Alzheimer Disease: Riemenschneider M

Kurz A, Riemenschneider M, Drzezga A, Lautenschlager N. · Department of Psychiatry, Technische Universität München, Federal Republic of Germany. · J Neural Transm Suppl. · Pubmed #12456058 No free full text.

Abstract: Biological markers can be used to identify the neurodegenerative process of Alzheimer's disease (AD) and to differentiate it from other brain diseases which may cause similar symptoms. Structural imaging can detect atrophic changes which are largely non-specific and provide little diagnostic information in single patients. Increasing atrophy upon repeated measurement is much more specific to AD. Functional imaging can demonstrate regional alterations of cerebral blood flow and metabolism but is not sufficiently sensitive at the stage of mild dementia. The measurement of neuronal proteins in the cerebrospinal fluid including tau, phospho-tau, and beta amyloid, achieve high diagnostic sensitivity and specificity even at the stage of pre-dementia. Genetic tests for mutations in the amyloid precursor and presenilin genes are applicable in very few cases. Apolipoprotein E genotyping is not useful as a diagnostic test. With respect to the limitations of biological markers clinical expertise will continue to be an essential element of the early and differential diagnosis of AD.

Riemenschneider M, Mahmoodzadeh S, Eisele T, Klopp N, Schwarz S, Wagenpfeil S, Diehl J, Mueller U, Foerstl H, Illig T, Kurz A. · Department of Psychiatry, Neurochemistry and Neurogenetics Laboratory, TU-München Ismaningerstr. 22, 81675 München, Germany. · Neurobiol Aging. · Pubmed #15465627 No free full text.

Abstract: Epidemiological studies identified a higher risk of developing Alzheimer's disease (AD) among subjects with elevated cholesterol levels. This association may be caused by a modulation of the amyloid precursor protein (APP) processing in response to the cellular cholesterol content. High cholesterol levels may favor the amyloidogenic pathway by inhibition of the alpha-secretase probably leading to elevated beta-Amyloid (Abeta) production. The identification of a linkage peak on chromosome 10q using high Abeta as quantitative trait led us to examine polymorphisms of genes located on chromosome 10 involved in cholesterol metabolism, like Lipase A (LIPA), Cholesterol 25 hydroxylase (CH25H), and FLJ22476, a high density lipoprotein binding related protein. Using 286 patients with AD and 162 controls we analyzed several single nucleotide polymorphisms (SNPs) within LIPA, CH25H, and FLJ22476. None of the polymorphisms showed significant association with AD which contradicts recent findings on CH25H. From our results we conclude that the investigated genetic variations do not contribute to the genetic risk of AD.

Drzezga A, Lautenschlager N, Siebner H, Riemenschneider M, Willoch F, Minoshima S, Schwaiger M, Kurz A. · Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675, München, Germany, · Eur J Nucl Med Mol Imaging. · Pubmed #12764551 No free full text.

Abstract: A high percentage of patients with mild cognitive impairment (MCI) develop clinical dementia of the Alzheimer type (AD) within 1 year. The aim of this longitudinal study was to identify characteristic patterns of cerebral metabolism at baseline in patients converting from MCI to AD, and to evaluate the changes in these patterns over time. Baseline and follow-up examinations after 1 year were performed in 22 MCI patients (12 males, 10 females, aged 69.8+/-5.8 years); these examinations included neuropsychological testing, structural cranial magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography (PET) evaluation of relative cerebral glucose metabolic rate (rCMRglc). Individual PET scans were stereotactically normalised with NEUROSTAT software (Univ. of Michigan, Ann Arbor, USA). Subsequently, statistical comparison of PET data with an age-matched healthy control population and between patient subgroups was performed using SPM 99 (Wellcome Dept. of Neuroimaging Sciences, London, UK). After 1 year, eight patients (36%) had developed probable AD (referred to as MCI(AD)), whereas 12 (55%) were still classified as having stable MCI (referred to as MCI(MCI)). Compared with the healthy control group, a reduced rCMRglc in AD-typical regions, including the temporoparietal and posterior cingulate cortex, was detected at baseline in patients with MCI(AD). Abnormalities in the posterior cingulate cortex reached significance even in comparison with the MCI(MCI) group. After 1 year, MCI(AD) patients demonstrated an additional bilateral reduction of rCMRglc in prefrontal areas, along with a further progression of the abnormalities in the parietal and posterior cingulate cortex. No such changes were observed in the MCI(MCI) group. In patients with MCI, characteristic cerebral metabolic differences can be delineated at the time of initial presentation, which helps to define prognostic subgroups. A newly emerging reduction of rCMRglc in prefrontal cortical areas is associated with the transition from MCI to AD.

