Alzheimer Disease: Peters J

Griffin-Pierce T, Silverberg N, Connor D, Jim M, Peters J, Kaszniak A, Sabbagh MN. · Department of Anthropology, University of Arizona, Tucson, AZ, USA. · Alzheimers Dement. · Pubmed #18631981 No free full text.

Abstract: Little is known about Alzheimer's disease (AD) and related neurodegenerative diseases in American Indian (AI) populations. To provide appropriate health care to elder AIs, whose population is expected to increase dramatically during the next 50 years, it is imperative to attain a better understanding of the interaction of culture and disease in this underserved population. Raising awareness in the AI population regarding the nature of dementia as it compares to normal aging and the development of culturally appropriate instruments to detect and stage AD are essential for future health care efforts. Barriers restricting clinical service to this population include historical factors relating to access to health care, cultural beliefs regarding aging, demographic diversity of the population, competing epidemiologic risk factors, and lack of proper assessment tools for clinicians.

Yakushev I, Hammers A, Fellgiebel A, Schmidtmann I, Scheurich A, Buchholz HG, Peters J, Bartenstein P, Lieb K, Schreckenberger M. · Department of Nuclear Medicine, University of Mainz, Mainz, Germany. · Neuroimage. · Pubmed #18691659 No free full text.

Abstract: Statistical comparisons of [(18)F]FDG PET scans between healthy subjects and patients with Alzheimer's disease (AD) or amnestic mild cognitive impairment (aMCI) using Statistical Parametric Mapping (SPM) usually require normalization of regional tracer uptake via ROIs defined using additional software. Here, we validate a simple SPM-based method for count normalization. FDG PET scans of 21 mild, 15 very mild AD, 11 aMCI patients and 15 age-matched controls were analyzed. First, we obtained relative increases in the whole patient sample compared to controls (i.e. areas relatively preserved in patients) with proportional scaling to the cerebral global mean (CGM). Next, average absolute counts within the cluster with the highest t-value were extracted. Statistical comparisons of controls versus three patients groups were then performed using count normalization to CGM, sensorimotor cortex (SMC) as standard, and to the cluster-derived counts. Compared to controls, relative metabolism in aMCI patients was reduced by 15%, 20%, and 23% after normalization to CGM, SMC, and cluster-derived counts, respectively, and 11%, 21%, and 25% in mild AD patients. Logistic regression analyses based on normalized values extracted from AD-typical regions showed that the metabolic values obtained using CGM, SMC, and cluster normalization correctly classified 81%, 89% and 92% of aMCI and controls; classification accuracies for AD groups (very mild and mild) were 91%, 97%, and 100%. The proposed algorithm of fully SPM-based count normalization allows for a substantial increase of statistical power in detecting very early AD-associated hypometabolism, and very high accuracy in discriminating mild AD and aMCI from healthy aging.

Schindowski K, Eckert A, Peters J, Gorriz C, Schramm U, Weinandi T, Maurer K, Frölich L, Müller WE. · Institute of Pharmacology, Biocenter building N260, Johann Wolfgang-Goethe-University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany. · Neuromolecular Med. · Pubmed #17963048 No free full text.

Abstract: Neuroinflammation is observed in neurodegenerative diseases like Alzheimer's disease (AD). However, a little is known about the mechanisms of neural-immune interactions. The involvement of peripheral T-cell function in AD is still far from clear, though it plays an important role in immunotherapy. The aim of this study was to determine peripheral T-cell reactivity in AD patients and in an AD mouse model. Mitogenic activation via ligation of the T-cell receptor (TCR) with PHA-L was measured in T lymphocytes from AD patients and Thy1(APP 751SL) x HMG(PS1 M146L)-transgenic mice (APP x PS1). In order to uncover failures in TCR signaling, the TCR was also bypassed by PMA and ionomycin treatment. All patients were sporadic late onset cases and the transgenic mice expressed no mutant APP in lymphocytes, so that direct interactions of mutant APP on T-cell function can be excluded. CD4+ and CD8+ T-cell showed increased reactivity (tyrosine phosphorylation, CD69 expression, and proliferation) in AD, while APP x PS1 transgenic mice displayed hyporeactive CD8+ T-cells after TCR ligation. Increased levels of CD8+ T memory cells and down regulation of CD8 receptor were found in AD and the animal model. Anergic TCR uncoupling was associated with loss of MAPK signaling (p38, ERK1 and ERK2) in APP x PS1. Our data implicate the generation of reactive memory T-cell in AD and of anergic memory T-cells in transgenic mice and should be taken into concern when designing immunotherapy.

