Luis I. Brusco

Monozygotic twins with Alzheimer's disease treated with melatonin: Case report

Brusco LI, Márquez M, Cardinali D.P. Monozygotic twins with Alzheimers disease treated with melatonin: Case report. J. Pineal Res. 1998; 25:260–263.

Possible therapeutic value of melatonin in mild cognitive impairment : a retrospective study

Abstract:  Mild cognitive impairment (MCI) is an etiologically heterogeneous syndrome characterized by cognitive impairment preceding dementia. Approximately 12% of MCI patients convert to Alzheimer’s disease (AD) or other dementia disorders every year. In the present report we retrospectively examined the initial and final neuropsychological assessment of 50 MCI outpatients, 25 of whom had received daily 3–9 mg of a fast‐release melatonin preparation p.o. at bedtime for 9–18 months. Melatonin was given in addition to the standard medication prescribed by the attending psychiatrist. Patients treated with melatonin showed significantly better performance in Mini Mental State Examination and the cognitive subscale of the Alzheimer’s Disease Assessment Scale. After application of a battery of neuropsychological tests including Mattis’ test, Digit‐symbol test, Trail A and B tasks and the Rey’s verbal test, better performance was found in melatonin‐treated patients, except for the Digit‐symbol test score which remained unchanged. Abnormally high Beck Depression Inventory scores decreased in melatonin‐treated patients, concomitantly with an improvement in wakefulness and sleep quality. The results suggest that melatonin can be a useful add‐on drug for treating MCI in a clinical setting.

Clinical Aspects of Melatonin Intervention in Alzheimer's Disease Progression

Melatonin secretion decreases in Alzheimer´s disease (AD) and this decrease has been postulated as responsible for the circadian disorganization, decrease in sleep efficiency and impaired cognitive function seen in those patients. Half of severely ill AD patients develop chronobiological day-night rhythm disturbances like an agitated behavior during the evening hours (so-called “sundowning”). Melatonin replacement has been shown effective to treat sundowning and other sleep wake disorders in AD patients. The antioxidant, mitochondrial and antiamyloidogenic effects of melatonin indicate its potentiality to interfere with the onset of the disease. This is of particularly importance in mild cognitive impairment (MCI), an etiologically heterogeneous syndrome that precedes dementia. The aim of this manuscript was to assess published evidence of the efficacy of melatonin to treat AD and MCI patients. PubMed was searched using Entrez for articles including clinical trials and published up to 15 January 2010. Search terms were “Alzheimer” and “melatonin”. Full publications were obtained and references were checked for additional material where appropriate. Only clinical studies with empirical treatment data were reviewed. The analysis of published evidence made it possible to postulate melatonin as a useful ad-on therapeutic tool in MCI. In the case of AD, larger randomized controlled trials are necessary to yield evidence of effectiveness (i.e. clinical and subjective relevance) before melatonin´s use can be advocated.

Low urinary 6-sulphatoxymelatonin levels in patients with coronary artery disease.

A decrease in nocturnal serum melatonin levels was reported in patients with clinically uncharacterized coronary artery disease. To assess whether there was a correlation between melatonin production and disease stage, we measured the nocturnal urinary excretion of 6‐sulphatoxymelatonin (an index of blood melatonin concentration) in patients with chronic stable or unstable coronary disease and in a group of age‐matched controls. Three groups of individuals were studied: a) 24 healthy subjects (mean age: 63±13 yr); b) 32 patients with chronic, stable, coronary disease (62±11 yr); and c) 27 patients with unstable angina (62±12 yr). For 6‐sulphatoxymelatonin measurement, urine was collected from 18:00 to 06:00 hr, within 48 hr of hospitalization in the case of unstable angina. 6‐Sulphatoxymelatonin was measured by a specific radioimmunoassay. Urinary 6‐sulphatoxymelatonin excretion was significantly lower in unstable angina patients than in healthy subjects or in patients with stable angina. 6‐Sulphatoxymelatonin correlated negatively with age in healthy subjects, but not in coronary patients. 6‐Sulphatoxymelatonin excretion in patients treated with β‐adrenoceptor blockers did not differ significantly from coronary patients not receiving β‐blockers. The results indicate that patients with coronary disease have a low melatonin production rate, with greater decreases in those with higher risk of cardiac infarction and/or death.

