REM sleep parameters in the discrimination of probable Alzheimer's disease from old-age depression.

Thirteen dementia of the Alzheimer type (DAT) patients and fifteen old-age major depressive disorder (OAD) patients were investigated by polysomnography. The sleep was recorded during two nights after a 1 week wash-out period of psychotropic drugs. No statistically significant differences between the two groups were found concerning sleep continuity or architecture. The amount of REM sleep was significantly lower in DAT in comparison with OAD patients (11.7% verses 18.5%). Also, total REM density as well as the density of the first REM period were significantly lower in the DAT compared with the OAD patient group (15.8% verses 32.5%, 14.9% verses 38.1%, respectively). REM latency did not differ between both groups. Because REM latency is known from other studies to be shortened in depressed patients due to a cholinergic hyperactivity, the opposite finding, i.e., prolongation of REM latency, was expected for DAT patients. This assumption, however, could not be confirmed in the present study. It is concluded that REM density may better differentiate between DAT and OAD.

Longitudinal stability of CSF tau levels in Alzheimer patients.

BACKGROUND: Antemortem levels of tau in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients have repeatedly been demonstrated to be elevated when compared to controls. Although CSF tau has been reported to be elevated even in very mild AD, it is unknown how tau levels change during the course of the disease. METHODS: We have followed 29 mild-to-moderately affected AD subjects over 2 years with repeated CSF taps. Clinical measures of dementia severity (Clinical Dementia Rating Scale, Global Deterioration Scale and Mini-Mental Status Examination) were obtained at the start and conclusion of the observation period, and CSF tau was measured with a standard enzyme-linked immunoabsorbent assay (ELISA) using two monoclonal antibodies. RESULTS: Despite significant changes in the clinical measures consistent with progression of the disease, no significant overall change in CSF tau levels (548 +/- 355 vs. 557 +/- 275 pg/mL, NS) was observed. None of the clinical variables was significantly correlated with either baseline measures of CSF tau or delta CSF tau (last-first). Similarly, CSF tau at baseline and changes over time were not significantly related to Apolipoprotein E (APO E) phenotype. CONCLUSIONS: These data suggest that CSF tau levels are stable over extended periods of time in a group of mild-to-moderately demented AD subjects and that CSF tau levels do not predict the severity or rate of progression of AD, at least not during the middle stages of the illness.

Physostigmine challenge before and after chronic cholinergic blockade in elderly volunteers.

BACKGROUND: As a test of possible muscarinic up-regulation, the cortisol response to intravenous (i.v.) physostigmine (an anticholinesterase) was measured in 9 elderly volunteers before and after chronic cholinergic blockade with the muscarinic cholinergic antagonist scopolamine. METHODS: Each of the 9 elderly control subjects was given two physostigmine (0.5 mg i.v.) infusions separated by 21 doses of nightly scopolamine (1.2 mg p.o.). No scopolamine was administered the night before infusions, and glycopyrrolate (0.2 mg i.v.) was administered prior to physostigmine, to block its peripheral effects. Vital signs were monitored and blood samples were collected at six time points surrounding the physostigmine infusion (-10, +10, +20, +30, +50, and +70 min). Behavioral measures and cognitive tests were administered prior to and 30 min after the physostigmine. RESULTS: The cortisol response to physostigmine was greater after the second (post-chronic scopolamine) infusion study compared to the first (p < .05) as measured by an area under the curve analysis of all time points. When individual time points were compared, the mean cortisol response was significantly increased after the second physostigmine infusion at the +50- and +70-min time points (p < .05). There were no significant changes in behavioral rating scales, cognitive tests, or vital signs between the two physostigmine infusion study days. CONCLUSIONS: This study demonstrates increased hypothalamic-pituitary-adrenocortical axis responsivity to a central nervous system cholinergic stimulus after chronic muscarinic blockade in 9 elderly control subjects. It also gives further evidence to support previous suggestions of muscarinic plasticity, specifically postsynaptic up-regulation, in the aging brain following exposure to chronic anticholinergic treatment.

Interactions of prefrontal cortex during eyeblink conditioning as a function of age.

