Faculty Bibliography

Introduction: The ApoE4 allele is a major risk factor for development of Alzheimer Disease (AD). Symptoms of AD include early deficits in spatial orientation and alterations in sleep. The effects of ApoE4 on sleep architecture and sleep-dependent memory consolidation are less known, particularly at earlier time points before clinical manifestations are apparent. We investigated the effects of ApoE4 allele on sleep architecture and overnight spatial navigational memory consolidation in cognitively normal elderly individuals. Methods: We recruited 29 cognitively normal elderly subjects (age = 67 +/- 9 years) who underwent one night of standard polysomnography. Subjects performed training and 3 timed trials before and after sleep on the same computer-generated 3D spatial maze. Improvement in average completion time after sleep was calculated. A 20-minute psychomotor vigilance test (PVT) was performed in the morning prior to the maze trials. ApoE genotype was determined from serum. Individuals with at least 1 ApoE4 were considered at risk carriers. Results: Of 29 subjects, 17 were control and 12 had at least one ApoE4 allele. Both groups were similar in age, total sleep time, sleep efficiency, sleep architecture, severity of sleep disordered breathing, PVT performance, and pre-sleep baseline maze performance. The control group had significant improvements in maze performance after sleep (390 + 135 sec vs 302 + 121 sec, p < 0.002) while ApoE4 carriers had no significant change in performance (349 + 159 sec vs 358 + 178 sec, p = 0.82). We observed a trend toward a difference in the median of individual changes in overnight performance between groups (28.8% vs-11.8% respectively, p = 0.066). Conclusion: Cognitively normal subjects with at least one ApoE4 allele showed a decreased ability to consolidate spatial navigational memory during sleep. Sleep-dependent spatial memory deficits observed may represent an endophenotype of ApoE4 genotype or may help establish risk for development of subsequent AD

Introduction: Both hippocampal electrophysiology and behavioral performance evidence support a role for sleep in spatial navigational memory, but the role of particular sleep stages is less clear. While rodent models suggest REM sleep's importance in spatial navigational memory, a similar role for REM sleep has never been examined in humans. Materials and methods: Given the increased severity of obstructive sleep apnea (OSA) in REM associated with REM skeletal muscle atonia, we hypothesized disrupting human REM sleep via sleepstage specific OSA would impair proper consolidation of spatial memories. We recruited subjects with severe OSA who are well treated and adherent with continuous positive airway pressure (CPAP). Restricting CPAP withdrawal to REM through real-timemonitoring of the polysomnogram (PSG) provides a novel way of addressing the role of REM sleep in spatial navigational memory with a physiologically relevant stimulus. Individual subjects spent two different nights in the lab, during which subjects performed timed trials before and after sleep on one of two unique but equally difficult computer-generated 3D spatial mazes. One night's sleepwas normally consolidated with use of therapeutic CPAP throughout, while on the other night, CPAP was reduced only in REM sleep allowing REM OSA to recur. Results: REM disruption via this method caused reduction of REM sleep and significantly fragmented any remaining REM sleep without affecting total sleep time, sleep efficiency, or slow wave sleep. We observed improvements in maze completion time, distance traveled, and distance spent backtracking after a night of normal sleep that were significantly attenuated after a night of REM disruption without changes in psychomotor vigilance. Furthermore, the degree of improvement in maze completion time significantly positively correlated with the mean REM run duration across both sleep conditions. Conclusion: In conclusion, we demonstrate a novel role for REM sleep in human memory formation and highlight a significant cognitive consequence of OSA

Introduction: Familial dysautonomia (FD)-patients are at risk of sudden unexplained death, particularly during sleep. Respiratory abnormalities and reduced arousability might contribute to fatalities. Aim: To assess respiratory abnormalities and arousability in FD during sleep. Methods: 11 FD-patients (28 +/- 11 years) and 11 healthy persons (28 +/- 11 years) underwent polysomnographic recording during one night. We assessed sleep stages, apneas (>90% air flow reduction) and hypopneas (>30% decrease in airflow with >4% oxygen-desaturation). Arousals were defined as >3 sec abrupt shift in electroencephalographic frequencies to alpha- or theta-activity or frequencies >16Hz. We tested differences between FD-patients and controls by U-test or Fisher's exact test (significance: p < 0.05). Results: Percentage of sleep stages was similar in FD-patients and controls. 107 apneas occurred in 10 FD-patients. Apneas were followed by 74 oxygen-desaturations and 4 arousals. 9 Apneas were followed by desaturation and arousal. Only 5 apneas (p < 0.001) occurred in 2 controls (p > 0.05) and were followed by 2 oxygen desaturations (p=0.001) and 1 arousal (p > 0.05). No apneas were followed by desaturation and arousal. Hypopneas were the most frequent respiratory event and occurred primarily during sleep stage 1 and 2. In all FD-patients, we recorded 362 hypopneas with subsequent oxygen-desaturation that were followed by only 51 arousals. 12 hypopneas (p < 0.001) occurred in 3 controls (p=0.085) and were followed by 3 arousals (p=0.002)

