Abstract
Abstract. Circadian mechanisms and the sleep-wakefulness rhythms guarantee survival, adaptation, efficient action in everyday life or in emergencies and well-being. Disordered circadian processes at central and/or cellular levels, sleep disorders, and unhealthy wakefulness/sleep rhythms can impair the physiological circadian organization and result in subjective, professional, or behavioral changes ranging from functional inadequacy to higher risks at work or on the road to medical relevance. Circadian rhythms and the sleep organization change ontogenetically; major changes result from normal aging and from the multiple diseases that are often associated. There are circular functional interactions involving sleep/sleep disorders, the autonomic and immune systems, and the functional changes in the circadian system due to aging that deserve attention but have been overlooked thus far.
References
2003). Correlation between electroencephalography and heart rate variability during sleep. Psychiatry and Clinical Neuroscience, 57(1), 59–65. https://doi.org/10.1046/j.1440-1819.2003.01080.x
(2011). Complaints of difficulty to fall asleep increase the risk of depression in later life: The health in men study. Journal of Affective Disorders, 134(1–3), 208–216. https://doi.org/10.1016/j.jad.2011.05.045
(2013). Does self-reported sleep quality predict poor cognitive performance among elderly living in elderly homes? Aging & Mental Health, 17(7), 788–792. https://doi.org/10.1080/13607863.2013.790930
(2001). Circadian profile of Per gene mRNA expression in the suprachiasmatic nucleus, paraventricular nucleus, and pineal body of aged rats. Journal of Neuroscience Research, 66(6), 1133–1139. https://doi.org/10.1002/jnr.10010
(2013). Cognitive deficit is associated with phase advance of sleep-wake rhythm, daily napping, and prolonged sleep duration – a cross-sectional study in 2,947 community-dwelling older adults. Age, 35(2), 479–486. https://doi.org/10.1007/s11357-011-9366-6
(2016). Sleep disorder or simple sleep ontogeny? Tendency for morningness is associated with worse sleep quality in the elderly. Brazilian Journal of Medical and Biological Research, 49(10), Article e5311. https://doi.org/10.1590/1414-431X20165311
(2012). Circadian topology of metabolism. Nature, 491(7424), 348–356. https://doi.org/10.1038/nature11704
(2003). Melanopsin in the circadian timing system. Journal of Molecular Neurosciences, 21, 73–89. https://doi.org/10.1385/JMN:21:1:73
(1986). Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science, 233(4764), 652–654. https://doi.org/10.1126/science.3014662
(2003). A mechanism converting psychosocial stress into mononuclear cell activation. Proceedings of the National Academy of Sciences, 100(4), 1920–1925. https://doi.org/10.1073/pnas.0438019100
(2011). Association of sleep characteristics and cognition in older community-dwelling men: The MrOS sleep study. Sleep, 34(10), 1347–1356. https://doi.org/10.5665/SLEEP.1276
. (2005). Sleep loss-related decrements in planning performance in healthy elderly depend on task difficulty. Journal of Sleep Research, 14(4), 409–417. https://doi.org/10.1111/j.1365-2869.2005.00484.x
(1997). Heart rate variability: Sleep stage, time of night, and arousal influences. Electroencephalography and Clinical Neurophysiology, 102(5), 390–396. https://doi.org/10.1016/S0921-884X(96)96070-1
(2003). Age-related changes in cardiac autonomic control during sleep. Journal of Sleep Research, 12(3), 173–180. https://doi.org/10.1046/j.1365-2869.2003.00353.x
(2011). Multiple hypothalamic cell populations encoding distinct visual information. Journal of Physiology, 589(Pt 5), 1173–1194. https://doi.org/10.1113/jphysiol.2010.199877
(2003). Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people. Clinical and Experimental Immunology, 132(1), 24–31. https://doi.org/10.1046/j.1365-2249.2003.02137.x
