Alzheimer Disease: Vanderstichele H

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.

Olsson A, Vanderstichele H, Andreasen N, De Meyer G, Wallin A, Holmberg B, Rosengren L, Vanmechelen E, Blennow K. · Institute of Clinical Neuroscience, Sahlgrenska University Hospital, Mölndal, Sweden. · Clin Chem. · Pubmed #15563479 links to  free full text

Abstract: BACKGROUND: To simultaneously study several biomarkers for Alzheimer disease (AD), we used the xMAP technology to develop and evaluate a multiparametric bead-based assay for quantification of beta-amyloid((1-42)) [Abeta((1-42))], total tau (T-TAU), and hyperphosphorylated tau [P-TAU((181P))] in cerebrospinal fluid (CSF). METHODS: We compared the new multianalyte assay format with established ELISA techniques for the same proteins. We then performed a clinical study using CSF samples from patients with AD or mild cognitive impairment with progression to AD, healthy controls, and patients with other neurologic disorders. RESULTS: The INNO-BIA AlzBio3 selectively and specifically measured Abeta((1-42)), T-TAU, and P-TAU((181P)) in the CSF. The new assay format had intra- and interassay CVs <10% for all analytes, even at low concentrations. The measurement range of the new assay was 3 to 4 logs compared with 1 to 2 logs for ELISAs. By plotting the mean of the values obtained in ELISA and the xMAP technology against the difference, we found that a correction factor could be used to convert xMAP results to ELISA values. The clinical study demonstrated that the new multiparametric assay could accurately distinguish patients with AD from patients with other neurologic disorders or control patients, with the diagnostic accuracy reaching recommended consensus criteria for specificity and sensitivity. CONCLUSION: The new multiparametric method may be able to replace the corresponding ELISA methods.

Höglund K, Wiklund O, Vanderstichele H, Eikenberg O, Vanmechelen E, Blennow K. · Institute of Clinical Neuroscience, The Sahlgrenska Academy at Göteborg, Sweden. · Arch Neurol. · Pubmed #15023808 links to  free full text

Abstract: BACKGROUND: Epidemiological studies suggest that statins reduce the risk of developing Alzheimer disease. Cell and animal experiments have revealed a connection between cholesterol metabolism and the processing of amyloid precursor protein. To our knowledge, the mechanism for statins in risk reduction of Alzheimer disease is unknown. OBJECTIVE: To test the effect of statin treatment on beta-amyloid (A beta) metabolism in humans. DESIGN: A prospective, randomized, dose-finding 36-week treatment trial with statins. Plasma samples were taken at baseline (week 0) and at weeks 6, 12, and 36. SETTING: Outpatient clinical study at a university hospital. PATIENTS: Thirty-nine patients who met the criteria for hypercholesterolemia. INTERVENTIONS: Patients were randomized to oral treatment with either simvastatin or atorvastatin calcium according to the following regimen: simvastatin, 40 mg/d, or atorvastatin, 20 mg/d, for 6 weeks; followed by simvastatin, 80 mg/d, or atorvastatin, 40 mg/d, for 6 weeks; and finally, simvastatin, 80 mg/d, or atorvastatin, 80 mg/d, for 24 weeks. MAIN OUTCOME MEASURES: Plasma levels of A beta(1-40) and A beta(1-42) were measured using 2 enzyme-linked immunosorbent assays, and total A beta was quantified by Western blotting. RESULTS: Treatment with both statins reduced total plasma cholesterol levels by 56% (P =.00). The plasma levels of A beta(1-40), A beta(1-42), and total A beta were stable in individual patients during the treatment period. No significant change in the level of A beta(1-40), A beta(1-42), or total A beta was found. CONCLUSION: This study questions the effect of statins on the processing of amyloid precursor protein in humans.

Andreasen N, Vanmechelen E, Vanderstichele H, Davidsson P, Blennow K. · NEUROTEC, Department of Geriatric Medicine, B84, Huddinge University Hospital, Stockholm, Sweden. · Acta Neurol Scand Suppl. · Pubmed #12603251 No free full text.

