Sleep-Wake Cycle in Alzheimer’s Disease Is Associated with Tau Pathology and Orexin Dysregulation

Abstract

Background:

Alzheimer’s disease (AD) is the most common form of dementia. It is mainly characterized by a progressive deterioration of cognition, but sleep-wake cycle disturbances frequently occur. Irregular sleep-wake cycle, insomnia, and daytime napping usually occur in patients with AD in the course of the disease.

Objective:

The aim of the present study was to verify the sleep-wake cycle in mild to moderate AD patients compared to controls, and to evaluate the relationship between the sleep-wake cycle impairment and the neuropsychological testing, CSF AD biomarkers, and CSF orexin concentrations.

Methods:

Mild to moderate AD patients were enrolled and underwent 14-day actigraphic recording, sleep diary, neuropsychological testing, and CSF biomarkers analysis. All patients were compared to controls.

Results:

Eighteen AD patients were compared to ten controls. AD patients showed the alteration of the sleep-wake cycle, featured by sleep dysregulation and daytime wake fragmentation, with respect to controls. Considering the correlation analysis, we documented the correlation between tau proteins and orexin CSF levels and sleep-wake cycle dysregulation.

Conclusion:

This study confirmed the dysregulation of sleep-wake cycle in AD patients, as reflected by the daytime wake fragmentation, irregular sleep-wake rhythm, and nocturnal sleep impairment. This sleep-wake cycle disorder correlates with AD neuropathological in vivo features and brain orexin activity. Hence, we suppose that a more marked AD pathology coupled with orexinergic system dysregulation may promote sleep-wake cycle impairment in AD patients.

Keywords

Alzheimer’s disease cognition orexin sleep-wake cycle tau proteins

INTRODUCTION

Alzheimer’s disease (AD) is the main cause of dementia in the elderly population; however, not only cognitive deficits are present in patients with AD, but behavioral disturbances and sleep disorders can also be present [1]. Consistently, sleep disturbances can occur in 25–44% of patients with AD [2]. The most common sleep disturbance is represented by sleep-disordered breathing (SDB), followed by insomnia and irregular sleep-wake rhythm disorder (ISWRD) [3]. In the past, actigraphic recordings in AD patients documented alteration of the sleep-wake rhythm with reduced amplitude of the sleep-wake cycle, insomnia, and daytime napping [4, 5]. In the more recent literature, actigraphic studies documented circadian rhythm dysfunction during aging, which appears to be more altered in subjects showing biomarkers consistent with amyloid pathology (and considered preclinical AD) [6]. Moreover, alterations of circadian rhythmicity, particularly pronounced in patients with AD, tend to progress over the course of the disease [7]. At the basis of the ISWRD, the dysregulation of several sleep structures, such as anterior hypothalamus, reticular activating system, suprachiasmatic nucleus, and pineal gland, has been hypothesized since the documentation of AD pathology in those brain regions [8 –12]. Recently, orexinergic system dysregulation has been documented in AD patients [13]. Considering the role of orexin in regulating the sleep-wake rhythm by maintaining alertness, in this study we aimed at identifying the sleep-wake rhythm by using the actigraphic recording in patients with AD compared to controls, and its possible relationship with orexin, CSF AD biomarkers, and the cognitive performances measured by neuropsychological tests.

METHODS

Patients and study design

We included in our study patients referred to the Neurological Clinic of the University Hospital of Rome “Tor Vergata”, who met the criteria for AD diagnosis according to the recently proposed versions of the diagnostic guidelines [14]. All patients underwent a diagnostic and experimental study protocol including history, physical and neurological examination, standard neuropsychological evaluation, 14-night actigraphic recording, and lumbar puncture for CSF analysis.

We enrolled a group of non-demented elderly controls, similar for age and sex with AD patients, who underwent 14-night actigraphic recording.

Patients and controls provided their informed consent to the study, which was approved by the Independent Ethical Committee of the University Hospital of Rome “Tor Vergata”.

Actigraphic monitoring

All patients and caregivers were instructed to wear the wrist actigraphy (Actiwatch2, Philips Respironics) on non-dominant arm for 14 days and to push the button on the side of the watch at bedtime and wake time and to complete a sleep home diary each morning [15, 16].

