[Pain measurement in cognitively impaired patients with the Doloshort scale]. / Schmerzmessung bei kognitiv beeinträchtigten Patienten mit der Doloshort-Skala.

BACKGROUND: Until recently the measurement of pain in cognitively impaired patients represented a neglected field in the diagnostics and treatment of pain. Investigations indicate a prevalence of pain in nursing home residents of between 45 % and 80 %. MATERIAL AND METHODS: This study investigated the reliability of the German translation of the Doloshort scale and compared it with the visual analog scale (VS). The aim of this study was to determine the practical applicability of this scale in the clinical routine and to calculate the intrarater reliability (retest) and interrater reliability. RESULTS: The interrater and intrarater reliability of the Doloshort scale was between 0.949 and 0.970. There was a highly significant correlation between the values of the Doloshort scale and the VAS. CONCLUSION: The Doloshort scale is a well suited measurement instrument for the evaluation of pain in cognitively impaired patients. Because of the short form only simple instructions are necessary and it has a high acceptance with users.

Serial position effects in patients with mild cognitive impairment and early and moderate Alzheimer's disease compared with healthy comparison subjects.

BACKGROUND/AIMS: This study aimed to investigate whether the serial position effects in memory can differentiate patients with different subtypes of mild cognitive impairment (MCI) from healthy controls and patients with different stages of Alzheimer's disease (AD). METHODS: The serial position effects was tested with the CERAD word list task in 184 persons (39 healthy control subjects, 15 amnestic MCI single domain subjects, 23 amnestic MCI multiple domain subjects, 31 nonamnestic MCI subjects, 45 early or mild AD patients, and 31 moderate AD patients). RESULTS: With progression of dementia, memory deficits increased and the impairment in the primacy effect during the learning trials advanced, whereas the recall of recent items was less impaired. The serial position profile of nonamnestic MCI patients resembled that of healthy control subjects, whereas amnestic MCI patients showed poorer performance in all 3 positions but no significant difference as a function of serial word position. CONCLUSION: Analyses of the serial position effect may be a useful complement to clinical neuropsychological measures for distinguishing amnestic MCI patients from normal aging and patients with different stages of dementia.

Ubiquitin enzymes, ubiquitin and proteasome activity in blood mononuclear cells of MCI, Alzheimer and Parkinson patients.

Alzheimer's disease (AD) is a severe chronic neurodegenerative disease. During aging and neurodegeneration, misfolded proteins accumulate and activate the ubiquitin-proteasome system. The aim of the present study is to explore whether ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, ubiquitin or proteasome activity are affected in peripheral blood mononuclear cells (PBMC) of AD, mild cognitive impairment (MCI) and Parkinson's disease (PD) patients compared to healthy subjects. PBMCs were isolated from EDTA blood samples and extracts were analyzed by Western Blot. Proteasome activity was measured with fluorogenic substrates. When compared to healthy subjects, the concentration of enzyme E1 was increased in PBMCs of AD patients, whereas the concentration of the enzyme E2 was decreased in these same patients. Ubiquitin levels and proteasome activity were unchanged in AD patients. No changes in enzyme expression or proteasome activity was observed in MCI patients compared to healthy and AD subjects. In PD patients E2 levels and proteasomal activity were significantly reduced, while ubiquitin and E1 levels were unchanged. The present investigation demonstrates the differences in enzyme and proteasome activity patterns of AD and PD patients. These results suggest that different mechanisms are involved in regulating the ubiquitin-proteasomal system in different neurodegenerative diseases.

