Richard Mahlberg

A two‐part, double‐blind, placebo‐controlled trial of exogenous melatonin in REM sleep behaviour disorder

Rapid eye movement (REM) sleep behaviour disorder (RBD) has been suggested to predict the development of neurodegenerative disorders. Patients with RBD are acting out dream behaviour associated with loss of normal muscle atonia of REM sleep. The aim of the present study was to confirm that exogenous melatonin improves RBD. Eight consecutively recruited males (mean age 54 years) with a polysomnographically (PSG) confirmed diagnosis of RBD were included in a two‐part, randomized, double‐blind, placebo‐controlled cross‐over study. Patients received placebo and 3 mg of melatonin daily in a cross‐over design, administered between 22:00 h and 23:00 h over a period of 4 weeks. PSG recordings were performed in all patients at baseline, at the end of Part I of the trial and at the end of Part II of the trial. Compared to baseline, melatonin significantly reduced the number of 30‐s REM sleep epochs without muscle atonia (39% versus 27%; P = 0.012), and led to a significant improvement in clinical global impression (CGI: 6.1 versus 4.6; P = 0.024). Interestingly, the number of REM sleep epochs without muscle atonia remained lower in patients who took placebo during Part II after having received melatonin in Part I (–16% compared to baseline; P = 0.043). In contrast, patients who took placebo during Part I showed improvements in REM sleep muscle atonia only during Part II (i.e. during melatonin treatment). The data suggest that melatonin might be a second useful agent besides clonazepam in the treatment of RBD.

Examining the gateway to the limbic system with diffusion tensor imaging: the perforant pathway in dementia.

Current treatments for Alzheimers disease (AD) are only able to slow the progression of mental deterioration, making early and reliable diagnosis an essential part of any promising therapeutic strategy. In the initial stages of AD, the first neuropathological alterations occur in the perforant pathway (PP), a large neuronal fiber tract located at the entrance to the limbic system. However, to date, there is no sensitive diagnostic tool for performing in vivo assessments of this structure. In the present bimodal magnetic resonance imaging (MRI) study, we examined 10 elderly controls, 10 subjects suffering from mild cognitive impairment (MCI), and 10 AD patients in order to evaluate the sensitivity of diffusion tensor imaging (DTI), a new MRI technique, for detecting changes in the PP. Furthermore, the diagnostic explanatory power of DTI data of the PP should be compared to high-resolution MRI volumetry and intervoxel coherences (COH) of the hippocampus and the entorhinal cortex, two limbic regions also involved in the pathophysiology of early AD. DTI revealed a marked decrease in COH values in the PP region of MCI (right side: 26%, left side: 29%, as compared to controls) and AD patients (right side: 37%, left side: 43%, as compared to controls). Reductions in COH values of the PP region were significantly correlated with cognitive impairment. DTI data of the PP zone were the only parameter differing significantly between control subjects and MCI patients, while the volumetric measures and the COH values of the hippocampus and the entorhinal cortex did not. DTI of medial temporal brain regions is a promising non-invasive tool for the in vivo diagnosis of the early/preclinical stages of AD.

Brain-derived neurotrophic factor serum concentrations are increased in drug-naïve schizophrenic patients with chronic cannabis abuse and multiple substance abuse

Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are critically implicated in development and maintenance of function of neurons. Neurodevelopment is reported to be impaired in schizophrenia and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin, may be more harmful to schizophrenic brains than to non-schizophrenic brains when used chronically. And neurotoxic events may promote disease-onset and lead to exaggerated release of neurotrophins. We investigated 157 drug-naive first-episode schizophrenic patients and found significantly elevated BDNF serum concentrations (by up to 34%) in patients with chronic cannabis abuse (n = 35, p < 0.001) or multiple substance abuse (n = 20, p < 0.001) prior to disease onset. Drug-naive schizophrenic patients without cannabis consumption showed similar results to normal controls and cannabis controls without schizophrenia. Thus, raised BDNF serum levels are not related to schizophrenia and/or substance abuse itself but may reflect a cannabis-related idiosyncratic damage of the schizophrenic brain. In line with this hypothesis, disease onset was 5.2 years earlier in the cannabis-consuming group (p = 0.0111).