EFFECTS OF MELATONIN IN ELDERLY PATIENTS WITH SLEEP DISTURBANCE: A PILOT STUDY

Abstract This open-label, short-term pilot study was designed to assess the efficacy and tolerability of melatonin in the treatment of sleep disturbances in elderly patients. The 41 patients (28 women and 13 men; mean age [±SD], 74 ± 12 years) were separated into three groups: (1) patients with sleep disturbances alone (n = 22); (2) patients with sleep disturbances and signs of depression (n = 9); and (3) patients with sleep disturbances and dementia of the degenerative or vascular type (n = 10). All patients received 3-mg gelatin capsules of melatonin orally 30 minutes before expected sleep time for 21 days. Overall sleep quality and daytime alertness were assessed by means of structured clinical interviews and sleep logs completed by the patients (or their caregivers in the case of dementia patients). Starting from day 2 or 3 of treatment, melatonin significantly improved sleep quality and decreased the number of awakenings in patients with sleep disturbances with or without associated depression. Patients with dementia did not show significant improvement of sleep quality. Estimates of next-day function (ie, alertness in the morning and during the day) improved significantly only in patients exhibiting sleep disturbances alone. Clinical assessment indicated that symptoms improved in 16 (73%) of the patients with sleep disturbances alone and 4 (44%) of those with sleep disturbances associated with depression, and that agitated behavior at night (sundowning) decreased significantly in 7 (70%) of the patients with dementia. This was reflected by the coefficient of variation of bedtime, which averaged 58% in patients with dementia compared with 27% and 33% in nondepressed and depressed patients, respectively, on days 0 to 2 of treatment, and which decreased significantly only in dementia patients when reassessed on days 19 to 21. Four (31%) of the 13 patients with primary insomnia who were receiving benzodiazepines concomitantly reduced their benzodiazepine use (by 50% to 75% of initial doses) and 4 (31%) discontinued use of these agents; of the 7 patients with depression and 7 with dementia who were receiving benzodiazepines concomitantly, 2 (29%) in each group reduced benzodiazepine use by up to 50%. No side effects considered to be attributable to treatment were reported. The results of this trial suggest that melatonin may be useful for the treatment of primary sleep disturbances in elderly patients.

Lack of changes in serum prolactin, FSH, TSH, and estradiol after melatonin treatment in doses that improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly patients.

An open pilot study on the safety and efficacy of melatonin in the treatment of insomniac patients was conducted in 22 subjects (16 females), mean±S.D. age 60.1±9.5 years. All patients received 3 mg of gelatin melatonin capsules per os daily for 6 months, 30 min before expected sleep time. Twenty of 22 patients were on benzodiazepine treatment and they continued this treatment for part of or for the entire melatonin administration period. Serum concentrations of prolactin, follicle‐stimulating hormone (FSH), thyroid‐stimulating hormone (TSH), or estradiol were measured by radioimmunoassay (RIA) in morning samples at the beginning and after 6 months of melatonin administration, and standard clinical laboratory tests for blood components were performed. Urinary 6‐sulphatoxymelatonin (aMT6s) excretion was measured by RIA before treatment. Serum concentrations of prolactin, FSH, TSH, or estradiol did not exhibit changes after 6 months of melatonin administration, nor were any indications of hematologic or blood biochemistry alteration found. Melatonin augmented significantly the quality and duration of sleep, and decreased sleep latency and the number of awakening episodes, as assessed from sleep logs filled by the patients (first 21 days) and from structured interviews performed by incumbent physicians (up to 6 months). Estimates of next‐day function (i.e., alertness in the morning and during the day) also improved significantly during melatonin treatment. The observed effect lasted for the entire period examined (up to 6 months), with 22 out of 22 patients showing improved sleep at the end of treatment. The urinary excretion of aMT6s before starting administration of melatonin correlated negatively and significantly with age, but not with the intensity of sleep the disorder or the outcome of treatment. In 13 of 20 patients taking benzodiazepines together with melatonin, benzodiazepine use could be stopped, and in another four patients, benzodiazepine dose could be decreased to 25–66% of the initial dose. The results of this open, subacute administration trial indicate that melatonin is a safe and useful treatment for sleep disturbances in middle‐aged or elderly patients, either by itself or together with benzodiazepines.

