Faculty Bibliography

BACKGROUND:Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by small (<1 °C) decreases in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. METHODS:Tb was continuously measured with ingestible telemetry sensors for 48-h. This period also included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later. RESULTS:Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF Ptau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05). CONCLUSIONS:These results, the first available for human, suggest that lower Tb in older adults may be associated with increased soluble and aggregated tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation. CLINICAL TRIAL NUMBER/BACKGROUND:NCT03053908.

Due in part to overall improvements in health, the population of elderly individuals is increasing rapidly. Similarly, obstructive sleep apnoea (OSA) is both gaining increased recognition and also increasing due to the worldwide obesity epidemic. The overlap of OSA and ageing is large, but there is strong plausibility for causation in both directions: OSA is associated with pathological processes that may accelerate ageing and ageing-related processes; ageing may cause physical and neurological changes that predispose to obstructive (and central) apnoea. In addition, the common symptoms (e.g. excessive daytime sleepiness, and defects in memory and cognition), possible physiological consequences of OSA (e.g. accelerated cardiovascular and cerebrovascular atherosclerosis), and changes in metabolic and inflammatory markers overlap with the symptoms and associated conditions seen in ageing. There is also the possibility of synergy in the effects of these symptoms and conditions on quality of life, as well as a need to separate treatable consequences of OSA from age-related complaints. Taken together, the aforementioned considerations make it essential to review the interaction of OSA and ageing, both proven and suspected. The present review examines some aspects of what is known and points to the need for further investigation of the relationships, given the large number of potentially affected subjects.

STUDY OBJECTIVES/OBJECTIVE:Determine if changes in K-complexes associated with sustained inspiratory airflow limitation (SIFL) during N2 sleep are associated with next-day vigilance and objective sleepiness. METHODS:Data from thirty subjects with moderate-to-severe OSA who completed three in-lab polysomnograms: diagnostic, on therapeutic continuous positive airway pressure (CPAP), and on suboptimal CPAP (4cmH20 below optimal titrated CPAP level) were analyzed. Four 20-min psychomotor vigilance tests (PVT) were performed after each PSG, every two hours. Changes in proportion of spontaneous K-complexes and spectral characteristics surrounding K-complexes were evaluated for K-complexes associated with both delta (∆SWAK), alpha (∆αK) frequencies. RESULTS:Suboptimal CPAP induced SIFL (14.7(20.9) vs. 2.9(9.2); %total sleep time, p<0.001) with a small increase in apnea hypopnea index (AHI3A: 6.5(7.7) vs. 1.9(2.3); p<0.01) versus optimal CPAP. K-complex density (num./min of stage N2) was higher on suboptimal CPAP (0.97±0.7 vs. 0.65±0.5, #/min, mean±SD, p<0.01) above and beyond the effect of age, sex, AHI3A, and duration of SIFL. A decrease in ∆SWAK with suboptimal CPAP was associated with increased PVT lapses and explained 17% of additional variance in PVT lapses. Within-night during suboptimal CPAP K-complexes appeared to alternate between promoting sleep and as arousal surrogates. EEG changes were not associated with objective sleepiness. CONCLUSIONS:Sustained inspiratory airflow limitation is associated with altered K-complex morphology including increased occurrence of K-complexes with bursts of alpha as arousal surrogates. These findings suggest that sustained inspiratory flow limitation may be associated with non-visible sleep fragmentation and contribute to increased lapses in vigilance.

BACKGROUND:Recent advancement in deep learning provides a pivotal opportunity to potentially supplement or supplant the limiting step of manual sleep scoring. NEW METHOD/UNASSIGNED:In this paper, we characterize the WaveSleepNet (WSN), a deep convolutional neural network (CNN) that uses wavelet transformed images of mouse EEG/EMG signals to autoscore sleep and wake. RESULTS:WSN achieves an epoch by epoch mean accuracy of 0.86 and mean F1 score of 0.82 compared to manual scoring by a human expert. In mice experiencing mechanically induced sleep fragmentation, an overall epoch by epoch mean accuracy of 0.80 is achieved by WSN and classification of non-REM (NREM) sleep is not compromised, but the high level of sleep fragmentation results in WSN having greater difficulty differentiating REM from NREM sleep. We also find that WSN achieves similar levels of accuracy on an independent dataset of externally acquired EEG/EMG recordings with an overall epoch by epoch accuracy of 0.91. We also compared conventional summary sleep metrics in mice sleeping ad libitum. WSN systematically biases sleep fragmentation metrics of bout number and bout length leading to an overestimated degree of sleep fragmentation. COMPARISON WITH EXISTING METHODS/UNASSIGNED:In a cross-validation, WSN has a greater macro and stage-specific accuracy compared to a conventional random forest classifier. Examining the WSN, we find that it automatically learns spectral features consistent with manual scoring criteria that are used to define each class. CONCLUSION/CONCLUSIONS:These results suggest to us that WSN is capable of learning visually agreeable features and may be useful as a supplement to human manual scoring.

