The circadian rest‐activity patterns in mild‐moderate Alzheimer’s disease patients

Abstract Background: Regulator of calcineurin 1 (RCAN1) is overexpressed in Down syndrome (DS), but RCAN1 levels are also increased in Alzheimer's disease (AD) and normal aging. AD is highly comorbid among individuals with DS and is characterized in part by progressive neurodegeneration that resembles accelerated aging. Importantly, abnormal RCAN1 levels have been demonstrated to promote memory deficits and pathophysiology symptomatic of DS, AD, and aging. Anomalous diurnal rest-activity patterns and circadian rhythm disruptions are also common in DS, AD, and aging and have been implicated in facilitating age-related cognitive decline and AD progression. However, no prior studies have assessed whether RCAN1 dysregulation may also promote the age-associated alteration of rest-activity profiles and circadian rhythms, which could in turn contribute to neurodegeneration in DS, AD, and aging. Methods: The present study examined the impacts of RCAN1 deficiency and overexpression on the photic entrainment, circadian periodicity, intensity and distribution, diurnal patterning, and circadian rhythmicity of wheel running in young (3-6 months old) and aged (9-14 months old) mice. All data were initially analyzed by multifactorial ANOVA with variables of genotype, age, treatment, and sex considered as dependent variables.Results: We found that daily RCAN1 levels in the hippocampi of light-entrained young mice are generally constant and that balanced RCAN1 expression is necessary for normal circadian locomotor activity rhythms. While the light-entrained diurnal period was unaltered, RCAN1-null and -overexpressing mice displayed lengthened endogenous (free-running) circadian periods like mouse models of AD and aging. In light-entrained young mice, RCAN1 knockout and overexpression also recapitulated the general hypoactivity, diurnal rest-wake pattern fragmentation, and attenuated amplitudes of circadian activity rhythms reported in DS, preclinical and clinical AD, healthily aging individuals, and rodent models thereof. Under constant darkness, RCAN1-null and -overexpressing mice displayed altered locomotor behavior indicating circadian clock dysfunction. Using the Dp(16)1Yey/+ (Dp16) mouse model for DS, which expresses three copies of Rcan1, we found reduced wheel running activity and rhythmicity in both light-entrained and free-running young Dp16 mice like young RCAN1-overexpressing mice. Critically, these diurnal and circadian deficits were rescued in part or entirely by restoring Rcan1 to two copies in Dp16 mice. Conclusions: Collectively, this study's findings suggest that both loss and aberrant gain of RCAN1 precipitate anomalous light-entrained diurnal and circadian activity patterns emblematic of DS, AD, and aging.

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Effects of High-Frequency Cranial Electrostimulation on the Rest-Activity Rhythm and Salivary Cortisol in Alzheimer’s Disease

Dementia and Geriatric Cognitive Disorders ◽

10.1159/000095108 ◽

2006 ◽

Vol 22 (4) ◽

pp. 267-272 ◽

Cited By ~ 9

Author(s):

Erik Scherder ◽

Dirk Knol ◽

Marie-Jose van Tol ◽

Eus van Someren ◽

Jan-Berend Deijen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Salivary Cortisol ◽

High Frequency ◽

Activity Rhythm ◽

Rest Activity

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Effects of Low-Frequency Cranial Electrostimulation on the Rest-Activity Rhythm and Salivary Cortisol in Alzheimer's Disease

Neurorehabilitation and Neural Repair ◽

10.1177/0888439003017002004 ◽

2003 ◽

Vol 17 (2) ◽

pp. 101-108 ◽

Cited By ~ 15

Author(s):

Erik Scherder ◽

Dirk Knol ◽

Eus van Someren ◽

Jan-Berend Deijen ◽

Rob Binnekade ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Activity Rhythm ◽

