038). Conclusions: Delirium burden throughout hospitalization independently predicts long term neurologic outcomes and death up to 2.5 years after critical illness, and is more predictive than delirium burden in the ICU alone and number of delirium days.

Backgrounds: Sleep disturbances are prevalent among elderly individuals. While polysomnography (PSG) serves as the gold standard for sleep monitoring, its extensive setup and data analysis procedures impose significant costs and time constraints, thereby restricting the long-term application within the general public. Our laboratory introduced an innovative biomarker, utilizing artificial intelligence algorithms applied to PSG data to estimate brain age (BA), a metric validated in cohorts with cognitive impairments. Nevertheless, the potential of exercise, which has been a recognized means of enhancing sleep quality in middle-aged and older adults to reduce BA, remains undetermined. Methods: We conducted an exploratory study to evaluate whether 12 weeks of moderate-intensity exercise can improve cognitive function, sleep quality, and the brain age index (BAI), a biomarker computed from overnight sleep electroencephalogram (EEG), in physically inactive middle-aged and older adults. Home wearable devices were used to monitor heart rate and overnight sleep EEG over this period. The NIH Toolbox Cognition Battery, in-lab overnight polysomnography, cardiopulmonary exercise testing, and a multiplex cytokines assay were employed to compare pre- and post-exercise brain health, exercise capacity, and plasma proteins. Results: In total, 26 participants completed the initial assessment and exercise program, and 24 completed all procedures. Data are presented as mean [lower 95% CI of mean, upper 95% CI of mean]. Participants significantly increased maximal oxygen consumption (Pre: 21.11 [18.98, 23.23], Post 22.39 [20.09, 24.68], mL/kg/min; effect size: −0.33) and decreased resting heart rate (Pre: 66.66 [63.62, 67.38], Post: 65.13 [64.25, 66.93], bpm; effect size: −0.02) and sleeping heart rate (Pre: 64.55 [61.87, 667.23], Post: 62.93 [60.78, 65.09], bpm; effect size: −0.15). Total cognitive performance (Pre: 111.1 [107.6, 114.6], Post: 115.2 [111.9, 118.5]; effect size: 0.49) was significantly improved. No significant differences were seen in BAI or measures of sleep macro- and micro-architecture. Plasma IL-4 (Pre: 0.24 [0.18, 0.3], Post: 0.33 [0.24, 0.42], pg/mL; effect size: 0.49) was elevated, while IL-8 (Pre: 5.5 [4.45, 6.55], Post: 4.3 [3.66, 5], pg/mL; effect size: −0.57) was reduced. Conclusions: Cognitive function was improved by a 12-week moderate-intensity exercise program in physically inactive middle-aged and older adults, as were aerobic fitness (VO₂max) and plasma cytokine profiles. However, we found no measurable effects on sleep architecture or BAI. It remains to be seen whether a study with a larger sample size and more intensive or more prolonged exercise exposure can demonstrate a beneficial effect on sleep quality and brain age.

Backgrounds: Exercise is an attractive, widely accessible intervention to promote cardiovascular health; however, evidence that exercise improves brain health is sparse. Here, we hypothesized that aerobic exercise would improve brain health of sedentary older adults, as reflected by cognition health, sleep macro- and micro-architecture, and brain age index (BAI), a biomarker of brain health derived from the overnight sleep electroencephalogram (EEG). Methods: Sedentary older adults were recruited to complete a 12-week aerobic exercise. Home wearable devices were used to monitor heart rate and overnight sleep EEG over the period. NIH Toolbox Cognition Battery, in-lab overnight polysomnography, cardiopulmonary exercise testing and multiplex cytokine assay were employed to determine pre- and post-exercise brain health, exercise capacity and plasma proteins. Results: 26 participants completed the initial assessment and exercise program, and 24 completed all procedures. Participants significantly increased maximal oxygen consumption (VO2max) and decreased resting and sleeping heart rate after the exercise regimen. Cognition performances were significantly improved following the exercise program while no significant differences were seen in BAI and sleep macro- and micro-architecture. Plasma IL-4 was elevated while IL-8 was reduced after the exercise regimen. Home sleep data revealed a 3.59% increase in the percentage of N3 sleep over a 12-week. Conclusions: We conclude that cognitive function and N3 sleep were improved by a 12-week moderate-intensity exercise program in sedentary older adults, associated with improvements in VO ₂ max and plasma cytokine profiles. Our data show the value of integrating multi-modal assessments to study the effect of brain health targeted approaches. Funding: Dr. Westover received support during this work from the McCance Center for Brain Health, the Glenn Foundation for Medical Research and the American Federation for Aging Research through a Breakthroughs in Gerontology Grant; through the American Academy of Sleep Medicine through an AASM Foundation Strategic Research Award; by the Football Players Health Study (FPHS) at Harvard University; from the Department of Defense through a subcontract from Moberg ICU Solutions, Inc, and by grants from the NIH (R01NS102190, R01NS102574, R01NS107291, RF1AG064312, R01AG062989, R01AG073410), and NSF (2014431). Dr. Wrann was supported by a SPARC Award from the McCance Center for Brain Health. Dr. Tanzi and Dr. Zhang were supported by the Cure Alzheimer’s Fund. Clinical trial number: National Clinical Trial: NCT04210882 One Sentence Summary: We observed that exercise improved slow wave sleep, increased circulating neuroprotective cytokines and improved cognition health in older adults.