Melatonin rhythmicity: effect of age and Alzheimer's disease

The circadian rhythm of the pineal gland hormone, melatonin is generated within the hypothalamic suprachiasmatic nuclei (SCN), site of the circadian clock. The circadian clock and its output melatonin rhythm is synchronized to the 24h day by environmental light which is transmitted from the retina to the SCN primarily via the retinohypothalamic tract. Changes in both the amplitude and timing of the melatonin rhythm have been reported with aging in humans. Whether these age-related changes (reduced melatonin amplitude, earlier timing of melatonin rhythm) are a result of aging of the retina, the SCN clock, the pineal gland, their neural connections or a combination of some or all of these is not known. The fragmented sleep/wake patterns observed in the elderly and to a greater extent in patients with Alzheimer's disease have been shown to be partly related to an altered retina-SCN-pineal axis. Therapies designed to reinforce the circadian axis (for example, administration of melatonin or light) have been reported to alleviate the disturbed circadian rhythms and disrupted sleep. Future research needs to pinpoint the site(s) of age-related dysfunction so that therapies can be specifically tailored to correct the abnormality in addition to reinforcing any of the intact processes.

[1]  D. Cardinali,et al.  Effect of Melatonin in Selected Populations of Sleep-Disturbed Patients , 1999, Neurosignals.

[2]  M. Barris,et al.  Abnormal pattern electroretinograms in patients with senile dementia of the alzheimer type , 1989, Annals of neurology.

[3]  D. Skene,et al.  6‐Sulphatoxymelatonin Production in Breast Cancer Patients , 1990, Journal of pineal research.

[4]  M. Hofman,et al.  Alterations in circadian rhythmicity of the vasopressin-producing neurons of the human suprachiasmatic nucleus (SCN) with aging , 1994, Brain Research.

[5]  M. Vitiello,et al.  Circadian temperature variation in healthy aged and in Alzheimer's disease. , 1984, Journal of gerontology.

[6]  P. Pévet,et al.  Calcium content and concretions of pineal glands of young and old rats , 1991, Cell and Tissue Research.

[7]  G. Cornelissen,et al.  Do plasma melatonin concentrations decline with age? , 2000, The American journal of medicine.

[8]  Yasuo Hishikawa,et al.  Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer’s type with disturbed sleep–waking , 1999, Biological Psychiatry.

[9]  R. Reiter,et al.  Actions of Melatonin in the Reduction of Oxidative Stress , 2000, Journal of Biomedical Science.

[10]  H. Iguichi,et al.  Age-dependent reduction in serum melatonin concentrations in healthy human subjects. , 1982, The Journal of clinical endocrinology and metabolism.

[11]  R. Kronauer,et al.  Stability, precision, and near-24-hour period of the human circadian pacemaker. , 1999, Science.

[12]  R. Reiter,et al.  An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer's disease , 2000, Journal of Neural Transmission.

[13]  M. Mirmiran,et al.  Indirect bright light improves circadian rest-activity rhythm disturbances in demented patients , 1997, Biological Psychiatry.

[14]  R. Blanks,et al.  Retinal pathology in Alzheimer's disease. I. Ganglion cell loss in foveal/parafoveal retina , 1996, Neurobiology of Aging.

[15]  G. Brainard,et al.  Action Spectrum for Melatonin Regulation in Humans: Evidence for a Novel Circadian Photoreceptor , 2001, The Journal of Neuroscience.

[16]  E Peli,et al.  Retinal nerve fiber layer abnormalities in Alzheimer's disease. , 2009, Acta ophthalmologica Scandinavica.

[17]  D. Kripke,et al.  Variations in circadian rhythms of activity, sleep, and light exposure related to dementia in nursing-home patients. , 1997, Sleep.

[18]  D. Price,et al.  The human pineal gland in aging and Alzheimer's disease: patterns of cytoskeletal antigen immunoreactivity , 2004, Acta Neuropathologica.

[19]  A. Satlin,et al.  Bright light treatment of behavioral and sleep disturbances in patients with Alzheimer's disease. , 1992, The American journal of psychiatry.

[20]  F. Pasquier,et al.  Sundowning syndrome in demented patients without neuroleptic therapy. , 1996, Archives of gerontology and geriatrics.

