Alzheimer Disease: Marksteiner J

Kerer M, Marksteiner J, Hinterhuber H, Mazzola G, Steinberg R, Weiss EM. · Abteilung für Allgemeine Psychiatrie, Medizinische Universität Innsbruck. · Neuropsychiatr. · Pubmed #19272287 No free full text.

Abstract: Patients suffering from dementia are nevertheless still able to render exceptional musical performances. For example, they can recognize music from childhood and reproduce lyrics and melodies of songs with four verses. Furthermore, behavioural symptoms such as psycho- motor agitation and crying, but also aggressive behaviour can be positively influenced by music and motivation and positive emotions can be increased. A variety of physiological and psychological changes occur when patients are listening to music. Previous research could show that music activated different parts of the brain especially in the temporal cortex, but also motoric areas in the frontal cortex, thalamus and cerebellum were essential for rhythm, melody and harmony perception and processing. Music therapy is an interpersonal process in which music is used within a therapeutic relationship to address physical, emotional, cognitive, and social needs of individuals with various psychiatric or medical conditions. However, until now only little research has been directed towards non-pharmacological treatments like music therapy in dementia patients. Further research is warranted to investigate the long term influence of music therapy on patients suffering from dementia.

Schmidt R, Neff F, Lampl C, Benke T, Anditsch M, Bancher C, Dal-Bianco P, Reisecker F, Marksteiner J, Rainer M, Kapeller P, Dodel R. · Universitätsklinik für Neurologie, Medizinische Universität Graz. · Neuropsychiatr. · Pubmed #18826870 No free full text.

Abstract: Cholinesterase inhibitors and memantine can slow the course of Alzheimer's disease. In Austria the frequency of treatment is in the upper third among countries of the EU. Yet, the majority of Alzheimer patients does not receive adequate medication. Compliance to treatment is low. Studies on cholinesterase inhibitors show that only one third and one fifth of patients adhere to medication after 3 months and 12 months, respectively. Causes for low compliance are only partly patient-related, many factors are system-inherent. Knowledge of these factors is a pre-requisite for the treating physician to improve current unfavourable situation. Present treatment strategies are symptomatic, causal disease-modifying therapies are urgently needed. Research activity in the field is high and dominated by the amyloid hypothesis. We here review the basis and recent studies on secretase-inhibitors, immunization, aggregation of Abeta, statins and PPARgamma-agonists. Research towards strategies against tau-pathology is less dominant and focuses on inhibition of kinases and increase of activity of phosphatases. Causal therapies would have great effects on a population basis even if efficacy is only moderate. A disease-modifying therapy which delays the onset of Alzheimer disease by 5 years, will probably reduce the number of patients by nearly 50% during the next 50 years.

Schmidt R, Kienbacher E, Benke T, Dal-Bianco P, Delazer M, Ladurner G, Jellinger K, Marksteiner J, Ransmayr G, Schmidt H, Stögmann E, Friedrich J, Wehringer C. · Univ.-Klinik für Neurologie, Medizinische Universität Graz. · Neuropsychiatr. · Pubmed #18381051 No free full text.

Abstract: The prevalence of Alzheimer disease is higher in women than in men. In the age group 65-69 years 0.7% of women and 0.6% of men suffer from the disease with increasing frequencies of 14.2% and 8.8% in individuals aged 85-89 years. The incidence is also higher in demented women. In Austria 74.1% of Alzheimer patients older than 60 years are women. Several studies report more pronounced language, mnestic, semantic and orientation deficits in women, but methodological shortcomings might be responsible for this finding. The validity of results reporting a more rapid cognitive decline in women can also be questioned. Women have a broader spectrum of dementiarelated behavioural symptoms with a predominance of depression, while aggression is more frequent in men than in women. Biological explanations for gender-specific differences in the phenotype of Alzheimer s disease include different brain morphology and function with higher susceptibility for pathological lesions in women and greater cognitive reserve in men. Sex differences were also reported for expression of antioxidative enzymes and post-menopausal hormonal changes. Interactions between gender nd response to treatment, if any, are subtle and have large intra-individual variability. In Austria, two thirds of patients receiving attendance allowance are women. Care takes place in 80% by the families and is provided by women in 78%. The rate of female care-givers in partly institutionalized care units in 91% in nursing homes it is 84%.

