1 Sleep and Circadian Rhythms Functions of Sleep and Circadian - - PDF document

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Phyllis C. Zee, MD, PhD Benjamin and Virginia

• T. Boshes Professor in Neurology

Director Center for Circadian and Sleep Medicine Chief, Division of Sleep Medicine Northwestern University Feinberg School of Medicine

Sleep-Circadian Rhythms in Aging and Women: A Bi-directional Relationship?

Disclosures

Current research funding (Northwestern University)

• NIH (NHLBI, NIA)
• DARPA
• Jazz
• Alzheimer’s Association
• Dixon Family Foundation

Scientific Advisory Board (consultant)

• Merck
• Philips
• Wellcome Trust
• Jazz
• Galderma (Nestle)

Other

Stock ownership: Teva ABIM Sleep Medicine Examination and Policy Committee

As the world turns…there are prominent dynamic changes in our biology, from molecules to behavior…. WAKE-SLEEP

Fundamental Basic Science Discoveries Have Changed How We Think About the Role of Sleep and Circadian Rhythms in Health Fundamental Basic Science Discoveries Have Changed How We Think About the Role of Sleep and Circadian Rhythms in Health Sleep and Circadian Rhythms

• Sleep is of the brain for the brain and

all tissues of the body!

• Sleep is cellular, molecular in tissues

and organs

• Circadian clock genetic machinery

exits in virtually all cells-tissues Circadian rhythms and sleep are integrated into metabolic, inflammatory, neural pathways…. AND their proper alignment with each other is essential for optimal health.

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Sleep and Circadian Rhythms Implications for Aging, Health and Disease

CNS/PNS Neurological Disorders Inflammation

Heart, Vessel, Endothelium

Cardiovascular disease Tract Nocturia, Incontinence Muscle Insulin resistance DIABETES Liver Insulin resistance Pancreas Abnormal insulin Adipose Obesity GI tract Peptic ulcer

Clocks- Sleep

Cancer

• Breast
• Prostate

Functions of Sleep and Circadian Rhythm Functions of Sleep and Circadian Rhythm

“If sleep does not serve an absolutely vital function, then it is the biggest mistake the evolutionary process ever made.”

• A. Rechtschaffen

– Psychomotor performance – Learning and memory – Mental/emotional health – Neurological health – Cardio-metabolic health

Sleep Markedly Increases Convective Exchange of CSF with Interstitial Fluid (Glymphatic System)

(Xie L, et al, Science 342:373, 2013)

Garbage Removal for Brain During Sleep

Ei Eiko Oj Ojala, NY NYT

Xie et al., Science, 2013

Glymphatic ymphatic Flow is

• w is Modulat

Modulated b d by Sleep Sleep

Brain water dynamics and organized flow CSF-ISF exchange with perivascular convective flow Sleep stage dependence of parenchymal impedance and extracellular volume

3 Functions of Sleep/Circadian Rhythm: Brain Health

Disrupted Sleep

Neurodegenerative Disease

Alzheimer’s Parkinson’s Traumatic Brain Injury

References Schlosser Covell et al. 2012 Aziz et al. 2009 Morton et al. 2005, Pallier, et al. 2007 Boone et al. 2012 Mathias, Alvaro 2012;

Neurotoxins Inflammation Oxidative stress Glymphatic flow Glia, astrocyte etc

Xie et al 2013 Science, Musiek and Holtzman, Science 2016

Metabolic Autonomic Vascular, etc

Functions of Sleep/Circadian Rhythm: Brain Health

Sleep/circadian dysfunction

Neurodegenerative Disease

Alzheimer’s Parkinson’s Traumatic Brain Injury

References Schlosser Covell et al. 2012 Aziz et al. 2009 Morton et al. 2005, Pallier, et al. 2007 Boone et al. 2012 Mathias, Alvaro 2012 Xie et al 2013 Science, Musiek and Holtzman, Science 2016

Neurotoxins Inflammation Oxidative stress Glymphatic flow Glia, astrocyte etc

Metabolic Autonomic Vascular, etc

Mechanism Linking Sleep and Health

• In the laboratory setting, short-term sleep restriction leads to a

variety of adverse physiologic sequelae, including

– Impaired glucose control – Increased cortisol – Increased blood pressure – Sympathetic activation – Increased markers of inflammation – Decreased leptin level

• These data suggest that chronic sleep restriction may have

long-term health consequences

Zee PC, et al. Arch Intern Med. 2006;166:1686-1688.