[21]  D. Cardinali,et al.  Monozygotic twins with Alzheimer's disease treated with melatonin: Case report , 1998, Journal of pineal research.

[22]  C A Czeisler,et al.  CONTRIBUTION OF CIRCADIAN PHYSIOLOGY AND SLEEP HOMEOSTASIS TO AGE-RELATED CHANGES IN HUMAN SLEEP , 2000, Chronobiology international.

[23]  E. Haus,et al.  Modifications of circadian and circannual rhythms with aging , 1997, Experimental Gerontology.

[24]  R. Blanks,et al.  Retinal pathology in Alzheimer's disease. II. Regional neuron loss and glial changes in GCL , 1996, Neurobiology of Aging.

[25]  M. Mirmiran,et al.  Alterations in the circadian rest-activity rhythm in aging and Alzheimer's disease , 1990, Biological Psychiatry.

[26]  D. Garfinkel,et al.  Melatonin for treatment of sundowning in elderly persons with dementia - a preliminary study. , 2000, Archives of gerontology and geriatrics.

[27]  K. Jobst,et al.  Myelinated axon number in the optic nerve is unaffected by Alzheimer's disease. , 1995, The British journal of ophthalmology.

[28]  H Kergoat,et al.  An evaluation of the retinal nerve fiber layer thickness by scanning laser polarimetry in individuals with dementia of the Alzheimer type. , 2001, Acta ophthalmologica Scandinavica.

[29]  C. Soto,et al.  Inhibition of Alzheimer β-Fibrillogenesis by Melatonin* , 1998, The Journal of Biological Chemistry.

[30]  W. Kamphorst,et al.  Comparison of β-protein/A4 deposits and Alz-50-stained cytoskeletal changes in the hypothalamus and adjoining areas of Alzheimer’s disease patients: amorphic plaques and cytoskeletal changes occur independently , 1998, Acta Neuropathologica.

[31]  C. Alessi,et al.  Nighttime Urinary Incontinence and Sleep Disruption Among Nursing Home Residents , 1998, Journal of the American Geriatrics Society.

[32]  D. Dijk,et al.  Circadian Phase Resetting in Older People by Ocular Bright Light Exposure , 2001, Journal of Investigative Medicine.

[33]  M Terman,et al.  Light Treatment for Sleep Disorders: Consensus Report , 1995, Journal of biological rhythms.

[34]  A. Lewy,et al.  Effects of Aging on the Intrinsic Circadian Period of Totally Blind Humans , 2001, Journal of biological rhythms.

[35]  M. Okawa,et al.  Different manifestations of circadian rhythms in senile dementia of Alzheimer's type and multi-infarct dementia , 1997, Neurobiology of Aging.

[36]  M. Lawton,et al.  Phototherapy for patients with Alzheimer disease with disturbed sleep patterns: results of a community-based pilot study. , 1997 .

[37]  K. Ohara,et al.  Daily rhythm of serum melatonin in patients with dementia of the degenerate type , 1996, Brain Research.

[38]  N. Kutner,et al.  Observed sleep/wakefulness and severity of dementia in an Alzheimer's disease special care unit. , 1995, The journals of gerontology. Series A, Biological sciences and medical sciences.

[39]  J. C. Zimmerman,et al.  Chronobiology of aging: Temperature, sleep-wake rhythms and entrainment , 1982, Neurobiology of Aging.

[40]  C. M. Singer,et al.  Human Melatonin Production Decreases With Age , 1986, Journal of pineal research.

[41]  J. Arendt,et al.  FACTORS INFLUENCING URINARY 6‐SULPHATOXYMELATONIN, A MAJOR MELATONIN METABOLITE, IN NORMAL HUMAN SUBJECTS , 1990, Clinical endocrinology.

[42]  Scott S. Campbell,et al.  Exposure to light in healthy elderly subjects and alzheimer's patients , 1988, Physiology & Behavior.

[43]  A. Bird,et al.  Relationship between Napping and Melatonin in the Blind , 1997, Journal of biological rhythms.

[44]  D. F. Swaab,et al.  The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia , 1985, Brain Research.

