Alzheimer Disease: Leblhuber F

Greilberger J, Koidl C, Greilberger M, Lamprecht M, Schroecksnadel K, Leblhuber F, Fuchs D, Oettl K. · Institute of Physiological Chemistry, Center for Physiological Medicine, Medical University of Graz,8010 Graz, Austria. · Free Radic Res. · Pubmed #18654878 No free full text.

Abstract: The question arises as to whether oxidative stress has a primary role in neurodegeneration or is a secondary end-stage epiphenomenon. The aim of the present study was to determine oxidative stress parameters like malondialdehyde (MDA), carbonyl proteins (CP) and Albumin-disulphide (Alb-SSR) and relate these parameters to the immune parameter neopterin, folic acid and vitamin B12 as vitamins and homocysteine in patients with neuro-degenerative diseases (NDD), namely mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to an aged matched control group. MDA, CP and Alb-SSR were significantly increased in the NDD group compared to controls, but not vitamin B12, folic acid and neopterin. Significant correlations were found between CP and Alb-SSR, CP and MDA and between MDA and Alb-SSR including patients with NDD and the control group. These results support the hypothesis that oxidative damage to lipids and proteins is an important early event in the pathogenesis of neurodegenerative diseases.

Völkel W, Sicilia T, Pähler A, Gsell W, Tatschner T, Jellinger K, Leblhuber F, Riederer P, Lutz WK, Götz ME. · Department of Toxicology, University of Würzburg, Würzburg, Germany. · Neurochem Int. · Pubmed #16483694 No free full text.

Abstract: In the last decade an important role for the progression of neuronal cell death in Alzheimer's disease (AD) has been ascribed to oxidative stress. trans-4-Hydroxy-2-nonenal, a product of lipid peroxidation, forms conjugates with a variety of nucleophilic groups such as thiols or amino moieties. Here we report for the first time the quantitation of glutathione conjugates of trans-4-hydroxy-2-nonenal (HNEGSH) in the human postmortem brain using the specific and very sensitive method of electrospray ionization triple quadrupole mass spectrometry (ESI-MS-MS). Levels of HNEGSH conjugates calculated as the sum of three chromatographically separated diastereomers were determined in hippocampus, entorhinal cortex, substantia innominata, frontal and temporal cortex, as well as cerebellum from patients with AD and controls matched for age, gender, postmortem delay and storage time. Neither age, nor postmortem delay, nor storage time did correlate with levels of HNEGSH conjugates which ranged between 1 and 500 pmol/g fresh weight in the brain areas examined. The brain specimen from patients with clinically and neuropathologically probable AD diagnosed according to criteria of the consortium to establish a registry for AD (CERAD) show increased levels of HNEGSH in the temporal and frontal cortex, as well as in the substantia innominata. Classification of disease severity according to Braak and Braak, which takes into consideration the amount of neurofibrillary tangles and neuritic plaques, revealed highest levels of HNEGSH in the substantia innominata and the hippocampus, two brain regions known to be preferentially affected in AD. These results substantiate the link between conjugates of glutathione with a product of lipid peroxidation and Alzheimer's disease and justify further studies to evaluate the role of HNE metabolites as potential biomarkers for disease progression in AD.

Schroecksnadel K, Leblhuber F, Frick B, Wirleitner B, Fuchs D. · Institute of Medical Chemistry and Biochemistry, Medical University of Innsbruck, Innsbruck, Austria. · Alzheimer Dis Assoc Disord. · Pubmed #15494618 No free full text.

Abstract: In patients with dementias including Alzheimer disease (AD), elevated blood concentrations of homocysteine are common, often going along with low normal folate and vitamin B12. Immune activation leading to oxidative stress also seems to play an important role in the pathogenesis of AD. To find out a possible relationship between immune activation and the development of moderate hyperhomocysteinemia, we determined serum concentrations of homocysteine, folate, vitamin B12 and immune activation markers 75 kD soluble TNF receptor (sTNF-R75) and neopterin in 38 patients with clinically diagnosed AD. A subgroup of patients (45%) presented with increased homocysteine concentrations in comparison to reference ranges in healthy controls of similar age. Also, concentrations of immune activation markers were elevated in a significant proportion of patients. In 17 patients with moderate hyperhomocysteinemia, concentrations of neopterin were higher than in those with lower homocysteine (p < 0.001). Homocysteine correlated with folate (rs= -0.43; p < 0.01) and neopterin (rs= 0.506; p < 0.001). The data suggest that immune activation and concomitant production of reactive oxygen species in patients with AD could be involved in the development of hyperhomocysteinemia via an enhanced decomposition of folate.

Götz ME, Wacker M, Luckhaus C, Wanek P, Tatschner T, Jellinger K, Leblhuber F, Ransmayr G, Riederer P, Eder E. · Department of Toxicology, University of Würzburg, Germany. · Neurosci Lett. · Pubmed #11983292 No free full text.

Abstract: In recent years, an important role for the pathogenesis of Alzheimer's disease (AD) has been ascribed to oxidative stress. Trans-4-hydroxy-2-nonenal, a product of lipid peroxidation, forms stable adducts with a variety of nucleophilic substituents such as thiols or amino moieties. Here, we report the quantification of 1,N2-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal (HNE-dGp) using the specific and very sensitive method of 32P-postlabeling of deoxyguanosine adducts derived from nuclear DNA in neuron rich areas of the hippocampus, the parietal cortex, and the cerebellum of postmortem brains from patients with AD and age matched controls. Adduct levels were highest in the hippocampus, followed by the cerebellum and parietal cortex irrespective of the disease. Neither age, postmortem delay time, gender, nor the extent of neurofibrillary deposits affected tissue adduct levels in the brain areas examined. Although distinctively present in the human brain, the level of HNE-dGp adducts appears not to be useful as a biomarker for AD.