Abstract: Cerebrospinal fluid (CSF) biochemical diagnostic markers may be valuable to help in the diagnosis early in the course of Alzheimer's disease (AD), especially in the phase before clinically overt dementia, i.e. in patients with mild cognitive impairment (MCI). We studied 44 patients with MCI who, at 1-year follow-up investigation, had progressed to AD with dementia, and 32 controls. Three CSF biomarkers related to the central pathogenic processes in AD were analysed, including CSF total-tau (T-tau) (as a marker for neuronal degeneration), CSF phospho-tau (P-tau) (as a marker for hyperphosphorylation of tau and possibly for the formation of neurofibrillary tangles), and CSF A beta 42 (as a marker for A beta metabolism, and possibly for the formation of senile plaques). At baseline, 35/44 (79.5%) of the MCI patients had high CSF T-tau, 31/44 (70.4%) high CSF P-tau, while 34/44 (77.3%) had low CSF-A beta 42 levels. The positive likelihood ratio was 8.45 for CSF T-tau, 7.49 for CSF P-tau and 8.20 for CSF A beta 42. These findings suggest that these CSF-markers are abnormal before the onset of clinical dementia, and that they may help to identify MCI patients that will progress to AD. CSF diagnostic markers will be especially important when drugs with potential effects on the progression of AD (e.g. gamma-secretase inhibitors) will reach the clinical phase.

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.

Andreasen N, Minthon L, Davidsson P, Vanmechelen E, Vanderstichele H, Winblad B, Blennow K. · Department of Rehabilitation, Piteå River Valley Hospital, PO Box 715, SE-941 28 Piteå, Sweden. · Arch Neurol. · Pubmed #11255440 links to  free full text

Abstract: OBJECTIVE: To evaluate the diagnostic potential of cerebrospinal fluid (CSF) levels of tau and beta-amyloid protein ending at amino acid 42 (Abeta42) as biomarkers for Alzheimer disease (AD) in clinical practice. DESIGN: A 1-year prospective study. SETTING: Community population-based sample of all consecutive patients admitted for investigation of cognitive symptoms to the Piteå River Valley Hospital, Piteå, Sweden. PATIENTS: A total of 241 patients with probable AD (n = 105), possible AD (n = 58), vascular dementia (n = 23), mild cognitive impairment (n = 20), Lewy body dementia (n = 9), other neurological disorders (n = 3), and psychiatric disorders (n = 5) and nondemented individuals (n = 18). MAIN OUTCOME MEASURES: Cerebrospinal fluid tau and CSF-Abeta42 were assayed each week as routine clinical neurochemical analyses. Sensitivity and specificity were defined using the regression line from 100 control subjects from a multicenter study. Positive and negative predictive values were calculated for different prevalence rates of AD. RESULTS: We found increased CSF-tau and decreased CSF-Abeta42 levels in probable and possible AD. Sensitivity was 94% for probable AD, 88% for possible AD, and 75% for mild cognitive impairment, whereas specificity was 100% for psychiatric disorders and 89% for nondemented. Specificity was lower in Lewy body dementia (67%) mainly because of low CSF-Abeta42 levels and in vascular dementia (48%) mainly because of high CSF-tau levels. Sensitivity for CSF-tau and CSF-Abeta42 increased in patients with AD possessing the ApoE epsilon4 allele, approaching 100%. At a prevalence of AD of 45%, the positive predictive value was 90% and the negative predictive value was 95%. CONCLUSIONS: Cerebrospinal fluid tau and CSF-Abeta42 have so far been studied in research settings, under conditions providing data on the optimal performance. We examined a prospective patient sample, with assays run in clinical routine, giving figures closer to the true performance of CSF-tau and CSF-Abeta42. The predictive value for AD was greater than 90%. Therefore, these biomarkers may have a role in the clinical workup of patients with cognitive impairment, especially to differentiate early AD from normal aging and psychiatric disorders.

Hesse C, Rosengren L, Andreasen N, Davidsson P, Vanderstichele H, Vanmechelen E, Blennow K. · Institute of Clinical Neuroscience, Unit of Neurochemistry, University of Göteborg, Sahlgren's University Hospital/Mölndal, SE-431 80, Mölndal, Sweden. · Neurosci Lett. · Pubmed #11137759 No free full text.