Riemenschneider M, Schmolke M, Lautenschlager N, Vanderstichele H, Vanmechelen E, Guder WG, Kurz A. · Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry, Technische Universität München, Germany. · Neurobiol Aging. · Pubmed #11804704 No free full text.

Abstract: A significant association between CSF Abeta42 and cognition in patients with Alzheimer's disease (AD) homozygous for the epsilon3 allele of the apolipoprotein E (apoE) has been described. In this study we extended our observations on apoE, as another plaque component, and investigated the association between CSF apoE concentrations and cognitive performance after stratification for the apoE genotype in 62 patients with AD, 19 other forms of dementia and 18 controls. CSF Abeta42 and apoE concentrations were significantly and positively associated with Mini Mental State Examination (MMSE) score in AD (Abeta42: r = 0.332; P = 0.026; apoE: r = 0.386; P = 0.006). For Abeta42 this association was exclusively present in epsilon3 homozygotes (r = 0.44; P = 0.014), whereas apoE was correlated with MMSE in epsilon4 hetero- or homozygotes subjects (epsilon4/epsilonX: r = 0.638; P = 0.004: epsilon4/epsilon4; r = 0.812; P = 0.05). No association was observed between CSF concentrations of Abeta42 and apoE. The significant relationship between MMSE and CSF Abeta42 in epsilon3 homozygotes and apoE in epsilon4 hetero- and homozygotes respectively may suggest that both proteins may be associated independently from each other with cognitive decline.

Drzezga A, Grimmer T, Henriksen G, Mühlau M, Perneczky R, Miederer I, Praus C, Sorg C, Wohlschläger A, Riemenschneider M, Wester HJ, Foerstl H, Schwaiger M, Kurz A. · Department of Nuclear Medicine, Klinikum Rechts der Isar, Technischen Universität München, Ismaninger Str. 22, D-81675 München/Munich, Germany. · Neurology. · Pubmed #19339712 No free full text.

Abstract: OBJECTIVE: To examine the influence of the APOE genotype on levels of beta-amyloid (Abeta) plaque load and atrophy in patients with Alzheimer disease (AD) in vivo. METHODS: Thirty-two patients with moderate AD were divided into carriers and noncarriers of the epsilon4 allele. These groups were matched for age, disease duration, education, and cognitive impairment. In all subjects, [11C]PIB-PET was performed for measurement of cerebral Abeta plaque deposition and cranial MRI for the assessment of gray matter volume by voxel-based morphometry (VBM) and for correction of partial volume effects (PVE) in the PET data. Voxel-based comparisons (SPM5) were performed between patient groups and healthy control populations and completed with multiple regression analyses between imaging data and epsilon4 allele frequency. RESULTS: Compared to controls, AD-typical patterns of [11C]PIB retention and atrophy were detected in both epsilon4-positive and epsilon4-negative patient groups. In direct comparison, significantly stronger and more extended [11C]PIB uptake was found in epsilon4-positive patients in bilateral temporoparietal and frontal cortex, surviving PVE correction. VBM analysis demonstrated comparable levels of atrophy in both patient groups. Regression analyses revealed a linear association between higher epsilon4 allele frequency and stronger temporoparietal Abeta plaque deposition, independently of other confounds. No major correlation between epsilon4 allele frequency and gray matter decrease was observed. CONCLUSION: These results indicate that the epsilon4-positive APOE genotype not only represents a risk factor for Alzheimer disease (AD), but also results in higher levels of Abeta plaque deposition in epsilon4-positive patients with AD compared to age-matched epsilon4-negative patients with similar levels of cognitive impairment and brain atrophy. The potential role of Abeta plaque imaging for patient inclusion and follow-up in anti-amyloid therapy trials is strengthened by these findings.

Laws SM, Friedrich P, Diehl-Schmid J, Müller J, Eisele T, Bäuml J, Förstl H, Kurz A, Riemenschneider M. · Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany. · Mol Psychiatry. · Pubmed #17179995 No free full text.

Abstract: In addition to senile plaques, neurofibrillary tangles are characteristic of Alzheimer's disease (AD) pathology, suggesting a clear involvement of the microtubule-associated protein tau (MAPT) in AD. Recent findings, suggesting that the H1c haplotype is associated with increased risk, now also implicate MAPT genetically. In this study, we aim to clarify this association by a fine mapping approach using both a traditional phenotypic association analysis and a quantitative trait (QT) analysis using cerebrospinal fluid (CSF) tau protein levels in the German population. Here, we report that both methodologies identify that the H1c haplotype may play important role in AD (AD risk, P=0.007, uncorrected; CSF tau levels, P=0.027, uncorrected). Further, the use of a sliding window approach in the QT analysis allowed for the narrowing down of the region where a probable causal variant may be located. The data suggest that this may lie at or within close proximity to the rs242557 single nucleotide polymorphism as association with CSF tau levels seems to be primarily driven by rs242557 in a gene dosage-dependent manner (trend model: P=0.002, uncorrected). These findings provide functional evidence to support the genetic association of MAPT with AD.

