[Stopping antidepressants: withdrawal symptoms and rebound effects : Review and practical recommendations]. / Absetzen von Antidepressiva ­ Absetzsymptome und Rebound-Effekte : Übersicht und praktische Empfehlungen.

Stopping antidepressants can cause withdrawal (discontinuation) symptoms, the return of the original illness, and rebound. The latter means that the disease will return stronger, faster, or with greater likelihood than if it had not been treated with medication. The Psychiatry Working Group of the Drug Commission of the German Medical Association (AkdÄ) presents the scientific findings and provides practical recommendations for action. Withdrawal symptoms are multiform; unspecific physical symptoms are predominant. Distinguishing them from the recurrence of depressive symptoms can be difficult. Most of them are mild and self-limiting. There is insufficient evidence on the extent and frequency of rebound depression. The rebound risk implies that when establishing the medication, the short-term benefit must be weighed against the possible long-term risk of chronic depression or the possible need for long-term medication. Patients should be informed about the risk of withdrawal both as early as the joint decision-making process about treatment initiation and regularly during the course of treatment. Withdrawal should take place gradually, except in emergency situations, whereby small steps should be taken, especially in the low-dose range.

[Antipsychotics for treatment of neuropsychiatric disorders in dementia]. / Antipsychotika zur Behandlung neuropsychiatrischer Störungen bei Demenz.

Antipsychotics, when used to treat neuropsychological symptoms associated with dementia, are associated with low effectiveness but a high risk of side effects. Some of these unwanted effects are severe and include an increased rate of cerebrovascular events and increased mortality. Although neuropsychiatric symptoms are frequently associated with dementia, it appears that antipsychotics are often used without clear indications and for too long time periods. Antipsychotics should be used only when all non-pharmacological strategies have failed. A clear definition of the treatment target in advance and a continuous monitoring of the therapy are mandatory.

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study.

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins alpha and beta (sAPP alpha and sAPP beta) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination >or=20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloid beta peptides, Tau and phospho-Tau. sAPP alpha and sAPP beta were measured with multiplexing method based on electrochemiluminescence. sAPP alpha and sAPP beta CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPP alpha and sAPP beta CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPP alpha and sAPP beta highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPP alpha: cutoff, 117.4 ng ml(-1), sensitivity, 68%, specificity, 85%, P<0.001; sAPP beta: cutoff, 181.8 ng ml(-1), sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPP alpha and sAPP beta might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

[Diagnosis without therapy: early diagnosis of Alzheimer's disease in the stage of mild cognitive impairment]. / Diagnose ohne Therapie : Frühdiagnostik der Alzheimer-Krankheit im Stadium der leichten kognitiven Beeinträchtigung.

Alzheimer's disease (AD) is a histopathologically defined progressive neurodegenerative disorder. Its clinical manifestation can be subdivided into the stage of mild cognitive impairment (MCI) and the stage of dementia. According to ICD-10 the diagnosis of AD can only be made in the stage of dementia. The indication for anti-dementia drugs is restricted to the stage of dementia in AD, too. Diagnostic tools to detect AD have improved considerably in recent years. They include the MRI findings of atrophy of the medial temporal lobe, cerebrospinal fluid (CSF) biomarkers ß-amyloid and τ, the visualisation of metabolic deficits on positron emission tomography (PET) using [(18)F]-fluoro-2-deoxy-D-glucose (FDG) and the emerging possibility to demonstrate amyloid deposits in vivo using PET ligands. The application of these methods allows the diagnosis of AD to be established already in the stage of MCI. While diagnostic methods improve and enable us to make the diagnosis of AD very early, there is no such progress in the development of treatment options. Early diagnosis of AD appears to have benefits and drawbacks. It is most important to include the patient in the decision on early diagnosis and to make clear that there is a lack of therapeutic options if the diagnosis is positive.

Critical evaluation of self-rated quality of life in mild cognitive impairment and Alzheimer's disease--further evidence for the impact of anosognosia and global cognitive impairment.