The actigraphy recorded light data through silicon photo-diode sensor and the acceleration of movement on three axes (x, y, z) through a piezoelectric accelerometer, using bandpass 0.5–11 Hz to reduce gravitational artifacts, sampling rate 32 Hz and sensitivity 0.025 G [17]. Data were acquired in 15-s epochs (high sensitivity setting), confirmed with daily sleep diaries.

In order to be more accurate as possible, subjects included in this study (patients were helped by caregivers) were requested to complete a detailed sleep diary during the actigraphic monitoring. All the subjects were asked to indicate bedtime by a “cross sign”, estimated “sleep start” and estimated “sleep end” by a continuous line. Wake phases during the nights were disclosed by breaks in the continuous line. Measures derived from the diary helped to identify the correct periods during the actogram analysis.

Manual analysis was performed to determine the nocturnal sleep period (NSP) and diurnal sleep period (DSP), based on motor activity, environmental light and sleep diaries. The onset of the NSP was defined as the first epoch, after 10 min of immobility, with lights off and wrist activity lower than the threshold value of the wake. The NSP ended with the first epoch of sustained motor activity higher than the threshold value occurring in coincidence with environmental light exposure or concurrently with a period of wake reported on the sleep diary of the patient. The actigram was also visually inspected to determine recording failures or to reject any epoch in which the actigraph had been removed. Then the file was exported in AWD format, to perform sleep and Non Parametric Circadian Rhythm Activity (NPRCA) analysis with CamNTech MotionWare 1.2.26 [18, 19].

The parameters taking into account were: time in bed (TIB, mins), total elapsed time between the ‘Lights Out’ and ‘Got Up’ times; actual sleep time (AST, mins), total time spent in sleep according to the epoch-by-epoch wake/sleep categorization; actual wake time (AWT, mins), total time spent in wake according to the epoch-by-epoch wake/sleep categorization; sleep efficiency (SE, %), actual sleep time expressed as a percentage of TIB; sleep latency (SL, mins), the time between ‘Lights Out’ and ‘Fell Asleep’; wake bouts (Wb), number of contiguous sections categorized as wake in the epoch-by-epoch wake/sleep categorization; total activity score (TAS), the total of all the activity counts during the ASP; fragmentation index (FI), the sum of the ‘Mobile time (%)’ and the ‘Immobile bouts< = 1 min (%)’, and can be used as an indication of sleep quality or the lack of it; central phase measure (CPM, mins), the number of minutes past midnight.

Regarding NPCRA analysis we decided to use: least 5 average (L5), providing the average activity level for the sequence of the most least five consecutive hours, and reflecting how restful (inactive) and regular are the sleep periods; most 10 average (M10), providing the average activity level for the sequence of the most active ten consecutive hours, and indicating how active and regular the wake periods are. Moreover, NPCRA analysis included inter-daily stability (IS), which quantifies the degree of regularity in the activity-rest pattern, where higher values correspond to higher synchronization; intra-daily variability (IV), which quantifies the degree of fragmentation of activity-rest periods, where higher values represent a very fragmented sleep-wake cycle; relative amplitude (RA), calculated by considering both L5 and M10 and representing the rest-activity cycle synchronized with the normal 24-h cycle [20, 21].

CSF collection and analysis

All the CSF samples were obtained after the actigraphic recording by lumbar puncture performed in the decubitus position between 8:00 and 9:30 AM, using an atraumatic needle. We collected CSF samples in polypropylene tubes using standard sterile techniques. The first 4 ml CSF sample was used for biochemistry routine analysis including total cell count and lactate levels. A second 4 ml CSF sample was centrifuged to eliminate cells and cellular debris and immediately frozen at –80°C until the analysis to assess total tau (t-tau), phosphorylated tau (p-tau), orexin, amyloid-β₄₀ (Aβ₄₀), amyloid-β₄₂ (Aβ₄₂) levels, as previously reported [22].