Riemenschneider M, Konta L, Friedrich P, Schwarz S, Taddei K, Neff F, Padovani A, Kölsch H, Laws SM, Klopp N, Bickeböller H, Wagenpfeil S, Mueller JC, Rosenberger A, Diehl-Schmid J, Archetti S, Lautenschlager N, Borroni B, Müller U, Illig T, Heun R, Egensperger R, Schlegel J, Förstl H, Martins RN, Kurz A. · Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psychotherapy, Technische Universitat München, Ismaningerstrasse 22, 81675 Munich, Germany. · Hum Mol Genet. · Pubmed #16825285 links to  free full text

Abstract: A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21-q22. Within this region the plasminogen activator urokinase gene (PLAU) was considered as a reasonable candidate from its functional implication in plasmin generation, a serine protease capable of degrading beta-Amyloid (Abeta) protein. We screened 56 single nucleotide polymorphisms (SNPs) around PLAU using 1751 individuals from four independent case-control samples (Munich, N=679; Bonn N=282; Brescia (Italy) N=219; Perth (Australia) N=557 and one discordant sib-pair sample (Munich N=622). In brain tissue samples of neuropathologically confirmed cases with AD (N=33) we analyzed plaque counts according to the risk allele. We identified that one functional exonic SNP (rs2227564) is associated with development of AD using the four independent case-control samples (Munich, P=0.02; Bonn, P=0.005; Brescia (Italy), P=0.001; Perth (Australia), P=0.03) and the discordant sib-pair sample (P=0.001). In brain tissue, from neuropathologically confirmed cases with AD, we identified significantly higher plaque counts in carriers of the risk allele (N=6; 60.3+/-16.9) compared with non-carriers (N=9; 26.3+/-8.8; P=0.007). This study provides compelling evidence of a genetic and functional involvement of a common PLAU variant into the pathogenesis of AD. Further functional investigations are warranted to elucidate the specific role of PLAU, respectively, PLAU variants in the metabolism of Abeta proteins.

Riemenschneider M, Schoepfer-Wendels A, Friedrich P, Konta L, Laws SM, Mueller JC, Kurz A, Förstl H. · Laboratory of Neurochemistry and Neurogenetics, Department of Psychiatry and Psychotherapy, TU-Munich, 81675 Munich, Germany. <> · Neurobiol Aging. · Pubmed #16784798 No free full text.

Abstract: Using a case-control sample we evaluated a possible involvement of the Vacuolar protein sorting 26 (VPS26) gene in the pathogenesis of AD. VPS26 located at 10q22.1 denotes a retromer subunit functionally involved in the cellular trafficking of Memapsin 2 (BACE). Genotyping of eight single nucleotide polymorphisms covering the complete VPS26 gene and haplotypic analysis revealed no association with AD. Thus, we conclude that VPS26 can be excluded as a major positional and functional candidate gene conferring risk to AD.

Mueller JC, Riemenschneider M, Schoepfer-Wendels A, Gohlke H, Konta L, Friedrich P, Illig T, Laws SM, Förstl H, Kurz A. · Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psychotherapy, Technical University Munich (TUM), Ismaningerstr. 22, 81675 München, Germany. · Neurobiol Aging. · Pubmed #16675064 No free full text.

Abstract: Functional and genetic studies suggest that insulin-degrading enzyme (IDE) may be a strong functional and positional candidate. As there is a lack of consensus in regards to the level and location of IDE association signals we aimed to clarify these discrepancies through genotyping 28 SNPs in a large case-control collective together with quantitative measures of cognitive ability (MMSE). Four SNPs (rs11187007, rs2149632_ide12, rs11187033, rs11187040) were found to be associated with AD (nominal p<0.01). Tests with MMSE scores adjusted for disease duration identified associations, with the most significant result for rs1999763 (nominal p=0.008). Similarly, different reconstructed IDE haplotypes were associated with AD and higher MMSE scores. The association signals are only borderline significant after adjustment for multiple testing, but add further evidence to previous published results on the association between IDE and AD or MMSE. A subgroup analysis indicated more prominent associations with AD in younger, and with MMSE in older patients. There may be two independent effects mediated by IDE variants, risk for AD and modification of disease progression.