(2005). The siesta and mortality: Twelve years of prospective observations in 70-year-olds. Sleep, 28(3), 345–357. https://doi.org/10.1093/sleep/28.3.345
(2005). Effects of a nap on nighttime sleep and waking function in older subjects. Journal of American Geriatric Society, 53(1), 48–53. https://doi.org/10.1111/j.1532-5415.2005.53009.x
(1999). Are age differences in sleep due to phase differences in the output of the circadian timing system? Chronobiology International, 16(1), 79–91. https://doi.org/10.3109/07420529908998714
(2013). SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell, 153(7), 1448–1460. https://doi.org/10.1016/j.cell.2013.05.027
(2014). Perceived sleep quality is associated with depression in a Korean elderly population. Archives of Gerontology and Geriatrics, 59(2), 468–473. https://doi.org/10.1016/j.archger.2014.04.007
(2016). Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. Proceedings of the National Academy of Sciences, 113(1), 206–211. https://doi.org/10.1073/pnas.1508249112
(2013). Electrical stimulation of the rostral ventrolateral medulla promotes wakefulness in rats. Sleep Medicine, 14(11), 1076–1084. https://doi.org/10.1016/j.sleep.2013.06.011
(2008). Sleep disturbance and depression recurrence in community-dwelling older adults: a prospective study. American Journal of Psychiatry, 165(12), 1543–1550. https://doi.org/10.1176/appi.ajp.2008.07121882
(2009). Sleep and autonomic nervous system changes – enhanced cardiac sympathetic modulations during sleep in permanent night shift nurses. Scandinavian Journal of Work Environment & Health, 35(3), 180–187. https://doi.org/10.5271/sjweh.1324
(2013). Frailty in elderly people. Lancet, 381(9868), 752–762. https://doi.org/10.1016/S0140-6736(12)62167-9
(2001). Effects of aging and cardiac denervation on heart rate variability during sleep. Circulation, 103(1), 84–88. https://doi.org/10.1016/S0895-7061(01)01838-6
(2016). Sleep-related autonomic overactivity in a general elderly population and its relationship to cardiovascular regulation. Heart Vessels, 31(1), 46–51. https://doi.org/10.1007/s00380-014-0573-9
(2007). Sleep, circadian rhythms, and delayed phase in adolescence. Sleep Medicine, 8(6), 602–612. https://doi.org/10.1016/j.sleep.2006
(1992). Association of sleep–wake habits in older people with changes in output of circadian pacemaker. Lancet, 340(8825), 933–936. https://doi.org/10.1016/0140-6736(92)92817-y
(2008). From inflammation to sickness and depression: When the immune system subjugates the brain. Nature Reviews Neuroscience, 9(1), 46–56. https://doi.org/10.1038/nrn2297
(2004). Effect of cognitive arousal on sleep latency, somatic and cortical arousal following partial sleep deprivation. Journal of Sleep Research, 13(4), 295–304. https://doi.org/10.1111/j.1365-2869.2004.00424
(2006). Proteins in the Neurospora circadian clockworks. Journal of Biological Chemistry, 281(39), 28489–28493. https://doi.org/10.1074/jbc.R600018200
(1993). Cardiovascular disease in women. Circulation, 88(4 Pt 1), 1999–2009.
(2005). Neural circuitry in the regulation of adrenal corticosterone rhythmicity. Endocrine, 28(3), 325–332. https://doi.org/10.1385/ENDO:28:3:325
(2012). Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock. Journal of Neuroscience, 32(17), 5891–5899. https://doi.org/10.1523/JNEUROSCI.0469-12.2012
(2017). Sleep in the elderly: Unanswered questions. Clinics in Geriatric Medicine, 33(4), 579–596. https://doi.org/10.1016/j.cger.2017.06.009
(1995). Sleep complaints among elderly persons: An epidemiologic study of three communities. Sleep, 18(6), 425–432. https://doi.org/10.1093/sleep/18.6.425
(1975). Mini-Mental State. A practical method for grading the state of patients for the clinician. Journal of Psychiatric Research, 12(3), 189–198. https://doi.org/10.1016/0022-3956(75)90026-6