Normative data on the daily profile of urinary 6-sulfatoxymelatonin in healthy subjects between the ages of 20 and 84

Although the hormone melatonin is a key factor for the proper functioning of the circadian timing system (CTS) and exogenous melatonin has been shown to be beneficial in cases of CTS disturbances, a deficit of melatonin has yet to be defined as a disorder. The aim of our study was to collect a normative data set on 24-h melatonin excretion in healthy human adults living in a natural environment. Urine samples were collected from 75 healthy subjects (45 women/30 men; mean age 47.2, SD 19.5, range 20-84) after five consecutive periods: 2300-0700, 0700-1100, 1100-1800, 1800-2300 and 2300-0700 h. 6-Sulfatoxymelatonin (aMT6s) concentrations were analyzed in duplicate by IBL (Hamburg) using a highly sensitive, competitive ELISA kit. Twenty-four hour-aMT6s total amount (rho=-0.68, p<0.001), aMT6s nighttime excretion (rho=-0.69, p<0.001), aMT6s morning excretion (rho=-0.66, p<0.001) and evening excretion (r=-0.26, p=0.023) were negatively associated with age, whereas daytime excretion (r=-0.17, p=0.15) was not. The intra-subject night-day ratio varied up to 10.5 (mean 6.0) in young subjects (aged 20-35) and up to 5.4 (mean 2.8) in older individuals (age>65). The total amount of 24 h-aMT6s (range 7.5-58 microg) as well as the amount of aMT6s excreted during the nighttime period (range 327-6.074 ng/h) varied as much as 20-fold between individuals. Our data show an age-related decline in melatonin excretion in healthy subjects living in a natural environment. The high inter-individual variability of excretion rates may explain why a normative data set is of no use in replacement strategies.

Pineal calcification in Alzheimer's disease: an in vivo study using computed tomography.

Melatonin has been postulated to have diverse properties, acting as an antioxidant, a neuroprotector, or a stabilizer within the circadian timing system, and is thus thought to be involved in the aging process and Alzheimers disease (AD). We used computed tomography to determine the degree of pineal calcification (DOC), an intra-individual melatonin deficit marker, as well as the size of uncalcified pineal tissue, in 279 consecutive memory clinic outpatients (AD: 155; other dementia: 25; mild cognitive impairment: 33; depression: 66) and 37 age-matched controls. The size of uncalcified pineal tissue in patients with AD (mean 0.15 cm(2) [S.D. 0.24]) was significantly smaller than in patients with other types of dementia (0.26 [0.34]; P=0.038), with depression (0.28 [0.34]; P=0.005), or in controls (0.25 [0.31]; P=0.027). Additionally, the DOC in patients with AD (mean 76.2% [S.D. 26.6]) was significantly higher than in patients with other types of dementia (63.7 [34.7]; P=0.042), with depression (60.5 [33.8]; P=0.001), or in controls (64.5 [30.6]; P=0.021). These two findings may reflect two different aspects of melatonin in AD. On the one hand, the absolute amount of melatonin excretion capability, as indicated by uncalcified pineal volume, refers to the antioxidant properties of melatonin. On the other hand, the relative reduction in melatonin production capability in the individual, as indicated by DOC, refers to the circadian properties of melatonin.

Chronic Cannabis Abuse Raises Nerve Growth Factor Serum Concentrations in Drug-Naive Schizophrenic Patients

Long-term cannabis abuse may increase the risk of schizophrenia. Nerve growth factor (NGF) is a pleiotropic neurotrophic protein that is implicated in development, protection and regeneration of NFG-sensitive neurones. We tested the hypothesis that damage to neuronal cells in schizophrenia is precipitated by the consumption of cannabis and other neurotoxic substances, resulting in raised NGF serum concentrations and a younger age for disease onset. The NGF serum levels of 109 consecutive drug-naive schizophrenic patients were measured and compared with those of healthy controls. The results were correlated with the long-term intake of cannabis and other illegal drugs. Mean (± SD) NGF serum levels of 61 control persons (33.1 ± 31.0 pg/ml) and 76 schizophrenics who did not consume illegal drugs (26.3 ± 19.5 pg/ml) did not differ significantly. Schizophrenic patients with regular cannabis intake (> 0.5 g on average per day for at least 2 years) had significantly raised NGF serum levels of 412.9 ± 288.4 pg/ml (n = 21) compared to controls and schizophrenic patients not consuming cannabis (p < 0.001). In schizophrenic patients who abused not only cannabis, but also additional substances, NGF concentrations were as high as 2336.2 ± 1711.4 pg/ml (n = 12). On average, heavy cannabis consumers suffered their first episode of schizophrenia 3.5 years (n = 21) earlier than schizophrenic patients who abstained from cannabis. These results indicate that cannabis is a possible risk factor for the development of schizophrenia. This might be reflected in the raised NGF-serum concentrations when both schizophrenia and long-term cannabis abuse prevail.

Evaluation of time memory in acutely depressed patients, manic patients, and healthy controls using a time reproduction task.