Riemenschneider M, Blennow K, Wagenpfeil S, Andreasen N, Prince JA, Laws SM, Förstl H, Kurz A. · Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany. · Hum Mutat. · Pubmed #16652347 No free full text.

Abstract: The lysosomal protease cathepsin D (CtsD, EC 3.4.23.5; gene, CTSD) has been associated with Alzheimer disease (AD) due to its cerebral expression being increased early in the course of AD; additionally, a CTSD exon 2 polymorphism (rs17571; NT_009237.17:g.569834T>C) may confer risk to AD. Functionally, it may be implicated in amyloid precursor protein (APP) processing and tau protein degradation. The objective of this study was to determine whether the CTSD exon 2 polymorphism affects cerebrospinal fluid (CSF), concentrations of beta-amyloid (Abeta42) and tau in two independent samples from Germany (n=73) and Sweden (n=66). Patients carrying the CTSD rs17571-T allele had significantly decreased CSF levels of tau (Munich, p=0.003; Swedish, p=0.029; combined sample, p<0.001), whereas no significant effect was observed on Abeta42 concentrations. Likewise, no significant impact was observed on Mini Mental State Examination (MMSE) scores. The data of both independent samples suggest that the CTSD rs17571 polymorphism does not affect APP processing but shows significant effects on tau processing. The result may corroborate the implication of the lysosomal system in the pathogenesis of AD and is of particular importance if CSF tau is used as a diagnostic biomarker.

Depboylu C, Lohmüller F, Du Y, Riemenschneider M, Kurz A, Gasser T, Müller U, Dodel RC. · Department of Neurology, Philipps University Marburg, Rudolph-Bultmann-Str. 8, 35039 Marburg, Germany. · Neurosci Lett. · Pubmed #16650578 No free full text.

Abstract: Alpha2-macroglobulin (alpha2M) as well as its receptor, the low-density lipoprotein receptor-related (LRP) and the receptor-associated protein (RAP) are involved in the clearance of cerebral A beta. Current evidence suggests that polymorphisms in the genes of alpha2M, LRP and RAP may have functional effects on the proteins. Two independent association samples of 271 AD patients and 280 representative controls were investigated whether the risk for developing AD is altered in carriers of polymorphisms in the alpha2M-gene (Va1000Ile), in the LRP-gene (Ala216Val) and in the RAP-gene (Val311Met). Genotypes were determined by standard PCR and restriction fragment length polymorphism. The results were adjusted for age, gender and apolipoprotein E-epsilon4 (APOE) polymorphism. Inheritance of alpha2M conferred a small increased risk for sporadic AD with an estimated Mantel-Haenszel odds ratio of 1.47. There was no age- or gender-dependent increase in alpha2M Val1000Ile allele frequencies in AD patients compared to controls. There was no significant difference in the allele frequencies among control and AD subjects for the LRP and RAP polymorphisms. We found no evidence of an interaction between the alpha2M and RAP or LRP with regard to conferred risk. Our data suggest that the alpha2M Val1000Ile polymorphism is weakly associated with AD. Although LRP as well as RAP seem to play an essential role in the metabolism of alpha2M and APOE, there is no increase in the genetic risk for AD in patients carrying the investigated polymorphisms.

Bickel H, Riemenschneider M, Kurz A. · Klinik und Poliklinik für Psychiatrie und Psychotherapie der Technischen Universität München, Klinikum rechts der Isar. · Psychiatr Prax. · Pubmed #16583352 No free full text.

Abstract: OBJECTIVE: The aim of the study was to examine the relationship of head circumference as a marker of maximal attained brain size to late-life cognitive impairment and dementia. METHODS: Cognitive performance was assessed and the presence of dementia was diagnosed in a cross-sectional study of 442 Catholic sisters aged 65 years and over. RESULTS: A head circumference below average was significantly associated with the presence of dementia even after adjustment for age, body mass index and presence of one or two apolipoprotein E epsilon4 alleles (OR = 2.0; 95% CI: 1.1-3.6). The combination of small head circumference and apolipoprotein E epsilon4 strongly increased the risk of dementia (OR = 3.59; 95% CI: 1.44-8.97). CONCLUSIONS: The findings support the hypothesis that a larger head size reduces the risk of cognitive decline and dementia in old age.

