[Sleep disorders in dementia patients]. / Schlafstörungen bei Demenzkranken.

Dementia is characterized by cognitive and also behavioral and psychological symptoms of dementia (BPSD). The most prominent BPSD are depression and apathy but sleep disorders also complicate the clinical course of dementia. These symptoms are a severe burden for patients and caregivers and are difficult to treat partly due to comorbidities. Common sleep disorders in dementia are insomnia, hypersomnia, circadian rhythm alterations and aberrant nocturnal motor behavior. Sleep duration and rapid eye movement (REM) sleep are reduced. The diagnostic assessment of sleep disorders should include an evaluation of the underlying risk factors and a detailed sleep history for which several assessment instruments are available. The therapy of sleep disorders of dementia is primarily nonpharmacological: sleep counseling, sleep hygiene regulation, relaxation and psychotherapy techniques are given priority. Pharmacological treatment often has severe side effects in this elderly, vulnerable population and can only be considered if other nonpharmacological options have been unsuccessful. The application of medication should be limited in time and dosage. The pharmacological therapeutic options are critically discussed in detail.

[Delirium and multimorbidity in the elderly]. / Delir und Multimorbidität im Alter.

Delirium is an acute confusion state of multifactorial genesis, commonly seen in the elderly with multimorbidity. Age and dementia, followed by infections and polypharmacy, are known as the most important risk factors. Increased disease interactions and medication use in the multimorbid elderly might precipitate delirium. Serious consequences of multimorbidity often are psychiatric diseases such as depression. Also anxiety and schizoprenia show a high comorbidity with somatic diseases. The therapy of elderly multimorbid patients is risky and must be preceded by profound assessment of all pathogenic factors. Pharmacotherapy needs an ongoing screening for side effects and indication.

[The emotional memory in the elderly and depression]. / Das emotionale Gedächtnis im Alter und bei Depression.

The recognition of emotional stimuli such as facial expressions is an important component of emotion processing contributing to interactional behavior. Healthy individuals recognize positive emotional stimuli better than negative stimuli. The ability to recognize both facial identity and emotional expression decline with advanced age but the positive bias remain stable. In depressive patients, on the other hand, there is a negative bias favoring negative emotional stimuli which leads to dysfunctional behavior and social isolation. Early diagnostic and treatment of depression can help to overcome the devastating consequences of cognitive disturbances of the disease.

Pineal and cortical melatonin receptors MT1 and MT2 are decreased in Alzheimer's disease.

The pineal hormone melatonin is involved in physiological transduction of temporal information from the light dark cycle to circadian and seasonal behavioural rhythms, as well as possessing neuroprotective properties. Melatonin and its receptors MT1 and MT2, which belong to the family of G protein-coupled receptors, are impaired in Alzheimer's disease (AD) with severe consequences to neuropathology and clinical symptoms. The present data provides the first immunohistochemical evidence for the cellular localization of the both melatonin receptors in the human pineal gland and occipital cortex, and demonstrates their alterations in AD. We localized MT1 and MT2 in the pineal gland and occipital cortex of 7 elderly controls and 11 AD patients using immunohistochemistry with peroxidase-staining. In the pineal gland both MT1 and MT2 were localized to pinealocytes, whereas in the cortex both receptors were expressed in some pyramidal and non-pyramidal cells. In patients with AD, parallel to degenerative tissue changes, there was an overall decrease in the intensity of receptors in both brain regions. In line with our previous findings, melatonin receptor expression in AD is impaired in two additional brain areas, and may contribute to disease pathology.

