PMC

Data are mean ± SEM REM sleep and NREM sleep amounts in P30–50 ferret kits and adult ferrets (AD) and P30–32 cats (K31). P30 NREM < P40-AD, AD vs. K31; P30 REM > P40-AD, AD vs. K31; p<0.05. Adult comparison data are indicated by “Ad”, P30–32 cat data by “K31”.

Mean (± SEM) REM latency was calculated as (A) the time elapsed (in minutes) between REM sleep episodes or (B) time elapsed from the longest waking period to the first REM sleep episode. A: P30< P35-AD & K31, AD vs. K31 p<0.05; B: P30< P35-AD, AD vs. K31 p<0.05. Adult comparison data are indicated by “Ad”, P30–32 cat data by “K31”.

(A–C) Mean ± SEM vigilance state amounts as a % of total recording time (TRT) [P30 REM>P40-AD, AD vs. K31: p<0.05; NREM, all comparisons: ns; P30 wake < P40 & AD, K31 vs. AD: p<0.05]. (D–F) Mean ± SEM vigilance state durations in minutes [P30 REM < P35-AD & K31, K31 vs. AD; P30 NREM < P35-AD & K31, K31 vs. AD; P30 wake < P40 & AD: p<0.05]. (G–I) Mean ± SEM frequency of vigilance state episodes [P30 REM > P35-AD & K31; P30 NREM > all; P30 wake frequency > all: p<0.05]. Adult comparison data are indicated by “Ad”, P30–32 cat data by “K31”.

(A) Top trace is filtered in the 250–500Hz frequency, rectified to show HFOs during a representative sleep period that includes both SWS (blue) and REM (green). Detection threshold for HFOs is denoted by a red dotted line and theta/delta ratio by a green line. Bottom trace shows raw EEG during SWS (blue) and REM (green). Note frequent HFOs during SWS and reduced number of HFOs during REM, which corresponds to an increased theta/delta ratio.
(B) Number of HFOs during wakefulness, SWS and REM sleep in Tg2576 transgenic mice (n=8). One-way ANOVA revealed a significant difference (Kruskal-Wallis test, H(3)=16.56, p=0.0003) and post-hoc tests showed a significantly greater number of HFOs during SWS vs. REM (p=0.01) or wakefulness (p=0.0003). There was no significant difference between the mean number of HFOs in wakefulness vs. REM (p=0.90).
(C) Same as in B but for PS2KO transgenic mice (n=4). One-way ANOVA revealed a significant difference (F(2, 9)=30.39, p<0.0001). Post-hoc tests showed a significantly greater number of HFOs during SWS vs. REM (p=0.0002) or wakefulness (p=0.0002), but not between wakefulness and REM (p=0.81).
(D) Same as in C but for Ts65Dn transgenic mice (n=4). One-way ANOVA revealed a significant difference (F(2, 9)=9.90, p<0.01). Post-hoc tests showed a significantly greater number of HFOs during SWS vs. REM (p=0.02) or wakefulness (p=0.006), but not wakefulness and REM (p=0.80).

The reduction in REM sleep time in MCH^−/− mice during fasting reflects both an excessive reduction in the number of episodes of REM sleep combined with a failure to increase the mean episode duration. (A) Histograms of the distributions of REM sleep latencies for both genotypes, comparing both ad libitum feeding and fasting conditions. These distributions are different only during fasting, reflecting the shift to long latencies (≥20 min) in MCH^−/− mice. Under ad libitum feeding, although the overall distributions are not different, a deficit in the occurrence of shorter REM sleep latencies (i.e., ≤ 3 min) is apparent in the MCH^−/− mice. (B) The mean REM sleep episode duration (min + SEM) displaying the increase in this parameter in wild-type mice during fasting in contrast with the lack of change in the MCH^−/− mice. A significant difference between wild-type and MCH^−/− mice is indicated by an asterisk.

Time spent in NREM sleep (A) and REM sleep (B), on an hourly basis (min/h ± SEM) and the total times in these states over 24 h (min/24 h), displayed for each genotype during 24 h of ad libitum feeding, followed by 24 h fasting. Although MCH^−/− mice respond similarly to wild-type mice during fasting with a reduction NREM sleep, the effect on REM sleep is disproportionately greater in MCH^−/− mice. See text and table for details. A significant difference between wild-type and MCH^−/− mice is indicated by an asterisk.

(A) Topoplots of averaged MFDE values during REM sleep at scale 5 (top row) and scale 20 (middle row), and the ratio of MFDE at scale 20 to scale 5 (SFAR-entropy, bottom row) for HC, MCI, and DEM. (B) SFAR-entropy in the frontal (ANOVA, p = 1e-03), temporal (ANOVA, p = 2e-05), central (ANOVA, p = 2e-03) parietal (ANOVA, p = 1e-03), and occipital (ANOVA, p = 3e-05) regions for HC, MCI, and DEM. ANOVA p-values are Bonferroni corrected. Group differences with p-values < 0.05, 0.01, 0.001, 0.0001, and 0.00001 are shown with *, **, ***, ****, and *****, respectively.

AD = Alzheimer disease; FTD = frontotemporal degeneration; SYN = cognitive impairment due to presumed synuclein pathology; SM = submentalis muscle; AT = anterior tibialis muscle.

AD = Alzheimer disease; CLSA = Canadian Longitudinal Study on Aging; PD = Parkinson disease; pRBD = possible REM sleep behavior disorder; RLS = restless leg syndrome.

