Alzheimer Disease: Grünblatt E

Grünblatt E. · University of Würzburg, Clinic and Policlinic for Psychiatry, Psychosomatic and Psychotherapy, Neurochemistry Laboratory, Füchsleinstr. 15, D-97080 Würzburg, Germany. · Expert Rev Neurother. · Pubmed #19086884 No free full text.

Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative diseases that have a tremendous impact on the lives of affected individuals. There is a great probability of developing concurrent parkinsonism in AD and vice versa than would be predicted by independent prevalence of each disease. Both diseases have genetic familial forms with a prevalence of less than 5-10%, but the majority of the cases are sporadic. Several hypotheses exist regarding the etiology of these diseases, such as oxidative stress, inflammatory processes, ubiquitin-proteasome system dysfunction, energy deficits, cell cycle deficiencies and glutamate exitotoxicities. Since diagnosis occurs in late-stage disease after neuronal loss, it decreases the opportunity for neuroprotective/neurorestorative therapies. Therefore, early and specific diagnosis is required as well as new therapy approaches for the growing burden of AD and PD.

Wiltfang J, Lewczuk P, Riederer P, Grünblatt E, Hock C, Scheltens P, Hampel H, Vanderstichele H, Iqbal K, Galasko D, Lannfelt L, Otto M, Esselmann H, Henkel AW, Kornhuber J, Blennow K. · Molecular Neurobiology Lab, Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. · World J Biol Psychiatry. · Pubmed #16156480 No free full text.

Abstract: Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Abeta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

Grünblatt E. · Bayerische Julius-Maximilians-University of Würzburg, Clinic for Psychiatry and Psychotherapy, Neurochemical Laboratory, Germany. · Drugs Today (Barc). · Pubmed #15045036 No free full text.

Abstract: DNA microarray technology is currently an area of great interest. These microarray or "gene chip" technologies, which arose out of the development of large-scale sequencing approaches, are now coming increasingly into use, generating a far greater volume of data than the data representing the sequences themselves. This technology is a powerful tool for the analysis of the organization and regulation of the brain in both diseased and healthy subjects. It can provide new insights into gene function, disease pathophysiology, disease classification and drug development. In this review, the basic theory of microarray technology and its analysis methods are presented, and technical problems are discussed. Additionally, some current results from microarray technology conducted in neuropsychiatry are presented.

Riederer P, Danielczyk W, Grünblatt E. · Neurochemical Laboratory, Clinic for Psychiatry and Psychotherapy, Bayerische Julius-Maximilians-Universität Würzburg, Füchsleinstr 15, 97080 Würzburg, Germany. · Neurotoxicology. · Pubmed #14697902 No free full text.

Abstract: Alzheimer's disease (AD) is the most common cause of dementia in late life. There is still no clear-cut consensus whether this disease involves genetic or environmental factors or both. There is a great need to find a way to delay the disease, as delaying the onset of the disease will bring a great relieve on social and medical resources. The monoamine oxidase-B (MAO-B) inhibitors were shown to be effective in treating Parkinson's disease and possibly AD, with concomitant extension of life span. This article gives a short review on MAO-B inhibitors and their mechanism for neuroprotective effects in AD.

Grünblatt E, Bartl J, Zehetmayer S, Ringel TM, Bauer P, Riederer P, Jacob CP. · Clinical Neurochemistry, National Parkinson Foundation Centre of Excellence Research Laboratories, Clinic and Policlinic for Psychiatry, Psychosomatic and Psychotherapy, University of Würzburg, Würzburg, Germany. · J Alzheimers Dis. · Pubmed #19276557 No free full text.

Abstract: Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease. At present, diagnosis of AD is rather late in the disease. Therefore, we attempted to find peripheral biomarkers for the early diagnosis of AD. We investigated the profiles of 33 genes, previously found by our group to have altered expression in postmortem brains of AD. The gene profiles were studied via quantitative-real-time-reverse-transcription-polymerase-chain-reaction, in whole blood samples (collected with the PAXgene blood RNA system) isolated from a population clinically diagnosed with AD and healthy controls (1-year period/ up to 4 samples). Five genes showed significant correlation to the dementia score, Mini-Mental State Examination (MMSE). Focusing on the two genes with the smallest p-value, H3-histone and cannabinoid-receptor-2, notable increases in these genes were found in peripheral blood mRNA in subjects with lower MMSE scores. Seasonal variations in gene expression were not significant due to sample size, but did seem to vary due to time of sample withdrawal. In conclusion, gene expression profiling might be a promising method to investigating a large population with the aim of developing an early diagnosis of AD.

Grünblatt E, Zehetmayer S, Bartl J, Löffler C, Wichart I, Rainer MK, Jungwirth S, Bauer P, Danielczyk W, Tragl KH, Riederer P, Fischer P. · Ludwig Boltzmann Society, L. Boltzmann Institute of Aging Research, Vienna, Austria. · J Psychiatr Res. · Pubmed #18603262 No free full text.

