Spatiotemporal characteristics of neurophysiological changes in patients with four-repeat tauopathies.

INTRODUCTION: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are the most common four-repeat tauopathies (4RT), and both frequently occur with varying degree of Alzheimer's disease (AD) copathology. Intriguingly, patients with 4RT and patients with AD are at opposite ends of the wakefulness spectrum-AD showing reduced wakefulness and excessive sleepiness whereas 4RT showing decreased homeostatic sleep. The neural mechanisms underlying these distinct phenotypes in the comorbid condition of 4RT and AD are unknown. The objective of the current study was to define the alpha oscillatory spectrum, which is prominent in the awake resting-state in the human brain, in patients with primary 4RT, and how it is modified in comorbid AD-pathology. METHOD: In an autopsy-confirmed case series of 4R-tauopathy patients (n = 10), whose primary neuropathological diagnosis was either PSP (n = 7) or CBD (n = 3), using high spatiotemporal resolution magnetoencephalography (MEG), we quantified the spectral power density within alpha-band (8-12 Hz) and examined how this pattern was modified in increasing AD-copathology. For each patient, their regional alpha power was compared to an age-matched normative control cohort (n = 35). RESULT: Patients with 4RT showed increased alpha power but in the presence of AD-copathology alpha power was reduced. CONCLUSIONS: Alpha power increase in PSP-tauopathy and reduction in the presence of AD-tauopathy is consistent with the observation that neurons activating wakefulness-promoting systems are preserved in PSP but degenerated in AD. These results highlight the selectively vulnerable impacts in 4RT versus AD-tauopathy that may have translational significance on disease-modifying therapies for specific proteinopathies.

Sleep Spindles Favor Emotion Regulation Over Memory Consolidation of Stressors in Posttraumatic Stress Disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a trauma-induced condition, characterized by intrusive memories and trauma-associated anxiety. Non-rapid eye movement (NREM) sleep spindles might play a crucial role in learning and consolidating declarative stressor information. However, sleep and possibly sleep spindles are also known to regulate anxiety, suggestive of a dual role for sleep spindles in the processing of stressors. Specifically, in individuals with high PTSD symptom burden, spindles might fail to regulate anxiety levels after exposure and instead might maladaptively consolidate stressor information. METHODS: To disentangle the role of spindles in declarative memory versus anxiety regulation after stressor exposure and to examine the role of PTSD in these processes, we measured nap sleep after a cohort of 45 trauma-exposed participants were exposed to laboratory stress. Participants (high vs. low PTSD symptoms) completed 2 visits: a stress visit involving exposure to negatively valent images before nap and a control visit. In both visits, sleep was monitored via electroencephalography. A stressor recall session occurred after the nap in the stress visit. RESULTS: Stage 2 NREM (NREM2) spindle rates were higher in stress versus control sleep, indicative of stress-induced changes in spindles. In participants with high PTSD symptoms, NREM2 spindle rates in stress sleep predicted poorer recall accuracy of stressor images relative to participants with low PTSD symptoms, while correlating with greater reduction in stressor-induced anxiety levels after sleep. CONCLUSIONS: Contrary to our expectations, although spindles are known to play a role in declarative memory processes, our findings highlight an important role for spindles in sleep-dependent anxiety regulation in PTSD.

Alzheimer's disease phenotypes show different sleep architecture.

INTRODUCTION: Sleep-wake disturbances are a prominent feature of Alzheimer's disease (AD). Atypical (non-amnestic) AD syndromes have different patterns of cortical vulnerability to AD. We hypothesized that atypical AD also shows differential vulnerability in subcortical nuclei that will manifest as different patterns of sleep dysfunction. METHODS: Overnight electroencephalography monitoring was performed on 48 subjects, including 15 amnestic, 19 atypical AD, and 14 controls. AD was defined based on neuropathological or biomarker confirmation. We compared sleep architecture by visual scoring and spectral power analysis in each group. RESULTS: Overall, AD cases showed increased sleep fragmentation and N1 sleep compared to controls. Compared to atypical AD groups, typical AD showed worse N3 sleep dysfunction and relatively preserved rapid eye movement (REM) sleep. DISCUSSION: Results suggest differing effects of amnestic and atypical AD variants on slow wave versus REM sleep, respectively, corroborating the hypothesis of differential selective vulnerability patterns of the subcortical nuclei within variants. Optimal symptomatic treatment for sleep dysfunction in clinical phenotypes may differ. HIGHLIGHTS: Alzheimer's disease (AD) variants show distinct patterns of sleep impairment. Amnestic/typical AD has worse N3 slow wave sleep (SWS) impairment compared to atypical AD. Atypical AD shows more rapid eye movement deficits than typical AD. Selective vulnerability patterns in subcortical areas may underlie sleep differences. Relatively preserved SWS may explain better memory scores in atypical versus typical AD.