Chromogranin peptides in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which primarily affects motor neurons. Eight cases of ALS and seven control cases were studied with semiquantitative immunocytochemistry for chromogranin A, chromogranin B and secretogranin II that are soluble constituents of large dense core vesicles, synaptophysin as a membrane protein of small synaptic vesicles and superoxide dismutase 1. Among the chromogranin peptides, the number and staining intensity of motor neurons was highest for chromogranin A. In ALS, the staining intensity for chromogranin peptides and synaptophysin was significantly lower in the ventral horn of ALS patients due to a loss in immunoreactive motor neurons, varicose fibers and varicosities. For all chromogranins, the remaining motor neurons displayed a characteristic staining pattern consisting of an intracellular accumulation of immunoreactivity with a high staining intensity. Confocal microscopy of motor neurons revealed that superoxide dismutase 1-immunopositive intracellular aggregates also contained chromogranin A, chromogranin B and secretogranin II. These findings indicate that there is a loss of small and large dense core vesicles in presynaptic terminals. The intracellular co-occurrence of superoxide dismutase 1 and chromogranins may suggest a functional interaction between these proteins. This study should prompt further experiments to elucidate the role of chromogranins in ALS patients.

[Mild cognitive impairment with predictors of rapid decline]. / Leichte kognitive Beeinträchtigung mit Vorzeichen rascher Verschlechterung.

Half the patients with mild cognitive impairment (MCI) will develop dementia over a four-year period. The scientific literature was searched and analysed for predictors of rapid decline (MCI-plus) in patients with MCI. The most important predictors of fast cognitive deterioration were found to be: old age, previous rapid decline, severity and multiplicity of cognitive deficits, somatic co-morbidity, vascular and Alzheimer-type changes in the brain, Alzheimer-type cerebrospinal fluid findings and apolipoprotein E4 polymorphism. Many patients with MCI suffer from anxiety, depression or apathy and subtle, but subjectively significant, difficulties in the activities of daily living. It is concluded that MCI-plus offers a window for medical and psychological prophylaxis and rehabilitation.

Beta-amyloid expression, release and extracellular deposition in aged rat brain slices.

Alzheimer's disease (AD) is characterized by beta-amyloid plaques, tau pathology, cholinergic cell death and inflammation. The aim of this study was to investigate whether beta-amyloid is generated, released and extracellularly deposited in organotypic brain slices. In developing slices, no amyloid-precursor protein (APP) was detectable; however, there was a strong upregulation in aging slices. In such slices, rat beta-amyloid(1-42) and -(1-40) peptides were found using four sequence-specific antibodies. APP and beta-amyloid were expressed in neurons and to a lesser extent in astrocytes. Beta-amyloid was secreted into the medium. Beta-amyloid was located extracellularly when aging slices were incubated with medium at pH 6.0 including apolipoprotein E4 (ApoE4). It is concluded that aging organotypic brain slices express beta-amyloid and that acidosis induces cell death with efflux of beta-amyloid and extracellular depositions, which is triggered by ApoE4. This novel in vitro model may enable us to investigate further the pathological cascade for AD and may be useful to explore future therapeutics.

Successful mirtazapine treatment of an 81-year-old patient with syndrome of inappropriate antidiuretic hormone secretion.

Elderly patients are at a higher risk for inappropriate antidiuretic hormone secretion when treated with antidepressants. In response to severe depressive symptoms, we initiated treatment with citalopram of an 81-year-old female patient with slightly reduced sodium and chloride levels. The sodium and chloride levels decreased continuously during treatment with citalopram; six days after the citalopram was discontinued, sodium and chloride levels returned to normal. We then switched treatment to mirtazapine. Close monitoring revealed that the patient's sodium and chloride levels never decreased and the patient did not relapse for more than two months. This case study indicates that treatment with citalopram may worsen preexisting hyponatremia. Mirtazapine appears to be safe for use in high-risk, elderly patients.

[Differences between men and women in side effects of second-generation antipsychotics]. / Neuere Antipsychotika. Unterschiede im Nebenwirkungsprofil bei Frauen und Männern.