Levels of classical CSF biomarkers were measured by using commercially available assays, following standard procedures. In particular, Aβ₄₂ and t-tau were determined by using an automated chemiluminescent enzyme immunoassays (CLEIA) (Lumipulse, Fujirebio), whereas p-tau and Aβ₄₀ were analyzed by using the corresponding manual sandwich enzyme-linked immunosorbent assay ELISA (Innotest, Fujirebio). Results of our laboratory are in line with those of the external quality control program for the CSF biomarkers, promoted by the Alzheimer’s Association [23]. CSF orexin levels were detected according to previously published standard procedures with commercially available radioimmunoassay kit (Orexin A/Hypocretin-1 RIA Kit; Phoenix Pharmaceuticals, Burlingame, CA) [24]. The researchers (MN, GS) who performed the analysis were blinded to the clinical status of participants.

Neuropsychological assessments

A complete neuropsychological evaluation containing screening and specific-domain tests was performed by trained neuropsychologists (FF, SDS) [25].

The Mini-Mental State Examination (MMSE) [26] was administered to assess the global cognitive functions. Short and long term episodic verbal memory were evaluated through Rey auditory verbal learning test (RAVLT), in which patients are at first asked to memorize fifteen common words (RAVLT-Immediate, RAVLT-I [27]) and then, after 15 min, to recall them (RAVLT-Delayed, RAVLT-D [27]). The delayed recall of a complex figure, which was previously copied (Rey Osterrieth complex figure test, ROCFT-D [28]) was administered for visuo-spatial memory, while the immediate recall of the same test, in which the patient has to copy the abstract figure (ROCFT-Immediate, ROCFT-I [28]), was administered for the evaluation of constructive-praxia and visuo-spatial planning. Moreover, the frontal assessment battery (FAB [29]) was performed to evaluate other executive skills such as cognitive flexibility, motor planning, interference and inhibition ability. Finally, the ability in verbal production through semantic and phonologic criteria was evaluated by semantic fluency (SF [30]) and phonologic fluency (PF [30]), respectively. In these tests, the patient has the task to enumerate the highest amount of words, in one minute, within the category that has been provided to him/her (e.g., animal’s name or words that begin with “S”).

Statistical analysis

The statistical analysis was performed using commercial software Statistica 10.0 program, StatsoftInc, Tulsa, OK, USA [31]. Descriptive data were expressed as mean and standard deviation for quantitative analyses. The Mann-Whitney U test was used to compare descriptive data between the 2 groups (AD patients vs controls), and p value was set at p < 0.05 for statistical significance. Only in the group of AD patients, we decided to separately analyze the correlations among the clinical, demographical, actigraphic, and neuropsychological variables, by using the Spearman’s rank correlation test.

RESULTS

Sample description and demographic data

We include in this study 18 AD patients compared to 10 controls, similar for age, sex, and education. As expected, AD patients showed lower MMSE scores compared to controls. Descriptive information (mean, standard deviation, maximal and minimal values) of the sample are summarized in Table 1.

Table 1

Clinical, demographical, neuropsychological, and CSF data of AD patients and controls

	AD (n = 18)	Controls (n = 10)
	(Mean±SD)	(Mean±SD)
Age (y)	71.0±5.9	61.8±11.2
Gender	8 M, 10 F	6 M, 4 F
Disease duration (y)	2.89±1.18	NA
Education	13.7±1.97	14.5±2.1
apoE4 positivity	14/18	5/11
MMSE	23.7±4.7	29.0±1.3
RAVLT-I	24.7±12.4	NA
RAVLT-D	4.5±4.4	NA
ROCFT-D	6.5±6.4	NA
ROCFT-I	16.5±9.7	NA
PF	17.4±12.7	NA
SF	19.3±10.0	NA
FAB	12.7±4,1	NA
T-tau (pg/mL) range	407.3±304.5	NA
	(62–1125)
P-tau (pg/mL) range	74.6±42.1	NA
	(18–141)
Aβ₄₂ (pg/mL) range	725.6±409.9	NA
	(357–1974)
Aβ₄₀ (pg/mL) range	9479.5±4359.9	NA
	(3577–17726)
Aβ₄₂/Aβ₄₀	0.08±0.03	NA
T-tau/Aβ₄₂	0.59±0.38	NA
Orexin (pg/mL) range	439.8±190.7	NA
	(234–830)	NA

MMSE, Mini-Mental State Examination; RAVLT-I, Immediate Recall – Rey Auditory Verbal Learning Test; RAVLT-D, Rey Auditory Verbal Learning Test-Delayed Recall; ROCFT-D, Rey Osterrieth Complex Figure Test-Delayed Recall; ROCFT-I, Rey Osterrieth Complex Figure Test-immediate recall; PF, phonologic fluency; SF, semantic fluency; FAB, Frontal Assessment Battery; T-tau, total tau; P-tau, phosphorylated tau; Aβ₄₂, amyloid-β 42; Aβ₄₀, amyloid-β 40.