BACKGROUND: Following the World Trade Center disaster, a large number of individuals involved in rescue and recovery activity were exposed to significant amounts of dust, and reported symptoms of chronic nasal and sinus inflammation. An unusually high prevalence of obstructive sleep apnea (OSA) has also been observed in this World Trade Center Responder population. This project aims to examine the relationship between nasal pathology and OSA. Our hypothesis is that increased nasal resistance due to nasal inflammation predisposes to OSA in this population. Continuous Positive Airway Pressure (CPAP) is the standard therapy for OSA but despite its efficacy has poor adherence. Subjects with high nasal resistance may have greater difficulty in tolerating this therapy than those who do not have high nasal resistance. Reduction of excess expiratory positive pressure by the modality known as Cflex during Continuous Positive Airway Pressure therapy (CPAPFlex) has been suggested to improve comfort without compromising efficacy. We will compare CPAP to CPAPFlex in subjects with OSA. STUDY DESIGN: Subjects with new onset habitual snoring will be screened for OSA using home sleep studies and rhinomanometry will be used to determine nasal resistance. In 400 subjects with OSA we will perform a randomized double blind cross-over study comparing CPAP to CPAPflex, and relate nasal resistance to adherence to CPAP therapy. DISCUSSION: This is the first multicenter trial designed to test the hypothesis that adherence to CPAP therapy relates to nasal resistance and CPAPFlex will improve adherence to CPAP in those subjects with high nasal resistance. We anticipate the following results from this trial: 1. Increased nasal resistance is associated with decreased adherence to CPAP therapy. 2. Use of CPAPFlex improves adherence with CPAP therapy in subjects with high nasal resistance, but not in those with low nasal resistance. 3. The benefit of CPAPFlex on adherence is greatest when offered at CPAP therapy initiation rather than as a "rescue" therapy in subjects with high nasal resistance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01753999 , Date: 12 December 2012.

BACKGROUND: This paper addresses the problem of detecting sleep spindles and K-complexes in human sleep EEG. Sleep spindles and K-complexes aid in classifying stage 2 NREM human sleep. NEW METHOD: We propose a non-linear model for the EEG, consisting of a transient, low-frequency, and an oscillatory component. The transient component captures the non-oscillatory transients in the EEG. The oscillatory component admits a sparse time-frequency representation. Using a convex objective function, this paper presents a fast non-linear optimization algorithm to estimate the components in the proposed signal model. The low-frequency and oscillatory components are used to detect K-complexes and sleep spindles respectively. RESULTS AND COMPARISON WITH OTHER METHODS: The performance of the proposed method is evaluated using an online EEG database. The F1 scores for the spindle detection averaged 0.70 +/- 0.03 and the F1 scores for the K-complex detection averaged 0.57 +/- 0.02. The Matthews Correlation Coefficient and Cohen's Kappa values were in a range similar to the F1 scores for both the sleep spindle and K-complex detection. The F1 scores for the proposed method are higher than existing detection algorithms. CONCLUSIONS: Comparable run-times and better detection results than traditional detection algorithms suggests that the proposed method is promising for the practical detection of sleep spindles and K-complexes.

Background: Recently, several studies have provided evidence that Abeta dynamics are influenced by the sleep-wake cycle. In transgenic mice, soluble Abeta levels are higher in the interstitial space during wakefulness and lower during sleep, while sleep deprivation increases Abeta concentrations and accelerates Abeta plaque deposition. In humans, in a study where serial cerebrospinal fluid (CSF) samples were collected for 36 hours, Abeta42 concentrations fluctuated with a diurnal pattern, with the lowest Abeta42 levels in the morning sampling. This CSF Abeta diurnal pattern has been related to higher synaptic activity during wakefulness and decreased synaptic activity during slow wave sleep (SWS). In the elderly, brain soluble Abeta42 levels may be relatively increased as a result of: a) agedependent loss of SWS; and, b) sleep disturbances common in late-life that disrupt SWS. The present study examined whether SWS was associated with CSF Abeta42 levels in a morning lumbar puncture (LP) performed between 11:00 AM-01:00 PM. Methods: In a sample of 22 cognitively normal elderly (age 66.5+/-6.7; range 56-83) with available CSF results, we performed a nocturnal polysomnography (NPSG) (average time interval between the NPSG and the LP 12.9+/-10.1 months, range 0-31). 3 subjects had a CSF P-tau/ Abeta42 ratio suggestive of preclinical AD (based on our own dataset of cognitively normal and AD patients modeled to determine the optimal cut-off for diagnostic prediction of AD) and were excluded. Subjects were further divided by median Abeta42 levels (671.95 pg/mL) into High/Low Abeta42. Results: The percent time spent in SWS (%SWS) and absolute SWA were inversely associated with CSF Abeta42 levels (r=-0.70, p<0.01; r=-0.74, p<0.01). There were no associations with the percent time spent in N1, N2 or REM. Results were also significant after controlling for BMI, age, ApoE4 or after including the preclinical AD subjects in the analysis. In group comparisons, normalized SWA in the first cycle was lower in the 'High' Abeta42 group (C3 p<0.05; F4 p <0.1) (Figure 1). Conclusions: In the absence of AD pathology, reduced %SWS or SWA are associated with increases in CSF Abeta42. (Figure Presented)