Abstract: OBJECTIVES: In ageing population, both Alzheimer's disease (AD) and depression are common. Significant depressive symptoms are often co-morbid with cognitive impairment and dementia. In this study, we attempted to find various factors and markers for both AD and depression in a longitudinal cohort, the Vienna-Transdanube-Aging (VITA)-study. METHODS: The VITA-Study consisted of 305 healthy subjects, 174 subjects with depression only, 55 subjects diagnosed with AD only and 72 subjects with depression as well as AD. Associations between AD and/or depression to gene polymorphisms APO E (epsilon4), choline acetyltransferase (ChAT) 4G to A, serotonin-transporter gene promoter-length, dopamine-D4-receptor, ciliary-neurotrophic-factor-null mutation and brain-derived neurotrophic factor (C270T) and to various known factors were analyzed. RESULTS: AD and depression were significant associated. Significant risk factors found for AD were low education, low folic acid and depressive-symptoms, while for depression were low education and higher nonsteroidal anti-inflammatory drugs (NSAID) consume. Moreover, the ChAT polymorphism associated significant to depression. Gender, education, and ChAT significantly associated with the combination AD and/or depression. CONCLUSION: Such studies must be conducted cautiously, as co-morbidities and gene-environmental-social influences may sway the results dramatically. We found in the VITA-study significant association between depression and AD and between ChAT polymorphism and depression.

Grünblatt E, Zander N, Bartl J, Jie L, Monoranu CM, Arzberger T, Ravid R, Roggendorf W, Gerlach M, Riederer P. · Neurochemistry Laboratory, National Parkinson Foundation Centre of Excellence Laboratories, Clinic and Policlinic for Psychiatry and Psychotherapy, University of Würzburg, Germany. · J Alzheimers Dis. · Pubmed #18198416 No free full text.

Abstract: Sporadic Alzheimer's (AD) and Parkinson's disease (PD) are late-onset neurodegenerative diseases with tremendous impact on lives of affected individuals. There is a great probability of developing concurrent Parkinsonism in AD and vice-versa than would be predicted by independent prevalence of each disease. We hypothesize that in sporadic AD as well as PD a combination of environmental effects and gene expression may affect specific brain areas leading to neurodegeneration. We profiled gene expression of AD compared to PD and age matched controls post-mortem in the hippocampus, the gyrus-frontalis-medius (Gfm) and the cerebellum using Gene-Chip microarray (Affymetrix) and quantitative-real-time-RT-PCR. Twelve genes altered in similar manner in AD and PD, while four genes showed differential expression profiles between AD and PD in different brain regions (cannabinoid-receptor-2, Histone-cluster-1-H3e, nicotinic-cholinergic-receptor-alpha6 and beta-site-APP-cleaving enzyme-1). Knowledge of selective gene expression profile can lead to better understanding of disease pathology and development of specific diagnosis and effective therapy.

Jacob CP, Koutsilieri E, Bartl J, Neuen-Jacob E, Arzberger T, Zander N, Ravid R, Roggendorf W, Riederer P, Grünblatt E. · Clinical Neurochemistry and National Parkinson Foundation Centre of Excellence Research Laboratories, Clinic and Policlinic for Psychiatry and Psychotherapy, University of Würzburg, Germany. · J Alzheimers Dis. · Pubmed #17361039 No free full text.

Abstract: Excitatory neurotransmitter dysfunction has been discussed to be involved in the pathophysiology of Alzheimer's disease (AD). In the current study we investigated gene and protein expression patterns of glutamatergic receptors and transporters in brains of AD patients in various stages of disease using gene chip arrays, real time PCR and immunohistochemistry. We found marked impairment in the expression of excitatory amino acid transporters (EAAT1 and EAAT 2) at both gene and protein levels in hippocampus and gyrus frontalis medialis of AD patients, already in early clinical stages of disease. The loss of EAAT immunoreactivity was particularly obvious in the vicinity of amyloid plaques. In contrast, EAAT expression was up-regulated in the cerebellum of these patients. Furthermore, a significant up-regulation of the glutamatergic kainate (GRIK4) receptor observed by gene arrays was confirmed by quantitative RT-PCR in late stages in the hippocampus of AD patients. Moreover, there were down-regulations of other glutamatergic receptors such as NMDA (GRINL1A) and AMPA (GRIA4) receptors. Our data show marked changes in the functional elements of the glutamatergic synapses such as glutamatergic receptors and transporters and indicate impaired glutamate clearing rendering neurons susceptible to excess extracellular glutamate and support further the involvement of excitotoxic mechanisms in the pathogenesis of AD.

Grünblatt E, Koutsilieri E, Hoyer S, Riederer P. · Institute of Clinical Neurochemistry, National Parkinson Foundation Centre of Excellence Laboratories, Bayerische Julius-Maximilians- University of Würzburg, D-97080 Würzburg, Germany. · J Alzheimers Dis. · Pubmed #16914836 No free full text.