The sleep physiology of nightmares in veterans with psychological trauma: Evaluation of a dominant model using participant-applied electroencephalography in the home environment.

Nightmares are a core feature of posttraumatic stress disorder, are poorly understood, and are associated with serious negative outcomes. Their biology has been difficult to study, and the feasibility of capturing them in the naturalistic home environment has been poor. This said, the published research and dominant scientific model has focused on nightmares as a manifestation of noradrenergic hyperarousal during rapid eye movement sleep. The current study used at-home, participant-applied devices to measure nightmare physiology in posttraumatic stress disorder treatment-seeking veterans, by examining heartrate measures as indicators of noradrenergic tone, and sleep-stage characteristics and stability in the sleep preceding time-stamped nightmare awakenings. Our data indicate the high feasibility of participant-administered, at-home measurement, and showed an unexpected stability of -rapid eye movement sleep along with no evidence of heartrate elevations in sleep preceding nightmare awakenings. Altogether, these data highlight new opportunities for the study of nightmares while questioning the sufficiency of dominant models, which to date are largely theoretically based.

Non-REM sleep with hypertonia in Parkinsonian Spectrum Disorders: A pilot investigation.

INTRODUCTION: From an ongoing multicenter effort toward differentiation of Parkinsonian spectrum disorders (PSD) from other types of neurodegenerative disorders, the sleep biomarker non-rapid-eye-movement sleep with hypertonia (NRH) emerged. METHODS: This study included in the PSD group patients with dementia with Lewy bodies/Parkinson disease dementia (DLB/PDD = 16), Parkinson disease (PD = 16), and progressive supranuclear palsy (PSP = 13). The non-PSD group included patients with Alzheimer disease dementia (AD = 24), mild cognitive impairment (MCI = 35), and a control group with normal cognition (CG = 61). In-home, multi-night Sleep Profiler studies were conducted in all participants. Automated algorithms detected NRH, characterized by elevated frontopolar electromyographic power. Between-group differences in NRH were evaluated using Logistic regression, Mann-Whitney U and Chi-squared tests. RESULTS: NRH was greater in the PSD group compared to non-PSD (13.9 ± 11.0% vs. 3.1 ± 4.7%, P < 0.0001). The threshold NRH≥5% provided the optimal between-group differentiation (AUC = 0.78, P < 0.001). NRH was independently associated with the PSD group after controlling for age, sex, and SSRI/SNRI use (P < 0.0001). The frequencies of abnormal NRH by subgroup were PSP = 92%, DLB/PDD = 81%, PD = 56%, MCI = 26%, AD = 17%, and CG = 16%. The odds of abnormal NRH in each PSD subgroup ranged from 3.7 to 61.2 compared to each non-PSD subgroup. The night-to-night and test-retest intraclass correlations were excellent (0.78 and 0.84, both P < 0.0001). CONCLUSIONS: In this pilot study, NRH appeared to be a novel candidate sleep biomarker for PSD-related neurodegeneration. Future studies in larger cohorts are needed to confirm these findings, understand the etiology of NRH magnitude/duration, and determine whether it is an independent prodromal marker for specific neurodegenerative pathologies.

Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases.