Patients with affective disorders have often been reported to experience subjective changes in how they perceive the flow of time. Time reproduction tasks provide information about the memory component of time perception and are thought to remain unaffected by pulse rate disturbances in the pacemaker of the internal clock. In our study, 30 patients with acute depression, 30 patients with acute mania, and 30 healthy subjects of all age groups were presented with a time reproduction task. Participants were asked to observe a stimulus presented on a computer screen for a certain length of time and, subsequently, to reproduce the stimulus for a similar length of time by pressing the space bar on the computer keyboard. Stimuli were presented to each subject for 1, 6, and 37s. On average, the time intervals reproduced by manic patients were shorter than those reproduced by depressed patients. Manic patients reproduced the short time interval (6s) correctly, but under-reproduced the long time interval (37s, P<0.001). Depressed patients correctly reproduced the long time interval, but over-reproduced the short time interval (P<0.001). Remembering time intervals as having been longer than they actually were may lead to a slowed experience of time, as has been described in depressed patients; precisely the converse seems to apply to manic patients.

AGE EFFECTS ON TRAIL MAKING TEST DURING ACUTE DEPRESSIVE AND MANIC EPISODE

Impairment of executive functions and attention has been found in patients with acute depressive episodes but has rarely been investigated in manic patients to date. At the same time, executive functions decline with age. Thus, it is currently a matter of debate how to best measure decreased executive performance in elderly patients with affective disorders. In our study, we examined 30 depressed patients, 28 manic patients, and 30 healthy subjects of all age groups, using the Trail Making Test (TMT). Both depressed and manic patients needed twice as long as healthy subjects to perform the TMT Part A. In addition to this reduced performance due to affective disorders, we were also able to detect a decline in performance due to age. One could thus postulate that age and affective disorders each influence a different neuropsychological function, age affecting executive performance and affective disorders affecting attention, as measured in both cases by the TMT.

Low effective organizational strategies in visual memory performance of unmedicated alcoholics during early abstinence.

Objective: Alcohol-dependent patients in early abstinence show an impairment of cognitive functions which can be seen in poor implementation of newly learned skills for avoiding relapse. Executive dysfunction may persist during abstinence in alcohol-dependent persons, thus mitigating long-term abstinence. This study assessed visual memory function and choice of organizational strategies in alcoholics, as these are major factors necessary to implement ongoing behavior changes which are required for maintaining abstinence. Methods: We investigated 25 severely alcohol-dependent male patients between days 7 to 10 of abstinence, immediately after clinical withdrawal symptoms have ceased, compared to 15 healthy age, sex, and education matched controls. Pharmacological therapy had been terminated at least four half-lifes before inclusion into the study. Visual perceptual learning and organizational strategies were assessed with the Rey-Osterrieth Complex Figure Test (R-OCF). Results: There were no group differences in copying or recalling the figure, but time differences occurred. Alcoholics and healthy controls performed worse in recalling than in copying. But, alcoholics used less effective organizational strategies. Conclusions: There was a deficit in choice of organizational strategy in newly abstinent and unmedicated alcohol-dependent patients. Due to the imperfect organizational strategies, alcoholics might need auxiliary therapeutic care to strengthen their cognitive ability.

Decreased verbal learning but not recognition performance in alcohol-dependent individuals during early abstinence

OBJECTIVE Alcoholism ultimately leads to impairment of memory and other cognitive functions. This can interfere with treatment, if cognitively impaired alcohol-dependent individuals have difficulties recalling and implementing skills acquired during therapy. We investigate if alcohol-dependent individuals without clinically apparent withdrawal symptoms may still be impaired in higher-order cognitive functions. METHODS Thirty-four alcohol-dependent patients and 20 matched healthy controls were tested with the Verbal Learning and Memory Test which includes seven measurement points. The test comprises free recall, free recall after distraction and after 30 minute delay, and a word recognition task. Testing was performed between day seven and day 10 after the beginning of abstinence, when clinical withdrawal symptoms had ceased. RESULTS Compared to healthy controls, alcohol-dependent patients performed worse in free recall after delay, but not in word recognition. Healthy controls showed a more linear progression of improvement in verbal memory performance. Overall, alcohol-dependent individuals showed reduced verbal learning efficiency. The extent of impaired recall after distraction was positively associated (one-tailed test) with history of delirium (r=0.34, p=0.04), seizures (r=0.46, p=0.01), and years since diagnosis for alcohol dependency (r=0.39, p=0.01). CONCLUSIONS Our results provide evidence that unmedicated alcohol-dependent patients without obvious withdrawal symptoms had impaired verbal recall, but normal recognition performance, at seven to 10 days after onset of abstinence. This deficit may deteriorate treatment outcomes due to poorer implementation of skills newly-learned during this time period.