Diurnal rhythms in norepinephrine and acetylcholine synthesis of sympathetic ganglia, heart and adrenals of aging rats: Effect of melatonin

The effect of aging and melatonin on 24-h rhythms in tyrosine hydroxylase activity and 3H - choline conversion into 3H - acetylcholine were examined in cervical, stellate, coeliac-mesenteric and hypogastric ganglia, and in the adrenal medulla and heart of rats. Young (50 days old) and old (18 months old) rats received evening injections of 10 or 100 microg of melatonin or its vehicle for 17 days. In superior cervical, stellate and coeliac-superior mesenteric ganglia, as well as in the adrenal medulla, norepinephrine and acetylcholine synthesis attained maximal values at night (c.a. 2030-0100 h). In the hypogastric ganglion, maximal tyrosine hydroxylase activity occurred at night at both studied ages. Two maxima in acetylcholine synthesis were detected in hypogastric ganglion of young rats (c.a. 1300 h and 0100 h, respectively) while in old rats a single maximum was observed at noon. Cardiac tyrosine hydroxylase activity peaked at early night (c.a. 2200-2300 h) while cardiac acetylcholine synthesis peaked at the afternoon (c.a. 1700-1900 h). Old rats exhibited a significant decrease of rhythm amplitude and increase of mean values in tyrosine hydroxylase activity in autonomic ganglia and adrenal medulla, and abolition of tyrosine hydroxylase rhythm in the heart. Twenty-four hour rhythmicity in acetylcholine synthesis was impaired or abolished in aged rats. Treatment of old rats with 10 or 100 microg melatonin generally augmented amplitude of rhythms and reinduced the nocturnal peak of acetylcholine synthesis in the hypogastric ganglion. Only the high melatonin dose significantly augmented rhythm amplitude of tyrosine hydroxylase activity (superior cervical and coeliac-superior mesenteric ganglia) and acetylcholine synthesis (superior cervical, stellate and coeliac-superior mesenteric ganglia) in young rats. The results indicate that the activity of the central oscillator, driven to the organs in part via the autonomic nervous system, deteriorates significantly with aging and that melatonin may restore partially such a deterioration.

Effect of Melatonin on Changes in Locomotor Activity Rhythm of Syrian Hamsters Injected with Beta Amyloid Peptide 25–35 in the Suprachiasmatic Nuclei

Abstract1. Alzheimers disease is associated with circadian rhythm disturbances, probably because of beta amyloid-induced neuronal damage of hypothalamic suprachiasmatic nuclei (SCN).2. Since there is no published study on the circadian consequences of injecting beta amyloid peptide in experimental animals, one objective of the present study was to examine circadian locomotor activity in Syrian hamsters injected with beta amyloid peptide 25–35 into both SCN.3. Because one of the proposed therapies for circadian alterations in dementia is the administration of melatonin, a chronobiotic agent with antioxidant properties, the preventive effect of melatonin on the circadian changes produced by beta amyloid microinjection into SCN was also assessed.4. Wheel running activity was recorded by using the Dataquest III system in male golden hamsters kept under 14:10 light–dark photoperiods. Animals received microinjections of beta amyloid peptide 25–35 (100 μM solution, 1 μL) or saline in each SCN. Only those animals with neuronal lesions larger than 10% of SCN after beta amyloid injection were considered for further analysis.5. To assess the effect of melatonin on beta-amyloid peptide activity, melatonin was given in the drinking water (25 μg/mL) starting 15 days in advance to the microinjection of beta amyloid peptide into SCN.6. Beta amyloid-treated hamsters exhibited a significant phase advance of onset of running activity of about 22 min as compared to saline-injected animals. They also showed a significantly greater variability in onset time of wheel running activity, mainly evident from 6 to 15 days of treatment.7. Melatonin administration in the drinking water prevented the phase advance of onset time and the increased variability of onset time brought about by beta amyloid peptide.8. The results support the existence of a neuroprotective effect of melatonin on beta amyloid-induced circadian changes in hamsters.