Marksteiner J, Hinterhuber H, Humpel C. · Department of General Psychiatry, Innsbruck Medical University, Innsbruck, Austria. · Drugs Today (Barc). · Pubmed #17612711 No free full text.

Abstract: Alzheimer's disease is a chronic progressive neurodegenerative disease and it is the most prevalent type of dementia. Diagnostic means, including neuroimaging methods, are continuously improving. Nevertheless, it is still a challenge to increase the sensitivity and specificity of a diagnosis of Alzheimer's disease. Two diagnostic areas are especially challenging: first, differentiating early stages of Alzheimer's disease from mild cognitive impairment and normal aging; and second, increasing diagnostic specificity especially when similar clinical symptoms are shared by various types of dementia. To date, the analysis of beta-amyloid(1-42), total tau and phospho-tau-181 from cerebrospinal fluid (CSF) are the best biological markers to diagnose Alzheimer's disease and differentiate it from other forms of dementia with a high reliability and validity. This article reviews the use of CSF biomarkers and of putative blood-related markers.

Humpel C, Marksteiner J. · Laboratory of Exp. Alzheimer's Research, Department of Psychiatry, Innsbruck Medical University, Austria. · Curr Neurovasc Res. · Pubmed #16181125 No free full text.

Abstract: Alzheimer's disease is a progressive brain disorder that gradually destroys a patient's memory function and ability to carry out daily activities. According to the prevailing amyloid cascade hypothesis, Alzheimer's disease is initiated by amyloid beta-peptide accumulation leading to neuronal toxicity. The neurofibrillary tangle deriving from hyperphosphorylated tau and synapse loss are also key features for Alzheimer's disease. Recent studies revealed a significant co-morbidity of Alzheimer's disease and cerebrovascular disease suggesting that cerebrovascular dysregulation is an important feature of Alzheimer's disease. This mini-review will discuss the hypothesis that a dysfunction of the vascular system may result in damage of the neurovascular unit, initiating a cascade of events. An overlap with other forms of cognitive impairment, such as mild cognitive impairment, or vascular dementia will be discussed.

Weiss EM, Kohler CG, Vonbank J, Stadelmann E, Kemmler G, Hinterhuber H, Marksteiner J. · Department of General Psychiatry, Innsbruck Medical University, Innsbruck, Austria. · Am J Geriatr Psychiatry. · Pubmed #19038896 No free full text.

Abstract: OBJECTIVE: To investigate emotion discrimination abilities in healthy comparison subjects, patients with mild cognitive impairment (MCI), early and moderate Alzheimer disease (AD). DESIGN: Prospective study design. SETTING: Outpatient memory clinic, Department of Psychiatry, Innsbruck, Austria. METHODS: One hundred forty-one subjects older than 60 years were included in the study. Thirty-five subjects were classified as healthy comparison subjects, 51 subjects as MCI (21 subjects with amnestic MCI single domain, 31 subjects with amnestic MCI multiple domain), 32 subjects with early AD and 23 subjects with moderate AD. MEASUREMENTS: All subjects were tested on an extensive neuropsychological test battery including the Penn Emotion Recognition Tests and depression symptoms were assessed additionally. RESULTS: Healthy subjects and patients with MCI, early and moderate AD differed significantly in the recognition of all emotions and neutral faces combined. When separated by emotion, the authors found significant differences in emotion recognition between the diagnostic groups for happy, sad, fearful, and neutral faces. Compared with comparison subjects, amnestic MCI patients single domain did not differ significantly in their emotion recognition abilities, but amnestic MCI multiple domain patients were already impaired in the recognition of overall emotions, sad, fearful, and neutral faces and the deficits increased with the severity of AD. Depression had a significant influence on the recognition of overall emotion and neutral faces and increased the probability of misinterpreting neutral faces as sad leading to a negative bias. CONCLUSIONS: Diminished abilities for emotion discrimination are already present in patients with MCI and further decreased with AD progression.

Marksteiner J, Pirchl M, Ullrich C, Oberbauer H, Blasko I, Lederer W, Hinterhuber H, Humpel C. · Department of General Psychiatry, Innsbruck Medical University, Innsbruck, Austria. · Pharmacology. · Pubmed #18810245 No free full text.