Abstract: An increase in cerebrospinal fluid (CSF)-total-tau, and recently also in CSF-phospho-tau, has been found in Alzheimer's disease (AD). However, the mechanisms for these changes are not known. We examined longitudinal CSF samples from nine patients with acute stroke. As compared with baseline levels (day 0-1), CSF-total-tau showed an increase at day 2-3 (179%; P=0.018), day 7-9 (257%; P=0.003), and after 3 weeks (425%; P=0.002) and returned to normal levels after 3-5 months (140%; NS). In contrast, there was no significant change in CSF-phospho-tau. These findings suggest that total tau and phospho-tau in CSF reflect different pathogenic processes in the brain; total-tau the degree of neuronal damage and phospho-tau the phosphorylation state of tau and thus possibly the formation of neurofibrillary tangles.

Andreasen N, Minthon L, Vanmechelen E, Vanderstichele H, Davidsson P, Winblad B, Blennow K. · Department of Rehabilitation, Piteå River Valley Hospital, Sweden. · Neurosci Lett. · Pubmed #10505638 No free full text.

Abstract: We studied CSF-tau and CSF-Abeta42 in 16 patients with mild cognitive impairment (MCI) who at follow-up investigations 6-27 months later had progressed to Alzheimer's disease (AD) with dementia. For comparison, we studied 15 age-matched healthy individuals. At baseline, 14/16 (88%) of MCI patients had high CSF-tau and/or low CSF-Abeta42 levels. These findings show that these CSF-markers are abnormal before the onset of clinical dementia and that they may help to identify MCI patients that will develop AD. This is especially important when drugs with potential effects on the progression of AD will reach the clinical phase.

Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee VM, Trojanowski JQ, Anonymous00044. · Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Ann Neurol. · Pubmed #19296504 links to  free full text

Abstract: OBJECTIVE: Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. METHODS: Amyloid-beta 1 to 42 peptide (A beta(1-42)), total tau (t-tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy-confirmed AD cases and 52 age-matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t-tau and A beta(1-42) in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy-confirmed CSF data. RESULTS: CSF A beta(1-42) was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for A beta(1-42), t-tau, and APO epsilon 4 allele count provided the best assessment delineation of mild AD. An AD-like baseline CSF profile for t-tau/A beta(1-42) was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study. INTERPRETATION: The CSF biomarker signature of AD defined by A beta(1-42) and t-tau in the autopsy-confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD.

Chafekar SM, Zwart R, Veerhuis R, Vanderstichele H, Baas F, Scheper W. · Neurogenetics Laboratory, VU university medical center, 1081 HV Amsterdam, The Netherlands. · Curr Alzheimer Res. · Pubmed #18855588 No free full text.

Abstract: Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (Abeta) peptide. The unfolded protein response (UPR) is activated by misfolded protein stress in the endoplasmic reticulum (ER). In previous studies we demonstrated mild activation of the UPR by extracellularly applied oligomeric but not fibrillar Abeta1-42. In addition, we showed that oligomeric Abeta1-42 is internalized by cells, whereas fibrillar Abeta1-42 remains on the outside of the cell. Inhibition of Abeta uptake specifically inhibits toxicity of Abeta1-42 oligomers, underscoring the toxic potential of intracellular Abeta. Therefore, in the present study, we investigated the connection between intracellularly produced Abeta and the ER stress response, using human neuroblastoma cells overexpressing either wild type APP695 (APPwt) or APP695V717F (APPmut). Both cell lines secrete higher levels of Abeta1-40 and Abeta1-42 compared to the parental line. In addition, APPmut produces more Abeta1-42 than APPwt. Whereas the basal levels of UPR markers are not different, we find augmented UPR induction in response to ER stress in both APP overproducing cell lines compared to the parental cell line, with the strongest UPR activation in APPmut cells. In addition, ER stress toxicity was highest in APPmut cells, strongly suggesting a connection with the production of Abeta1-42. The difference in ER stress mediated toxicity between the APPwt and APPmut cell lines is alleviated by pretreatment with gamma-secretase inhibitor, indicating that it is dependent on Abeta production and in particular on Abeta1-42. Our data indicate that increased Abeta1-42 production sensitizes neuroblastoma cells for ER stress toxicity.