4 HOURS IN BED 3h48' OF SLEEP 1.5 3.5 5.5 LEPTIN (ng/ml) 8 HOURS IN BED 6h52' OF SLEEP 12 HOURS IN BED 8h52' OF SLEEP 20 40 CORTISOL (µg/dL) 9 13 17 21 1 5 9 CLOCK TIME 9 13 17 21 1 5 9 CLOCK TIME 9 13 17 21 1 5 9 CLOCK TIME HOMA (INSULIN (mU/L) * GLUCOSE(mmol/L) / 22.5) 5 10 15 Modified from Spiegel et al., J Clin Endocrinol Metab, 2004

Impact of Sleep Duration on Hormonal and Metabolic Profiles

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12 Hours in Bed 4 Hours in Bed

rRR

• High rRR = Decreased Heart Rate Variability =

Increased Sympathetic Nervous Activity and/or Decreased Parasympathetic Nervous Activity

Spiegel K, et al. J Clin Endocrinol Metab. 2004;89:5762-5771. Spiegel K, et al. J Clin Endocrinol Metab. 2004;89:5762-5771.

• Clock Time
• Clock Time

Sleep Restriction and Heart-Rate Variability

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10 21 to 31 Mean Antibody Titers (10 ) 6 0.25 0.50 0.75 1.00 1.25 1.50 Sleep Deprived, n=11 Control, n=14 ns p<0.03 ns Time relative to influenza vaccination (days)

RESPONSE TO INFLUENZA VACCINATION

Spiegel et al, 2000

Demographics of Aging and Sleep Disturbance in America

57 12 10 20 30 40 50 60 Sleep disturbance No Sleep Complaints

43 30 29 25 19 19 13 10 20 30 40 50 Initiating/Maintenance Nocturnal Waking Insomnia Daytime Napping Waking Too Early Waking Not Rested

Percent

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• Meta-analysis of 65 sleep studies in healthy persons

– 3557 total subjects aged 5-102 years

• Most age-related sleep changes occur in early and mid-

years of human life span

• In healthy older adults:

– Sleep remains relatively constant from age 60 to mid-90s

• Except for sleep efficiency which decreases
• Wake after sleep onset increases
• Slow wave sleep decreases

Changes in Sleep with Age

Ohayon MM, et al. Sleep. 2004;27:1255-1273

Circadian Rhythms and Aging Circadian Rhythms and Aging

• Decreased amplitude

– Advanced /delayed phase – Internal desynchronization, – Increase in variability

• Cellular/Molecular changes

– Expression of Clock genes – Neurochemical changes in the SCN – Decreased ability of SCN to drive peripheral

• scillators
• Decreased light input

– Age related losses in photoreception (cataracts) – Decreased exposure? Decreased response?

Naylor E, Zee PC. Sleep Med Clin. 2006;1:187-196; Hofman MA et al (2006) Ageing Res Rev; 5:33-51; Gibson EM et al (2009) Exp Gerontol; 44:51-56; Hofman MA and Swaab DF (1994) Brain Res; 651: 134-142; Yamazaki et al (2002) PNAS; 99:10801-10806; Turner PL and Mainster MA (2008) Br J Ophthalmol; 92:1439-1444; Campbell et al (1988) Physiol Behav; 42: 141-144; Lim et al, Sleep 2012

Wang JL, Ann Neurol, 2015

Circadian and Sleep Disturbances in Aging Circadian and Sleep Disturbances in Aging

GI, gastrointestinal; PG, pineal gland; RHT, retinohypothalamic tract; SCN, suprachiasmatic nucleus; WBC, white blood cell. Beckett M, Roden LC. S Afr J Sci. 2009;105(11-12):415-420; Dibner C, et al. Annu Rev Physiol. 2010;72:517-549; Young M, et al. Sleep Med. 2007;8(6):656-667.

Peripheral clocks

Pancreas

Information about the light/dark environment

Activity Liver Adipose Heart GI tract Muscle WBCs Kidney Breast RHT SCN

PG Melatonin

X X X X Wang JL, Ann Neurol, 2015

Sleep-Wake Disturbance and Co- Morbidities

Common Conditions

Altered Sleep Regulation & Circadian Rhythms1

Medical, Neurologic, & Psychiatric Conditions1

Psychosocial Factors2

Difficulty Initiating & Maintaining Sleep Sleep Loss Chronic Pain Nocturia Depression Sleep Disorders SDB (Sleep Apnea) Restless Legs Late-Life Stressors

Barthlen GM. Geriatrics. 2002;57:34-39. Ancoli-Israel S, Cooke JR. J Am Geriatr Soc. 2005;53(suppl):S264-

• S271. Foley DJ et al. Sleep. 1995;18:425-432.