AD patients also underwent neuropsychological assessment, apoE4 and CSF biomarkers analysis, which are reported in Table 1.

Comparison analysis

Comparing AD patients to controls, we documented lower SE, longer SL, and more Wb in AD patients than controls. AD patients also showed a FI higher than controls. Considering NPRCA analysis, lower M10, RA and IS were documented in AD patients than controls. Moreover, AD patients showed higher IV compared to controls. Results of the comparison analysis are shown in Table 2.

Table 2

Sleep-wake rhythm data of AD patients and controls

	AD (n = 18)	Controls (n = 11)	p
	(Mean±SD)	(Mean±SD)
L5 AVG	1025.3±811.2	806.2±233.3	NS
M10 AVG	14198.0±5389.5	22703.0±6228.5	0.004
RA	0.85±0.09	0.92±0.02	0.030
IS	0.58±0.13	0.73±0.08	0.010
IV	0.83±0.14	0.72±0.17	0.04
TIB (min)	544.2±56.9	486.5±84.2	NS
AST (min)	429.3±65.5	409.9±70.4	NS
AWT (min)	75.9±28.7	61.9±24.2	NS
SE (%)	78.9±8.4	84.5±5.7	0.020
SL (min)	26.4±22.7	12.4±11.2	0.010
Wb	64.9±29.0	46.7±15.8	NS
TAS	9735.3±4117.5	7961.7±4316.9	NS
FI	52.5±15.4	34.7±9.8	0.002
CPM (min)	174.8±61.3	190.9±77.6	NS

L5 AVG, least 5 average; M10 AVG, most 10 average; RA, Relative Amplitude; IS, interdaily stability; IV, intradaily variability; TIB, Time in bed; AST, actual sleep time; AWT, actual wake time; SE, sleep efficiency; SL, sleep latency; Wb, wake bouts; TAS, total activity score; CPM, central phase measure.

Correlation analysis

The correlation matrix shown in Table 3 contains the Spearman correlation coefficients (and the significance level) between the actigraphic parameters and both cognitive and CSF data (Table 3). Overall, moderate to strong correlations (r≥0.50) were found between the dysregulation of the sleep-wake cycle and the impairment of cognitive performances as well as the alteration of CSF biomarkers.

Table 3

Correlations between actigraphic parameters and cognitive/CSF data

	MMSE	RAVLT-I	RAVLT-D	ROCFT-D	ROCFT-I	PF	SF	FAB	T-tau (pg/mL)	P-tau (pg/mL)	Aβ₄₂ (pg/mL)	Aβ₄₀ (pg/mL)	Orexin (pg/mL)
L5 AVG	–0.451	–0.271	–0.384	0.017	0.559	–0.501	–0.721^**	–0.107	–0.246	–0.197	–0.102	–0.341	–0.038
M10 AVG	0.2	–0.071	0.417	0.016	0.179	–0.02	0.045	0.208	–0.743^**	–0.737^**	0.017	–0.639^*	–0.13
RA	0.512	0.082	0.486	–0.086	–0.448	0.378	0.605^*	0.245	–0.205	–0.263	0.033	–0.085	–0.145
IS	0.066	0.021	–0.121	–0.501	–0.389	–0.472	–0.219	–0.049	–0.327	–0.239	0.126	–0.249	0.351
IV	–0.539^*	–0.22	–0.17	–0.384	–0.496	–0.064	–0.282	–0.169	0.105	0.109	–0.267	–0.005	–0.125
TIB (min)	–0.08	–0.438	–0.148	–0.326	–0.145	–0.212	–0.375	–0.492	0.462	0.628^*	0.293	0.519	0.181
AST (min)	0.362	0.253	0.405	0.1	–0.422	0.423	0.521	0.152	–0.216	–0.373	0.156	–0.055	–0.223
AWT (min)	–0.362	–0.253	–0.405	–0.1	0.422	–0.423	–0.521	–0.153	0.216	0.373	–0.156	0.055	0.223
SE (%)	0.369	0.281	0.227	0.254	–0.196	0.309	0.374	0.162	–0.146	–0.262	0.307	0.079	–0.035
SL (min)	–0.453	–0.457	–0.126	–0.433	–0.002	–0.332	–0.32	–0.373	0.016	0.117	–0.335	–0.209	–0.114
Wb	–0.264	–0.249	–0.558^*	–0.261	0.426	–0.538	–0.568	–0.109	0.219	0.343	0.157	0.191	0.434
TAS	–0.481	–0.586^*	–0.328	–0.184	0.356	–0.328	–0.653^*	–0.162	0.045	0.225	–0.066	–0.017	0.031
FI	–0.352	–0.053	–0.433	–0.187	0.212	–0.419	–0.362	–0.199	0.282	0.37	–0.093	0.109	0.259
CPM (min)	–0.183	–0.118	–0.422	0.013	0.373	–0.386	–0.683^*	–0.132	0.455	0.576^*	0.437	0.506	0.468