In this review we investigate whether sex differences exist for side effects of second-generation antipsychotics. Results are based on a MEDLINE search for the years 1974 through 2005. Even if pharmacokinetics differ between females and males, significantly higher plasma levels for women have been demonstrated only for olanzapine and clozapine. Hyperprolactinaemia is mainly induced by treatment with risperidone and amisulpride, and there is evidence for more pronounced prolactin levels in females. Most studies reviewed indicate that clozapine and olanzapine are associated with more body weight gain, once more especially in female patients. Furthermore, the few published studies indicate that metabolic syndrome is more frequent in females and there are likely no gender-specific differences between the new antipsychotic medications concerning frequency and degree of acute or chronic movement disturbance. The risk of QT prolongation with torsades de pointes arrhythmia is again higher in females. In conclusion, there is some evidence of sex differences in the side effects of second-generation antipsychotics. For better understanding of the basic mechanisms in sex differences, future studies with a primary focus on this topic are required. More specific data will help to determine how these differences shall affect clinical management.

Effects of age and mild cognitive impairment on direct and indirect access to arithmetic knowledge.

The present study aimed at investigating age-related changes and mild cognitive impairment (MCI) related effects in simple arithmetic. To pursue this goal, MCI patients, healthy old adults and young adults performed three computerised tasks. The production (e.g., 3 x 4=?) and the verification task (3 x 4 12?) evaluated direct access to multiplication knowledge, the number-matching task (3 x 4 34?, 'do 3 x 4 and 34 have the same digits?') tested indirect access. In verification and number-matching, interference from related distractors (e.g., 3 x 4 followed by 16) relative to unrelated distractors (17) reflects access to stored fact representations as well as efficiency of inhibition processes. Results indicated that, compared to young adults, MCI and healthy old adults were slower in responding across tasks. In production and verification, analyses of individual latency regression slopes and intercepts suggested that these age effects were related to differences at peripheral processing stages (e.g., encoding) rather than at the central (arithmetic retrieval) stage. Differences between MCI and healthy elderly emerged only in the number-matching task. While in verification effects were comparable between groups, in number-matching MCI patients were more susceptible to interference from irrelevant information than healthy old participants. Overall, the present findings indicate that aging has a general effect on peripheral processing speed, but not on arithmetic memory retrieval. Parietal cortico-subcortical circuits mediating arithmetic fact retrieval (Dehaene, S., & Cohen, L. (1995). Towards an anatomical and functional model of number processing. Mathematical Cognition, 1, 83-120; Dehaene, S., & Cohen, L. (1997). Cerebral pathways for calculation: Double dissociation between rote verbal and quantitative knowledge of arithmetic. Cortex, 33, 219-250) thus seem to be preserved in normal aging and MCI. In contrast, MCI patients show enhanced interference in number-matching. This task-specific lack of inhibition may point to dysfunctional frontal cortico-subcortical networks in MCI.

First localization and biochemical identification of chromogranin B- and secretoneurin-like immunoreactivity in the fetal human vagal/nucleus solitary complex.

The human vagal/nucleus solitary complex is a primary visceral relay station and an integrative brain stem area which displays a high density of chromogranin B- and secretoneurin-like immunoreactivity. In this study, we localized and biochemically identified these proteins during prenatal development. At prenatal week 11, 15, 20 and 37, we performed a chromatographic analysis to identify the molecular forms of PE-11, a peptide within the chromogranin B sequence, and secretoneurin, a peptide within secretogranin II. Their localization was studied with immunocytochemistry, and was compared to that of substance P which is well established as a functional neuropeptide in the vagal/nucleus solitary complex. At prenatal week 11, chromogranin B-, secretoneurin- and substance P-like immunoreactivities were detected consisting of varicosities, varicose fibers and single cells. At the same time, PE-11 and secretoneurin appeared as a single peak in chromatographic analysis. Prohormone convertases PC1- and PC2-like immunoreactivities were also present at week 11. In general, the density for each peptide increased during later fetal stages with the highest density at week 37. These results demonstrate that each chromogranin peptide is expressed during human fetal life in neurons of the vagal/nucleus solitary complex indicating that these peptides could be important during prenatal development.