Altered Sleep Regulation & Circadian Rhythms1

Difficulty Initiating & Maintaining Sleep Sleep Loss

Altered Sleep Regulation & Circadian Rhythms1

Difficulty Initiating & Maintaining Sleep

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Normal age associated changes in sleep and circadian rhythms contribute to vulnerability NOT primarily responsible for very high prevalence of sleep- wake disturbances in older adults Highest contribution is physical, neurological mental health, socioeconomic and environmental factors. Not inevitable with aging!

Foley DJ et al. Sleep. 1995;18:425-432; Foley D et al. J Psychosom Res 2004;56:497– 502; Ohayon et al., Sleep. 2004 Nov 1:27(7):1255-73

Sleep/Circadian Rhythm

Learning /memory Metabolic Cardiovascular Neurologic / Mental

HEALTH

Behavioral lifestyle Psychological well-being Socio-economic status Work schedules Physical activity level

Inflammation Metabolism Autonomic Oxidative stress Synaptic plasticity/ connectivity

Sleep and Circadian Health

Sleep Disorder

Insomnia Sleep apnea Restless legs Narcolepsy

PERFORMANCE AND SAFETY

Genetic vulnerability

AGING

Cardio‐Metabolic Neurologic Psychiatric Health

Clocks Sleep/Wake Neural, Cardio- Metabolic Function Sleep, Circadian Rhythm and Sex: Implication for Health and Disease in the Era of Precision Medicine

Circadian and sleep disruption contribute to cardio-metabolic and brain disorders common with aging Circadian and sleep function essential for cell function, neural connectivity and plasticity Improving circadian rhythms and sleep as targets for prevention and disease modification

Role of Sex on expression and treatment?

Women: A Population at Risk

60% say they only get a good night’s sleep a few nights per week or less

http://www.sleepfoundation.org/_content/hottopics/2007SleepInAmericaPoll.pdf.

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Sex Differences in Sleep

1.

Mauri, M. 1990, Health Care for Women International, 11:409-421; Sleep and the reproductive cycle: A review

2.

Hunter M, et al. Maturitas. 1986;8:217-228

3.

National Sleep Foundation: Women and Sleep Poll. 1998

• Complaints of sleep disturbance are more

prevalent for women than men across the lifespan1

• Compared to men and younger women,

menopausal women are more likely to take hypnotics for sleep2,3

Biological changes impact sleep Biological changes impact sleep  Hormonal changes throughout the lifespan impact

women’s ability to get a good night’s sleep

– Menstrual cycle related insomnia – 40% of pregnant and 55% of post partum women report getting a good night’s sleep a few nights a month or less – 25% of perimenopausal women and 30% of post menopausal women report getting a good night’s sleep a few nights a month or less

http://www.sleepfoundation.org/_content/hottopics/2007SleepInAmericaPoll.pdf.

Sex Differences in Sleep and Circadian Regulation Sex Differences in Sleep and Circadian Regulation

 Women generally show longer sleep durations and

perhaps have a higher sleep need than do men.

 Women show earlier sleep times as well as faster

circadian clocks than do men.

 Sleep and the circadian clock characteristics are sensitive

to female sex hormones.



Sex differences in slow wave sleep; women show a smaller age-related decline.

“There is ambiguity about whether the onset of sleep difficulties in post-menopausal women is due to hormone changes, effects of normal aging on sleep, or the onset of a sleep disorder such as periodic limb movements or sleep apnea.”

Krystal,A, Edinger,J,Wohlgenmuth,W & Marsh,G (1998). Sleep in peri-menopausal and post-menopausal women, Sleep Medicine Reviews, 2, 243-253.

Menopause

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Sleep Disturbance During Menopause

• 25%-75% menopausal women report sleep problems

vs 15% of the general population1,2 – Difficulty falling asleep3,4 – Difficulty in sleep maintenance4 – Early morning awakening4

• Hot flashes, mood disorders, and sleep-disordered

breathing, and aging may contribute5-7

• 1. Eichling PS, Sahni J. J Clin Sleep Med. 2005;1:291-300.
• 2. Schnatz PF et al. Menopause. 2005;12:623-629.
• 3. Shaver JL, Paulsen VM. Fam Pract Res J. 1993;13:373-384.
• 4. Chung KF, Tang MK. Maturitas. 2006;53:396-404.
• 5. Hsu HC, Lin MH. J Nurs Res. 2005;13:153-164.
• 6. Anttalainen U et al. Acta Obstet Gynecol Scand. 2006;85:1381-1388.
• 7. Moline ML et al. Sleep Med Rev. 2003;7:155-177.