Abstract: Alzheimer's disease (AD) is a severe, progressive and chronic disorder with strong cognitive deficits. Diagnosis of probable AD can be performed by measuring biomarkers in cerebrospinal fluid (CSF). The aim of the present study was to measure CSF levels of nerve growth factor (NGF), the anti-NGF auto-antibody, and the cholinesterases AChE and BChE, and to correlate them with beta-amyloid, tau and phospho-tau-181. We could show that NGF-like immunoreactivity, but not anti-NGF auto-antibody, was significantly enhanced in AD patients compared to healthy subjects, while both cholinesterases were not changed. beta-Amyloid(1-42) was decreased, while tau and phospho-tau-181 were increased. The commercial Promega NGF ELISA detected mature NGF but not wild-type-human-pro-NGF. Using a bioassay of brain slices, we showed that recombinant mature NGF enhanced survival of cholinergic neurons, while wild-type human pro-NGF displayed a less pronounced effect. The addition of CSF to brain slices exhibited strong toxic effects on the survival of cholinergic neurons. We conclude that in CSF of AD patients (at least partly) mature NGF-like immunoreactivity is enhanced, and is masked in a bioassay by the toxic properties of CSF.

Marksteiner J, Humpel C. · Laboratory of Psychiatry and Exp. Alzheimer's Research, Department of General Psychiatry, Innsbruck Medical University, Innsbruck, Austria. · Mol Psychiatry. · Pubmed #17712316 No free full text.

Abstract: 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.

Willis M, Hutter-Paier B, Wietzorrek G, Windisch M, Humpel C, Knaus HG, Marksteiner J. · Department of General Psychiatry, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. · Brain Res. · Pubmed #17328871 No free full text.

Abstract: Substance P-like immunoreactivity (-LI) is found in neuritic plaques, and is reduced in patients suffering from Alzheimer disease (AD). In this study, we examined the distribution and expression of substance P in transgenic mice overexpressing human amyloid precursor protein (hAPP) APP751 with the London (V717I) and Swedish (K670M/N671L) mutations. Immunohistochemistry was performed to localize substance P- and glial fibrillary acidic protein-LI by confocal microscopy. In hAPP transgenic mice, the number of beta-amyloid plaques significantly increased from 6 to 12 months. About 5% of beta-amyloid plaques were substance P-immunoreactive. In transgenic mice, the morphology of substance P-immunoreactive structures changed by consisting of swollen and dystrophic neurites mostly associated with beta-amyloid plaques. The overall localization and the relative substance P densities were not different between wild type and transgenic mice at 6 and 12 months. At month 12, a dramatic change in the distribution pattern of substance P-LI was observed as it was now expressed in a high number of reactive astrocytes. This expression of substance P in astrocytes was mainly found in the hippocampal formation and thalamic nuclei with a preferential association with beta-amyloid plaques, whereas in cortical regions only faintly substance P-immunoreactive astrocytes were observed. This study indicates that substance P undergoes complex changes in this animal Alzheimer disease model. Future experiments including substance P antagonists are necessary to further explore the interaction between beta-amyloid deposits and substance P.

Pirchl M, Marksteiner J, Humpel C. · Laboratory of Experimental Alzheimer's Research, Department of General Psychiatry, Innsbruck Medical University, Austria. · Neurol Res. · Pubmed #16945219 No free full text.

Abstract: Alzheimer's disease is a progressive brain disorder which is neuropathologically characterized by an increased number of beta-amyloid plaques, tau pathology and synapse loss. Recent research suggests that vascular pathology may be also important for the development and progression of Alzheimer's disease. It is still unknown whether there is a relation between damage of brain capillary endothelial cells (BCEC) and subsequent cholinergic cell death. The aim of this study was to examine the effects of acidosis on cell death of BCEC and cholinergic neurons in an organotypic brain slice model. We show that BCEC were heavily damaged in medium at pH<6.6. Cholinergic neurons incubated in medium pH 6.0 degenerated within 2-3 days and were not rescued by nerve growth factor (NGF). Lactate did not affect the survival of BCEC or cholinergic neurons. Both BCEC and cholinergic cells were not affected at pH 7.4, 7.0 or 6.6. It is concluded that both endothelial cells and cholinergic neurons have a high capacity to compensate for pH changes. At a certain pH, however, the vascular and neuronal cells show the same vulnerability, indicating that a low pH is deleterious for the cerebral microenvironment. Future studies are necessary to explore whether temporary pH changes could be responsible for cerebrovascular damage and cholinergic cell death. Acidosis may play an important role in the development of vascular dementia and Alzheimer's disease.