(2007). An autonomic flexibility-neurovisceral integration model of anxiety and cardiac vagal tone. Biological Psychology, 74(2), 185–199. https://doi.org/10.1016/j.biopsycho.2005.08.009
(2014). Cognitive impairment in obstructive sleep apnea. Pathologie Biologies, 62(5), 233–240. https://doi.org/10.1016/j.patbio.2014.05.015
(2014). Circadian clock control of endocrine factors. Nature Reviews Endocrinology, 10(8), 466–475. https://doi.org/10.1038/nrendo.2014.78
(2017). Poor sleeping has underrepresented medical, healthcare, and social costs? European Journal of Internal Medicine, 38, e15–e16. https://doi.org/10.1016/j.ejim.2016.10.020
(2016). Co-morbidity, mortality, quality of life and the healthcare/welfare/social costs of disordered sleep: A rapid review. International Journal of Environmental Research and Public Health, 13(8), 831. https://doi.org/10.3390/ijerph13080831
(2019). Circadian rhythms, sleep, and the autonomic nervous system: A position paper. Journal of Psychophysiology, 34(1), 1–9. https://doi.org/10.1027/0269-8803/a000236
(2003). Central and autonomic nervous system integration in emotion. Brain and Cognition, 52(1), 79–87. https://doi.org/10.1016/s0278-2626(03)00011-3
(2009). Adolescent changes in the homeostatic and circadian regulation of sleep. Developmental Neuroscience, 31(4), 276–284. https://doi.org/10.1159/000216538
(2015). Association between sleep duration and mortality is mediated by markers of inflammation and health in older adults: The health, aging and body composition study. Sleep, 38(2), 189–195. https://doi.org/10.5665/sleep.4394
(2003). A clockwork web: Circadian timing in brain and periphery, in health and disease. Nature Reviews Neuroscience, 4(8), 649–661. https://doi.org/10.1038/nrn1177
(2008). The physiology of sleep in infants. Archives of Diseases in Childhood, 93(11), 982–985. https://doi.org/10.1136/adc.2006
(2015). Changes in orexin (hypocretin) neuronal expression with normal aging in the human hypothalamus. Neurobiology of Aging, 36(1), 292–300. https://doi.org/10.1016/j.neurobiolaging.2014.08.010
(2011). Insomnia symptoms in older adults: Associated factors and gender differences. American Journal of Geriatric Psychiatry, 19(1), 88–97. https://doi.org/10.1097/JGP.0b013e3181e049b6
(2016). Impaired sleep predicts cognitive decline in old people: Findings from the prospective KORA age study. Sleep, 39(1), 217–226. https://doi.org/10.5665/sleep.5352
(2004). Melatonin, human aging, and age-related diseases. Experimental Gerontology, 39(11–12), 1723–1729. https://doi.org/10.1016/j.exger.2004.04.012
(2009). Insomnia, depression, and physical disorders in late life: A 2-year longitudinal community study in Koreans. Sleep, 32(9), 1221–1228. https://doi.org/10.1093/sleep/32.9.1221
(2018). Circadian rhythm sleep-wake disorders in older adults. Sleep Medicine Clinics, 13(1), 39–50. https://doi.org/10.1016/j.jsmc.2017.09.004
(2010). Sleep apnea in adult myotonic dystrophy patients who have no excessive daytime sleepiness. Sleep Breath/Schlaf Atmung, 14(1), 19–24. https://doi.org/10.1007/s11325-009-0270-6
(2012). The circadian clock and pathology of the ageing brain. Nature Reviews Neuroscience, 13(5), 325–335. https://doi.org/10.1038/nrn3208
(2006). The regulation of neuroendocrine function: Timing is everything. Hormones and Behavior, 49(5), 557–574. https://doi.org/10.1016/j.yhbeh.2005.12.011
(2012). Performance of the frequency domain indices with respect to sleep staging. Clinical Neurophysiology, 123(7), 1338–1345. https://doi.org/10.1016/j.clinph.2011.11.003
(2012). Sleep disturbance among spontaneously hypertensive rats is mediated by an alpha1-adrenergic mechanism. Hormones and Behavior, 25(10), 1110–1117. https://doi.org/10.1038/ajh.2012.93
(2016). Differential changes and interactions of autonomic functioning and sleep architecture before and after 50 years of age. Age, 38(1), 5. https://doi.org/10.1007/s11357-015-9863-0