Hot Flashes and Sleep

Woodward S, Freeman R. Sleep. 1994;17:497-501.

Frequency Distribution of Hot Flashes over 24-hr Period N = 19

Number of Hot Flashes Time of Day 15 12 9 6 3

10 2 2 4 6 8 4 noon 6 8 midn 10

Arousal frequency ↑ Sleep efficiency ↓

• No. stage changes

↑ Stage 3/4 sleep ↓ First REM period ↓

Sleep Characteristics Associated with Hot Flashes in Menopausal and Postmenopausal Women

Control Group CE 0.3+MPA CE 0.3+P Sleep Score Weeks 4 8 12 10 8 6 4 2

Effects of Hormone Replacement Therapy

• n Subjective Measures of Sleep

VAS Sleep Scores in Women Randomized to Low-Dose HRT or Control (Calcium + Vitamin) Groups1

*P < 0.05 vs baseline and control group levels.

†P < 0.05 vs corresponding control and CE + MPA group values.

N = 60 * * *

† † †

CE = conjugated equine estrogens; HRT = hormone replacement therapy; MPA = medroxiprogesterone acetate; P = natural micronized progesterone; VAS = visuonalogic score. 1.Gambacciani M et al. Maturitas. 2005;50:91-97. 2.Sarti CD et al. Menopause. 2005;12:545-551.

Sleep quality ↑

Trouble falling asleep ↓ Nighttime awakening ↓ Morning sleepiness ↓

Effects of HRT on Subjective Sleep Measures1,2

Effects of Hormone Replacement Therapy

• n Objective Measures of Sleep

HRT = hormone replacement therapy; REM = rapid eye movement 1. Thomson J, Oswald I. Br Med J. 1977;2:1317-1319. 2. Manber R et al. Sleep. 2003;26:163-168.

Sleep Duration ↑ Intervening wakefulness ↓ REM sleep ↑ Sleep-disordered breathing ↓

Effects of HRT on Objective Sleep Measures1,2

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Sleep Disorders in Women Sleep Disorders in Women

Young T, Ancoli-Israel S, et al. SLEEP. 2001. Mant E, et al. Age and Ageing. 1992. Ancoli-Israel S, et al. SLEEP. 1993. Phillips BA, et al. SLEEP. 1994. Hoch CC, et .al. SLEEP. 1994. O’Keefe ST, et al. Age and Ageing. 1994. Phillips B, et al. Arch Int Med.

• 2000. Allen R, et al. Arch Int Med. 2005.

Krystal,A, Edinger,J,Wohlgenmuth,W & Marsh,G (1998). Sleep in peri-menopausal and post- menopausal women, Sleep Medicine Reviews, 2, 243-253.

Insomnia Disorder (all ages) Obstructive sleep apnea (pregnancy and menopause) Restless legs syndrome (pregnancy and menopause) Sleep Apnea: Sex Differences!

• Snoring
• Sleepiness
• Gasping arousals
• Witnessed apneas
• Depression
• Overweight/Obesity
• Hypertension
• Diabetes
• Heart Disease

Women with sleep apnea:

• Standard sleep questionnaires

used to assess someone’s risk

• f having sleep apnea- it may

be less sensitive in picking up sleep apnea in women than men

• Insomnia symptoms
• Differences in risk factors and
• utcomes?

Women are a population at particular risk for sleep disturbances… YET

Sex differences in the presentation, consequences and response to treatment of sleep disorders are lacking. It took over 25 years to recognize that sex plays a role in zolpidem levels leading to a recent change in the prescribing guidelines for women.

Health Sleep

Nutrition Physical Activity

Thomas Dekker, English Dramatist (1572-1632)

“Sleep is the golden chain that ties health and our bodies together” “Sleep is the golden chain that ties health and our bodies together”

Improving sleep and circadian fucntion: targets for prevention and disease modification.

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Women and Sleep: Summary

Rather than attributing sleep problems to only hormonal changes, other factors:

• Medical disorders
• Sleep disorders (insomnia, sleep apnea, restless

legs)

• Medications
• Psychiatric/Psychological (depression, anxiety,

stress)

• Life style (diet, exercise, alcohol/caffeine

Are likely to play a major role and all treatable conditions/situations

“Worried About Growing Old? Don’t Lose Sleep Over it.”

Good clocks, good sleep = Successful Aging

Maintain regular sleep/wake schedule Exercise daily, but not within 3 hours sleep Allow 7-8 hours/night for sleep

Basic Advice

Appropriately-timed light and feeding!