Changes in regional cerebral blood flow (rCBF) in eleven elderly subjects during pairings of tone and air puff were compared to rCBF changes during pairings in young subjects. Although all subjects reported being aware of the relationship between tone and air puff, elderly subjects did not condition as well as young subjects and their rCBF measures were attenuated. Covarying the performance differences between young and old subjects did not change this conclusion suggesting that differences in neural activation during learning are related to binding of CS-US information prior to the impact of the association on performance. Both groups showed learning-specific rCBF changes in cerebellum, inferior right prefrontal cortex and posterior cingulate. However, only in young subjects were there learning-specific changes in rCBF in left temporal cortex, midbrain, caudate, and inferior left prefrontal cortex. Analysis of learning-dependent patterns of functional connectivity of inferior left prefrontal cortex showed only young subjects had a strong left prefrontal functional connectivity with cerebellum, hippocampus, thalamus and temporal cortex. Thus, beyond changes in regional activity, these data also suggest that age may alter the operations of functional networks underlying learning and memory.

Regional and laminar distributions of alpha 1-adrenoceptors and their subtypes in human and rat hippocampus.

The distributions of the alpha 1-adrenoceptor and its subtypes (alpha 1A and alpha 1B) in human and rat hippocampus are analysed by quantitative receptor autoradiography. alpha 1-Adrenoceptors are labelled by [3H]prazosin. The alpha 1A subtype is visualized by [3H]prazosin after irreversible blockade of alpha 1B adrenoceptors with chloroethylclonidine or directly by [3H]5-methyl-urapidil. The alpha 1B subtype is investigated by [3H]prazosin binding in the presence of the alpha 1A antagonist 5-methyl-urapidil. Considerable differences in the regional and laminar patterns of alpha 1-adrenoceptors are found between rat and human hippocampi. The rat hippocampus is characterized by a low overall density and a rather homogeneous regional and laminar distribution. This is in contrast to the human pattern, which shows a much higher overall level of alpha 1 receptor density and a restriction of alpha 1 receptors to the CA3 region of Ammon's horn and the dentate gyrus. Moreover, alpha 1A and alpha 1B receptors of the human hippocampus are differentially distributed with the alpha 1A subtype concentrated in the hilus and lucidum layer of CA3, and the alpha 1B subtype concentrated in the molecular layer of the dentate gyrus. Additionally, the distribution of alpha 1 receptors is compared with the distribution of 5-hydroxytryptamine 1A receptors. The subtype specific pattern is correlated with the distribution of glutamatergic systems in the human (but not in the rat) hippocampus. alpha 1A Receptor localization coincides with the target area of the mossy fibre system, and alpha 1B receptors are preferentially localized in the target area of the hippocampal associational fibres and partly of the perforant pathway. This result points to possible interactions between noradrenaline- and glutamate-mediated neurotransmission differentiated by topographically segregated alpha 1-adrenoceptor subtypes.

The effects of scopolamine, lorazepam, and glycopyrrolate on classical conditioning of the human eyeblink response.

Human eyeblink conditioning, a relatively simple form of learning and memory, has previously been shown to be impaired by the central and peripheral anticholinergic scopolamine. The present study compared the behavioral effects of scopolamine with the benzodiazepine lorazepam and a peripherally active anticholinergic, glycopyrrolate. Thirty-six healthy normal volunteers (mean age: 23.7 years) were studied with 12 assigned double-blind to each of three drug conditions (0.5 mg scopolamine IV, 2 mg lorazepam PO, or 0.2 mg glycopyrrolate IV). Subjects underwent classical conditioning of the eyeblink response in which the conditioned stimulus was an 80 dB binaural tone, and the unconditioned stimulus was a 2 psi airpuff to the right eye. Ten trials of unpaired stimulus presentations were followed by 60 paired trials and finally by an extinction period of five tone-alone presentations. An eyeblink response that occurred during the tone but before the airpuff was scored as a conditioned response (CR). Subjects treated with lorazepam (43% mean CRs) and scopolamine (51% mean CRs) exhibited a significantly lower asymptotic level of conditioning than those treated with glycopyrrolate (85% mean CRs; P < 0.01). However, during extinction, lorazepam-treated subjects (35% CRs) showed a lower overall level of responding to the tone than either scopolamine (60% CRs) or glycopyrrolate (62% CRs) treated subjects (P < 0.05). It seems unlikely that these differences could be accounted for by drug-induced alterations in motor responses because there were no significant differences between the three drug conditions in the frequency, latency, or amplitude of unconditioned responses to the airpuff. Overall, our data indicate that scopolamine and lorazepam impair eyeblink conditioning and suggest that some of the effects of benzodiazepines and anticholinergics on learning and memory can be differentiated using this paradigm.

