[CERAD and NOSGER. Comparing predictive scales for dementia in a Swiss gerontopsychiatric patient population]. / CERAD und NOSGER. Der prädiktive Wert dieser Verfahren in der Demenzdiagnostik einer Schweizer gerontopsychiatrischen Patientenpopulation.

BACKGROUND: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) is an established screening instrument for the diagnosis of Alzheimer's disease. The Nurses Observation Scale for Geriatric Patients (NOSGER), actually developed for rating the frequency of behavioral disturbances, appears suitable for dementia screening as well. MATERIAL AND METHOD: In this retrospective study we analyze the neuropsychological data of 400 consecutive patients at our hospital with several psychiatric diagnoses and cognitive deficits. By means of logistic calculation in single and multivariable models, the predictive value of CERAD and NOSGER for dementia diagnosis was studied. RESULTS: All CERAD subtests were significant single predictors for dementia. The multivariable model with the highest prediction for probability of dementia diagnosis contained the subtests Verbal Fluency Test, Word List Recall, Constructional Practice Recall, and the Mini-Mental State Examination. However, NOSGER could not differentiate between demented and nondemented patients. CONCLUSION: In our gerontopsychiatric population, CERAD separates demented patients from nondemented ones with high predictive potency. The NOSGER does not reveal any predictive value for the diagnosis of dementia.

Unrecognised long-lasting tramadol-induced delirium in two elderly patients. A case report.

We present the cases of two elderly patients with intermittent long-term tramadol intake against chronic back pain. Over a period of more than two years they experienced fluctuating confusional states and cognitive deficits, reversible only after discontinuation of tramadol. According to the DSM IV-criteria, an unrecognised recurrent tramadol-induced delirium can be diagnosed in both cases. Although tramadol may represent a well established safe therapy for chronic non-malignant pain in the elderly, these cases demonstrate that it should be applied with caution even in healthy subjects.

[Alzheimer's dementia or cerebral toxoplasmosis? Case study of dementia following toxoplasmosis infection]. / Alzheimer-Demenz oder zerebrale Toxoplasmose? Falldarstellung einer Patientin mit Demenz nach Toxoplasmose-Infektion.

Cerebral toxoplasmosis can lead to dementia in AIDS and in immunodeficient patients. We present a case study in which cerebral toxoplasmosis was associated with a dementia of Alzheimer type. Half a year to one year before the cognitive impairment began, the patient suffered a subacute infection of toxoplasmosis at the age of 56. Neuropsychological examination as well as MRI suggested a diagnosis of dementia with infectious genesis. However, serological tests showed only little evidence of infection. Since the results of the PET examination indicated changes in the glucose metabolism typical of Alzheimer's disease, we infer a comorbidity of cerebral toxoplasmosis and dementia of Alzheimer type.

[A comparison of cholinesterase inhibitors and ginkgo extract in treatment of Alzheimer dementia]. / Ein Vergleich von Cholinesterasehemmern und Ginkgo-Extrakt in der Behandlung der Alzheimer-Demenz.

AIM: To compare the effectiveness of second-generation cholinesterase inhibitors (donepezil, rivastigmine, metrifonate) with that of the special ginkgo extract EGb 761R in Alzheimer's disease. METHOD: Analysis of the effect on cognition with the aid of the ADAS-cog.scale, placebo-adjusted, within six months; statistical evaluation of the effect using the confidence interval for the potential mean improvement. RESULTS: All medications are statistically significantly superior to placebo. The mean improvement is larger for the cholinesterase inhibitors than for the ginkgo extract. In the statistically unfavorable case, the effect of the cholinesterase inhibitors is still appreciable, but not for the ginkgo extract. CONCLUSION: Until the results of direct comparative studies are available, the present results indicate a superior effect of cholinesterase inhibitors over the ginkgo extract in the treatment of mild to moderate Alzheimer's disease.

Discrimination of Alzheimer's disease and normal aging by EEG data.

Quantitative EEG results in Alzheimer's disease may be summarized by the term 'slowing', i.e. slow frequencies (delta, theta) are increased and fast frequencies (alpha, beta) are decreased. But how can EEG data be used to discriminate AD patients from controls by means of EEG data? Discriminant analysis may produce false predictions using too many predictors, as is often the case in EEG studies. We studied 4 approaches to this problem: Classification by group means, stepwise discriminant analysis, a neuronal network using back propagation and discriminant analysis preceded by principal components analysis (PCA). A maximum of 86.6% correct classifications was reached using the last mentioned approach with EEG data alone. Including age as a moderator variable in a subgroup, 95.9% correct classifications were reached.