STUDY OBJECTIVES/OBJECTIVE:Obstructive sleep apnea (OSA) prevalence increases with age, but whether OSA-related sleep disruption could interrupt the processing of previously encoded wake information thought to normally occur during sleep in cognitively normal older adults remains unknown. METHODS:Fifty-two older (age = 66.9 ± 7.7 years, 56 % female), community-dwelling, cognitively normal adults explored a 3D maze environment and then performed 3 timed trials before (evening) and after (morning) sleep recorded with polysomnography (PSG) with a 20-minute morning psychomotor vigilance test (PVT). RESULTS:Twenty-two (22) subjects had untreated OSA (Apnea Hypopnea Index (AHI4%) ≥ 5/hour) where severity was mild on average [median (interquartile range (IQR))] AHI4% = 11.0 (20.7)/hour) and 30 subjects had an AHI4% < 5/hour. No significant differences were observed in overnight percent change in completion time or in the pattern of evening pre-sleep maze performance. However, during the morning post-sleep trials, there was a significant interaction between OSA group and morning trial number such that participants with OSA performed worse on average with each subsequent morning trial, whereas those without OSA showed improvements. There were no significant differences in morning PVT performance suggesting that vigilance is unlikely to account for this difference in morning maze performance. Increasing relative frontal slow wave activity (SWA) was associated with better overnight maze performance improvement in participants with OSA (r= 0.51, p = 0.02) but not in those without OSA, and no differences in slow wave activity were observed between groups. CONCLUSIONS:OSA alters morning performance in spatial navigation independent of a deleterious effect on morning vigilance or evening navigation performance. Relative frontal slow wave activity is associated with overnight performance change in older subjects with OSA, but not those without.

RATIONALE/BACKGROUND:) may reduce discomfort in those with high nasal resistance and improve adherence in this subgroup. OBJECTIVES/OBJECTIVE:improves adherence over CPAP in subjects with high nasal resistance. METHODS:versus CPAP in World Trade Center dust-exposed subjects with OSA stratified by nasal resistance measured by 4-Phase Rhinomanometry. RESULTS:(mean Δ hours (95% CI)) in subjects with low resistance (0.33h (-0.10, 0.76)) or high nasal resistance (0.26h (-0.14, 0.66)). No significant differences were observed in any of the secondary outcomes between PAP modes. CONCLUSIONS:than to CPAP in subjects with high or low nasal resistance, and, show clinically insignificant better adherence overall with CPAP. Clinical Trial registered with Clinicaltrials.gov (NCT01753999).

BACKGROUND:Sleep difficulties are common among older adults, and clinical management of sleep difficulties commonly includes sleep medication (pharmacological and non-pharmacological). Our research examines sleep medication use and incident dementia over 8 years using nationally representative data from older adults ages 65 years and older in the United States. METHODS:We used data collected from the National Health and Aging Trends Study (NHATS), a nationally-representative longitudinal study of Medicare beneficiaries. Routine sleep medication use (pharmacological and non-pharmacological) was defined as use "most nights" or "every night." Participants were screened for dementia with validated instruments that assessed memory, orientation, and executive function. We conduct prospective analyses to examine the relationship between routine sleep medication use and incident dementia using Cox proportional hazards modeling and estimated survival curves. Analyses controlled for age, sex, marital status, education, and chronic conditions. RESULTS:Among respondents at baseline (n = 6373), most participants (21%) were age 70-74 years of age. Participants were 59% female and the sample comprised non-Hispanic White (71%). At baseline, 15% of our study sample reported using sleep medication routinely, which is representative of 4.6 million older adults in the US. Covariate adjusted proportional hazard models revealed that routinely using sleep medication was associated with incident dementia (HR = 1.30, 95%CI: 1.10 to 1.53, p < 0.01). CONCLUSIONS:Our study observed, in a nationally representative study of older adults in the US across 8 years of data that 15% of older adults report routinely using sleep medication, yet routine use of sleeping medication was associated with incident dementia across the follow-up interval. Future research may examine behavioral approaches to improving sleep among older adults.