Drzezga A, Grimmer T, Riemenschneider M, Lautenschlager N, Siebner H, Alexopoulus P, Minoshima S, Schwaiger M, Kurz A. · Department of Nuclear Medicine, Technische Universität, München, Munich, Germany. · J Nucl Med. · Pubmed #16204712 links to  free full text

Abstract: Patients with mild cognitive impairment (MCI) represent a risk population for progressing to dementia of the Alzheimer type (DAT). However, clinical criteria do not ensure reliable individual prognosis in these patients. The objective of this longitudinal, prospective study was to examine the value of (18)F-FDG PET of cerebral glucose metabolism and of genetic susceptibility, as defined by an APOEepsilon4-positive genotype, with regard to the early diagnosis of DAT in patients with MCI. METHODS: In 30 patients with the diagnosis of MCI (16 female, 14 male; age, 70 +/- 8 y), baseline and follow-up examinations (mean observation period, 16 mo) were performed. In all patients, the APOE genotype was assessed and cerebral glucose metabolism was evaluated at baseline using cranial (18)F-FDG PET. Individual PET data were screened for findings suggestive of Alzheimer's disease (AD), with the help of an automated computer program. After stereotactical normalization of the PET images, this program performs an observer-independent statistical comparison with an age-matched reference database (n = 22). RESULTS: In 43% of all MCI subjects, a PET scan suggestive of AD pathology according to our predefined criteria was observed at baseline (PET+); 57% of all MCI patients were carriers of the APOE epsilon4 allele (e4+). In 40% of all patients, progression of symptoms within the observation period justified the clinical diagnosis of probable DAT at the time of follow-up reevaluation. Statistical evaluation revealed the best results for PET with regard to early diagnosis of DAT in MCI patients (sensitivity, 92%; specificity, 89%). Classification according to the APOE genotype was significantly less successful (sensitivity, 75%; specificity, 56%). However, a combination of both diagnostic tests allowed early diagnosis with either very high specificity (PET+ AND e4+: sensitivity, 67%; specificity, 100%) or very high sensitivity (PET+ OR e4+: sensitivity, 100%; specificity, 44%). CONCLUSION: (18)F-FDG PET of cerebral glucose metabolism is a valuable diagnostic tool for the prediction of clinical outcome in individual MCI patients. Results are superior to the exclusive assessment of the APOE genotype. A combination of both functional imaging and genotyping may allow an early high-risk or low-risk stratification of patients with either very high sensitivity or very high specificity. This may be valuable, for example, for patient selection in scientific studies.

Gohlke H, Illig T, Klopp N, Wagenpfeil S, Konta L, Laws SM, Kurz A, Riemenschneider M. · Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psychotherapy, Technische Universität München (TUM), Ismaningerstr. 22, D-81675 Munich, Germany. · Neurobiol Aging. · Pubmed #16026902 No free full text.

Abstract: Several studies have reported conflicting results concerning the genetic association between Alzheimer's disease (AD) and the microsatellite marker D10S1423 on chromosome 10p12-14. In an ethnically homogeneous German population of 422 patients with AD and 254 cognitively healthy controls, the 238-bp allele of the D10S1423 marker showed a weak, but after correction for multiple testing no longer significant association with AD (p = 0.015, uncorrected; p = 0.11, corrected). These findings do not support the presence of a relevant susceptibility locus for AD on chromosome 10p12-14.

Laws SM, Perneczky R, Wagenpfeil S, Müller U, Förstl H, Martins RN, Kurz A, Riemenschneider M. · Alzheimer's and Aging, School of Biomedical and Sports Science, Edith Cowan University, Joondalup, Australia. · Hum Mutat. · Pubmed #15895461 No free full text.

Abstract: Alzheimer disease (AD), vascular dementia, and stroke are all associated with inflammation though their respective initiating factors differ. Recently a polymorphism in the proinflammatory cytokine tumor necrosis factor (TNF), in association with apolipoprotein E (APOE), was reported to increase AD risk. Two SNPs, rs1799724 (-850C>T; NT_007592.14:g.22400733C>T) and rs1800629 (-308G>A; [NT_007592.14:g.22401282G>A]), and the APOE polymorphism were genotyped in 506 patients with sporadic AD and in 277 cognitively healthy controls. In a subset of 90 individuals we also investigated whether these SNPs exerted any functional effects on cerebrospinal fluid (CSF) beta-amyloid (Abeta) levels. The frequency of the rs1799724 genotypes and the rs1799724-T allele were significantly different in AD individuals (P=0.009; odds ratio [OR], 1.63; 95% confidence interval [CI], 1.13-2.34), while the rs1800629 SNP was not associated with AD. Significant interaction was observed between the rs1799724-T and APOE epsilon4 alleles in that the rs1799724-T allele significantly modified risk associated with possession of the epsilon4 allele only (epsilon4 in absence of rs1799724-T: OR, 2.92; 95% CI, 2.00-4.27; epsilon4 in presence of rs1799724-T: OR, 6.65; 95% CI, 3.26-13.55; P=0.03). Haplotyping analysis revealed a significant overrepresentation of an rs1799724-T/rs1800629-G haplotype in AD (P=0.012; OR, 1.60; 95% CI, 1.11-2.29), although to a lesser degree than rs1799724-T alone. Further, the rs1799724-T allele was found to be associated with lower levels of CSF Abeta42 (P=0.023), thus corroborating the genetic findings. Inheritance of the rs1799724-T allele appears to synergistically increase the risk of AD in APOEepsilon4 carriers and is associated with altered CSF Abeta42 levels. Further investigations are warranted to assess the significance of these novel findings.