Low Frequency ◽

Control Group ◽

Positive Effects ◽

Alternative Research ◽

Positive Effect ◽

Experimental Group ◽

Rest Activity

Objective. In previous studies, cranial electrostimulation (CES) had positive effects on sleep in depressed patients and in patients with vascular dementia. The present study examined the effects of low-frequency CES on the rest-activity rhythm and cortisol levels of patients with probable Alzheimer's disease (AD). Method. It was hypothesised that a decreased level of cortisol would parallel a positive effect of low-frequency CES on nocturnal restlessness. Sixteen AD patients were randomly assigned to an experimental group (n = 8) or a control group (n = 8). The experimental group was treated with CES, whereas the control group received sham stimulation, for 30 minutes a day, during 6 weeks. The rest-activity rhythm was assessed by actigraphy. Cortisol was measured repeatedly in the saliva throughout the day by means of salivette tubes. Results. Low-frequency CES did not improve the rest-activity rhythm in AD patients. Moreover, both groups showed an increase instead of a decrease in the level of cortisol. Conclusions: These preliminary results suggest that low-frequency CES has no positive effect on the rest-activity rhythm in AD patients. An alternative research design with high-frequency CES in AD is discussed.

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A Follow-Up Study of Actigraphic Measures in Home-Residing Alzheimer's Disease Patients

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/089198879801100103 ◽

1998 ◽

Vol 11 (1) ◽

pp. 7-10 ◽

Cited By ~ 31

Author(s):

Jerome A. Yesavage ◽

Leah Friedman ◽

Helena C. Kraemer ◽

Art Noda ◽

Deryl Wicks ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Circadian Rhythm ◽

Behavioral Disturbance ◽

Nocturnal Sleep ◽

Significant Deterioration ◽

Cross Sectional ◽

Sleep Parameters ◽

Rest Activity

This article reports cross-sectional and follow-up data with actigraphic measures of nocturnal sleep and rest/activity in 61 Alzheimer's disease (AD) patients as well as the relation of actigraphic measures to levels of behavioral disturbance across different stages of the disease. Over the course of approximately 1.5 years' follow-up, patients showed significant deterioration of nocturnal sleep parameters, but no significant change in rest/activity circadian rhythm parameters. There were also significant correlations among nocturnal sleep, rest/activity circadian rhythm, and behavioral disturbance measures, but only in relatively early stages of AD. It is argued that study of nocturnal sleep and circadian rhythm in relation to behavioral disturbance in AD requires longitudinal data and analyses that take into account the stage of disease at which patients are assessed.

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Daily Physical Activity Patterns During the Early Stage of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-160582 ◽

2016 ◽

Vol 55 (2) ◽

pp. 659-667 ◽

Cited By ~ 10

Author(s):

Vijay R. Varma ◽

Amber Watts

Keyword(s):

Physical Activity ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Activity Patterns ◽

Daily Physical Activity ◽

Physical Activity Patterns

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Treatment of behavioural, cognitive and circadian rest-activity cycle disturbances in Alzheimer's disease: haloperidol vs. quetiapine

The International Journal of Neuropsychopharmacology ◽

10.1017/s1461145705006036 ◽

2005 ◽

Vol 9 (05) ◽

pp. 507 ◽

Cited By ~ 24

Author(s):

Egemen Savaskan ◽

Corina Schnitzler ◽

Carmen Schröder ◽

Christian Cajochen ◽

Franz Müller-Spahn ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Activity Cycle ◽

Rest Activity

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The fragmentation of rest/activity cycles in Alzheimer's disease

International Journal of Geriatric Psychiatry ◽

10.1002/gps.930100406 ◽

1995 ◽

Vol 10 (4) ◽

pp. 299-304 ◽

Cited By ~ 3

Author(s):

Laura Ghali ◽

Robert W. Hopkins ◽

Peter Rindlisbacher

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Activity Cycles ◽

Rest Activity

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Assessing Sex-Specific Circadian, Metabolic, and Cognitive Phenotypes in the AβPP/PS1 and APPNL - F/NL - F Models of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210629 ◽

2021 ◽

pp. 1-17

Author(s):

Jesse Britz ◽

Emmanuel Ojo ◽

Asmita Dhukhwa ◽

Takashi Saito ◽

Takaomi C. Saido ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Cognitive Deficits ◽