Beta-amyloid modulates tyrosine kinase B receptor expression in SHSY5Y neuroblastoma cells: influence of the antioxidant melatonin.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in humans and is characterized by neuronal loss, neurofibrillary tangles and beta-amyloid deposition. The interaction between neurotrophins and their tyrosine kinase (trk) receptors is important for cellular differentiation and survival. Interestingly, marked reductions in neurotrophins and receptors have been reported in AD. The cause of the decrease in these molecules remains unclear. However, the role of beta-amyloid (A beta) appears central in understanding the mechanisms controlling neurotrophin/trk expression. In this study we exposed SHSY5Y neuroblastoma cells to A beta or hydrogen peroxide and measured the expression of trk B/truncated trk B, and brain-derived neurotrophic factor (BDNF)/NT4 at the protein and molecular level. We show that A beta or hydrogen peroxide (H(2)O(2)) induces oxidative stress and cell cytotoxicity. The exposure of cells to A beta results in an increased trk B expression with a concurrent reduction in truncated trk B levels. H(2)O(2) exposure decreased both trk B and truncated trk B levels at the cell surface. At the molecular level trk B RNA increased in the presence of A beta and was unaffected by H(2)O(2). Similarly, BDNF and NT4 levels increased in the presence of A beta. Pre-treatment of cells with the anti-oxidant melatonin returns trk receptor expression, mRNA and BDNF/NT4 secretion to normal levels. These results are significant as they can help in the planning and implementation of AD treatment strategies involving neurotrophins.

The effects of beta-estradiol on SHSY5Y neuroblastoma cells during heavy metal induced oxidative stress, neurotoxicity and beta-amyloid secretion.

The role of estrogen as a neurotrophic/neuroprotective agent in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases is increasingly being shown. In this study we examine the neuroprotective effects of beta-estradiol on SHSY5Y neuroblastoma cells which have been exposed to the heavy metals cobalt and mercury. The results show that cobalt and mercury are able to induce oxidative stress and cell cytotoxicity and increase the secretion of beta-amyloid 1-40 and 1-42. These deleterious effects are reversed by the pretreatment of cells with beta-estradiol. It is further shown that beta-estradiol exerts its neuroprotective action through mechanisms which reduce oxidative stress and reduce beta-amyloid secretion. Pre-treatment of the cells with alpha-estradiol did not alleviate the toxic effects of the heavy metals. Our results are significant as they contribute to a better understanding of the mode of action of estrogen with relevance to its use in the treatment of neurodegenerative disorders.

Melatonin MT-1-receptor immunoreactivity in the human eye.

AIM: To examine the distribution of melatonin 1a (MT1) receptors in the human eye. METHODS: Seven normal human eyes were examined by immunohistochemical staining of paraffin sections, using an anti-MT1 primary antibody and an ABC detection system. RESULTS: MT1 receptor immunoreactivity (MT1-IR) was detected primarily in the inner segments of rods and cones and in retinal ganglion cells. In addition, MT1-IR was present in the adventitia of retinal arteries and veins, including the papillary region, but absent in ciliary and choroidal vessels. Mild staining of corneal endothelial cells and keratocytes was observed in all but two eyes. CONCLUSION: MT1-IR is present in various ocular tissues with the highest density in photoreceptor cells and ganglion cells. The physiological function of these receptors deserves further investigation.

Oxidative stress modulates tyrosine kinase receptor A and p75 receptor (low-affinity nerve growth factor receptor) expression in SHSY5Y neuroblastoma cells.

The interaction of neurotrophins and their tyrosine kinase receptors (trks) is essential for differentiation and survival of brain cells. In Alzheimer's disease (AD), the number of neurotrophins and receptors is markedly decreased. The cause of this reduction is unclear, but the role of beta-amyloid (Abeta) seems central in understanding the mechanisms controlling neurotrophin and trk expression. In the study reported here, we exposed SHSY5Y neuroblastoma cells to Abeta or hydrogen peroxide (H(2)O(2)) and measured the expression of trk-A and p75 at the protein and molecular levels. Both Abeta and H(2)O(2) induced oxidative stress (measured by a decrease in cellular glutathione), which decreased trk-A levels and increased p75 levels, decreased messenger RNA (mRNA) levels of both receptors, and increased nerve growth factor (NGF) secretion. Pretreatment of cells with the antioxidant melatonin returned levels of protein expression, mRNA, and NGF secretion to normal. These results are significant, as they can help in the planning and implementation of AD treatment strategies involving neurotrophins.