Drzezga A, Riemenschneider M, Strassner B, Grimmer T, Peller M, Knoll A, Wagenpfeil S, Minoshima S, Schwaiger M, Kurz A. · Department of Nuclear Medicine, Technische Universität München, Munich, Germany. · Neurology. · Pubmed #15642911 No free full text.

Abstract: OBJECTIVE: To examine the influence of the APOE epsilon4 allele on cerebral glucose metabolism in a large series of patients with Alzheimer disease (AD). METHODS: Eighty-three patients (41 APOE epsilon4 positive and 42 epsilon4 negative) were selected from a pre-existing databank of patients with AD (n > 1,000). The patients were carefully matched for age, age at onset, approximate disease duration, educational level, and overall degree of cognitive impairment. Cerebral [18F]fluorodeoxyglucose PET imaging was performed in all patients by a standardized protocol. Statistical comparison of patient PET data vs a healthy control population was performed as well as an analysis of differences between groups (SPM99; Wellcome Department of Cognitive Imaging, London, UK). RESULTS: A similar pattern of cerebral hypometabolism was detected in the epsilon4-positive and -negative patient groups vs healthy volunteers in regions typically affected by AD (bilateral temporal, parietal, posterior cingulate, and prefrontal cortical areas). The comparison between epsilon4-positive and -negative patients additionally revealed stronger abnormalities in epsilon4 carriers in parietal, temporal, and posterior cingulate cortical regions. CONCLUSIONS: A generally similar pattern of cerebral hypometabolism was detected in APOE epsilon4-positive and -negative patients with Alzheimer disease. However, in direct comparison of the two matched groups, the abnormalities in the epsilon4-positive group were demonstrated to be more pronounced.

Riemenschneider M, Klopp N, Xiang W, Wagenpfeil S, Vollmert C, Müller U, Förstl H, Illig T, Kretzschmar H, Kurz A. · Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psychotherapy, Technische Universität München, Ismaningerstr. 22, 81675 Munich, Germany. · Neurology. · Pubmed #15277640 No free full text.

Abstract: The authors investigated the PRNP Met129Val polymorphism in 1,393 subjects including 482 patients with Alzheimer disease (AD) and two independent control groups. In patients, PRNP Met homozygosity conferred increasing risk with decreasing age at onset (onset: 61 to 70 years, n = 151, p = 0.02, odds ratio [OR] = 1.72, 95% CI = 1.2 to 2.53; onset: < or =60 years, n = 138, p = 0.013, OR = 1.92, 95% CI = 1.31 to 2.87), whereas no association was obtained in patients with onset at older than 70 years. The results suggest involvement of the prion protein in the pathogenesis of early-onset AD.

Schwarz S, Eisele T, Diehl J, Müller U, Förstl H, Kurz A, Riemenschneider M. · Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psychotherapy, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany. · Neurosci Lett. · Pubmed #12770689 No free full text.

Abstract: Alterations of the cholinergic system may account for typical clinical and pathophysiological disturbances of Alzheimer's disease (AD). In particular, a marked decline of choline acetyltransferase activity (CHAT) and as a consequence of acetylcholine during the course of the disease has been described. Due to the chromosomal localization of CHAT at 10q11.23 and its possible role in the pathophysiology of AD, CHAT may represent an appropriate candidate gene conferring risk to AD. In fact, a recent study identified a functional single nucleotide polymorphism (SNP) within the first common exon of CHAT, which was associated with AD giving an odds ratio of 3.8 (Neurosci. Lett. 333 (2002) 9). Because of the potential importance of this finding we analyzed this SNP and another functional SNP within exon 9 (rs868749) of the CHAT gene using a German case control sample consisting of 242 patients with AD and 143 cognitively healthy controls. No statistically significant differences were obtained for the previously described polymorphism. In addition, the exon 9 SNP (rs868749) was not polymorphic in the studied population. We conclude that the previously identified polymorphism is not associated with AD.