Schindowski K, Peters J, Gorriz C, Schramm U, Weinandi T, Leutner S, Maurer K, Frölich L, Müller WE, Eckert A. · Institute of Pharmacology, Biocenter, Johann Wolfgang-Goethe-University, Frankfurt, Germany. · Pharmacopsychiatry. · Pubmed #17124644 No free full text.

Abstract: BACKGROUND: Immunotherapy appears to be a potent treatment against Alzheimer's disease (AD), but the mechanisms underlying neural-immune interaction are still not known. METHODS: Here, we determined cell death and distribution of lymphocyte subsets of peripheral blood mononuclear cells (PBMC) in AD and aging, e.g. T (CD4+ CD3+, CD8+ CD3+), B (CD19+) and NK (CD16++CD56+) cells. RESULTS: Increased apoptosis was found in CD4+ T and NK cells in AD, while in aging all subsets were affected. The expression of anti-apoptotic Bcl2 correlated with observed cell death in T-helper and B cells irrespective of dementia. The levels of Bcl2 in T-cells were significantly increased in mild AD. Apoptosis and Bcl2 levels were also elevated in the APP (751SL)xPS1 (M146L) transgenic mouse model. CONCLUSION: The mechanisms triggering apoptosis and activation of lymphocytes in AD appear therefore to be different than those in immunosenescence and possibly bear an important biomarker to monitor immunotherapy in AD.

Berger G, Bernhardt T, Weimer E, Peters J, Kratzsch T, Frolich L. · Department of Psychiatry and Psychotherapy, Johann Wolfgang Goethe University, Frankfurt/Main, Germany. · J Geriatr Psychiatry Neurol. · Pubmed #16100100 No free full text.

Abstract: The objective was to evaluate the course and severity of dementia-related symptoms and their relationship to caregivers' subjective burden and depression over time. Forty-five patients with dementia and their caregivers were followed over a period of 2 years. Patients' cognition, function, and behavioral/psychological symptoms were assessed by the Mini Mental State Examination, Syndrome Kurz Test, Geriatric Depression Screening scale, Instrumental Activities of Daily Living Scale, Physical Self Maintenance Scale, Behavioral Abnormalities in Alzheimer's Disease Rating Scale, and Nurses Observation Scale for Geriatric Patients. Caregivers' depression and subjective burden were evaluated by the Geriatric Depression Screening scale or Beck Depression Inventory and the Caregiver Burden Interview. Global dementia severity, functional impairment, and behavioral disturbances increased significantly over the 2-year observation period. Caregivers' burden remained stable, and severe depression decreased over time. There were significant associations between burden and dementia-related symptoms. For deficits in activities of daily living as well as behavioral disturbances, these associations became stronger over time. It was concluded that stage of dementia, functional deficits, and behavioral disturbances are important factors when evaluating the relationship between patients' symptoms and caregivers' well-being.

Döbert N, Hamscho N, Menzel C, Peters J, Frölich L, Tsolakis A, Zaplatnikov K, Kratzsch T, Diener J, Maurer K, Grünwald F. · Department of Nuclear Medicine, University of Frankfurt, Frankfurt, Germany. · Acta Med Austriaca. · Pubmed #15055159 No free full text.

Abstract: AIM: Thyroid hormone status and thyroid antibodies were evaluated in patients suffering from dementia for further study of an association of hyperthyroidism with AD and vascular dementia (VD), respectively. PATIENTS: In 77 patients with dementia, and 42 controls, thyrotropin (TSH) and thyroid antibodies were correlated with the different types of dementia and the metabolic index (MI) based on imaging with F-18-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). RESULTS: Twenty-two of all patients with dementia (29%) had borderline (TSH 0.3-0.5 mU/l) or decreased TSH levels (TSH < 0.3 mU/L). TSH values were significantly lower in patients suffering from AD (median: 1.1 mU/l) and VD (0.5 mU/l) than in the control group (1.5 mU/l) (p < 0.01). Decreased or borderline TSH levels were present in 52% of the patients with VD, but in only 10% of the controls, and in 23% of the patients with AD. Antibodies to thyroid peroxidase were positive in 16% of all patients with dementia. The MI in patients suffering from AD with borderline TSH levels was 0.81 (0.70, 0.94). In contrast, patients suffering from AD with normal TSH values showed a slightly higher MI of 0.84 (0.76, 0.89) (p = n.s.). CONCLUSION: Decreased or borderline TSH values are associated with an increased probability of having dementia, especially VD.