Melatonin protects SHSY5Y neuroblastoma cells from cobalt-induced oxidative stress, neurotoxicity and increased beta-amyloid secretion.

Heavy metals are increasingly being implicated as causative agents in neurodegenerative diseases such as Alzheimer's disease (AD). Cobalt, a positively charged transition metal, has previously been shown to be in elevated levels in the brain of AD patients compared with age-matched controls. In this study, we investigate the effects of cobalt as an inducer of oxidative stress/cell cytotoxicity and the resultant metabolic implications for neural cells. We show that cobalt is able to induce cell cytotoxicity (reduced MTT metabolism) and oxidative stress (reduced cellular glutathione). The pre-treatment of cells with the pineal indoleamine melatonin, prevented cell cytotoxicity and the induction of oxidative stress. Cobalt treatment of SHSY5Y cells increased the release of beta-amyloid (Abeta) compared with untreated controls (ratio Abeta 40/42). Melatonin pre-treatment reversed the deleterious effects of cobalt. These findings are significant as cobalt is an essential nutritional requirement, usually bound to cobalamin (vitamin B12), for all animals which in the unbound form could lead to neurotoxicity.

Cortical alterations of angiotensin converting enzyme, angiotensin II and AT1 receptor in Alzheimer's dementia.

We investigated the immunohistochemical alterations of angiotensin converting enzyme (ACE), angiotensin II and AT1 receptor in the parietal cortex in Alzheimer's dementia (AD) to reveal the contributive role of the brain renin-angiotensin system in the disease process. In controls, ACE, angiotensin II and AT1 immunoreactivities were localized to pyramidal neurons of the cortex. The staining intensity was distinctly increased in AD for all three antigens, involving predominantly cortical layer V, which may reflect the enhanced brain renin-angiotensin system activity in the disease process. In addition, a prominent perivascular ACE and angiotensin II immunoreactivity surrounding some cortical vessels in aged controls and AD patients points to an underlying microvascular pathology in the process of neurodegeneration.

Cerebrovascular melatonin MT1-receptor alterations in patients with Alzheimer's disease.

The pineal hormone melatonin has two major functions: as a transducer of the circadian day-night signal across the seasons, and as a vasoactive substance regulating cerebral circulation. The vasoconstrictive effects of melatonin have been postulated to be mediated by the melatonin 1a-receptor (MT1). The objective of this study was to provide the first immunohistochemical evidence for the localization of vascular MT1 in human control hippocampus compared to Alzheimer's disease (AD) patients, since regional blood flow impairments contribute to the neurodegenerative course of the disease. Both superficial and intrahippocampal arteries revealed MT1 immunoreactivity in adventitia in controls, which was distinctly increased in AD patients. The increased MT1 in AD may indicate a regulatory response to impaired melatonin levels in those patients, contributing to the regulation of cerebral circulation.

Hippocampal estrogen beta-receptor immunoreactivity is increased in Alzheimer's disease.

Post-menopausal estrogen use reduces the risk and severity of Alzheimer's disease (AD). The present study investigates the distribution of both estrogen receptors ER alpha and ER beta in the human hippocampus in aged controls and in AD cases with immunohistochemistry. No ER alpha immunoreactivity was observed both in controls and in AD cases. On the other hand, ER beta was observed in some neuronal cells in the hippocampal subfields CA1--4, in astrocytes and in extracellular deposits both in controls and AD cases. The ER beta immunoreactivity was distinctly increased in all AD cases in cellular and extracellular localizations indicating a role for ER beta-mediated estrogen effects in AD-related neuropathology. This study provides the first demonstration of ER beta in human hippocampus in aged controls compared to AD cases.

Alterations in trk A, trk B and trk C receptor immunoreactivities in parietal cortex and cerebellum in Alzheimer's disease.