Blasko I, Knaus G, Weiss E, Kemmler G, Winkler C, Falkensammer G, Griesmacher A, Würzner R, Marksteiner J, Fuchs D. · Department of Psychiatry, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Tyrol, Austria. · J Psychiatr Res. · Pubmed #16542679 No free full text.

Abstract: The pro-inflammatory reaction of the immune system is a feature of healthy aging and might influence the progression of Alzheimer's disease (AD). Neopterin is a pteridine derivative, released from macrophages upon stimulation with pro-inflammatory cytokine interferon-gamma. Forty-three probable AD patients were investigated at baseline and follow up (14.5+/-0.5 months; mean+/-s.e.m.). We assessed the clinical progression by the Consortium to Establish a Registry for Alzheimer's disease (CERAD) battery and compared cognitive changes to serum concentrations of neopterin, C-reactive protein (CRP) and antibody to cytomegalovirus (CMV). The mean neopterin concentrations increased significantly from 9.8+/-1.0 to 13.6+/-2.1 nM (p=0.04). In contrast, mean CRP concentrations at baseline was 0.46+/-0.1 and non-significantly decreased to 0.28+/-0.04 mg/dl. Of AD patients 70% were CMV IgG-seropositive at baseline and CMV-antibody concentrations correlated with levels of neopterin (Spearman r=0.386, p=0.016). CERAD scores did not correlate with any of immune parameters at baseline. At follow up, the increase of neopterin correlated significantly with the decrease in the total CERAD and MMSE scores, according to the clinical progression (r=-0.353, p<0.05 and r=-0.401, p<0.01, respectively). Subdividing the sample with respect to baseline MMSE scores, neopterin concentrations significantly increased only in the group of MMSE<20. In the multiple testing covariated for age, gender, Apolipoprotein E-epsilon4 allele, time difference between both measurements, neopterin remained significantly associated with cognitive decline. In summary, neopterin concentrations correlated with cognitive decline in AD patients, which might be due to high CMV seropositivity in that population.

Blasko I, Lederer W, Oberbauer H, Walch T, Kemmler G, Hinterhuber H, Marksteiner J, Humpel C. · Department of Psychiatry, Innsbruck Medical University, Innsbruck, Austria. · Dement Geriatr Cogn Disord. · Pubmed #16244482 No free full text.

Abstract: Cerebrospinal fluid (CSF) biological markers may be of valuable help in the diagnosis of dementia. The aim of the present study was to evaluate CSF levels of 13 potential biomarkers in patients with Alzheimer's disease (AD), frontotemporal lobe dementia, alcohol dementia, major depression and control patients without any neuropsychiatric disease. The study was performed using beta-amyloid 1-42 (Abeta42), total tau and phosphorylated tau-181 (P-tau181) as core markers. The ratio P-tau181/Abeta42 could significantly distinguish AD patients from all other diagnostic subgroups. CSF levels of 5 growth factors (HGF, GDNF, VEGF, BDNF, FGF-2) and 3 cytokines/chemokines (TNF-alpha, TGF-beta1, MIP-1alpha) did not significantly differentiate between the studied groups. However, depending on the degree of neurodegeneration (as expressed by the ratio P-tau181/Abeta42), patients with AD displayed significantly increased CSF levels of nerve growth factor (NGF) as compared to healthy controls. CSF levels of monocyte chemoattractant protein 1 (MCP-1) were found to be significantly increased with age in all groups but did not distinguish AD patients from healthy controls. The results confirmed the suitability of the ratio P-tau181/Abeta42 for the diagnosis of AD, while CSF levels of NGF and MCP-1 are less specific and reliable for AD. It is suggested that the increase in NGF depends on the extent of neurodegeneration of the AD type and the increase in MCP-1 on age.

Blasko I, Bodner T, Knaus G, Walch T, Monsch A, Hinterhuber H, Marksteiner J. · Department of Psychiatry, University Hospital of Innsbruck, Austria. · Pharmacology. · Pubmed #15292648 No free full text.