Depboylu C, Du Y, Müller U, Kurz A, Zimmer R, Riemenschneider M, Gasser T, Oertel WH, Klockgether T, Dodel RC, Oertelf WH. · Department of Neurology, Friedrich-Wilhelms University, Sigmund-Freud-Strasse 25, 53105, Bonn, Germany. · Neurosci Lett. · Pubmed #12727335 No free full text.

Abstract: There is increasing evidence that immune mechanisms are involved in the pathogenesis of Alzheimer's disease (AD). Recently, polymorphisms of the interleukin (IL)-1 and IL-6 genes were found to be associated with late-onset AD. The immunoregulatory IL-10 downregulates synthesis of pro-inflammatory cytokines such as IL-1. Current evidence suggests that some polymorphisms in the IL-10 promoter may have functional effects on IL-10 transcription. A total of 406 German AD patients (mean age 70.2+/-10.0 years, range 50-95 years, 42% female) and 251 unrelated non-demented control subjects (mean age 66.8+/-10.6 years, range 50-93 years, 38% female) were investigated for the presence of three polymorphisms in the IL-10 promoter region (-1087A/G, -824C/T, -597C/A). No significant differences in the allelic distribution of the analyzed IL-10 polymorphisms have been found between AD patients and controls. We conclude that polymorphisms in the IL-10 promoter region do not increase the risk of developing AD.

Riemenschneider M, Wagenpfeil S, Vanderstichele H, Otto M, Wiltfang J, Kretzschmar H, Vanmechelen E, Förstl H, Kurz A. · Department of Psychiatry, Technische Universität München, Munich, Germany. · Mol Psychiatry. · Pubmed #12660807 No free full text.

Abstract: Early clinical symptoms of sporadic Creutzfeldt-Jakob disease (CJD) may overlap with other neurodegenerative diseases like Alzheimer's disease (AD) and frontotemporal degeneration (FTD). On entering an era in which pharmaceutical treatment of CJD occurs, reliable diagnostic markers like immunodetection of 14-3-3 proteins in the cerebrospinal fluid (CSF) are required. However, false negative results in autopsy-proven, sporadic CJD cases, as well as false positive results in several other disorders including AD and FTD showing high CSF tau protein levels, limit the potential of this marker. Due to neuronal lysis the cytosolic fraction of total tau containing phosphorylated and non-phosphorylated isoforms is partially liberated into the CSF. Since hyperphosphorylation of tau may specifically occur in neurodegenerative diseases associated with neurofibrillary changes, we hypothesized that the phospho-tau (P-tau)/total tau ratio in CSF may be a useful marker to discriminate CJD from other neurodegenerative disorders. The P-tau/total tau ratio discriminated patients with CJD from all other neuro-degenerative disorders including patients with AD and FTD without any overlap. Although the results have to be confirmed in a larger sample, the preliminary data suggest that simultaneous measurement of total tau and P-tau in CSF may be useful to identify patients with CJD.

Riemenschneider M, Lautenschlager N, Wagenpfeil S, Diehl J, Drzezga A, Kurz A. · Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany. · Arch Neurol. · Pubmed #12433260 links to  free full text

Abstract: CONTEXT: Cerebrospinal fluid tau protein and beta-amyloid 42 (Abeta42) protein are altered even in very mild Alzheimer disease (AD). So far, few data exist for subjects with mild cognitive impairment (MCI). OBJECTIVE: To investigate the potential of cerebrospinal fluid tau and Abeta42 for predicting progression from MCI to AD in a longitudinal study of 28 patients with MCI who received follow-up for 18 months. DESIGN: An 18-month prospective study. SETTING: Clinical follow-up study of community-residing subjects with MCI. MAIN OUTCOME MEASURES: Cerebrospinal fluid tau and Abeta42 concentrations were measured using enzyme-linked immunosorbent assay at baseline. The potential of both biomarkers was evaluated to predict the progression to dementia, the end point of this study, using multiple logistic regression analysis. RESULTS: Of 28 subjects with MCI, 12 progressed to dementia (2 to frontotemporal dementia; 10 to AD). Six subjects had progressive MCI, and 10 subjects showed stable MCI. Cerebrospinal fluid tau levels were significantly elevated in patients who progressed to probable AD (P =.002) and subjects with progressive MCI (P =.003) compared with subjects who had stable MCI. Cerebrospinal fluid Abeta42 levels were significantly lower in patients who progressed to probable AD (P =.007) and those with progressive MCI (P =.04) than in subjects with stable MCI. Logistic regression analysis identified elevated tau protein level as a predictor of cognitive deterioration (P =.02), whereas a delayed verbal recall score at baseline was significantly associated with the development of probable AD (P =.03). CONCLUSION: Our results indicate that altered tau and Abeta42 concentrations may be detectable in subjects who are clinically diagnosed as having MCI but demonstrate the pathological changes of AD.