[Self and informant perception of clinical manifestations of Alzheimer dementia: results of a structured interview (CAMDEX)]. / Die Selbst-und Fremdeinschätzung klinischer Störungen bei der Alzheimer-Demenz: Ergebnisse eines strukturierten Interviews (CAMDEX).

The correlations between (a) the patients' memory complaints, (b) the informants' rating of the patients' cognitive impairment, and (c) cognitive performance according to the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) were examined in 163 patients with probable or possible Alzheimer's disease. The patients' complaints were weakly correlated with informants' view (p < 0.05), closely correlated with depressive mood (p < 0.0001), but not with cognitive performance or the stage of dementia. The results of Clinical Dementia Rating, Mini-Mental State Examination and the Cambridge Cognitive Examination were significantly correlated with the informants' rating of cognitive impairment (p < 0.0001). These results are in line with previous studies and confirm (1) the suitability of CAMDEX for the structured examination of dementia patients and their caregivers, (2) the association between affective disturbances and the perception of cognitive deficits, and (3) the importance informants' rating for the valid evaluation of demented patients.

[Volumetric brain changes and quantitative EEG in normal aging and Alzheimer's dementia]. / Volumetrische Hirnveränderungen und quantitatives EEG bei normalem Altern und Alzheimer-Demenz.

We studied (1) the differences of volumetric estimates of brain atrophy in normal ageing and Alzheimer's disease (AD); (2) the correlation of these estimates with age and cognitive performance; (3) the differences between absolute EEG power between ageing and AD; (4) the correlation between EEG power and age or cognitive performance; and (5) the correlation between volumetric and EEG data. 84 patients with a clinical diagnosis of AD and 45 age-approximated non-demented controls between 48 and 91 years of age were examined. For statistical comparisons the volumetric estimates of intracranial cerebrospinal fluid (csf) spaces were converted into percentages of total intracranial volume. The EEG was recorded from 17 locations at resting conditions, eyes closed, according to the 10/20 system. Logtransformed absolute band powers were compared between the AD and control groups and correlated with clinical and volumetric findings. The total intracranial csf-space, both lateral ventricles, the third ventricle, anterior, lateral and posterior fissures were significantly larger in AD than in non-demented controls. In normal ageing the csf-volumes were significantly correlated with age, whereas age and cognitive performance were differentially correlated with these variables in AD. In AD, the absolute delta or theta power was significantly higher in all locations, whereas alpha power was lower than in normal controls. These differences were significantly correlated with cognitive performance. There were no significant correlations between the csf-volumes and EEG-power in AD and the control group with one exception: we found a significant inverse correlation between the volumes of the anterior and posterior fissure and the alpha-1 and alpha-2 power independent of electrode location in AD. We conclude that the morphological and EEG-changes in AD are largely independent and suggest that the functional relationship between alpha-power and anterior or posterior fissure volume needs further examination.

Frontal lobe degeneration and Alzheimer's disease: a controlled study on clinical findings, volumetric brain changes and quantitative electroencephalography data.

Ten patients with a clinical diagnosis of frontal lobe degeneration (FLD) were compared with a group of patients with probable Alzheimer's disease (AD) and with nondemented controls matched for gender and age. In comparison with AD, the duration of illness was slightly shorter and cognitive performance was better in patients with FLD. The greatest enlargement of cerebrospinal fluid volumes was found in FLD and this effect was most pronounced in the anterior fissure and lateral ventricles. Estimates of EEG band-power and EEG coherence in FLD were not remarkably different from nondemented controls, whereas delta- and theta-power were significantly increased in AD. These observations may indicate different disease processes with a dissociation of volumetric computed tomography and quantitative EEG changes, which may be of differential diagnostic value.

[Frontal and temporal onset of brain atrophy. Clinical and instrumental findings]. / Frontal und temporal beginnende Hirnatrophie. Klinische und apparative Befunde.

We report the cases of a 70-year old man with left temporal brain atrophy and of a 39-year-old man with neuropathologically verified frontal lobe degeneration (FLD) of Non-Alzheimer type. 10 patients with FLD collected during a prospective study on degenerative dementia had more severe volumetric brain changes and less severe quantitative band power changes than a group of matched patients with clinically diagnosed Alzheimer's disease.

Quantitative EEG analysis in early onset Alzheimer's disease: correlations with severity, clinical characteristics, visual EEG and CCT.