Abstract: In a pilot study designed as a case control study the efficacy of donepezil treatment was investigated in patients with Alzheimer's disease (AD). Patients were stratified according to radiological criteria into patients without (AD group) and with subcortical vascular lesions (AD+SVD group). Changes in cognition were assessed as the primary outcome measurement after 6 and 18 months of treatment by the Mini-Mental Status Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery. After 6 months, patients had improved from baseline by 0.7 points in MMSE score in the AD group and by 1.8 in the AD+SVD group. After 18 months of treatment, the AD+SVD group performed significantly worse in one CERAD subscore, whereas a deterioration in two subscores was observed in the AD group. A comparison between the 2 groups revealed that treatment did not lead to statistically significant differences between the AD and AD+SVD groups in any of CERAD parameters following 6 or 18 months of treatment. These data support previous observations that donepezil therapy is effective in AD patients with and without subcortical vascular lesions.

Brenneis C, Wenning GK, Egger KE, Schocke M, Trieb T, Seppi K, Marksteiner J, Ransmayr G, Benke T, Poewe W. · Department of Neurology, University Hospital of Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria. · Neuroreport. · Pubmed #15257132 No free full text.

Abstract: We determined brain atrophy patterns in dementia with Lewy bodies and Alzheimer's disease using voxel-based morphometry, an indirect volumetry. Ten patients with dementia with Lewy bodies, 10 patients with Alzheimer's disease and 10 controls were included. All groups were matched for age; sex and global differences in voxel intensities were included as confounding covariates. We observed basal forebrain atrophy discriminating dementia with Lewy bodies from Alzheimer's disease. Compared to controls, atrophy of lateral prefrontal cortex and left premotor cortex was seen in dementia with Lewy bodies whereas atrophy of the medial temporal cortex, posterior parietal cortex, thalamus and temporo-occipital areas was observed in Alzheimer's disease. Atrophy of insular cortex was found in both patient groups.

Marksteiner J, Schmidt R. · Department of Psychiatry, Medical University Innsbruck, Innsbruck, Austria. · Drugs Aging. · Pubmed #15132710 No free full text.

Abstract: Complex interactive effects of genetic predisposition, neurochemical changes and disease comorbidity have been elucidated in the genesis of dementia syndromes. Alzheimer's disease is the most prevalent type of dementia in developed Western countries. In Alzheimer's disease, pharmacological treatment aims at symptomatic relief, disease modification or disease prevention. Cholinesterase inhibitors are established for the treatment of mild-to-moderate Alzheimer's disease. In Europe and the US, memantine is approved for the treatment of moderate-to-severe Alzheimer's disease. To date, there are no drugs with a disease modifying action that have proven efficacy in randomised, double-blind, placebo-controlled clinical trials. In patients not fulfilling the diagnostic criteria for early Alzheimer's disease, e.g. mild cognitive impairment, the efficacy of several drugs, mainly cholinesterase inhibitors, is currently tested in prospective studies by determining the conversion rate to Alzheimer's disease. However, prevention and disease-modifying strategies raise ethical questions because interventions are focused on non-diseased elderly at risk, which means that emphasis should be not only on efficacy but also on long-term safety. No disease-modifying strategy can presently be offered to patients; however, given the pace of recent research there is optimism that slowing progression of Alzheimer's disease will soon be possible.

Lechner T, Adlassnig C, Humpel C, Kaufmann WA, Maier H, Reinstadler-Kramer K, Hinterhölzl J, Mahata SK, Jellinger KA, Marksteiner J. · Department of Psychiatry, Anichstrasse 35, Innsbruck A-6020, Austria. · Exp Gerontol. · Pubmed #14724070 No free full text.