Riemenschneider M, Schwarz S, Wagenpfeil S, Diehl J, Müller U, Förstl H, Kurz A. · Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany. · Mol Psychiatry. · Pubmed #12192623 links to  free full text

Abstract: Because of its implication in neuroprotection, formation of long lasting memories and a disturbed function in Alzheimer's disease (AD), brain-derived neurotrophic factor (BDNF) may represent an appropriate candidate gene conferring risk to AD. Recently, a single nucleotide polymorphism (C-270T) within the BDNF gene has been associated with late onset AD in a Japanese population giving an odds ratio (OR) of 3.8. Because of the importance of this finding we analysed the BDNF polymorphism in a German sample consisting of 210 patients with AD and 188 cognitively healthy controls. The T-allele frequency was higher in patients with AD (11.9%) compared to controls (6.9%) (P = 0.035; OR = 2.26; 95% CI: 1.04-4.48). The risk conferred by the T-allele was stronger in patients who lack the ApoE epsilon4 allele giving an OR of 2.61 (1.21-5.64) P = 0.015, particularly in patients with early onset of the disease; OR 3.13 (1.32-7.43); P= 0.01. Due to the small number of patients showing both, lack of the ApoE epsilon4 allele and the BDNF T allele (n = 18), the result needs to be confirmed in a larger sample. The results suggest that the BDNF C-270T polymorphism is a relevant risk factor for AD particularly in patients lacking the ApoE epsilon4 allele in this German sample.

Riemenschneider M, Wagenpfeil S, Diehl J, Lautenschlager N, Theml T, Heldmann B, Drzezga A, Jahn T, Förstl H, Kurz A. · Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psychotherapy, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany. · Neurology. · Pubmed #12058089 No free full text.

Abstract: BACKGROUND: CSF concentrations of tau and beta-amyloid protein-42 (Abeta42) have been extensively studied in AD. Few data are available concerning CSF levels of both proteins in patients with frontotemporal degeneration (FTD). METHODS: The authors investigated CSF tau and Abeta42 concentrations in 34 patients with FTD, 74 patients with AD, and 40 cognitively healthy control subjects. CSF levels of tau and Abeta42 were measured by ELISA. With use of receiver operating characteristic-derived cutoff points and linear discrimination lines, the diagnostic sensitivity and specificity of both markers were determined. RESULTS: CSF tau concentrations were significantly higher in FTD than in control subjects but were significantly lower than in AD. CSF Abeta42 levels were significantly lower in FTD than in control subjects but were significantly higher than in AD. In subjects with FTD, neither tau nor Abeta42 levels correlated with the severity of dementia. The best discrimination between the diagnostic groups was obtained by simultaneous measurement of tau and Abeta42, yielding a sensitivity of 90% at a specificity of 77% (FTD vs controls) and a sensitivity of 85% at a specificity of 85% (FTD vs AD). CONCLUSIONS: In FTD, CSF levels of tau are elevated and Abeta42 levels are decreased. With use of these markers, subjects with FTD can be distinguished from control subjects and from patients with AD with reasonable accuracy.

Dodel RC, Du Y, Depboylu C, Kurz A, Eastwood B, Farlow M, Oertel WH, Müller U, Riemenschneider M. · Department of Neurology, Philipps-University Marburg, Germany. · Neurology. · Pubmed #11865157 No free full text.

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Förstl H, Bickel H, Lautenschlager N, Riemenschneider M, Kurz A. · Klinik und Poliklinik für Psychiatrie und Psychotherapie, TU München. · MMW Fortschr Med. · Pubmed #11460413 No free full text.

Abstract: Forgetfulness is defined as a subjectively bothersome impairment of the ability to recall facts that are unequivocally known to be stored in the memory. Objectifiable memory deficits may accompany numerous physical and neurological illnesses, but may also be seen in depressive states. Below average-for-age cognitive performances that do not reach the level of dementia are referred to as mild cognitive impairment, which in some cases represents a pre-dementia stage of Alzheimer's disease. Its recognition and differentiation from age-related performance deficits is now possible using simple, but sensitive neuropsychological tests. An important aim of the diagnostic work-up is the recognition of potentially reversible causes. For this purpose, physical examination and laboratory investigations are helpful. Structural and functional imaging procedures can provide information about cerebral causes. Biochemical indicators of neurogenerative processes are currently being developed. Cognitive training measures possibly have only a small and temporary effect. In patients with mild cognitive impairment, nootropic agents apparently have a symptomatic effect. Whether antidementia agents are capable of stopping the progress of mild cognitive impairment to full-blown dementia is currently being investigated in ongoing trials.