(1999). Effect of aging on gender differences in neural control of heart rate. American Journal of Physiology, 277(6 Pt 2), H2233–H2239. https://doi.org/10.1152/ajpheart.1999.277.6.H2233
(2008). Asymmetry in sympathetic and vagal activities during sleep-wake transitions. Sleep, 31(3), 311–320. https://doi.org/10.1093/sleep/31.3.311
(1995). Age, race, and sex differences in autonomic cardiac function measured by spectral analysis of heart rate variability – the ARIC study: Atherosclerosis risk in communities. American Journal of Cardiology, 76(12), 906–912. https://doi.org/10.1016/s0002-9149(99)80260-4
(2003). Effects of estrogen on gender-related autonomic differences in humans. American Journal of Physiology-Heart and Circulatory Physiology, 285(5), H2188–H2193. https://doi.org/10.1152/ajpheart.00256.2003
(2019). Rhythms of life: Circadian disruption and brain disorders across the lifespan. Nature Review Neuroscience, 20(1), 49–65. https://doi.org/10.1038/s41583-018-0088-y
(1999). Night-to-night arousal variability and interscorer reliability of arousal measurements. Sleep, 22(7), 916–920. https://doi.org/10.1093/sleep/22.7.916
(1998). Sleep complaints in community-dwelling older persons: Prevalence, associated factors, and reported causes. Journal of the American Geriatrics Society, 46(2), 161–168. https://doi.org/10.1111/j.1532-5415.1998.tb02533.x
(2014). Impaired prefrontal sleep spindle regulation of hippocampal-dependent learning in older adults. Cerebral Cortex, 24(12), 3301–3309. https://doi.org/10.1093/cercor/bht188
(2017). Sleep and human aging. Neuron, 94(1), 19–36. https://doi.org/10.1016/j.neuron.2017.02.004
(1999). Rapid down-regulation of mammalian period genes during behavioral resetting of the circadian clock. Proceedings of the National Academy of Sciences, 96(26), 15211–15216. https://doi.org/10.1073/pnas.96.26.15211
(2012). Prevalence and correlates for sleep complaints in older adults in low and middle income countries: A 10/66 Dementia Research Group study. Sleep Medicine, 13(6), 697–702. https://doi.org/10.1016/j.sleep.2012.02.009
(2012). Gender differences in age related changes in cardiac autonomic nervous function. Journal of Aging Research, 2012, Article 679345. https://doi.org/10.1155/2012/679345
(2014). Effects of aging on sleep structure throughout adulthood: A population-based study. Sleep Medicine, 15(4), 401–409. https://doi.org/10.1016/j.sleep.2013.11.791
(1999). Circadian variation in cardiovascular events. American Journal of Hypertension, 12(2 Pt 2), 35S–42S. https://doi.org/10.1016/s0895-7061(98)00278-7
(2011). Age-related decline in circadian output. Journal of Neuroscience, 31(28), 10201–10205. https://doi.org/10.1523/JNEUROSCI.0451-11.2011
(2008). Brain correlates of autonomic modulation: Combining heart rate variability with fMRI. NeuroImage, 42(1), 169–177. https://doi.org/10.1016/j.neuroimage.2008.04.238
(1997). Sleep disturbance, psychosocial correlates, and cardiovascular disease in 5201 older adults: The Cardiovascular Health Study. Journal of the American Geriatrics Society, 45(1), 1–7. https://doi.org/10.1111/j.1532-5415.1997.tb00970.x
(2010). Changes in cardiac variability after REM sleep deprivation in recurrent nightmares. Sleep, 33(1), 113–122. https://doi.org/10.1093/sleep/33.1.113
(2005). Circadian rhythms: Clock coordination. Nature, 438(7065), 173–175. https://doi.org/10.1038/438173a
(2005). Age-related changes in electro-physiological properties of the mouse suprachiasmatic nucleus in vitro. Brain Research Bulletin, 65(2), 149–154. https://doi.org/10.1016/j.brainresbull.2004.12.006
(2005). Normative sleep data, cognitive function and daily living activities in older adults in the community. Sleep, 28(8), 981–989. https://doi.org/10.1093/sleep/28.8.981
(2002). Circadian rhythms from flies to human. Nature, 417, 329–335. https://doi.org/10.1038/417329a
(2010).