OBJECTIVES: The present study investigates the effect of anosognosia (impaired insight for an illness) and cognitive deficits on the reliability and validity of self-rated Quality of Life (QoL) in Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD). DESIGN: Cross-sectional study. SETTING: Cross-sectional study with a consecutive clinical sample from a memory clinic in Leipzig (Germany). SUBJECTS: 27 patients (aged 65 years or above) with a diagnosis of either MCI (N=12) or AD (N=15), each together with a caregiver. MEASUREMENTS: The patients' QoL was measured using the Dementia Quality of Life self and proxy ratings (DEMQoL and DEMQoLproxy). The degree of anosognosia was rated by means of the Clinical Insight Rating Scale (CIR). In addition the Mini-Mental-State Examination (MMSE), and for diagnostic purposes the Bayer Activities of Daily Living Scale (B-ADL) and the Consortium to Establish a Registry of Alzheimer;s Disease (CERAD) word list were applied. RESULTS: In accordance with the results of Ready et al. (1), patients with impaired insight were found to produce less reliable QoL ratings than those with unimpaired insight. The validity (concordance between self- and proxy QoL ratings) is influenced by cognitive deficits, anosognosia and the interaction between these factors. CONCLUSIONS: Data which are based on dementia patients' QoL self-ratings need to be interpreted with caution when anosognosia is present.

Evolution of Abeta42 and Abeta40 levels and Abeta42/Abeta40 ratio in plasma during progression of Alzheimer's disease: a multicenter assessment.

OBJECTIVE: To better understand the seemingly contradictory plasma beta-amyloid (Abeta) results in Alzheimer's disease (AD) patients by using a newly developed plasma Abeta assay, the INNO-BIA plasma Abeta forms, in a multicenter study. METHODS: A combined retrospective analysis of plasma Abeta isoforms on mild cognitive impairment (MCI) from three large cross-sectional studies involving 643 samples from the participating German and Swedish centers. RESULTS: Detection modules based on two different amino (N)-terminal specific Abeta monoclonal antibodies demonstrated that Abeta in plasma could be reliable quantified using a sandwich immunoassay technology with high precision, even for low Abeta42 plasma concentrations. Abeta40 and Abeta42 concentrations varied consistently with the ApoE genotype, while the Abeta42/Abeta40 ratio did not. Irrespective of the decrease of the Abeta42/Abeta40 ratio with age and MMSE, this parameter was strongly associated with AD, as defined in this study by elevated hyperphosphorylated (P-tau181P) levels in cerebrospinal fluid (CSF). CONCLUSION: A highly robust assay for repeatedly measuring Abeta forms in plasma such as INNO-BIA plasma Abeta forms might be a useful tool in a future risk assessment of AD.

[The situation of patients with dementia may be rectified by Ginkgo biloba. Results of a health services research study concerning the ability of patients with dementia, quality of life of the nursing family members and total treatment costs]. / Versorgungssituation von Demenzkranken kann durch Ginkgo biloba verbessert werden. Ergebnisse einer Studie zur Versorgungsforschung hinsichtlich der Leistungsfähigkeit der Demenzkranken, der Lebensqualität der Pflegenden und der Gesamtkosten der Behandlung.

UNLABELLED: BACKGROUND AND ISSSUES: Ginkgo biloba-extracts are often used in therapy of patients with dementia. In this study, benefit and structure of Ginkgo biloba-extract EGb 761 in treatment of patients with dementia was examined. PATIENTS AND METHODS: For the assessment of quality of life of care-taking relatives and patients as well as treatment costs were documented. The study was conducted as a non-randomised, two-armed cohort study with an open design for 683 slightly or moderately demented patients, aged between 65 and 80 years. Society's perspective was taken. Barthel-Index and MMST were also documented. Because of significant differences at inclusion of both cohorts, a matched-pairs-analysis and multiple regression analysis conducted. RESULTS: According to PLC a significant improvement in quality-of-life of care-taking relatives (p < 0.001) and patients (positive mood p = 0.018, negative mood p < 0.001) was only observed in the Ginkgo-cohort. Also Barthel-Index indicated an improvement in the Ginkgo-cohort (p < or = 0,001). MMST-scores increased significantly only in the Ginkgo-cohort (p < 0.001). Average total cost per patient amounted to 3.614,75 euro in the standard-cohort, whereas these costs per patient in the Ginkgo-cohort amounted to 3.031,78 euro (p = 0.067). Results were confirmed by matched-pairs-analysis. RESULTS: Ginkgo treatment has a valid place in caretaking structure of health services. Gingko attributes to a higher quality of life for both care-takers and patients, the progression of disease is slowed down and treatment costs are lower.

