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Decreased Melatonin Levels in Postmortem Cerebrospinal Fluid in Relation to Aging, Alzheimer’s Disease, and Apolipoprotein E-4/4 Genotype¹

Netherlands Institute for Brain Research (R.-Y.L., J.-N.Z., J.v.H., M.A.H., D.F.S.), 1105 AZ Amsterdam ZO, The Netherlands; and Anhui Geriatrics Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China

Address all correspondence and requests for reprints to: D. F, Swaab, M.D., Ph.D., Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam ZO, The Netherlands. E-mail: t.eikelboom{at}nih.knaw.nl

Sleep disruption, nightly restlessness, sundowning, and other circadian disturbances are frequently seen in Alzheimer’s disease (AD) patients. Changes in the suprachiasmatic nucleus and pineal gland are thought to be the biological basis for these behavioral disturbances. Melatonin is the main endocrine message for circadian rhythmicity from the pineal. To determine whether melatonin production was affected in AD, melatonin levels were determined in the cerebrospinal fluid (CSF) of 85 patients with AD (mean age, 75 ± 1.1 yr) and in 82 age-matched controls (mean age, 76 ± 1.4 yr). Ventricular postmortem CSF was collected from clinically and neuropathologically well defined AD patients and from control subjects without primary neurological or psychiatric disease. In old control subjects (>80 yr of age), CSF melatonin levels were half of those in control subjects of 41–80 yr of age [176 ± 58 (n = 29) and 330 ± 66 (n = 53) pg/mL, respectively; P = 0.016]. We did not find a diurnal rhythm in CSF melatonin levels in control subjects. In AD patients the CSF melatonin levels were only one fifth (55 ± 7 pg/mL) of those in control subjects (273 ± 47 pg/mL; P = 0.0001). There was no difference in the CSF melatonin levels between the presenile (42 ± 11 pg/mL; n = 21) and the senile (59 ± 8 pg/mL; n = 64; P = 0.35) AD patients. The melatonin level in AD patients expressing apolipoprotein E-3/4 (71 ± 11 pg/mL) was significantly higher than that in patients expressing apolipoprotein E-4/4 (32 ± 8 pg/ml; P = 0.02). In the AD patients no significant correlation was observed between age of onset or duration of AD and CSF melatonin levels. In the present study, a dramatic decrease in the CSF melatonin levels was found in old control subjects and even more so in AD patients. Whether supplementation of melatonin may indeed improve behavioral disturbances in AD patients should be investigated.

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