(Aging and circadian rhythms: General trends . In S. R. Pandi-PerumalJ. M. MontiA. A. MonjanEds., Principles and practice of geriatric sleep medicine (pp. 3–11). Cambridge University Press.2014). Sleep complaints and incident disability in a community-based cohort study of older persons. American Journal of Geriatric Psychiatry, 22(7), 718–726. https://doi.org/10.1016/j.jagp.2012.12.023
(2018). Age and immunity: What is “immunosenescence”? Experimental Gerontology, 105, 4–9. https://doi.org/10.1016/j.exger.2017.10.024
(2012). Sleep quality and sleep problems in Mexican Americans aged 75 and older. Aging Clinical and Experimental Research, 24(4), 391–397. https://doi.org/10.3275/8106
(2008). Is insomnia a perpetuating factor for late-life depression in the IMPACT cohort? Sleep, 31(4), 481–488. https://doi.org/10.1093/sleep/31.4.481
(2018). The association between subjectively impaired sleep and symptoms of depression and anxiety in a frail elderly population. Aging Clinical and Experimental Research, 30(7), 755–765. https://doi.org/10.1007/s40520-017-0837-1
(2012). Cognitive evoked potentials in obstructive sleep apnea syndrome: A review of the literature. Reviews in Neurosciences, 23(3), 311–323. https://doi.org/10.1515/revneuro-2012-0027
(2016). Sleep disturbances and cognitive decline in the Northern Manhattan Study. Neurology, 87(14), 1511–1516. https://doi.org/10.1212/WNL.0000000000003168
(2002). Coordination of circadian timing in mammals. Nature, 418, 935–941. https://doi.org/10.1038/nature00965
(2014). Heart rate variability and the two-way interaction between CNS and the central autonomic network. Experimental & Clinical Cardiology, 20(9), 5584–5595.
(2012). Heart rate variability, homeostasis, and brain function: A tutorial and review of application. Journal of Psychophysology, 26(4), 178–203. https://doi.org/10.1027/0269-8803/a000080
(1987). Changes in vasopressin cells of the rat suprachiasmatic nucleus with aging. Brain Research, 409(2), 259–264. https://doi.org/10.1016/0006-8993(87)90710-4
(2016). Human cerebral circuitry related to cardiac control: A neuroimaging meta-analysis. Annals of Neurology, 79(5), 709–716. https://doi.org/10.1002/ana.24642
(2018). Sleep, hippocampal volume, and cognition in adults over 90 years old. Aging Clinical and Experimental Research, 30(11), 1307–1318. https://doi.org/10.1007/s40520-018-1030-x
(2012). Does subjective sleep affect cognitive function in healthy elderly subjects? The Proof cohort. Sleep Medicine, 13(9), 1146–1152. https://doi.org/10.1016/j.sleep.2012.06.021
(2014). Self-reported quality of sleep is associated with bodily pain, vitality and cognitive impairment in Japanese older adults. Geriatrics & Gerontology International, 14(3), 628–635. https://doi.org/10.1111/ggi.12149
(2005). Hypothalamic regulation of sleep and circadian rhythms. Nature, 437(7063), 1257–1263. https://doi.org/10.1038/nature04284
(2003). Peripheral circadian oscillators in mammals: Time and food. Journal of Biological Rhythms, 18(3), 250–260. https://doi.org/10.1016/B978-0-12-396971-2.00004-X
(2012). Age-related changes in sleep and circadian rhythms: Impact on cognitive performance and underlying neuroanatomical networks. Frontiers in Neurology, 3, 118. https://doi.org/10.3389/fneur.2012.00118
(2011). Nocturnal regrets and insomnia in elderly people. International Journal of Aging and Human Development, 73(4), 371–393. https://doi.org/10.2190/AG.73.4.f
(1997). Vegetative background of sleep: Spectral analysis of the heart rate variability. Physiology & Behavior, 62(5), 1037–1043. https://doi.org/10.1016/S0031-9384(97)00234-5
(2017). The effects of an afternoon nap on episodic memory in young and older adults. Sleep, 40(5), Article zsx035. https://doi.org/10.1093/sleep/zsx035
(2005). Clues to the functions of mammalian sleep. Nature, 437(7063), 1264–1271. https://doi.org/10.1038/nature04285
(2014). Circadian rhythms have broad implications for understanding brain and behavior. European Journal of Neuroscience, 39(11), 1866–1880. https://doi.org/10.1111/ejn.12593