[45]  C. Pollak,et al.  Sleep Problems and Institutionalization of the Elderly , 1991, Journal of geriatric psychiatry and neurology.

[46]  Lockley,et al.  Correlation between urinary cortisol and 6‐sulphatoxymelatonin rhythms in field studies of blind subjects , 1999, Clinical endocrinology.

[47]  J. Taljaard,et al.  Melatonin prevents β‐amyloid‐induced lipid peroxidation , 1998 .

[48]  E. Ferrari,et al.  Changes in endocrine circadian rhythms as markers of physiological and pathological brain aging. , 1997, Chronobiology international.

[49]  P. Badia,et al.  Changes in circadian rhythms and sleep quality with aging: Mechanisms and interventions , 1995, Neuroscience & Biobehavioral Reviews.

[50]  M. Mirmiran,et al.  Non-pharmacological treatment of sleep and wake disturbances in aging and Alzheimer's disease: Chronobiological perspectives , 1993, Behavioural Brain Research.

[51]  S. Weintraub,et al.  Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation. , 2000, Free radical biology & medicine.

[52]  M. Schemper,et al.  Alterations in nocturnal serum melatonin levels in humans with growth and aging. , 1988, The Journal of clinical endocrinology and metabolism.

[53]  A. Wirz-Justice,et al.  Haloperidol Disrupts, Clozapine Reinstates the Circadian Rest–Activity Cycle in a Patient With Early-Onset Alzheimer Disease , 2000, Alzheimer disease and associated disorders.

[54]  M. Kondo,et al.  [The effect of age on short-wavelength sensitive cone electroretinograms and long-and middle-wavelength sensitive cone electroretinograms]. , 1997, Nippon Ganka Gakkai zasshi.

[55]  D. Dijk,et al.  Do plasma melatonin concentrations decline with age? , 1999, The American journal of medicine.

[56]  W. Kamphorst,et al.  Decreased Vasopressin Gene Expression in the Biological Clock of Alzheimer Disease Patients With and Without Depression , 2000, Journal of neuropathology and experimental neurology.

[57]  A. de Leiva,et al.  Brief report: melatonin-related hypogonadotropic hypogonadism. , 1992, The New England journal of medicine.

[58]  E. Ferrari,et al.  Pineal and pituitary-adrenocortical function in physiological aging and in senile dementia , 2000, Experimental Gerontology.

[59]  Dick F. Swaab,et al.  Influence of aging on the seasonal rhythm of the vasopressin-expressing neurons in the human suprachiasmatic nucleus , 1995, Neurobiology of Aging.

[60]  V. Iragui,et al.  Abnormal pattern electroretinogram in Alzheimer's disease: Evidence for retinal ganglion cell degeneration? , 1989, Annals of neurology.

[61]  R. Reiter,et al.  Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide , 1997, The Journal of Neuroscience.

[62]  D F Swaab,et al.  Bright light therapy: improved sensitivity to its effects on rest-activity rhythms in Alzheimer patients by application of nonparametric methods. , 1999, Chronobiology international.

[63]  A. Hofman,et al.  Is age-related maculopathy associated with Alzheimer's Disease? The Rotterdam Study. , 1999, American journal of epidemiology.

[64]  M. Okawa,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Diminished Melatonin Secretion in the Elderly Caused by Insufficient Environmental Illumination* , 2022 .

[65]  H. Chertkow,et al.  Neuroretinal function is normal in early dementia of the Alzheimer type , 2001, Neurobiology of Aging.

[66]  B. C. Manning,et al.  Sundowning and circadian rhythms in Alzheimer's disease. , 2001, The American journal of psychiatry.

[67]  Alfredo A. Sadun,et al.  Retinal ganglion cell degeneration in Alzheimer's disease , 1989, Brain Research.

[68]  M. Mirmiran,et al.  Circadian rhythms and the suprachiasmatic nucleus in perinatal development, aging and Alzheimer's disease. , 1992, Progress in brain research.

[69]  M Terman,et al.  Light Treatment for Sleep Disorders: Consensus Report , 1995, Journal of biological rhythms.

[70]  D. Dijk,et al.  Light Treatment for Sleep Disorders: Consensus Report , 1995, Journal of biological rhythms.