^*p < 0.05; ^**p < 0.01. MMSE, Mini-Mental State Examination; RAVLT-I, Immediate Recall – Rey Auditory Verbal Learning Test; RAVLT-D, Rey Auditory Verbal Learning Test-Delayed Recall; ROCFT-D, Rey Osterrieth Complex Figure Test-Delayed Recall; ROCFT-I, Rey Osterrieth Complex Figure Test- Immediate recall; PF, phonologic fluency; SF, semantic fluency; FAB, Frontal Assessment Battery; T-tau, total tau; P-tau, phosphorylated tau; Aβ_42, amyloid-β 42; Aβ₄₀, amyloid-β 40; L5 AVG, least 5 average; M10 AVG, most 10 average; RA, relative amplitude; IS, interdaily stability; IV, intradaily variability; TIB, Time in bed; AST, actual sleep time; AWT, actual wake time; SE, sleep efficiency; SL, sleep latency; Wb, wake bouts; TAS, total activity score; FI, fragmentation index; CPM, central phase measure.

DISCUSSION

The involvement of the rest-activity rhythm in AD has already been widely demonstrated [6 , 32]. On the one hand, daytime sleepiness with several naps and wake fragmentation frequently occurs in patients with AD, in particular in the moderate-severe stages of the disease. On the other hand, sleep impairment, with loss of sleep continuity and reduced sleep quality for increased sleep latency, night-time awakenings and nocturia, concurrently manifests in patients with AD [33]. Moreover, moderate AD patients tend to present longer TIB compared to mild AD; nevertheless, moderate to severe AD patients show a longer sleep time with increased superficial sleep than deep sleep [7, 13]. Hence, the dysregulation of the sleep-wake cycle is a fingerprint of the AD pathology producing not only the decrease of quality of life of patients but also affecting caregivers, producing stress and caregiver burden [33].

In this study we not only investigated the sleep-wake rhythm in patients with AD focusing on both sleep habits and daytime activity, but also correlated the sleep-wake cycle alteration to the core CSF AD biomarkers and orexin levels, and the neuropsychological status in patients with AD, ranging from the mild to the moderate stages of the disease. In keeping with the results of this study, we documented a more fragmented sleep in AD patients compared to controls, featured by the reduction in SE, the increase of Wb and the longer SL. Data about the sleep-wake rhythm were more interesting and novel, since they focused on the altered sleep-wake cycle of AD patients. In particular, AD patients showed the reduction of M10 (indicative of the motor activity score during the daytime hours), RA and IS and the increase of IV. The last three parameters are the main variables of the NPRCA, since they reveal the stability, regularity and variability of the sleep-wake rhythm. In brief, these variables quantify the main characteristics of the circadian rhythm: 1) IV quantifies the rhythm fragmentation; 2) IS quantifies the synchronization to the 24-h light–dark cycle; 3) RA explores the relationship between the average activity during the least active 5-h period, or nocturnal activity (L5) and the average activity during the most active 10-h period, or daily activity (M10) [18]. Combining the results of this study with the significance of the variables measured, we confirmed the dysregulation of the sleep-wake cycle in AD patients, reflecting the dysfunction of the circadian timing system [32]. The suprachiasmatic nucleus in the anterior hypothalamus, which was indicated as the main circadian clock, is connected with the pineal gland and has shown significant degeneration in the AD neurodegeneration [33 –35]. Pineal gland is also affected by AD pathology, with its volume reduction and calcifications correlated with cognitive decline [36, 37]. All considering, hypothalamus is widely affected by AD neurodegeneration, not only with the reduction of hypothalamic neurons, but also with the dysregulation in the neurotransmitters output and function [12 , 37–40]. This is the case of the orexinergic neurons, which appear reduced in number in the AD brain, but the levels of orexin are increased in the CSF and correlated with the diurnal sleepiness and the nocturnal sleep impairment [12 , 41].