We report EEG findings in 15 presenile Alzheimer patients (probable Alzheimer's disease according to NINCDS-ADRDA criteria) in relation to clinical characteristics. The quantitative EEG was analysed in terms of absolute band power while accounting for EOG and EMG artifacts, respectively. The degree of dementia is strongly reflected by an increase of power in the delta frequency band, accentuated on the left hemisphere, as well as decrease of alpha activity. Longer duration of disease is associated with a decrease of power in the alpha frequency band, earlier age at onset with an additional increase of power in the theta frequency band. Visual EEG evaluation correlates highly with the degree of dementia, in contrast to visually assessed CCT.

EEG coherence in Alzheimer disease.

A novel approach is introduced to examine EEG coherence in different frequency bands of 17 locations from the 10-20 system. Fifty patients with clinically diagnosed Alzheimer's disease were compared with 42 age-approximated non-demented controls. We determined the average coherence between individual electrodes and all neighbouring electrodes. Coherence was decreased in the sample of demented patients and this effect was most pronounced in the frontal and central derivations of the theta, alpha and beta frequency bands. The results can be interpreted as the effects of neuronal loss and neocortical disconnection.

[Incidence and importance of "non-cognitive" symptoms in dementia of the Alzheimer type: productive psychotic symptoms, depressive disorders and behavioral disorders]. / Häufigkeit und Bedeutung "nicht-kognitiver" Symptome bei der Demenz vom Alzheimer-Typ: produktiv psychotische Symptomatik, depressive Störungen und Störungen des Verhaltens.

A semi-structured interview was administered to the closest relatives of 50 patients with presenile or senile dementia of the Alzheimer type. The disturbances most frequently reported were: wandering/pacing (56%, cumulative percentage), aggressive behavior (44%) and - significantly related to more severe stages of dementia - apathy/loss of drive (58%), eating disturbances (46%) and disturbances of the sleep-waking cycle (32%). Depressive symptoms were observed in 58% of the patients, preferentially in the early stages of illness with preserved insight. Signs of paranoid delusions (46%), delusional misidentification (34%), visual (32%) and auditory hallucinations (16%) were encountered temporarily in a large number of patients. The importance of "non-cognitive" symptoms in Alzheimer's disease is underlined by their subjective significance for the caregivers.

Psychotic features and the course of Alzheimer's disease: relationship to cognitive, electroencephalographic and computerized tomography findings.

Thirty-one of 50 patients satisfying the NINCDS-ADRDA criteria of probable or possible Alzheimer's disease showed psychotic features during a 2-year observation period. Paranoid delusions were reported in 23 patients, delusional misidentification in 17, visual hallucinations in 16 and auditory hallucinations in 8. All of the 7 patients who died within the observation period had suffered from psychotic features even before the preterminal phase of illness. A faster progression of illness towards more severe stages of dementia was associated with paranoid delusions and hallucinations but not with delusional misidentification. We could not prove a significant influence of age, age of onset, cognitive performance, ventricular enlargement or the severity of quantitative electroencephalographic changes at initial examination on the course of illness. This may indicate that specific psychotic features and their potential organic substrate exert an effect on the progression of illness and on survival in Alzheimer's disease, which is not related to gross brain atrophy and generalized neurophysiological changes.

Quantitative EEG analysis in early onset Alzheimer's disease: a controlled study.

We report EEG findings in 15 presenile Alzheimer patients (probable Alzheimer's disease according to NINCDS-ADRDA criteria) and 15 age-matched controls. The quantitative EEG was analysed with respect to absolute power for each frequency band at each location accounting for EOG and EMG artifacts respectively. Compared to controls patients showed an increase of power in the slow frequency bands delta and theta which occurred quite uniformly over the different brain regions. In contrast, the decrease of the power of the fast frequency bands alpha 2, beta 1 and beta 2 was accentuated over temporo-parietal regions. In the fast bands patients had a rather flat topographic power profile. The alpha activity was on the average still of a rhythmic nature but the peak frequency was slowed. Differences in slow and fast frequency bands were more pronounced on the left hemisphere.

Alzheimer beta A4-amyloid protein precursor in immunocompetent cells.

The mechanism of proteolytic breakdown of the beta A4-amyloid protein precursor (APP) has attracted much attention because of its relevance for Alzheimer's disease. Apart from the pathological role of APP in the amyloidogenesis, many efforts have been made to identify the functional significance of this widely expressed protein in various biological processes. Employing biochemical techniques, we demonstrate that APP is involved in the initiation of the immune response. Upon stimulation, it is expressed by the major functional types of T-lymphocytes, i.e. CD4+ and CD8+ cells. As was demonstrated for the CD4+ lymphoid cell line H9, APP is predominantly secreted. The remaining COOH-terminal fragments generated upon secretion were highly unstable. Of the APP produced by immunocompetent cells, considerable amounts were shown to be leukocyte-derived APP (L-APP). In addition, we were able to identify the KPI-containing L-APP isoform, L-APP733, as the major expressed L-APP isoform in immunocompetent cells, including rat microglial cells and astrocytes. The L-APP expression pattern of these cells showed high similarity. These findings seem to be indicative of an important function of APP within the immune system. Therefore, APP may be involved in various immunopathogenic conditions of the periphery and in the central nervous system.