Results from a Phase II Study to Assess the Clinical and Immunological Activity of AFFITOPE® AD02 in Patients with Early Alzheimer's Disease.

OBJECTIVES: The primary objective of this clinical trial was to assess the clinical activity of various doses and formulations of AFFITOPE® AD02 following its repeated s.c. administration to patients with early Alzheimer´s disease (AD), based on the evaluation of cognitive and functional domains. DESIGN: It was designed as a randomized, placebo-controlled, parallel group, double blind, multicenter phase II trial with 10 regular outpatient visits and 6 telephone interviews. SETTING: The trial was performed at 32 sites in six countries. PARTICIPANTS: A total of 332 patients were enrolled and 265 patients completed the trial in 3 treatment groups with AD02 and 2 control groups with aluminum oxihydroxide, here named IMM-AD04. Patients were randomly assigned to 5 groups: two doses of IMM-AD04, 25µg AD02 (in two different formulations) and 75µg AD02. INTERVENTION: At months 0, 1, 2, 3, 9 and 15, each patient received a single s.c. injection of the corresponding preparations of AFFITOPE® AD02 or the control, IMM-AD04. MEASUREMENTS: Co-primary efficacy outcomes included a measure of cognition (adapted AD Assessment Scale cognitive [aADAS cog]), and a measure of function (adapted AD Cooperative Trial Activities of Daily Living [aADCS-ADL]). A primary composite score was the sum of these two scores. RESULTS: Treatments were generally well tolerated and adverse events (AEs) were seen at similar rates across all treatment groups, with the exception that more injection site reactions were seen in the groups with a higher level of adjuvant. None of the AD02 groups showed a benefit over the IMM-AD04 controls for primary or exploratory efficacy outcomes. The control groups differed on aADCS-ADL and therefore couldn't be pooled (p=0.039). Unexpectedly, the 2mg IMM-AD04 showed statistically significant effects over the other groups on several clinical outcomes including: aADAS-cog, aADL, Composite, ADAS-cog, CDR-sb, and QOL-AD Caregiver as well as two biomarker outcomes: right and total hippocampal volume (all p<0.05). 48% of patients in the IMM-AD04 2mg group had no decline in the composite outcome over 18 months compared to 17%-31% in the other groups, which is consistent with historical placebo groups. CONCLUSION: No significant treatment effects were seen for the investigational compound AD02. However, the IMM-AD04 2mg group showed statistically significant effects over all other groups on several clinical outcomes as well as a slowing of decline on right hippocampal volume. The data support further development of IMM-AD04 as a disease modifying agent in line with EMA/FDA definitions.

Cerebral blood vessel changes in old people.

We give an electron microscopic description of vascular convulates, which occur along with normal brain aging. They consist of up to 10 vessels which are surrounded by a common perivascular space. We can make clear that the convolutes consist exclusively of normal arterioles. Each single vessel shows endothelial cells without pores. The media is mostly composed of a single layer of smooth muscle cells which are surrounded by adventitial cells or their processes. The adventitial cells show a high amount of lipid inclusions. From microangiographic research it is obvious that the absolute increase in length of the vessels is the main factor in the genesis of vascular convolutes. According to experimental animal studies it seems likely that recurrent hypoxic conditions lead to a considerable increase in length in the cerebral arterioles in old people.

Glycogen accumulation of the aging human brain.

We describe light- and electron-microscopically a new type of intracytoplasmatic inclusions within cell processes of the cerebral cortex and the underlying white matter. These structures measure 5-50 micron in diameter and consist almost exclusively of densely packed alpha- or beta-glycogen granules, which never occur together in any single structure. Within their periphery, electron-dense amorphous spots and cell organelles, especially mitochondria, were seen. No membrane-bound glycogen was observed. We propose to call them granular glycogen bodies. They occur in 4 of 7 examined postmortem specimens of the cerebral cortex of people older than 60 years of age. They were not found in 4 younger controls aged 26-48. Their appearance may reflect a distinct turnover disorder of carbohydrate metabolism, which becomes manifest under diverse pathologic conditions and in the normal aging process.

Creutzfeldt-Jakob disease: correlation of MRI and neuropathologic findings.