The neurotrophins nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 bind to the tyrosine kinase (trk) receptors trk A, trk B and trk C, respectively, with high affinity. We investigated the expression of the trk receptors in the parietal cortex (PC) and cerebellum of patients with Alzheimer's disease (AD) and age-matched controls. Cortical layers II-VI displayed a distinct cellular immunoreactivity for trk A and C with an emphasis in the pyramidal neurons of layers III and V. Trk B immunoreactivity was primarily located in the deeper cortical layers with a predominance in layer V. There was a decrease in trk A and C immunoreactivity in the PC of AD cases, while trk B density appeared to be unchanged. In addition, cerebellar Purkinje cells revealed a distinct immunoreactivity for trk C both in control and AD cases, suggesting trk C may be important in the maintenance of these cells in the aged brain.

Haloperidol disrupts, clozapine reinstates the circadian rest-activity cycle in a patient with early-onset Alzheimer disease.

Measurement of the circadian rest-activity cycle in a patient with early-onset Alzheimer disease for 555 days revealed marked changes in the timing and amount of nocturnal activity. After neuroleptic medication was changed to haloperidol, the rest-activity cycle became completely arrhythmic for two months, concomitant with a marked worsening of cognitive state. Circadian integrity returned together with clinical improvement when the patient was subsequently treated with clozapine. This observation suggests that the known tendency for patients with Alzheimer disease to develop sleep-wake cycle disturbances may be aggravated by a classic neuroleptic; in contrast, the atypical neuroleptic clozapine may consolidate it. Similar observations in schizophrenic patients indicate that this chronobiological finding is drug- and not illness-related.

[Follow-up of a "culture-bound psychosis"]. / Verlauf einer "kulturgebundenen Psychose".

Today it is uncontested that some psychiatric disorders like schizophrenia occur transculturally despite their culture-dependent symptomatical variations. In the following text we discuss the case of a Chinese patient emigrated to Switzerland. Different culture-dependent appreciation of facts and therapeutic approaches by her family and by the treatment team influenced the course of the psychotic disorder.

Calbindin D-28k and monoamine oxidase A immunoreactive neurons in the nucleus basalis of Meynert in senile dementia of the Alzheimer type and Parkinson's disease.

In this study, calbindin D-28k (CaBP), monoamine oxidase A (MAO A) and nerve growth factor receptor (NGFr) immunoreactivities were investigated in the nucleus basalis of Meynert (NbM) in patients with senile dementia of the Alzheimer type (SDAT), with Parkinson's disease (PD) with or without dementia, and in controls. Immunocytochemistry using specific antibodies in differing serial sections was employed, and cell counts and NbM nuclear volume measurements were made. Most of the large multipolar NbM neurons showed CaBP immunoreactivity in the cytoplasm of their somata, dendrites and axons. In adjacent, NGFr-reacted sections, the large NbM neurons were also found to be intensely immunoreactive for NGFr on their cellular surfaces. In addition, a subpopulation of large NbM neurons and glial cells were found to be immunoreactive for MAO A. The number of CaBP-immunoreactive (CaBP-i) neurons was decreased by an average of 55% in the 6 SDAT patients, 70% in the 2 nondemented PD patients and 40% in the 1 demented PD patient. The volume calculated for the compact part of the NbM formed by the CaBP-i neuronal somata decreased by an average of 47% in SDAT. On the other hand, measurements in the volume of NGFr-i neurons (including the dendritic arborization) showed an average decrease of 25% in SDAT patients compared to controls. Although all SDAT and PD patients showed a decrease of CaBP-i neurons in the NbM, a loss of MAO-A-i NbM neurons was found only in those patients with dementia. Therefore, the relative proportions of MAO-A-i to CaBP-i neurons were increased in the nondemented PD patients (14.2 and 19.6%) when compared with those in the demented PD patient (2.2%) and with the SDAT patients (0.3-5.6%). These data indicate that a balanced presence of MAO-A-i cholinergic, large NbM neurons may be necessary for the proper maintenance of cognitive function. Functionally this may be translated to mean that dementing changes may cause a decrease from the normal amount of MAO A enzyme activity. This suggests that therapeutic strategies based upon correction of MAO-A activities by MAO-A inhibitors may be important to ameliorating some of the loss in cholinergic function in dementias of SDAT and PD.