Activity Patterns ◽

Spatial Learning And Memory ◽

Plaque Pathology ◽

Glucose Sensitivity ◽

Old Females ◽

Daily Activity Patterns

Background: Circadian disruption has long been recognized as a symptom of Alzheimer’s disease (AD); however, emerging data suggests that circadian dysfunction occurs early on in disease development, potentially preceding any noticeable cognitive deficits. Objective: This study compares the onset of AD in male and female wild type (C57BL6/J), transgenic (AβPP/PS1), and knock-in (APPNL - F/NL - F) AD mouse models from the period of plaque initiation (6 months) through 12 months. Methods: Rhythmic daily activity patterns, glucose sensitivity, cognitive function (Morris water maze, MWM), and AD pathology (plaques formation) were assessed. A comparison was made across sexes. Results: Sex-dependent hyperactivity in AβPP/PS1 mice was observed. In comparison to C57BL/6J animals, 6-month-old male AβPP/PS1 demonstrated nighttime hyperactivity, as did 12-month-old females. Female AβPP/PS1 animals performed significantly worse on a MWM task than AβPP/PS1 males at 12 months and trended toward increased plaque pathology. APPNL - F/NL - F 12-month-old males performed significantly worse on the MWM task compared to 12-month-old females. Significantly greater plaque pathology occurred in AβPP/PS1 animals as compared to APPNL - F/NL - F animals. Female AβPP/PS1 animals performed significantly worse than APPNL - F/NL - F animals in spatial learning and memory tasks, though this was reversed in males. Conclusion: Taken together, this study provides novel insights into baseline sex differences, as well as characterizes baseline diurnal activity variations, in the AβPP/PS1 and APPNL - F/NL - F AD mouse models.

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P3-360: Ambulatory activity patterns in Alzheimer's disease based on living situation: Preliminary results

Alzheimer s & Dementia ◽

10.1016/j.jalz.2011.05.1802 ◽

2011 ◽

Vol 7 ◽

pp. S630-S630

Author(s):

Kalpana Padala ◽

Mukul Mukherjee ◽

Prasad Padala ◽

William Burke ◽

Nicholas Stergiou

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Activity Patterns ◽

Ambulatory Activity ◽

Living Situation ◽

Preliminary Results

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Sleep and diurnal rest-activity rhythm disturbances in a mouse model of Alzheimer’s disease

SLEEP ◽

10.1093/sleep/zsaa087 ◽

2020 ◽

Vol 43 (11) ◽

Cited By ~ 2

Author(s):

Mikolaj J Filon ◽

Eli Wallace ◽

Samantha Wright ◽

Dylan J Douglas ◽

Lauren I Steinberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Eye Movement ◽

Rem Sleep ◽

Activity Levels ◽

Rapid Eye Movement ◽

Drug Bioavailability ◽

Activity Rhythms ◽

Delta Power ◽

Rest Activity

Abstract Study Objectives Accumulating evidence suggests a strong association between sleep, amyloid-beta (Aβ) deposition, and Alzheimer’s disease (AD). We sought to determine if (1) deficits in rest-activity rhythms and sleep are significant phenotypes in J20 AD mice, (2) metabotropic glutamate receptor 5 inhibitors (mGluR5) could rescue deficits in rest-activity rhythms and sleep, and (3) Aβ levels are responsive to treatment with mGluR5 inhibitors. Methods Diurnal rest-activity levels were measured by actigraphy and sleep-wake patterns by electroencephalography, while animals were chronically treated with mGluR5 inhibitors. Behavioral tests were performed, and Aβ levels measured in brain lysates. Results J20 mice exhibited a 4.5-h delay in the acrophase of activity levels compared to wild-type littermates and spent less time in rapid eye movement (REM) sleep during the second half of the light period. J20 mice also exhibited decreased non-rapid eye movement (NREM) delta power but increased NREM sigma power. The mGluR5 inhibitor CTEP rescued the REM sleep deficit and improved NREM delta and sigma power but did not correct rest-activity rhythms. No statistically significant differences were observed in Aβ levels, rotarod performance, or the passive avoidance task following chronic mGluR5 inhibitor treatment. Conclusions J20 mice have disruptions in rest-activity rhythms and reduced homeostatic sleep pressure (reduced NREM delta power). NREM delta power was increased following treatment with a mGluR5 inhibitor. Drug bioavailability was poor. Further work is necessary to determine if mGluR5 is a viable target for treating sleep phenotypes in AD.

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