Abstract: Synaptic disturbances may play a key role in the pathophysiology of Alzheimer's disease.To characterize differential synaptic alterations in the brains of Alzheimer patients, chromogranin A, chromogranin B and secretoneurin were applied as soluble constituents for large dense core vesicles, synaptophysin as a vesicle membrane marker and calbindin as a cytosolic protein.In controls, chromogranin B and secretogranin are largely co-contained in interneurons, whereas chromogranin A is mostly found in pyramidal neurons. In Alzheimer's disease, about 30% of beta-amyloid plaques co-labelled with chromogranin A, 20% with secretoneurin and 15% with chromogranin B. Less than 5% of beta-amyloid plaques contained synaptophysin or calbindin, respectively. Semiquantitative immunohistochemistry revealed a significant loss for chromogranin B- and secretoneurin-like immunoreactivity in the dorsolateral, the entorhinal, and orbitofrontal cortex. Chromogranin A displayed more complex changes. It was the only chromogranin peptide to be expressed in glial fibrillary acidic protein containing cells. About 40% of chromogranin A immunopositive plaques and extracellular deposits were surrounded and pervaded by activated microglia.The present study demonstrates a loss of presynaptic proteins involved in distinct steps of exocytosis. An imbalanced availability of chromogranins may be responsible for impaired neurotransmission and a reduced functioning of dense core vesicles. Chromogranin A is likely to be a mediator between neuronal, glial and inflammatory mechanisms found in Alzheimer disease.

Weiss U, Bacher R, Vonbank H, Kemmler G, Lingg A, Marksteiner J. · Department of Psychiatry, University of Innsbruck, Austria. · J Clin Psychiatry. · Pubmed #12716263 No free full text.

Abstract: BACKGROUND: In vivo proton magnetic resonance spectroscopy is a safe and noninvasive tool that can be used to study aspects of brain chemistry and metabolism. This study was designed to evaluate its role in routine application to reveal the diagnostic reasons for cognitive impairment. METHOD: 37 Alzheimer's disease patients (NINCDS-ADRDA criteria), 31 patients with subcortical ischemic vascular dementia (Chui et al. criteria), and 13 subjects with subjective cognitive impairment (DSM-IV criteria) were included in this retrospective study. Magnetic resonance images were used for atrophy rating; additionally, proton magnetic resonance spectroscopy was performed. RESULTS: Significantly reduced N-acetylaspartate levels (p <.05) were found in both patients with Alzheimer's disease and patients with subcortical ischemic vascular dementia compared to the group with subjective memory complaints. The ratios of N-acetylaspartate/creatine and N-acetylaspartate/myo-inositol were significantly lower in Alzheimer's disease patients compared to patients with vascular dementia (p =.012) or patients with subjective memory impairment (p =.002). N-acetylaspartate/creatine and N-acetylaspartate/myo-inositol ratios were positively correlated to the degree of cerebral atrophy. Disoriented patients displayed a low N-acetylaspartate/creatine ratio. In contrast, we were not able to relate concurrent psychotic or behavioral symptoms to any spectroscopic parameter. CONCLUSION: This study indicates that proton magnetic resonance spectroscopy parameters could provide additional information in differentiating between Alzheimer's disease, subcortical ischemic vascular dementia, and subjective cognitive impairment. Therefore, this method can contribute to the routine diagnosis of dementia. Psychiatric and behavioral symptoms associated with dementia or due to a major psychiatric disorder cannot be related to changes in the measured proton magnetic resonance spectroscopy parameters.

Marksteiner J, Kaufmann WA, Gurka P, Humpel C. · Institute for Biochemical Pharmacology, Department of Psychiatry, University Innsbruck, Austria. · J Mol Neurosci. · Pubmed #11931350 No free full text.

Abstract: Chromogranin A, chromogranin B, and secretogranin II are acidic proteins which are stored in large dense core vesicles of neurons. An antiserum, raised against a synthetic peptide (PE-11), present in the chromogranin B molecule, and an antiserum raised against secretoneurin contained in the secretogranin II sequence, was used to localize these peptides together with chromogranin A in the human hippocampal formation. The distribution of these peptides was investigated in Alzheimer's disease and compared to control subjects. Chromogranin A, chromogranin B, and secretogranin II are distinctly distributed with an overlap in their distribution patterns. They were only detected in neuronal structures. The highest density of immunoreactivity was found for chromogranin B. A layer specific distribution was especially obvious in the inner molecular layer of the dentate gyrus as secretoneurin-like immunoreactivity was restricted to its innermost part whereas that of chromogranin B was highly concentrated throughout the inner molecular layer. In Alzheimer's disease, about 10 to 20% of the amyloid-immunoreactive plaques contained either chromogranin A, chromogranin B or secretoneurin. The density of secretoneurin-and chromogranin B-like immunoreactivity was significantly reduced in the inner molecular layer of the dentate gyyrs, the CA1 area, the subiculum and in layers I, III and V of the entorhinal cortex. The present study demonstrates that chromogranin peptides are markers for human hippocampal pathways. Thee are particularly suitable to study nerve fibers, terminating at the inner molecular layer of the dentate gyrus. Chromogranin peptides have a potential as neuronal markers for synaptic degeneration in Alzheimer's disease.