The present study corroborates the evidence of the sleep-wake cycle dysregulation in AD patients; moreover, it investigated the possible influence of CSF biomarkers (such as Aβ₄₂ and Aβ₄₀, t-tau and p-tau, and orexin) on the sleep-wake cycle impairment and the relationship between this latter and the cognitive status of the patients. In agreement with the correlation analysis, we documented that tau proteins significantly correlates with the reduction of M10 and the alteration of nocturnal sleep, thus possibly reflecting the fact that increased tau-mediated neurodegeneration corresponds to a more marked sleep-wake rhythm alteration. Tau pathology may spread to different brain regions and the neurodegeneration induced can worsen cognitive decline and produce the neuropsychiatric symptoms [42, 43]. This finding increases the evidence that tau pathology causing dysfunction of synapses, which eventually lead to irreparable synaptic loss in AD, correlates with the neuropsychiatric symptoms and the cognitive impairment in AD patients [44]. Orexin is a neurotransmitter promoting wakefulness and reducing REM sleep, already documented promoting sleep fragmentation and nocturnal awakening in AD patients from the early stage of the disease [12 , 45]. In this study, CSF orexin levels were correlated with the sleep-wake cycle measured by actigraphy in order to better understand the role of this neurotransmitter dysfunction in the entire circadian rhythm in AD. In particular, it was documented the relationship between CSF orexin concentrations and the longer CPM, which reflects the delay in the phase of sleep, also appearing less continuous and more fragmented.

Hence, both nocturnal sleep alteration and circadian rhythm dysregulation are evident in the AD process. In keeping with our results, the sleep-wake cycle alteration has been previously documented along the course of AD pathology, and possibly starting in the early stages of the disease [6 , 47]. The etiology of circadian disruption is multifactorial and can be related to the loss of melanopsin retinal ganglion cells and the degeneration of the brain circuits regulating the sleep-wake cycle, but also to the reduced light exposure and prolonged immobility [48 –50]. Consistently, higher IV reflects the occurrence of daytime naps and a more evident nocturnal activity, thus serving as a marker of the sleep-wake cycle dysregulation. Moreover, it correlates with the decreased sleep quality, cognitive functions, and circadian rhythm amplitude [19 , 51–56]. Lower IS reflects the circadian rhythm instability, and is associated with the fragmentation of the circadian rhythm, more nocturnal activity, and lower cognitive performances [51, 53]. Finally, the reduced RA corresponds to the motor activity reduction during the day and increase during the night and is responsible for the behavioral symptoms in the AD pathology [55].

We are aware that limitations are present in this study: 1) the number of patients included; 2) controls were available exclusively for actigraphic data; 3) polysomnography was not performed to investigate nocturnal sleep and only actigraphic parameters were evaluated.

In conclusion, the present correlations found between the sleep-wake cycle dysregulation and the biomarkers of neurodegeneration (tau proteins), the cognitive status (MMSE), and the CSF orexin levels further link the circadian dysfunction to the AD pathology in patients with mild to moderate AD. These findings further support the hypothesis that disease-modifying therapeutic strategies may improve not only the pathological course of the disease but also the disabling cognitive and behavioral symptoms, other than the sleep-wake dysregulation.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-1124r2).

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