Zetterberg H, Pedersen M, Lind K, Svensson M, Rolstad S, Eckerström C, Syversen S, Mattsson UB, Ysander C, Mattsson N, Nordlund A, Vanderstichele H, Vanmechelen E, Jonsson M, Edman A, Blennow K, Wallin A. · Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at Göteborg University, Mölndal, Sweden. · J Alzheimers Dis. · Pubmed #18057559 No free full text.

Abstract: This study examines the intra-individual stability of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) over 2 years in 83 patients with mild cognitive impairment (MCI) and 17 cognitively healthy control individuals. All participants underwent clinical and neuropsychological evaluation and lumbar puncture at baseline and after 2 years at a university hospital memory clinic. CSF was analyzed for total tau (T-tau), phospho-tau(181) (P-tau(181)) and amyloid-beta(1-42) (Abeta(1-42)). During the 2-year observational time, 12 MCI patients progressed to AD and 3 progressed to vascular dementia, while 68 remained stable. Baseline T-tau and P-tau(181) levels were elevated in the MCI-AD group as compared to the stable MCI patients and the control group (p<0.01), while baseline Abeta(1-42) levels were lower (p<0.001). Stable MCI patients were biochemically indistinguishable from controls. The biomarker levels at baseline and after 2 years showed Pearson R values between 0.81 and 0.91 (p<0.001) and coefficients of variation of 7.2 to 8.7%. In conclusion, intra-individual biomarker levels are remarkably stable over 2 years. Thus, even minor biochemical changes induced by treatment against AD should be detectable using these biomarkers, which bodes well for their usefulness as surrogate markers for drug efficacy in clinical trials.

Lewczuk P, Kornhuber J, Vanderstichele H, Vanmechelen E, Esselmann H, Bibl M, Wolf S, Otto M, Reulbach U, Kölsch H, Jessen F, Schröder J, Schönknecht P, Hampel H, Peters O, Weimer E, Perneczky R, Jahn H, Luckhaus C, Lamla U, Supprian T, Maler JM, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Neurobiol Aging. · Pubmed #17239996 No free full text.

Abstract: In this report we evaluated the clinical performance of APOE genotyping and three protein biomarkers (total tau, beta-amyloid(1-42), and tau phosphorylated at threonine 181) in a prospective multicenter study using the INNO-BIA AlzBio3 assay applied on Luminex platform. Concentration of biomarkers of Alzheimer's disease in cerebrospinal fluid (CSF) was measured with multiplexing technology (n=223), and compared to the results of ELISA assays in patients with early dementias or mild cognitive impairment (MCI) collected at 12 gerontopsychiatric university departments, and APOE genotyping was performed. Concentrations of Abeta(1-42) were statistically significantly lower in MCI-AD subjects compared to MCI-O, and significantly lower in D-AD patients compared to MCI-O. P-tau(181P) concentrations were significantly higher in MCI-AD patients compared to MCI-O, and significantly higher in D-AD patients compared to MCI-O. The total tau concentrations in MCI-AD patients were significantly higher compared to MCI-O, and higher in D-AD compared to MCI-O, moreover, the concentration of total tau was significantly higher in D-AD compared to MCI-AD patients. For the differential diagnosis between D-AD and D-O, the optimal cutoff concentration of Abeta(1-42) was 197.7 pg/mL, and that for P-tau(181P) was 47.9 pg/mL. These cutoff values were also applied to discriminate between MCI-AD and MCI-O subjects. Simultaneous measurement of the biomarkers significantly improves management of the samples and quality control of the assays' performance.

Vanderstichele H, De Vreese K, Blennow K, Andreasen N, Sindic C, Ivanoiu A, Hampel H, Bürger K, Parnetti L, Lanari A, Padovani A, DiLuca M, Bläser M, Olsson AO, Pottel H, Hulstaert F, Vanmechelen E. · Innogenetics NV, Industriepark Zwijnaarde 7, 9052 Gent, Belgium. · Clin Chem Lab Med. · Pubmed #17163825 No free full text.