Importance: Sleep disturbance is common among patients with neurodegenerative diseases. Examining the subcortical neuronal correlates of sleep disturbances is important to understanding the early-stage sleep neurodegenerative phenomena. Objectives: To examine the correlation between the number of important subcortical wake-promoting neurons and clinical sleep phenotypes in patients with Alzheimer disease (AD) or progressive supranuclear palsy (PSP). Design, Setting, and Participants: This longitudinal cohort study enrolled 33 patients with AD, 20 patients with PSP, and 32 healthy individuals from the Memory and Aging Center of the University of California, San Francisco, between August 22, 2008, and December 31, 2020. Participants received electroencephalographic and polysomnographic sleep assessments. Postmortem neuronal analyses of brainstem hypothalamic wake-promoting neurons were performed and were included in the clinicopathological correlation analysis. No eligible participants were excluded from the study. Exposures: Electroencephalographic and polysomnographic assessment of sleep and postmortem immunohistological stereological analysis of 3 wake-promoting nuclei (noradrenergic locus coeruleus [LC], orexinergic lateral hypothalamic area [LHA], and histaminergic tuberomammillary nucleus [TMN]). Main Outcomes and Measures: Nocturnal sleep variables, including total sleep time, sleep maintenance, rapid eye movement (REM) latency, and time spent in REM sleep and stages 1, 2, and 3 of non-REM (NREM1, NREM2, and NREM3, respectively) sleep, and wake after sleep onset. Neurotransmitter, tau, and total neuronal counts of LC, LHA, and TMN. Results: Among 19 patients included in the clinicopathological correlation analysis, the mean (SD) age at death was 70.53 (7.75) years; 10 patients (52.6%) were female; and all patients were White. After adjusting for primary diagnosis, age, sex, and time between sleep analyses and death, greater numbers of LHA and TMN neurons were correlated with decreased homeostatic sleep drive, as observed by less total sleep time (LHA: r = -0.63; P = .009; TMN: r = -0.62; P = .008), lower sleep maintenance (LHA: r = -0.85; P < .001; TMN: r = -0.78; P < .001), and greater percentage of wake after sleep onset (LHA: r = 0.85; P < .001; TMN: r = 0.78; P < .001). In addition, greater numbers of LHA and TMN neurons were correlated with less NREM2 sleep (LHA: r = -0.76; P < .001; TMN: r = -0.73; P < .001). A greater number of TMN neurons was also correlated with less REM sleep (r = -0.61; P = .01). A greater number of LC neurons was mainly correlated with less total sleep time (r = -0.68; P = .008) and greater REM latency (r = 0.71; P = .006). The AD-predominant group had significantly greater sleep drive, including higher total sleep time (mean [SD], 0.49 [1.18] vs -1.09 [1.37]; P = .03), higher sleep maintenance (mean [SD], 0.18 [1.22] vs -1.53 [1.78]; P = .02), and lower percentage of wake after sleep onset during sleep period time (mean [SD], -0.18 [1.20] vs 1.49 [1.72]; P = .02) than the PSP-predominant group based on unbiased k-means clustering and principal component analyses. Conclusions and Relevance: In this cohort study, subcortical wake-promoting neurons were significantly correlated with sleep phenotypes in patients with AD and PSP, suggesting that the loss of wake-promoting neurons among patients with neurodegenerative conditions may disturb the control of sleep-wake homeostasis. These findings suggest that the subcortical system is a primary mechanism associated with sleep disturbances in the early stages of neurodegenerative diseases.

The relationship of fear-potentiated startle and polysomnography-measured sleep in trauma-exposed men and women with and without PTSD: testing REM sleep effects and exploring the roles of an integrative measure of sleep, PTSD symptoms, and biological sex.

STUDY OBJECTIVES: Published research indicates that sleep is involved in emotional information processing. Using a fear-potentiated startle (FPS) and nap sleep protocol, we examined the relationship of emotional learning with REM sleep (REMS) in trauma-exposed participants. We also explored the roles of posttraumatic stress disorder (PTSD) symptoms, biological sex, and an integrative measure of polysomnography-measured (PSG) sleep in the learning-sleep relationship. METHODS: After an adaptation nap, participants (N = 46) completed two more visits (counterbalanced): a stress-condition visit, which included FPS conditioning procedures prior to a nap and assessment of learning retention and fear extinction training after the nap, and a control visit, which included a nap opportunity without stressful procedures. FPS conditioning included a "fear" visual stimulus paired with an air blast to the neck and a "safety" visual stimulus never paired with an air blast. Retention and extinction involved presentation of the visual stimuli without the air blast. Primary analyses examined the relationship between FPS responses pre- and post-sleep with stress-condition REMS duration, controlling for control-nap REMS duration. RESULTS: Higher safety learning predicted increased REMS and increased REMS predicted more rapid extinction learning. Similar relationships were observed with an integrative PSG sleep measure. They also showed unexpected effects of PTSD symptoms on learning and showed biological sex effects on learning-sleep relationships. CONCLUSIONS: Findings support evidence of a relationship between adaptive emotional learning and REMS. They underscore the importance of examining sex effects in sleep-learning relationships. They introduce an integrative PSG sleep measure with potential relevance to studies of sleep and subjective and biological outcomes.