Gurka P, Marksteiner J. · Universitätsklinik für Psychiatrie, Anichstrasse 35, A-6020 Innsbruck. · Wien Med Wochenschr. · Pubmed #11925769 No free full text.

Abstract: 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.

Gurka P, Bacher R, Kohl C, Kemmler G, DeCol C, Weiss E, Bodner T, Hinterhuber H, Lingg A, Marksteiner J. · Department of Psychiatry, Anichstrasse 35, A-2060 Innsbruck, Austria. · Int J Geriatr Psychiatry. · Pubmed #11921159 No free full text.

This publication has no abstract.

Marksteiner J, Lechner T, Kaufmann WA, Gurka P, Humpel C, Nowakowski C, Maier H, Jellinger KA. · Department of Psychiatry, University of Innsbruck, Austria. · Acta Neuropathol. · Pubmed #10963369 No free full text.

Abstract: Synapse loss is crucially involved in cognitive decline in Alzheimer's disease (AD). This study was performed to investigate the distribution and density of chromogranin B-like immunoreactivity in the hippocampus of control compared to AD brain. Chromogranin B is a large precursor molecule found in large dense-core vesicles. For immunocytochemistry we used an antiserum raised against a synthetic peptide (PE- 11) present in the chromogranin B molecule. Chromogranin B-like immunoreactivity was concentrated in the terminal field of mossy fibers, the inner molecular layer of the dentate gyrus and in layer II of the entorhinal cortex. In AD, chromogranin B was detected in neuritic plaques. The density of chromogranin B-like immunoreactivity was significantly reduced in the inner molecular layer of the dentate gyrus and in layers II, III and V of the entorhinal cortex in AD brains. The present study demonstrates that chromogranin B is a marker for human hippocampal pathways. It is particularly suitable for studying nerve fibers terminating at the inner molecular layer of the dentate gyrus. It is present in neuritic plaques, and its density is reduced in a layer-specific manner.

Finckh U, Müller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A. · Department of Human Genetics, University Hospital Eppendorf, University of Hamburg, Germany. . · Am J Hum Genet. · Pubmed #10631141 links to  free full text

Abstract: Clinical differential diagnosis of early-onset dementia (EOD) includes familial Alzheimer disease (FAD) and hereditary prion disease. In both disease entities, postmortem brain histopathological examination is essential for unambiguous diagnosis. Mutations in the genes encoding the presenilins (PS1 and PS2) and amyloid precursor protein (APP) are associated with FAD, whereas mutations in the prion protein (PrP) gene are associated with prion disease. To investigate the proportion of EOD attributable to known genes, we prospectively (i.e., antemortem) screened these four genes for mutations by sequencing genomic PCR products from patients with EOD before age 60 years. Family history for dementia was positive (PFH) in 16 patients, negative (NFH) in 17 patients, and unknown (UFH) in 3 patients. In 12 patients, we found five novel mutations (in PS1, F105L; in PS2, T122P and M239I; and in PrP, Q160X and T188K) and five previously reported mutations (in APP, in three patients who were most likely unrelated, V717I; in PS1, A79V and M139V; and in PrP, P102L and T183A) that are all considered to be disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found two mutations (APP V717I) in two of the three UFH patients, and only one mutation (PrP T188K) in 1 of the 17 patients with NFH. We conclude that because of the lack of specific antemortem diagnostic markers for FAD and hereditary prion disease, all four genes should be included in a molecular diagnostic program in patients with EOD who had PFH.

Marksteiner J, Walch T, Bodner T, Gurka P, Donnemiller E. · No affiliation provided · Pharmacopsychiatry. · Pubmed #14571357 No free full text.

Abstract: 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.

Blasko I, Marx F, Grubeck-Loebenstein B, Marksteiner J. · No affiliation provided · Arch Neurol. · Pubmed #10404994 links to  free full text

This publication has no abstract.