Plaque load in 5xFAD cerebral cortex and hippocampus was negatively correlated with both NREM and REM sleep times. In the cerebral cortex: A, B, Correlation of light-phase NREM and REM time, and (C, D) dark-phase NREM and REM time plotted against plaque load in 10-month-old Bace1^fl/fl/5xFAD, AZD3293-treated Bace1^fl/fl/5xFAD, and Bace1^{fl/fl/UbcCreER/5xFAD} mice. In the hippocampus and subiculum: E, F, Correlation of light-phase NREM and REM time, and (G, H) dark-phase NREM and REM time plotted against plaque load in 10-month-old Bace1^fl/fl/5xFAD, AZD3293-treated Bace1^fl/fl/5xFAD, and Bace1^{fl/fl/UbcCreER/5xFAD} mice. r and p values are indicated in the plots.

Data represent linear regressions and corresponding Spearman r values between REM sleep duration and subsequent NREM sleep duration (in minutes) from P30–P50 in developing 33 kits, the adult ferret (AD) and P30–32 cats (K31). There were significant positive correlations at all ages in the ferret and in P30–32 cats (H). All other correlations between NREM sleep and REM sleep duration (or with wakefulness) were not significant.

(A–D) Percentage of wakefulness and NREM and REM sleep during 6-h SD period using dedicated chamber (A) or gentle handling (B) and each ad libitum sleep (C,D). (E,F) Total percentage of wakefulness and NREM and REM sleep during 6 h of SD or ad libitum sleep using dedicated chamber (E) or gentle handling (F). Error bars indicate SEM (N = 3–4). **p < 0.01 and ***p < 0.001 for the difference between ad libitum sleep mice and SD mice by Student’s t-test.

Exemplary EEG raw traces for the animals from (A) the age-matched controls and (B) the AD rats at different vigilance states—WAKE, NREM sleep, and REM sleep—that were recorded from the caudal or rostral EEG lead. NREMS: NREM sleep; REMS: REM sleep.

Possible intermediate mechanisms in the relationship between OSA and AD. The effect of OSA in increasing the risk for AD can be mediated by several of its associated mechanisms. Chronic exposure to intermittent hypoxia may lead to increased inflammation and oxidative stress, diabetes, hypertension and CVD, all potentially contributing to AD pathology development. Sleep fragmentation, both by itself and by leading to decreased REM and SWS stages, can additionally promote AD pathogenesis. Finally, intrathoracic pressure swings associated with OSA may disrupt CSF-ISF exchange integrity and lead to AD neuropathology accumulation. OSA: Obstructive Sleep Apnea; CVD: Cardiovascular Disease; REM: Rapid Eye Movement; SWS: Slow Wave Sleep; CSF-ISF: Cerebrospinal Fluid-Interstitial Fluid; AD: Alzheimer’s Disease.

Percentage of time spent awake, in NREM, or in REM in transgenic AD mice. No differences between the transgenic AD mice compared to wildtype control animals were seen in the percentage of time spent in awake, in NREM, or in REM sleep over a 24 h period for the 3xTgAD (A-C), Tg2576 (D-F), or APP/PS1 (G-I) mouse models of AD. All data are expressed as mean ± SEM.

Susceptibility to generalized EEG vs motor seizures in a control condition (clear bars) and after treatments to dissociate REM sleep polygraphic components (dark bars). Each bar reflects the mean and S.D. from multiple measure of seizure activity during alert waking, SWS or REM sleep per cat. For example, penicillin seizure activity is indexed by the mean number of spike- wave complexes (left) or myoclonic seizures (right) per 20-s epoch of each state. ECS thresholds represent at least three thresholds to generalized afterdischarge (AD; left) or convulsions (GTCs right) per state in each cat. A: EEG and motor seizure susceptibility before atropine (clear bars) and after atropine (dark bars) in penicillin (top) and ECS (bottom) epilepsy models. B: EEG and motor seizure susceptibility after pontine lesions which did not affect atonia in REM sleep (clear bars) and lesions which eliminated atonia during REM sleep (dark bars). Data are provided for penicillin (top) and ECS (bottom) epilepsy models. ECS data: note that threshold is inversely related to susceptibility; the ECS ordinate is inverted to so that high bars reflect increased seizure susceptibility in both epilepsy models.

A. Mean±SEM confusion matrix of WSN for the mechanically sleep disrupted dataset (n=10. Classification accuracy for REM sleep during mechanical sleep disruption was lower than it was during ad libitum sleep.
B. Box plots of accuracy and F1 score across all three classes where each dot represents one of 10 sleep disrupted animals.
C. Mean±SEM confusion matrix of WSN for the AccuSleep dataset (n=10, external site acquisition and scoring).
D. Box plots of accuracy and F1 score across all three classes where each dot represents one of 10 AccuSleep animals.

Representative EEG/EMG Polygraphic Trace. Examples of NREM sleep, REM sleep, and Wake EEG/EMG traces are shown for a cat from the RMDS group acquired during the ad lib. sleep recording session. Each trace represents 30 s.

Changes in ATN profiles. Sankey diagram showing changes in distribution of ATN profiles at baseline and follow-up. REM, rapid eye movement; MCI, mild cognitive impairment; AD, Alzheimer’s disease

(A) Mean ± SEM sleep cycle lengths in minutes [P30 < P35-AD & K31, p<0.05] (B) Mean ± SEM REM amounts as a % of each cycle [P30 > P40-AD, AD vs. K31, p<0.05] (C) Mean ± SEM number of sleep cycles per hour [P30 > P45-AD & K31, p<0.05]. Adult comparison data are indicated by “Ad”, P30–32 cat data by “K31”.