[Gender differences in cognitive functions]. / Geschlechtsunterschiede kognitiver Leistungen -- populärwissenschaftliche Stereotypien oder evidenzbasierte Studienergebnisse?

Gender differences in neuropsychological functioning of patients with psychiatric disorders have been studied extensively in the last years. The available studies provide conflicting results, which can be attributed to the complexity of variables influencing cognitive sex differences. In this article we review the literature about gender differences in cognitive functions in healthy men and women and discuss the relevance of hormones, socio-cultural factors, educational factors and training on the occurrence of these sex differences. Furthermore we summarize the results from functional MRI experiments, which is a useful tool for noninvasively localizing areas in the brain involved in specific cognitive functions.

Subacute dementia and imaging correlates in a case of Fahr's disease.

We report a case of idiopathic bilateral basal ganglia calcinosis, or Fahr's disease (FD) in a 50 year old patient who developed rapidly progressive behavioural abnormalities and severe neuropsychological impairments, but no movement disorder. Neuropsychological deficits included a severe dysexecutive syndrome, anterograde amnesia, and attentional impairment. Neuropsychiatric features comprised apathy with intermittent disinhibition, anxiety, irritability, frequent mood changes, ritualistic and antisocial behaviour, and psychosis. Fluorodeoxyglucose positron emission tomography showed a massive reduction of glucose metabolism in the basal ganglia and the frontal brain. The observed abnormalities possibly result from a disruption of frontostriatal circuits, presumably at the basal ganglia level. This case indicates that FD may cause exclusively behavioural alterations and that the associated hypometabolism in certain frontal areas is closely related to the clinical picture.

Distribution of catestatin-like immunoreactivity in the human auditory system.

Chromogranin A (CgA) belongs to the family of chromogranin peptides which are contained in large dense-core vesicles. The novel CgA fragment catestatin (bovine CgA(344-364); RSMRLSFRARGYGFRGPGLQL) is a potent inhibitor of catecholamine release by acting as a nicotinic cholinergic antagonist. Catestatin is a recently characterized neuropeptide, consisting of 21 amino acids, which might play an autocrine regulatory role in neuroendocrine secretion through its interaction with different nicotinic acetylcholine receptor subtypes. This study investigates for the first time the distribution of this peptide in the human auditory system using immunohistochemistry. A high density of catestatin-like immunoreactivity (catestatin-LI) is located in the spiral ganglion cells. In the dorsal cochlear nucleus, a high density of catestatin-LI consists of varicose fibers, immunoreactive varicosities and immunoreactive neurons. A moderate density is detected in the ventral cochlear and the medial vestibular nucleus. A low density is found in the inferior colliculus and superior olivary complex. The study indicates that catestatin is distinctly distributed in the auditory system, suggesting a role as a neuromodulatory peptide. Further studies should elucidate a possible interaction with other neurotransmitters in the auditory system.

Fluoxetine in Alzheimer's disease with severe obsessive compulsive symptoms and a low density of serotonin transporter sites.

The treatment of behavioral disturbances is particularly challenging in patients suffering from dementia. In an 80-year-old female patient with probable AD and severe obsessive and compulsive symptoms, we demonstrated a significant reduction in the density of serotonin transporter sites using 1231-beta-CIT SPECT. Treatment with fluoxetine for 6 months resulted in significant symptom relief and an increasing density of serotonin transporter sites when compared to the beginning of treatment. Therefore, this report provides evidence that fluoxetine is a treatment option for patients with AD and severe obsessive-compulsive symptoms and highlights the importance of the serotoninergic system.

Pharmacological treatment strategies of residential primary care providers in dementia diseases--results of a representative survey in western Austria.