Differential cholinergic regulation in Alzheimer's patients compared to controls following chronic blockade with scopolamine: a SPECT study.

The effects of low-dose chronic scopolamine on measures of cerebral perfusion and muscarinic receptors were tested in eight Alzheimer's disease (AD) subjects and eight elderly controls. Single photon emission computed tomography (SPECT) scans using technetium-labelled hexamethypropylene amine oxide (99mTc-HMPAO) to measure cerebral perfusion before and after chronic scopolamine revealed a significant 12% increase in the normal controls (P < 0.01) while the AD subjects showed no significant change. In contrast, the controls showed decreased muscarinic binding as evidenced by 123I-quinuclidinyl-4-iodobenzilate (123I-QNB) labelling after chronic drug (-10%, P < 0.01) whereas the AD subjects showed increased 123I-QNB labelling (+8%, P < 0.05). The difference between AD and control subjects was even more marked when the ratio of I-QNB to HMPAO uptake was compared, pointing to a double dissociation in the SPECT results. These data cannot be explained by group differences in cerebral perfusion alone and suggest a differential sensitivity between AD and elderly controls to chronic cholinergic blockade.

The value of REM sleep parameters in differentiating Alzheimer's disease from old-age depression and normal aging.

Pseudodementia as a common trait in elderly depressives presents a major problem in gerontopsychiatry, especially for the differential diagnosis between Old-Age Depression (OAD) and Dementia of the Alzheimer Type (DAT). The present polysomnographic study examined parameters of sleep continuity, sleep architecture, and REM sleep to differentiate DAT from OAD. The investigation was based on the theoretical framework of the cholinergic-aminergic imbalance model of depression, the cholinergic deficit hypothesis of Alzheimer's disease and the reciprocal interaction model of Non-REM/REM sleep regulation, according to which REM sleep parameters should have high discriminative value to differentiate OAD and DAT. We investigated 35 DAT patients, 39 OAD patients and 42 healthy controls for two consecutive nights in the sleep laboratory. The DAT patients were in relatively early/mild stages of the disease, the severity of depression in the OAD group was moderate to severe. Depressed patients showed characteristic 'depression-like' EEG sleep alterations, i.e. a lower sleep efficiency, a higher amount of nocturnal awakenings and decreased sleep stage 2. Sleep continuity and architecture in DAT was less disturbed. Nearly all REM sleep measures differentiated significantly between the diagnostic groups. OAD patients showed a shortened REM latency, increased REM density and a high rate of Sleep Onset REM periods (SOREM), whereas in DAT REM density was decreased in comparison to control subjects. REM latency in DAT was not prolonged as expected. To assess the discriminative power of REM sleep variables a series of discriminant analyses were conducted. Overall, 86% of patients were correctly classified, using REM density and REM latency measures. Our findings suggest that REM density as an indicator of phasic activity appears to be more sensitive as a biological marker for the differential diagnosis of OAD and DAT than REM latency. The results support the role of central cholinergic neurotransmission in REM sleep regulation and the pathogenesis of DAT and OAD.

Cholinergic neurotransmission, REM sleep and depression.

