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”.

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.

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.

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.

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.

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.

(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”.

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

Data are normalized (mean ± SEM) NREM sleep delta and theta EEG power values from P30–P50 with adult normative values and P30–32 cat (mean age=P31.7) values provided for comparison. P30 delta < P35-AD & K31; P30 theta vs. AD, p<0.05. Adult comparison data are indicated by “Ad”, P30–32 cat data by “K31”.

Cortical atrophy on group analysis. A) The AD group showed bilateral parieto-temporal cortex and bilateral frontal cortex atrophy compared to controls (FWE p < 0.05). B) The IPD group had bilateral frontal cortical atrophic changes compared to controls (uncorrected p < 0.001). AD, Alzheimer’s disease; IPD, idiopathic Parkinson’s disease; RBD, REM sleep behavior disorder; FWE, family-wise error.

The prebiotic diet improves recovery sleep post-sleep disruption. Twenty-four hours of ad libitum sleep was recorded after the completion of the 5-day sleep disruption protocol. (A) Total sleep, (B) NREM EEG delta power, (C) NREM sleep, (D) median NREM bout duration, (E) number of NREM bouts over 24 h, (F) REM sleep, (G) median REM bout duration, and (H) number of REM bouts over 24 h are depicted above for the control (ad libitum sleep throughout) and sleep-disrupted (with no social defeat) groups. Aligned rank transform ANOVA testing for an effect of diet, sleep disruption, and interaction was performed for each measure, and significant or near significant results are reported in the figure. Data are mean ± SEM. Symbols: ***p < 0.001, *p < 0.05, Bonferroni’s post hoc test. ^a p < 0.001 vs both control diet, ad libitum sleep and prebiotic diet, ad libitum sleep groups, Bonferroni’s post hoc test. Con, control diet; NREM, non-rapid eye movement sleep; Pre, prebiotic diet; REM, rapid eye movement sleep; SD, sleep disruption. n = 8–10/group.

Summary of the topographic and frequency-specific EEG features of cortical activity during wakefulness and sleep in MCI and AD
Topography of the frequency-specific significant differences in cortical activity in MCI and AD as compared to HC (one-way ANOVAs, p ≤ 0.0102) during evening wakefulness, NREM and REM sleep, and morning wakefulness (upper). The direction of the difference in the pairwise comparisons is given by the red and blue arrows representing significant increased and decreased cortical activity (two-tails unpaired t-tests, p ≤ 0.05) in MCI and AD compared to HC and in AD compared to MCI, respectively. The gradual disappearance of the changes in delta power between pre-sleep and post-sleep wakefulness EEG from HC to AD condition (bottom) is also shown. The maps represent AM log₁₀(Delta power) – PM log₁₀(Delta power) differences for HC, MCI, and AD groups. The negative values of the blue scale indicates that delta power decreases after sleep. The scatterplots show the linear correlation among this delta power change at a frontal representative site (F4) and the high-frequency activity during NREM and REM sleep at a posterior representative site (O1) in the AD group. F4 and O1 derivations were respectively chosen as representative for delta power changes in waking EEG and posterior beta power activity during sleep since they showed the highest correlation in the analysis reported in C.

Investigations of the role of adenosine (AD) as a neuromodulatory sleep factor. A: extracellular AD concentrations in the feline basal forebrain (BF) for 10-min consecutive samples from an individual animal, showing elevated levels during wakefulness. Labels indicate behavioral state: W, wakefulness; S, slow wave (NREM) sleep; R, REM sleep. [Adapted from Porkka-Heiskanen et al. (). Reprinted with permission from AAAS.] B: AD concentrations in the feline BF rise during 6 h of sleep deprivation (SD) and decrease towards baseline levels during 3 h of spontaneous recovery sleep. [Adapted from Porkka-Heiskanen et al. (). Reprinted with permission from AAAS.] C: AD and nitric oxide (NOx, red) concentrations in the rat BF rise during 11 h of SD. The rise of NOx during SD precedes the rise of AD. AD levels are significantly elevated by hour 2 of SD and remain elevated until recovery sleep, when levels fall towards baseline levels. Levels are normalized to baseline levels in the 2 h preceding SD. [Adapted from Kalinchuk et al. (), with permission from John Wiley and Sons.] D: AD and NOx levels in the rat frontal cortex also rise during SD. Again, the rise of NOx during SD precedes the rise of AD. The rise of AD is significant by hour 6 of SD and is delayed compared with the rise seen in BF, as shown in C. Levels are normalized to baseline levels in the 2 h preceding SD. [Adapted from Kalinchuk et al. (), with permission from John Wiley and Sons.] E: graphic depiction of the intracellular signaling pathway of the AD A1 receptor in BF observed following sleep deprivation in rats. Steps of the pathway: 1) AD binds to the A1 receptor; 2) activation of PLC pathway, releasing inositol 1,4,5-trisphosphate (IP₃); 3) IP₃ receptor-mediated intracellular calcium mobilization and activation of protein kinase C; 4) phosphorylation of Iκ-B and release of nuclear factor-κB (NF-κB) dimer; 5) nuclear translocation of NF-κB dimer; 6) promoter DNA binding of NF-κB and transcriptional activation of target genes including A1 receptor; 7) protein synthesis (A₁ receptor synthesis). This signaling cascade appears to be confined to cholinergic neurons of BF. (Adapted from Basheer et al. Neuroscience 104: 731–739, 2001, with permission from Elsevier.