OBJECTIVE: The goal of this study was to investigate pharmacological treatment strategies used by residential primary care providers for patients with dementia. METHODS: A postal questionnaire survey was sent to all residential primary care providers, internists, neurologists and psychiatrists (n = 689) in the western region of Austria. RESULTS: The response rate (53 %) was similar in all four physician groups. Acetylcholinesterase inhibitors are considered to have a higher efficacy (p < 0.0005) compared to nootropic drugs. However, the vast majority of primary care providers (95 %) prescribe nootropic drugs. Two thirds (64 %) of the primary care providers prescribe acetylcholinesterase inhibitors. The dementia subtype influences the prescription frequency of acetylcholinesterase inhibitors, but not the specific choice of nootropic compound. Half of the primary care providers (52 %) combine antidementia drugs. Nearly two-thirds (62 %) of all primary care providers frequently prescribe antidepressants. Specific serotonin reuptake inhibitors are applied by the majority of primary care providers (96 %). About one-third (39 %) of primary care providers and internists (29 %) prescribe tricyclic antidepressants. Antipsychotics are applied frequently by around a quarter (29 %) of all physicians. More than half of primary care providers (62 %) and internists (58 %) treat patients with typical antipsychotics. Psychiatrists and neurologists are significantly more reluctant to prescribe tricyclic antidepressants and typical antipsychotics. CONCLUSIONS: Despite the lack of scientific evidence, residential primary care providers combine antidementia drugs very frequently. Therefore, controlled studies on combination therapies are urgently needed; in contrast to neurologists and psychiatrists, primary care providers and internists frequently prescribe tricyclic antidepressants and typical antipsychotics. The reasons for this should be clarified in further studies.

[Psychosocial therapy of patients with dementia]. / Die psychosoziale Therapie von Patienten mit Demenz.

The progressive cognitive and behavourial disturbancies in dementia diseases cause great emotional burden to patients, their families and caregivers. To relief this burden and to facilitate adequate coping strategies, psychosocial therapies intend to improve cognitive functions, self care abilities and emotional wellbeing of dementia patients. The therapeutic interventions address the patients, their caregivers and the adaption of the environment. Psychosocial therapies can be divided into cognitive training methods, behaviour orientated concepts, emotional orientated approaches and family interventions (1, 2, 12, 19). Most of these psychosocial therapies are only poor validated in randomized controlled trials. Nevertheless, they hold great promise to improve the quality of life and wellbeing of dementia patients and their caregivers. Thus they should be considered to be an integral part of a comprehensive therapeutic approach to dementia patients and their families.

[Alcohol-induced cognitive disorder: alcohol dementia]. / Alkoholinduzierte kognitive Störung: Alkoholdemenz.

Cognitive impairment is frequently observed in patients with alcohol misuse or alcohol addiction. Multiple cognitive functions are reduced in these patients. Frontal lobe functions, as planning, abstract thinking, set shifting or continuous performance are most frequently affected. Alcohol amnestic syndrome, alcohol dementia and the Wernicke-Korsakow-Syndrome constitute distinct entities. Alcohol dementia follows the diagnostic criteria of dementia with clear evidence for alcohol abuse or alcohol addiction. The diagnostic procedure of alcohol-induced cognitive impairment includes medical history, physical and neuropsychiatric examinations; laboratory examinations, neuropsychological assessment, brain imaging and electroencephalographic recordings. At the moment, there are no established treatment options for alcohol-induced cognitive impairment. Some evidence is provided that nootropics might be of benefit. Alcohol abstinence is a most important step. Psychosocial interventions are essential to support the patients in their daily activities.

Striatal dopamine transporter function in dementia with Lewy bodies and Parkinson's disease.