In a patient with Creutzfeldt-Jakob Disease (CJD), MRI showed increased signal intensity in striatum, thalamus, and cerebral cortex in images obtained with TR 1,600 msec, and TE 35 and 70 msec. In postmortem examination, all affected areas showed the hallmarks of CJD, such as status spongiosus, gliosis, and nerve cell loss. MRI can help to differentiate CJD from other dementing processes.

Review about Ginkgo biloba special extract EGb 761 (Ginkgo).

Ginkgo biloba extracts (EGb) are well-defined plant extracts. It has several indications as dementia, macula degeneration, tinnitus and winter depression. A review of the current and past literature about older people with Alzheimer's dementia or vascular dementia or age-associated memory impairment treated with Ginkgo biloba extract, reveals that EGb has reproducible effects on cognitive functions in Alzheimer's disease. The drug is well tolerated.

Cortical distribution of neurofibrillary tangles in Alzheimer's disease matches the pattern of neurons that retain their capacity of plastic remodelling in the adult brain.

The formation of neurofibrillary tangles in Alzheimer's disease shows a preferential involvement of certain cytoarchitecturally defined cortical areas suggesting systematic differences in regional neuronal vulnerability. The cellular and molecular nature of this selective neuronal vulnerability that follows a certain hierarchy of structural brain organization is largely unknown. In the present study, we compared the regional pattern of tangle density in Alzheimer's disease with systematic regional differences in neuronal plasticity that can be observed both during ageing and in Alzheimer's disease. Changes in dendritic length and arborization of Golgi-impregnated pyramidal neurons were analysed after three-dimensional reconstruction in 12 cortical areas. The intensity of dendritic remodelling that was observed during ageing as well as in Alzheimer's disease was regionally different and decreased in the following order: transentorhinal region > limbic areas (entorhinal region, hippocampus) > non-primary association areas (37, 40, 46) > primary sensory association areas (7, 18, 22) > primary sensory and motor cortex (17, 41, 4). These regional differences of neuronal plasticity follow the same pattern as the regional vulnerability to tangle formation in Alzheimer's disease. The results of the present study provide evidence that a high degree of structural neuronal plasticity might predispose neurons to tangle formation.

Pathological changes in dendrites of substantia nigra neurons in Parkinson's disease: a Golgi study.

Neurons of the substantia nigra show severe morphological changes in Parkinson's disease. Pathological alterations of cell bodies have been described, whereas those of neuronal processes have hardly been investigated. Golgi impregnation has been the chosen method for demonstrating neuronal processes and dendritic and somatic spines. We therefore used the Golgi-Braitenberg method to qualitatively and semi-quantitatively study the substantia nigra of eight patients with Parkinson's disease compared with eight control cases. Golgi impregnation of substantia nigra neurons was good in all control cases. In full agreement with the analysis of Braak and Braak (1986) three neuronal types within the substantia nigra were found. In cases of Parkinson's disease, severe pathological changes such as decrease of dendritic length, loss of dendritic spines and several types of dendritic varicosities were found only in the melanin-containing pars compacta neurons. Pars reticulata nerve cells were intact. These findings support the predominant role played by the dopaminergic efferent pathway in the degenerative process. The afferent pathway was not affected. This suggests that the substantia nigra lesion is primary in Parkinson's disease. Loss of neurons found in H & E sections corresponded to a lesser amount of impregnated pars compacta neurons in cases with Parkinson's disease when compared to controls. Evidences exist that the duration of the disease may be related to the extent of pathologically altered Golgi-impregnated pars compacta cells. The amount of Lewy bodies in H & E sections corresponded to the quantity of round varicosities in impregnated pars compacta neurons. These round dendritic varicosities were considered to be Lewy body inclusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Theta power in the EEG of humans during ongoing processing in a haptic object recognition task.

Dynamic changes in spectral theta power (TP) in the EEG over frontal regions were reported previously during the processing of visually presented spatial and verbal tasks [Cereb. Cortex, 7 (1997) 374-385]. Lower TP was found at the beginning compared to the end of processing. In order to test another modality, we examined theta power during the exploration of haptic stimuli with different complexity. A linear correlation between theta power and mean exploration time (as a measure of stimulus complexity) was found at the end of exploration but not at its beginning. These data are in line with our hypothesis since one could expect minimal load of working memory independent of stimulus complexity at the beginning of exploration whereas working memory would have integrated the stimuli of differing complexity into a perceptual model at the end of exploration.