Identification and differential expression of a novel alternative splice isoform of the beta A4 amyloid precursor protein (APP) mRNA in leukocytes and brain microglial cells.

The gene for the beta A4-amyloid precursor protein (APP) consists of 19 exons which code for a typical N- and O-glycosylated transmembrane protein with four extracellular domains followed by the transmembrane domain and a short cytoplasmic domain. The beta A4-amyloid sequence is part of exons 16 and 17. Several APP isoforms can be generated by alternative splicing of exons 7 and 8, encoding domains with homologies to Kunitz-type protease inhibitors and the MRC OX-2 antigen, respectively. The mechanism by which the pathological beta A4 is generated is unknown, it is however a critical event in Alzheimer's disease and is distinct from the normally occurring cleavage and secretion of APPs within the beta A4 sequence. We report here for the first time considerable APP mRNA expression by rat brain microglial cells. In addition we showed by S1 nuclease protection and polymerase chain reaction analysis of reverse transcribed RNA (RT-PCR) that T-lymphocytes, macrophages, and microglial cells expressed a new APP isoform by selection of a novel alternative splice site and exclusion of exon 15 of the APP gene. This leads to a transmembrane, beta A4 sequence containing APP variant, lacking 18 amino acid residues close to the amyloidogenic region. The use of this novel alternative splice site alters the structure of APP in close proximity to the beta A4 region and thus may determine a variant, potentially pathogenic processing of leukocyte-derived APP in brain.

Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer's disease cortices.

Recent studies indicated that the formation of a major constituent of Alzheimer's disease (AD) senile plaques, called beta A4-peptide, does not result from normal processing of its precursor, amyloid precursor protein (APP). Since proteolytic cleavage of APP inside its beta A4 sequence was found to be part of APP processing the formation of the beta A4-peptide seems to be prevented under normal conditions. We considered whether in AD one of the endogenous proteinase inhibitors might interfere with APP processing. After we had recently found that cultured human neuronal cells synthesize the most potent of the known human proteinase inhibitors, alpha-2-macroglobulin (alpha 2M), upon stimulation with the inflammatory mediator interleukin-6 (IL-6) we now investigated whether alpha 2M and IL-6 could be detected in AD brains. Here we report that AD cortical senile plaques display strong alpha 2M and IL-6 immunoreactivity while no such immunoreactivity was found in age-matched control brains. Strong perinuclear alpha 2M immunoreactivity in hippocampal CA1 neurons of Alzheimer's disease brains indicates that neuronal cells are the site of alpha 2M synthesis in AD brains. We did not detect elevated IL-6 or alpha 2M levels in the cerebrospinal fluid of AD patients. Our data indicate that a sequence of immunological events which seem to be restricted to the local cortical environment is part of AD pathology.

Quantitative changes in the amyloid beta A4 precursor protein in Alzheimer cerebrospinal fluid.

The major three secretory isoforms of Alzheimer beta A4 amyloid precursor protein (APP) were quantified in cerebrospinal fluid (CSF) using (1) a newly developed enzyme-linked immunosorbent assay (ELISA) and (2) densitometric analysis of CSF Western blots. The protease inhibitor-containing APP751/770 isoforms represented an average of 10.5% of total APP in CSF of patients with Alzheimer's disease (AD, n = 22), multi-infarct dementia (MID, n = 5) and normal controls (n = 10). APP levels in CSF did not depend on total CSF protein. Both findings are inconsistent with a hematogeneous origin of APP in CSF and suggest an intracerebral source. Total APP, APP695 and APP751/770 were significantly decreased in the AD and in the MID groups, but were not correlated to the ages of patients or controls.

Synthesis and secretion of Alzheimer amyloid beta A4 precursor protein by stimulated human peripheral blood leucocytes.

Alzheimer amyloid precursor proteins (APP) are actively secreted by stimulated human peripheral mononuclear blood leucocytes (PMBLs). Induction of APP transcription, translation and secretion was observed with several T cell mitogens but was highest with phytohemagglutinin. The time course of induction is similar to that reported for IL-2 and IL-2 receptor. We suggest that APP may play an important role in the construction of the immunological network and the differentiation of T cells.