The aim of this study was to compare parkinsonian features and loss of striatal dopamine transporter (DAT) function in patients with dementia with Lewy bodies (DLB) and Parkinson's disease (PD), matched for age and disease duration. Twenty patients with DLB. 24 PD patients and 10 matched controls were examined with SPET using a dual-head camera and the dopamine-transporter ligand 123I-beta-CIT (148 MBq). Moreover, in a subgroup of patients (16 DLB and 20 PD patients), subscores of the Unified Parkinson's Disease Rating Scale (UPDRS)-motor examination (ME) subscale were obtained during "practical off", i.e. 12 h following withdrawal of antiparkinsonian therapy. Compared with controls, striatal/cerebellar (S/C) ratios of DAT binding were significantly reduced in both DLB and PD, deficits being more marked in DLB patients (controls 7.2 +/- 1.2, DLB 3.3 +/- 1, PD 4.2 +/- 1.4; means +/- SD). The side-to-side differences in the S/C ratios were lower in the DLB group and the controls than in PD patients (0.4 +/- 0.4. 0.2 +/- 0.2 and 0.6 +/- 0.3, respectively, P<0.05). The total UPDRS-ME scores during practical-off were significantly higher in the DLB than in the PD group (41.2 +/- 12.7 vs 26.6 +/- 15.3, P<0.01). The side-to-side differences of the summed UPDRS extremity subscores were smaller in the DLB than in the PD group (2.2 +/- 2.3 vs 7.4 +/- 3.9, P<0.0001). Our findings suggest that parkinsonism evolves largely symmetrically and progresses more rapidly with more severe loss of striatal dopamine transporter function in DLB compared to PD. Whether these findings are helpful in the differential diagnosis of DLB and PD needs to be examined in further studies.

Magnetic stimulation induces neuronal c-fos via tetrodotoxin-sensitive sodium channels in organotypic cortex brain slices of the rat.

Repetitive transcranial magnetic stimulation is a novel non-invasive method with antidepressant properties, where electromagnetic fields are applied via an electrode. The aim of the present study was to investigate in an in vitro model if magnetic stimulation may activate the transcription factor c-fos. Organotypic brain slices of the parietal cortex were cultured for 2 weeks and then treated with a magnetic stimulator. Immunohistochemistry was used to detect c-fos like immunoreactivity. We show that magnetic stimulation (1 Hz, 10 min, 75% machine output/magstim 200 rapid stimulator) transiently enhanced c-fos 3-6 h after stimulation. Co-localization experiments revealed that c-fos was expressed in neurons but not astroglia. The activation of c-fos by magnetic stimulation was inhibited by the sodium-channel blocker tetrodotoxin (TTX) (10 microM). It is concluded that magnetic stimulation induces neuronal c-fos via TTX-sensitive sodium channels in organotypic cortex slices.

Differential regulation of chromogranin A, chromogranin B and secretogranin II in rat brain by phencyclidine treatment.

Chromogranin A, chromogranin B and secretogranin II belong to the chromogranin family which consists of large protein molecules that are found in large dense core vesicles. Chromogranins are endoproteolytically processed to smaller peptides. This study was designed to elucidate the regulation of chromgranin expression by acute and subchronic phencyclidine administration. The behavioral syndrome produced by phencyclidine represents a pharmacological model for some aspects of schizophrenia [Jentsch and Roth (1999) Neuropsychopharmacology 20, 201-225]. Tissue concentrations of chromogranins were measured with specific radioimmunoassays. Alterations in secretogranin II gene expression were investigated by in situ hybridization. A single dose of phencyclidine (10mg/kg) led to a transient decrease in secretoneurin tissue levels in the prefrontal cortex after 4h followed by an increase in secretoneurin tissue levels after 12h. Repeated phencyclidine treatment (10mg/kg/day) for five days resulted in elevated secretoneurin levels in cortical areas whereas chromogranin A and chromogranin B tissue levels were unchanged. After the same treatment, a significant increase in the number of secretoneurin containing neurons was found in cortical layers II-III, and V-VI as revealed by immunocytochemistry. The increases in secretoneurin levels were paralleled by an increased number of secretogranin II messenger RNA containing neurons as well as by an increased expression of secretogranin II by individual neurons. The present study shows that secretoneurin II tissue concentration and secretogranin II messenger RNA expression is distinctly altered after acute and subchronic phencyclidine application. From these results we suggest that phencyclidine may induce synaptic alterations in specific brain areas and may contribute to a better understanding of synaptic dysfunction which may also occur in schizophrenia.