INTRODUCTION: Inspiratory flow limitation (IFL) is defined as a "flattened shape" of inspiratory airflow contour detected by nasal cannula pressure during sleep and can indicate increased upper airway resistance especially in mild sleep-related breathing disorders (SRBD). The objective of this study was to investigate the association between upper airway abnormalities and IFL in patients with mild SRBD. METHODS: This study was derived from a general population study consisting of selected individuals with apnea-hypopnea index (AHI) below 5 events/h of sleep, ("no obstructive sleep apnea" group) and individuals with AHI between 5 and 15 events/h ("mild obstructive sleep apnea" group). A total of 754 individuals were divided into four groups: group 1: AHI <5/h and <30 % of total sleep time (TST) with IFL (515 individuals), group 2: AHI <5/h and >30 % of TST with IFL (46 individuals), group 3: AHI: 5-15/h and <30 % of TST with IFL (168 individuals), and group 4: AHI: 5-15/h and >30 % of TST with IFL (25 individuals). RESULTS: Individuals with complains of oral breathing demonstrated a risk 2.7-fold larger of being group 4 compared with group 3. Abnormal nasal structure increased the chances of being in group 4 3.2-fold in comparison to group 1. Individuals with voluminous lateral wall demonstrated a risk 4.2-fold larger of being group 4 compared with group 3. CONCLUSION: More than 30 % of TST with IFL detected in sleep studies was associated with nasal and palatal anatomical abnormalities in mild SRBD patients.

OBJECTIVE: To examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier age at mild cognitive impairment (MCI) or Alzheimer disease (AD)-dementia onset in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We also examined whether continuous positive airway pressure (CPAP) use is associated with delayed onset of cognitive decline. METHODS: From the ADNI cohort, 3 subsets with progressively stringent criteria were created in a step-wise manner. Age at MCI or AD-dementia onset was the main outcome variable. Analyses were performed separately for each subset in untreated SDB+ vs SDB- and untreated SDB+ vs CPAP+ groups. Chi-square and t tests were performed to examine between-group differences. Survival analyses were performed using the Kaplan-Meier method, compared by the log-rank test, and assessed by multivariate Cox regression adjusting for potential confounders. RESULTS: SDB+ patients had a younger age at MCI onset in all subsets (MC1: 72.63 vs 83.67; MC2: 72.15 vs 83.45; MC3: 77.40 vs 89.89; p < 0.01). SDB+ patients had a younger age at AD-dementia onset only in our most conservative subset (AC3: 83.46 vs 88.13; p < 0.05). In a combined outcome analysis, SDB+ patients had a younger age at onset to MCI or AD-dementia in all subsets. In subsets 1 and 2, CPAP use delayed the age at MCI onset (CMC1: 72.63 vs 82.10; CMC2: 72.11 vs 82.10; p < 0.01). CONCLUSIONS: Consistent with our hypothesis, the presence of SDB was associated with an earlier age at cognitive decline. Our findings in CPAP+ participants suggest that CPAP treatment of SDB may delay progression of cognitive impairment.

Introduction: In cognitively normal elderly, short sleep duration is associated with deficits in cognitive performance while physical activity has shown to be protective and improve cognitive function. Actigraph monitoring systems are used to objectively assess sleep but also capture measures of physical activity during the daytime. The purpose of this study is to determine whether daytime activity and sleep duration have independent effects on cognition in normal elderly. Methods: 44 community dwelling cognitively normal (Clinical Dementia Rating = 0) elderly (Age 66.2 +/- 7.3, Gender (36.4%Male, 63.6% Female), non-depressed (Geriatric Depression Scale < 7) participants wore an actigraph (Octagonal Basic Motionlogger, Ambulatory Monitoring Inc, NY) for 7 consecutive days. Data were analyzed in the zero crossing mode for total sleep duration (TST), and mean daytime activity using the provided automated algorithm. All subjects underwent a standard neuropsychological test battery with subscales assessing immediate and delayed recall of orally presented paragraphs and verbal paired associates, digit span (backward and forward), and executive function (trail making test B [TMTB]). Results: Daytime Activity and TST were not correlated with each other. Short sleep duration was associated with longer completion times in the TMTB (r = -0.3, p < 0.05) while Daytime Activity was associated with better performance in verbal paired associates (r = 0.4, p < 0.01) and digit span backward (r = 0.4, p < 0.01). Daytime Activity and TST showed additive effects on verbal paired associates (Daytime Activity F change = 5.95, p < 0.05 and TST F change = 3.18, p < 0.1). Conclusion: Daytime Activity had a significant effect on cognition independent of sleep duration. While these preliminary findings should be interpreted with caution due to small sample size, our data suggest that in studies examining cognition in elderly subjects, actigraphic data should be analyzed for daytime activity in addition to sleep duration