(2016). Modelling changes in sleep timing and duration across the lifespan: Changes in circadian rhythmicity or sleep homeostasis? Sleep Medicine Reviews, 28, 96–107. https://doi.org/10.1016/j.smrv.2015.05.011
(2016). Actigraphy- and polysomnography-measured sleep disturbances, inflammation, and mortality among older men. Psychosomatic Medicine, 78(6), 686–696. https://doi.org/10.1097/PSY.0000000000000312
. (2003). Melanopsin and non-melanopsin expressing retinal ganglion cells innervate the hypothalamic suprachiasmatic nucleus. Visual Neuroscience, 20(6), 601–610. https://doi.org/10.1017/s0952523803206027
(2015). Relationships between sleep stages and changes in cognitive function in older men: The MrOS sleep study. Sleep, 38(3), 411–421. https://doi.org/10.5665/sleep.4500
. (2009). Sleep quality and falls in older people living in self- and assisted-care villages. Gerontology, 55(2), 162–168. https://doi.org/10.1159/000146786
(2012). Heart rate variability, sleep and sleep disorders. Sleep Medicine Reviews, 16(1), 47–66. https://doi.org/10.1016/j.smrv.2011.02.005
(2007). The effects of acute psychological stress on circulating inflammatory factors in humans: A review and meta-analysis. Brain Behavior and Immunity, 21(7), 901–912. https://doi.org/10.1016/j.bbi.2007.03.011
(2012). Sleep problems: An emerging global epidemic? Findings from the INDEPTH WHO-SAGE study among more than 40,000 older adults from 8 countries across Africa and Asia. Sleep, 35(8), 1173–1181. https://doi.org/10.5665/sleep.2012
(1985). The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Research, 342(1), 37–44. https://doi.org/10.1016/0006-8993(85)91350-2
(2015). Subjective sleep and cognitive complaints in 65 year old subjects: A significant association. The PROOF cohort. Journal of Nutrition, Health & Aging, 19(4), 424–430. https://doi.org/10.1007/s12603-014-0547-8
(2012). A meta-analysis of heart rate variability and neuroimaging studies: Implications for heart rate variability as a marker of stress and health. Neuroscience & Biobehavioral Reviews, 36(2), 747–756. https://doi.org/10.1016/j.neubiorev.2011.11.009
(2006). Beyond heart rate variability: Vagal regulation of allostatic systems. Annals of the New York Academy of Science, 1088, 361–372. https://doi.org/10.1196/annals.1366.014
(2017). Association between light at night, melatonin secretion, sleep deprivation, and the internal clock: Health impacts and mechanisms of circadian disruption. Life Sciences, 173, 94–106. https://doi.org/10.1016/j.lfs.2017.02.008
(2005). Age-related change and its sex differences in histoarchitecture of the hypothalamic suprachiasmatic nucleus of F344/N rats. Experimental Gerontology, 40(3), 147–155. https://doi.org/10.1016/j.exger.2004.10.003
(1998). Twenty four hour time domain heart rate variability and heart rate: Relations to age and gender over nine decades. Journal of American College of Cardiology, 31(3), 593–601. https://doi.org/10.1016/s0735-1097(97)00554-8
(2001). Cardiovascular disease, interleukin-6, and risk of mortality in older women: The women’s health and aging study. Circulation, 103(7), 947–953. https://doi.org/10.1161/01.CIR.103.7.947
(2011). Short or long sleep duration is associated with memory impairment in older Chinese: The Guangzhou biobank cohort study. Sleep, 34(5), 575–580. https://doi.org/10.1093/sleep/34.5.575
(2002). Effects of aging on central and peripheral mammalian clocks. Proceedings of the National Academy of Sciences, 99(16), 10801–10806. https://doi.org/10.1073/pnas.152318499
(2004). Sensorimotor slowing with ageing is mediated by a functional dysregulation of motor-generation processes: Evidence from high-resolution event-related potentials. Brain, 127 Pt 2, 351–362. https://doi.org/10.1093/brain/awh042
(1999). Do plasma melatonin concentrations decline with age? American Journal of Medicine, 107(4), 432–436. https://doi.org/10.1016/s0002-9343(99)00266-1
(1995). VIP neurons in the human SCN in relation to sex, age, and Alzheimer’s disease. Neurobiology of Aging, 16(4), 571–576. https://doi.org/10.1016/0197-4580(95)00043-e
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