It is known from animal experiments that the regulation of REM and Non-REM sleep is governed by cholinergic and serotonergic/adrenergic neurons in the brain stem. Cholinergic neurons in the gigantocellular field of the tegmentum seem to be responsible for the triggering and maintenance of REM sleep. These findings are of special interest for interpreting abnormalities of REM sleep in depression. Psychiatric sleep research in the last two decades has demonstrated that an early onset of REM sleep and heightened REM density frequently occurs in patients suffering from depression. Extrapolating from animal data on REM sleep regulation, the premature onset of REM sleep in depression may be interpreted as the consequence of a central nervous cholinergic overactivity or muscarinic supersensitivity. In our experimental work we have tested assumptions of the so-called reciprocal interaction model of NonREM and REM sleep by cholinergic/anticholinergic stimulation strategies of sleep in healthy subjects. Furthermore, the impact of cholinergic stimulation on sleep in depression, healthy control subjects and other psychopathological conditions was investigated. These studies demonstrated that the most pronounced REM sleep response to cholinergic stimulation occurred in depression.

Involvement of autophagic degradation in ACTH-induced skeletal muscle atrophy.

Intracellular autophagic breakdown was investigated in skeletal myocytes undergoing atrophy under the influence of ACTH. Adult male Sprague-Dawley rats received s.c. injections of ACTH (12.5 U/kg body wt) or physiological saline as control twice daily. 5 experimental and 5 control animals were sacrificed by perfusion fixation after 6, 9, and 12 days of treatment. While the weight of the left pectoralis minor muscle decreased significantly in the ACTH-treated animals compared with controls, the volume fraction of autophagic vacuoles, as determined by quantitative electron microscopy, increased significantly after 9 days (2.6-fold) and 12 days (2.9-fold) in the atrophying skeletal myocytes of experimental animals compared with controls. Only non-myofibrillar components were detected as contents of autophagic vacuoles. Since, however, the ratio of myofibrils to other cytoplasmic components remained constant, the degradation of myofibrils seems to occur via a non-lysosomal pathway. The data suggest that the breakdown of cytoplasmic components by cellular autophagy is important for the development of skeletal muscle atrophy as observed following long-term ACTH treatment or in Cushing's syndrome.

Benzodiazepine administration induces exogenic psychosis: a case of child abuse.

An 11-year-old boy with psychiatric symptoms was brought to the pediatric clinic by his father. The boy exhibited anxiety, sometimes exaggerating to panic reactions, rage, and disorientation. Because of the boy's behavior it was presumed he was having delusions. Careful physical examination revealed evidence of physical abuse. This article alerts readers to the possible combination of physical abuse and purposeful drug administration.

Short-term stimulation by propranolol and verapamil of cardiac cellular autophagy.

The influence of propranolol and verapamil, i.e. two cardiodepressant drugs differing in their pharmacological actions, on cellular autophagy in the left ventricular myocardium of the rat was investigated. In the first experimental series 10 animals were given propranolol subcutaneously (3 mg/kg body weight). Ten controls received physiological saline. In the second series 8 animals were treated with verapamil subcutaneously (9 mg/kg body weight) and 8 controls with physiological saline. Two to 4 h after the injections in the first series and 1 3/4 to 3 h in the second series retrograde perfusion fixation was carried out via the abdominal aorta with a paraformaldehyde-glutaraldehyde mixture. Myocardial tissue from the left anterior wall was processed for electron microscopy and was morphometrically evaluated for volume fraction and numerical density of early stages of autophagic vacuoles (AVs). Propranolol and verapamil significantly increased the AV volume fraction 4.3- and 2.7-fold, respectively. The numerical density was increased by the two drugs, although to a lesser degree (2.3-fold, and 1.7-fold, respectively). As verapamil affects neither the beta-adrenoreceptors nor the intracellular levels of the second messenger cAMP, the only common denominator for the stimulation of cellular autophagy seems to be the cardiodepressive effect of the two drugs. The data suggest that the rise in cellular autophagy is an early regulatory step in the adaptation of heart muscle mass to reduced work load.

[Activation of resources in elderly depressed patients. An overview of current knowledge]. / Ressourcenaktivierung bei depressiven älteren Patienten. Ein Uberblick zum gegenwärtigen Kenntnisstand.