Effect of Melatonin on 24-Hour Rhythms of Ornithine Decarboxylase Activity and Norepinephrine and Acetylcholine Synthesis in Submaxillary Lymph Nodes and Spleen of Young and Aged Rats

Young (50 days old) and old (18 months old) Sprague-Dawley rats were injected with mycobacterial Freund’s adjuvant to produce an inflammatory disease of the joints and were studied the day before, and on days 6, 12 and 18 after injection. At every postinjection interval examined, old rats had significantly lower circadian amplitudes of pineal melatonin content. On day 18 of arthritis development, decreased levels of pineal melatonin were also seen in young rats. A second study, carried out 18 days after the injection of Freund’s complete adjuvant and after 17 daily injections of 10 or 100 µg of melatonin in the evening, indicated that melatonin treatment restored the inflammatory response in old rats (assessed plethysmographically in hind paws) to the level found in young animals. In young rats, an inflammation-promoting effect of 100 µg melatonin could be demonstrated. As a consequence of the immune reaction, submaxillary lymph node and splenic ornithine decarboxylase activity (an index of lymph cell proliferation) augmented significantly, with acrophases of 24-hour rhythms in the afternoon for lymph nodes or in the morning for spleen. Mesor and amplitude of ornithine decarboxylase rhythm were lowest in old rats, while melatonin injection generally augmented its amplitude. Lymph node and splenic tyrosine hydroxylase activity (a presynaptic adrenergic marker) reached maximal values during early night hours while maximal values of [3H]acetylcholine synthesis (a presynaptic cholinergic marker) occurred during the afternoon in lymph nodes. Amplitude and mesor of these rhythms were lowest in old rats, an effect generally counteracted by melatonin treatment. The results suggest that inflammation is accompanied by an age-dependent, significant depression of pineal melatonin synthesis during adjuvant-induced arthritis and a decreased amplitude of the circadian rhythm of immune cell proliferation and autonomic activity in lymph nodes and spleen. These effects are counteracted by injection of melatonin, mainly in old rats.

Diurnal rhythms in ornithine decarboxylase activity and norepinephrine and acetylcholine synthesis in submaxillary lymph nodes and spleen of young and aged rats during Freund's adjuvant-induced arthritis

Aging has been associated with attenuation of amplitude and changes in period of many circadian rhythms. The present study was carried out to examine, in young (50 days old) and old (18 months old) rats, whether 24-h rhythms of cell proliferation (as assessed by measuring ornithine decarboxylase activity) and of presynaptic adrenergic and cholinergic markers change in lymph nodes and spleen during Freunds adjuvant-induced arthritis. Groups of young and old Sprague-Dawley rats were studied the day before, and on days 6, 12 and 18 after Freunds adjuvant injection. On day 16 after adjuvant injection, inflammation of hind paws, mainly in the ankle joints, was less marked in old than in young rats. Lymph node and splenic ornithine decarboxylase activity exhibited significant 24-h variations with maximal activity during daily hours. Before treatment, enzyme activity values were significantly lower in old rats in both tissues examined. During the immune reaction, lymph node and splenic ornithine decarboxylase augmented 8-10-fold, with progressively smaller amplitude of daily variations as arthritis developed. In every case, mesor and amplitude of ornithine decarboxylase activity were lowest in old rats. Submaxillary lymph node and splenic tyrosine hydroxylase activity attained maximal values at night. At every time interval after mycobacterium adjuvant injection, amplitude and mesor of tyrosine hydroxylase activity rhythm were lowest in old rats. A maximum in submaxillary lymph node 3H-acetylcholine synthesis occurred at the afternoon. On day 6 and 12 after Freunds adjuvant injection, lymph node 3H-acetylcholine synthesis was significantly smaller in old rats. Day-night differences in submaxillary lymph node or splenic ornithine decarboxylase and tyrosine hydroxylase activities, or in submaxillary lymph node 3H-acetylcholine synthesis, of rats treated with the adjuvants vehicle, did not differ significantly from those seen in untreated controls. The results are compatible with an age-dependent decline of immune-mediated inflammatory responses. The activity of the central circadian oscillator, driven to the organs in part via the autonomic nervous system, seems also to deteriorate during aging.