[71]  A. McKee,et al.  Differential circadian rhythm disturbances in men with Alzheimer disease and frontotemporal degeneration. , 2001, Archives of general psychiatry.

[72]  Josephine Arendt,et al.  Melatonin and the Mammalian Pineal Gland , 1994 .

[73]  Daniel J Buysse,et al.  Amplitude reduction of the circadian temperature and sleep rhythms in the elderly. , 1996, Chronobiology international.

[74]  M. Iyo,et al.  Daily rhythm of serum melatonin levels and effect of light exposure in patients with dementia of the Alzheimer’s type , 1999, Biological Psychiatry.

[75]  S. Ancoli-Israel,et al.  Illumination levels in nursing home patients: effects on sleep and activity rhythms , 2000, Journal of sleep research.

[76]  A C Bird,et al.  Relationship between melatonin rhythms and visual loss in the blind. , 1997, The Journal of clinical endocrinology and metabolism.

[77]  G. Dowling.  Behavioral Intervention Strategies for Sleep-Activity Disruption , 1996, International Psychogeriatrics.

[78]  P. Lavie,et al.  Daily and seasonal variations in the concentration of melatonin in the human pineal gland , 1998, Brain Research Bulletin.

[79]  D. F. Swaab,et al.  Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer's disease , 1990, Brain Research.

[80]  D F Swaab,et al.  Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype. , 1999, The Journal of clinical endocrinology and metabolism.

[81]  J. Fourtillan,et al.  Melatonin secretion occurs at a constant rate in both young and older men and women. , 2001, American journal of physiology. Endocrinology and metabolism.

[82]  M. Okawa,et al.  Morning bright light therapy for sleep and behavior disorders in elderly patients with dementia , 1994, Acta psychiatrica Scandinavica.

[83]  D. Dijk,et al.  Later endogenous circadian temperature nadir relative to an earlier wake time in older people. , 1998, The American journal of physiology.

[84]  C. Miller,et al.  Optic-nerve degeneration in Alzheimer's disease. , 1986, The New England journal of medicine.

[85]  J. Arendt,et al.  Acute phase-shifting effects of melatonin associated with suppression of core body temperature in humans , 1994, Neuroscience Letters.

[86]  M. Burney-Puckett.  Sundown syndrome: etiology and management. , 1996, Journal of psychosocial nursing and mental health services.

[87]  D. Velis,et al.  Suprachiasmatic nucleus in aging, Alzheimer's disease, transsexuality and Prader-Willi syndrome. , 1987, Progress in brain research.

[88]  W. Herrmann,et al.  A New Concept for Melatonin Deficit: On Pineal Calcification and Melatonin Excretion , 1999, Neuropsychopharmacology.

[89]  D. Skene,et al.  An action spectrum for melatonin suppression: evidence for a novel non‐rod, non‐cone photoreceptor system in humans , 2001, The Journal of physiology.

[90]  I. M. Young,et al.  Constant Pineal Output and Increasing Body Mass Account for Declining Melatonin Levels During Human Growth and Sexual Maturation , 1988, Journal of pineal research.

[91]  D. Swaab,et al.  Increased light intensity prevents the age related loss of vasopressin-expressing neurons in the rat suprachiasmatic nucleus , 1995, Brain Research.

[92]  C. Curcio,et al.  Retinal ganglion cells in Alzheimer's disease and aging , 1993, Annals of neurology.

[93]  D. Dawson,et al.  Urinary 6‐sulfatoxymelatonin excretion and aging: New results and a critical review of the literature , 1999, Journal of pineal research.

[94]  E. Stopa,et al.  Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. , 1999, Journal of neuropathology and experimental neurology.

[95]  P. Prinz,et al.  Sleep/wake patterns In Alzheimer's disease: relationships with cognition and function , 1995, Journal of sleep research.

[96]  G. Bresnick,et al.  Lenses of diabetic patients "yellow" at an accelerated rate similar to older normals. , 1991, Investigative ophthalmology & visual science.

[97]  S. Endo,et al.  Effects of bright light on cognitive and sleep–wake (circadian) rhythm disturbances in Alzheimer‐type dementia , 2000, Psychiatry and clinical neurosciences.