Psychotherapeutic research has empirically proven the activation of resources to be a primary and pervasive activating principle. Equally empirically substantiated is psychotherapy with the aged. In the present article, the specific application of resources activation in psychotherapy for old-age depression is particularly emphasized and attempts at defining the concept of resources as well as hints towards the discovery of resources are explored. Contrary to earlier assumptions that ageing is a deficiency process, it has now been shown that despite evident losses in various life areas in aging, some resources can be defined which can be decisive for a sense of well-being among the elderly and for prophylaxis or therapy of old-age depression. Procedures and resource activation with content must be activated in parallel with problem actualization so that feelings of self-esteem and well-being increase, problems are solved and experiences of loss due to ageing are compensated. One of the most important resources among the elderly has proved to be the ability to accommodate and the social network. Group therapy as an effective and economical form of therapy as well as the therapeutic relationship itself can be employed as resources to promote social interaction among the aged.

[Depression in old age]. / Depressionen im Alter.

At least 4% of elderly patients living in the community suffer from a major depressive disorder and some 15% from less severe forms of depressive illness. However, physical and psychiatric comorbidity is high in elderly patients and the incidence of depression may reach 40% to 50% in common medical disorders such as diabetes mellitus or cardiac insufficiency. Therefore, elderly patients who are hospitalised or living in senior citizen homes suffer more frequently from depressive disorders, with prevalence rates up to 50%. The phenomenology and etiology of geriatric depression are very heterogeneous. Depression often presents atypically, e.g., behind a mask of complaints about physical symptoms or anxiety. Diagnostic and therapeutic measures follow the same standards as in younger adults, yet age-related differences must be taken into consideration. Thus, psychopharmacological management must be adapted to the altered metabolism of drugs in the elderly. Also, psychological treatment strategies should respect the distinctive psychosocial situation of elderly patients.

Short-term stimulation of cellular autophagy by furosemide in the thick ascending limb of Henle's loop in the rat kidney.

In an effort to investigate the functional relationship between cell-specific work and intracellular degradative processes, the effect of furosemide on cellular autophagy was investigated in two different portions of the nephron, namely, the thick ascending limb of Henle's loop (TAL), which is a main target of this drug, and the proximal convoluted tubule (PCT) as a reference structure. Eight male adult rats were treated with furosemide (60 mg/kg body weight, s.c.). Eight control animals received physiological saline. 1 to 4 h after the injections the animals were killed by perfusion fixation. Small specimens of kidney tissue from the inner stripe of the outer medulla and from the outer cortex were processed for electron microscopy; they were investigated morphometrically for volume fraction and numerical density of autophagic vacuoles (AVs). A significant increase of both parameters (volume fraction: 0.42 x 10(-4) to 1.09 x 10(-4); numerical density: 4.2 x 10(5)/mm3 to 15.5 x 10(5)/mm3) was seen under the influence of furosemide in TAL cells, whereas PCT cells did not show a significant increase in volume fraction or any increase in numerical density of AVs. These data suggest that the functional unloading of TAL, via blocking of the Na+-2Cl- -K+ co-transport by furosemide, results in adaptative "structural unloading", i.e., an increased sequestration of cytoplasmic components into AVs, within a short-time interval.

Short-term inhibition of cellular autophagy by isoproterenol in the submandibular gland.

The present study examines the short-term (i.e. 10 min after injection) influence of isoproterenol on cellular autophagy in the rat submandibular gland. The volume fraction of autophagic vacuoles was significantly reduced, suggesting that an anticatabolic reaction, namely inhibition of cellular autophagy, is an early and significant event in the growth of the submandibular gland which is known to occur with long-term isoproterenol treatment.

[Improving communication between ambulatory and inpatient care. A pilot project]. / Verbesserung der Kommunikation zwischen ambulanter und stationärer Versorgung. Ein Pilotprojekt.

Medical care of our population has made dramatic progress during recent decades. However, problems arose from an increasing specialization and subspecialization on the one hand and from the complexity of care structures on the other hand. In light of scarce financial resources and of increasing demands regarding quality by both recipients and payers of medical care the analysis of diagnostic and treatment processes gained considerable attention. In this context, a lack of cooperation between ambulatory and in-patient care has been complained about for a long time. The aim of our pilot project introduced here was therefore to assess the cooperation between physicians in private practice and our psychiatric hospital by means of a random sample query. The results are communicated here.