Schindowski K, Kratzsch T, Peters J, Steiner B, Leutner S, Touchet N, Maurer K, Czech C, Pradier L, Frölich L, Müller WE, Eckert A. · Department of Pharmacology, Biocenter, J.W. Goethe University of Frankfurt, Marie-Curie-Str. 9, D-60439 Frankfurt am Main, Germany. · Neuromolecular Med. · Pubmed #14716024 No free full text.

Abstract: The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer's disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell typespecific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4+ T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4+ T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4+ and CD8+ T cells.

Kratzsch T, Peters J, Frölich L. · Klinik für Psychiatrie und Psychotherapie I, Universitätsklinik der Johann-Wolfgang-Goethe-Universität Frankfurt am Main, Heinrich-Hoffmann-Strasse 10, D-60528 Frankfurt am Main, Deutschland. · Wien Med Wochenschr. · Pubmed #11925775 No free full text.

Abstract: Alzheimer's disease (AD) is the most common cause of primary dementia, characterized by a progressive process of pathophysiological restructuring of the brain over decades. The hallmark of Alzheimer's disease is the extracellular accumulation and deposition of insoluble amyloid, to be found in the parenchyma in the form of amyloid plaques and in meningeal and cerebral vessels as a congophile angiopathy. Equally conspicuous is the intraneuronal occurrence of neurofibrillary tangles, consisting mainly of hyperphosphorylated tau-protein. Amyloid plaques and neurofibrillary tangles are characteristic, but not specific to Alzheimer's disease. Similar changes can be found in healthy ageing processes and in various other neurodegenerative diseases. It is common to differentiate between an early-onset, familial Alzheimer's disease with an established genetic etiology, representing only about 5% of all cases, and the more typical late-onset, sporadic Alzheimer's disease with an age of onset above 65 years and no clear pattern of inheritance. Although there seems to be a large heterogeneity in the etiology of Alzheimer's disease, the amyloid-cascade-hypothesis has taken a central position as a model for the general etiopathogenesis. The regulation of amyloid plaques underlies a diversity of cellular and molecular factors. In addition to ageing, apolipoprotein E 4 is a firmly established risk factor. Disturbance in the cerebral glucose metabolism, especially in the hippocampal regions, is a further proposed factor in the pathogenesis of Alzheimer's disease. The wide-spread loss of cortical cholinergic neurotransmission associated with the cognitive deficits is of importance to the comprehension of the symptoms and the present pharmacotherapy of Alzheimer's disease.

Schramm U, Berger G, Müller R, Kratzsch T, Peters J, Frölich L. · Department of Psychiatry, JW Goethe University, Heinrich Hoffmann Strasse 100, D-60128 Frankfurt/Main, Germany. · Int J Geriatr Psychiatry. · Pubmed #11921154 No free full text.

Abstract: OBJECTIVE: To evaluate five different scoring methods of the Clock Drawing Test (CDT) and to examine whether a combination of Mini Mental State Examination (MMSE) or Short Performance Test (Syndrom Kurz Test, SKT), respectively, with CDT can be used for cognitive screening. METHODS: Retrospective blinded analysis of clock drawing performance using five scoring methods (Shulman et al. (1986), Sunderland et al. (1989), Wolf-Klein et al. (1989), Watson et al. (1997), Manos (1997)). A Memory Clinic at an academic psychiatric hospital (University of Frankfurt am Main, Germany). 123 consecutive patients (79 dementia patients, 44 controls). Inter-rater reliability and correlation of five different scoring methods of the CDT with established psychometric tests. Sensitivity and specificity of all five CDT's using the original and modified cut-off scores. Sensitivity, specificity and positive and negative predictive value of a combination of the CDT with MMSE and SKT, respectively. RESULTS: All scoring methods of the CDT showed a highly significant interrater reliability (0.82 to 0.94). Correlation with the MMSE and the SKT was also significant (p < 0.01) for all five CDTs. Highest sensitivity was achieved by the Shulman scoring method (81% sensitivity, specificity 79%). Sensitivity of all scoring methods could be improved up to 89% by modifying the originally proposed cut-off scores at the cost of lower specificity. By combining the CDT with the MMSE or the SKT, respectively, the sensitivity of each of the tests could be improved to 92% (SKT and Shulman scale). In patients with mild dementia (GDS 3), a combination of the Shulman Scale with the SKT (92%) and the MMSE (75%) achieved the highest sensitivity. CONCLUSIONS: The CDT in combination with the MMSE or SKT is an easily administered, non threatening and highly sensitive screening test for dementia in the setting of a memory clinic.