Impairment of mitogenic activation of peripheral blood lymphocytes in Alzheimer's disease.

Cell-cycle dysregulation might be critically involved in the process of neurodegeneration in Alzheimer's disease (AD). We now provide evidence for a dysfunction of the cell division cycle as a more general cellular phenomenon of the disease. Peripheral blood lymphocytes, stimulated with mitogenic compounds, were less able to express CD69, an early proliferation marker, in AD patients than in age-matched controls. Expression levels of CD69 of both T-cells and B-cells correlated inversely with the Mini-mental Scale. The results suggest that a systemic failure of cellular proliferation control might be of critical importance for the pathomechanism of AD.

Stability of cell size and nucleolar size in Lewy body containing neurons of substantia nigra in Parkinson's disease.

Samples of 9 brains of autopsied patients suffering from Parkinson's disease were examined. In H & E stained 20 microns thick sections of substantia nigra 10 Lewy body containing and 20 unaffected pigmented nerve cells of substantia nigra per case were measured for size of the perikarya and nucleolar size utilizing an interactive image processing unit. In affected cells the size of Lewy bodies was measured too. There was no significant difference in the size of the perikarya and nucleolar size between affected and unaffected cells. In Lewy body bearing cells nucleolar size was not correlated with the size of the Lewy bodies. There was a significant negative correlation between nucleolar size of substantia nigra neurons and the duration of the disease. Since nucleolar volume can serve as indicator of RNA synthesis of a cell, Lewy bodies do not seem to disturb nerve cell metabolism.

Aberrant expression of nNOS in pyramidal neurons in Alzheimer's disease is highly co-localized with p21ras and p16INK4a.

Aberrancies of growth and proliferation-regulating mechanisms might be critically involved in the processes of neurodegeneration in Alzheimer's disease (AD). Expression of p21ras and further downstream signalling elements involved in regulation of proliferation and differentiation as, for example, MEK, ERK1/2, cyclins, cyclin-dependent kinases and their inhibitors such as those of the p16INK4a family, are elevated early during the course of neurodegeneration. Activation of p21ras can also directly be triggered by nitric oxide (NO), synthesized in the brain by various isoforms of nitric oxide synthase (NOS) that might be differentially involved into the pathomechanism of AD. To study the potential link of NO and critical regulators of cellular proliferation and differentiation in the process of neurofibrillary degeneration, we analyzed the expression pattern of NOS-isoforms, p21ras and p16INK4a compared to neurofibrillary degeneration in AD. Additionally to its expression in a subtype of cortical interneurons that contain the nNOS-isoform also in normal brain, nNOS was detected in pyramidal neurons containing neurofibrillary tangles or were even unaffected by neurofibrillary degeneration. Expression of nNOS in these neurons was highly co-localized with p21ras and p16INK4a. Because endogenous NO can activate p21ras in the same cell which in turn leads to cellular activation and stimulation of NOS expression [H.M. Lander, J.S. Ogiste, S.F.A. Pearce, R. Levi, A. Novogrodsky, Nitric oxide-stimulated guanine nucleotide exchange on p21 ras, J. Biol. Chem. 270 (1995) 7017-7020], the high level of co-expression of NOS and p21ras in neurons vulnerable to neurofibrillary degeneration early in the course of AD thus provides the basis for an autocrine feedback mechanism that might exacerbate the progression of neurodegeneration in a self-propagating manner.

Stability of cell size and nucleolar size in tangle-bearing neurons of the hippocampus in Alzheimer's disease.

Samples of 14 brains of autopsied patients suffering from dementia of the Alzheimer type were examined. In Congo red-hemalum stained 14-microns-thick sections of the hippocampus 15 tangle-bearing and 25-30 unaffected nerve cells of area CA1 per case were measured for cell size and nucleolar size utilizing an interactive image processing unit. In affected cells tangle size was measured too. There was no significant difference in neuron size and nucleolar size between affected and unaffected cells. In tangle-bearing cells nucleolar size and cell size were not correlated with tangle size. Since nucleolar volume can serve as an indicator of RNA synthesis of a cell, tangles themselves seem not to disturb nerve cell metabolism.