Abstract: Streptozotocin is well known inducer of experimental diabetes mellitus when injected peripherally. However, when administered intracerebroventricular, streptozotocin showed a whole spectrum of specific biochemical and behavioural alterations with regard to cognitive functions, feeding, nociception, brain glucose metabolism, neurotransmission and oxidative stress, without producing arterial hyperglycaemia, similarly to Alzheimer's disease. In order to reveal the mechanism of action of neurodegeneration in streptozotocin rat model we investigated the expression of several genes involved in inflammation, oxidative stress, growth- and transcription-factors in the cortex, striatum and cerebellum, using real-time quantitative RT-PCR. Genes such as GDNF, BDNF and integrin-alpha-M were up-regulated, while immediate-early-gene-transcription-factor NGF-IB and metallothionein-1/2 were down-regulated in the cortex of streptozotocin-treated rats. Conversely, NGF-IB, GDNF and BDNF mRNA expression did not alter in the striatum and cerebellum. However, integrin alpha-M and metallothionein-1/2 expressions decreased significantly in the striatum and increased in the cerebellum. These gene changes may provide an insight into the cascade of physiological abnormalities following the inhibition of neuronal insulin signal transduction. Additionally, similarities to neuronal cell death in sporadic Alzheimer's disease may become apparent.

Grünblatt E, Hupp E, Bambula M, Zehetmayer S, Jungwirth S, Tragl KH, Fischer P, Riederer P. · Ludwig Boltzmann Society, L. Boltzmann Institute of Aging Research, Vienna, Austria. · J Affect Disord. · Pubmed #16797081 No free full text.

Abstract: BACKGROUND: Neurotrophic factors are known to play an important role in the survival and differentiation of many types of neurons during development. Both brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) may act cooperatively in modulating the development and functioning of synapses. Both these neurotrophic factors were intensely investigated with regard to depression without conclusive results. METHODS: We have investigated the possible use of both CNTF null-mutation and BDNF polymorphism C270T as biomarkers for depression in the Vienna Transdanube Aging (VITA) study. The VITA is a prospective community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. RESULTS: We found no association between CNTF null-mutation and BDNF C270T polymorphism to any depressive symptoms after exclusion of demented subjects. CONCLUSION: These results call in question the hypothesis that either BDNF or CNTF can be used as molecular markers for depression or late onset depression in the elderly.

Grünblatt E, Schlösser R, Fischer P, Fischer MO, Li J, Koutsilieri E, Wichart I, Sterba N, Rujescu D, Möller HJ, Adamcyk W, Dittrich B, Müller F, Oberegger K, Gatterer G, Jellinger KJ, Mostafaie N, Jungwirth S, Huber K, Tragl KH, Danielczyk W, Riederer P. · Clinic for Psychiatry and Psychotherapy, Department Clinical Neurochemistry, Bayerische Julius-Maximilians-University, Fuchsleinstr 15, Würzburg, Germany. · Neurobiol Aging. · Pubmed #15653171 No free full text.

Abstract: Oxidative stress seems to play an important role in the pathophysiology of Alzheimer's disease (AD). At present there are no easily accessible biochemical markers for AD. We performed activity assays for platelet MAO-B and erythrocyte Cu/Zn-SOD as well as Western blotting for these two proteins. Moreover, we assessed plasma lactoferrin and performed RFLP-analysis for the MAO-B-intron-13-polymorphism in patients from the Vienna-Transdanube Aging (VITA) and from the so called centenarian project. The first one, VITA, is a community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. The centenarian project investigates chronic care in-old patients suffering from AD. In both sexes platelet MAO-B activity increased significantly in the AD group, and Cu/Zn-SOD activity decreased, but the latter effect was significant only in females. No significant difference was found regarding plasma lactoferrin. No correlation was found between MAO-Bi13 and MAO-B platelet activity or allele MAO-Bi13 and disease frequency. These results point to the possibility that a combination of MAO-B and SOD activity levels might be useful tools for an early diagnosis of AD.

Grünblatt E, Hoyer S, Riederer P. · Department of Neurochemistry, Clinic for Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany. · J Neural Transm. · Pubmed #14991460 No free full text.

Abstract: Sporadic Alzheimer's disease (SAD), a progressive neurodegenerative disease, is the most common cause of dementia. The etiology of the disease is still unknown, but it is suspected to be a concert of genetic and environmental factors. Intracerebroventricular injection of streptozotocin (STZ), which inhibits insulin receptor function, develops long-term and progressive deficits in learning, memory and cognitive behavior as well as biochemical changes and neuronal degeneration in rats similar to SAD. Micro-array analysis provides a genome-wide, non-biased study of gene expression patterns. The aim of this study was to investigate the gene expression pattern in the STZ animal model for SAD. RNA from rat cortex, striatum and cerebellum were analyzed for gene expression pattern via Affymetrix neurobiology chip-array and confirmed by real-time RT-PCR. Genes such as potassium channels, GABA receptors and glutamate transporter were up regulated, while insulin-like growth factor receptor was down regulated in STZ rats. These pathways may reveal molecular events causing the neuronal death in SAD.

Luckhaus C, Spiegler C, Ibach B, Fischer P, Wichart I, Sterba N, Gatterer G, Rainer M, Jungwirth S, Huber K, Tragl KH, Grünblatt E, Riederer P, Sand PG. · No affiliation provided · Alzheimer Dis Assoc Disord. · Pubmed #17132983 No free full text.

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