Leblhuber F, Walli J, Artner-Dworzak E, Vrecko K, Widner B, Reibnegger G, Fuchs D. · Department of Gerontology, Landesnervenklinik Wagner Jauregg, Linz, Austria. · J Neural Transm. · Pubmed #11458999 No free full text.

Abstract: Hyperhomocysteinemia is a strong risk factor for atherosclerotic vascular disease, and elevated serum homocysteine is correlated with vitamin B deficiency. In this pilot study, significantly elevated homocysteine levels were found in patients with Alzheimer's disease as well as in patients with vascular dementia, probably indicating similar pathophysiological pathways. We found significant correlations between low folic acid concentrations as well as high homocysteine concentrations and cognitive decline. Supplementation with folic acid may be an inexpensive way to reduce elevated homocysteine levels in demented patients.

Widner B, Leblhuber F, Walli J, Tilz GP, Demel U, Fuchs D. · Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria. · J Neural Transm. · Pubmed #10821443 No free full text.

Abstract: Alzheimer's disease (AD) is likely associated with systemic immune activation. During immune response, interferon-gamma stimulates indoleamine 2,3-dioxygenase (IDO) converting tryptophan to N-formylkynurenine followed by kynurenine in an ensuing step. Thus, IDO activity is estimated by the kynurenine per tryptophan quotient (Kyn/Trp). In 21 patients suffering from AD, in 20 controls of similar age, and in 49 blood donors we measured serum tryptophan and kynurenine concentrations by HPLC. Lower tryptophan concentrations were found in elderly control subjects compared to blood donors (62.1 vs. 73.0 microM, p < 0.005). Tryptophan concentrations tended to be still lower in AD patients (54.4 microM, p = 0.07) compared to elderly controls. Enhanced tryptophan degradation in patients was reflected by significantly increased Kyn/Trp (46.1 vs. 34.1 in elderly controls, p < 0.05). Correlations were found in patients between Kyn/Trp and concentrations of soluble immune markers in serum, i.e., neopterin, interleukin-2 receptor and tumor necrosis factor receptor (all p < 0.001). Increased Kyn/Trp was associated with reduced cognitive performance. Tryptophan degradation due to immune activation may exert impact on the pathogenesis of AD.

Widner B, Leblhuber F, Walli J, Tilz GP, Demel U, Fuchs D. · Institute for Medical Chemistry and Biochemistry, University of Innsbruck, Austria. · Adv Exp Med Biol. · Pubmed #10721050 No free full text.

Abstract: In patients with neurodegenerative disorders, namely Alzheimer's disease and Huntington's disease, we compared serum concentrations of tryptophan, kynurenine and the kynurenine per tryptophan ratio with concentrations of soluble immune activation markers. Significantly lower tryptophan concentrations were observed in the patients, and lower tryptophan levels as well as higher kynurenine levels and higher kynurenine per tryptophan ratios correlated with higher concentrations of neopterin, and soluble receptors for TNF and interleukin-2. In both groups of patients tryptophan concentrations correlated inversely with the degree of mental retardation. No such association existed for the duration of the disease. The data show that systemic chronic immune activation in patients with Alzheimer's disease and Huntington's disease is associated with significant degradation of tryptophan, which is most likely due to activation of indoleamine (2,3)-dioxygenase by immunologic stimuli. Further studies will be necessary to investigate a potential role of tryptophan degradation in the pathogenesis of neurodegenerative disorders.

Leblhuber F, Walli J, Demel U, Tilz GP, Widner B, Fuchs D. · Abteilung für Gerontologie, Landesnervenklinik Wagner-Jauregg, Linz, Austria. · Clin Chem Lab Med. · Pubmed #10369114 No free full text.

Abstract: We measured serum neopterin concentrations in 24 patients with Alzheimer's disease (8 males, 16 females; age: 73.1+/-6.2 years; free of any infectious process) and fourteen controls of similar age (4 males, 10 females; age: 69.7+/-8.8 years). Compared to controls, significantly higher concentrations of neopterin (p< 0.01) were found in patients with Alzheimer's disease. Among patients, concentrations of neopterin were higher in those with lower mini-mental-state (p < 0.05), and an inverse correlation existed between mini-mental-state and neopterin concentrations. No such association existed with the duration of the disease. There were also significant correlations between neopterin and serum concentrations of immune activation markers such as soluble tumor necrosis factor (TNF) receptor and soluble interleukin-2 receptor (all p<0.01). Thus, increased concentrations of neopterin in serum of patients with Alzheimer's disease correlate with the severity of dementia. The data imply a chronic state of peripheral immune activation in Alzheimer's disease.

Leblhuber F, Haller H, Steiner K, Fuchs D. · No affiliation provided · Neurology. · Pubmed #15037728 No free full text.

This publication has no abstract.

Widner B, Leblhuber F, Fuchs D. · No affiliation provided · Lancet. · Pubmed #9929052 No free full text.

This publication has no abstract.