Abstract: BACKGROUND: Total tau (T-tau) and beta-amyloid((1-42)) (Abeta(1-42)) levels in cerebrospinal fluid (CSF) can differentiate Alzheimer's disease (AD) from normal aging or depressive pseudo-dementia. Differential diagnosis from dementia with Lewy bodies (DLB) in clinical settings is difficult. METHODS: The analytical performance of the INNOTEST PHOSPHO-TAU(181P) assay was validated in terms of selectivity, sensitivity, specificity, precision, robustness, and stability. Clinical utility of the assay alone, or combined with T-tau and Abeta(1-42), for discrimination of AD (n=94) from patients suffering from DLB (n=60) or from age-matched control subjects (CS) (n=60) was assessed in a multicenter study. RESULTS: CSF concentrations of tau phosphorylated at threonine 181 (P-tau(181P)) in AD was significantly higher than in DLB and CS. Discriminant analysis, a classification tree, and logistic regression showed that P-tau(181P) was the most statistically significant single variable of the three biomarkers for discrimination between AD and DLB. CONCLUSIONS: P-tau(181P) quantification is a robust and reliable assay that may be useful in discriminating AD from DLB.

Vanderstichele H, De Meyer G, Andreasen N, Kostanjevecki V, Wallin A, Olsson A, Blennow K, Vanmechelen E. · Innogenetics NV, Gent, Belgium. · Clin Chem. · Pubmed #16020497 links to  free full text

Abstract: BACKGROUND: Early identification of patients with mild cognitive impairment (MCI) progressing to Alzheimer disease (MCI-AD) by use of biomarkers in cerebrospinal fluid (CSF) is an essential step toward improving clinical diagnosis and drug development. We evaluated whether different beta-amyloid(42) (Abeta42) peptides can add further information to the combined use of tau and Abeta1-42 for predicting risk of progression of MCI to AD. METHODS: We used xMAP technology to simultaneously quantify different Abeta42 peptides modified at the amino terminus, tau, and phosphorylated tau (P-tau181P) in CSF. Abeta42 peptide concentrations were measured by use of immunoreactivity toward Abeta monoclonal antibodies [3D6 (Abeta42-3D6), WO2 (Abeta42-WO2), 6E10 (Abeta42-6E10), and 4G8 (Abeta42-4G8)]. The discriminant ability of the markers was evaluated by ROC curve analysis. RESULTS: The areas under the curves for the separation of MCI-AD from nonprogressing MCI (MCI-N) were significantly higher when we used Abeta42-3D6/Abeta42-WO2, Abeta42-3D6/Abeta42-6E10, or Abeta42-3D6/Abeta42-4G8 compared with Abeta42-3D6. In addition, differentiation of MCI-N from MCI-AD was improved by quantification of full-length Abeta1-42 (Abeta42-3D6) compared with Abeta42-WO2, Abeta42-6E10, or Abeta42-4G8. Several Abeta42 peptides truncated at the amino terminus (Abeta11-42 and Abeta8-42) were identified in CSF by surface-enhanced laser desorption/ionization time-of-flight technology. CONCLUSION: The CSF markers tau, Abeta42 forms, and P-tau181P, when used as adjuncts to clinical diagnosis, have the potential to help identify AD pathology and could be a valuable asset for early AD diagnosis.

Schoonenboom NS, Mulder C, Vanderstichele H, Pijnenburg YA, Van Kamp GJ, Scheltens P, Mehta PD, Blankenstein MA. · Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands. · Clin Chem. · Pubmed #15845801 links to  free full text

This publication has no abstract.

Hoglund K, Thelen KM, Syversen S, Sjogren M, von Bergmann K, Wallin A, Vanmechelen E, Vanderstichele H, Lutjohann D, Blennow K. · Section of Experimental Neurochemistry, Institute of Clinical Neuroscience, Göteborg University, Göteborg, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #15785028 No free full text.

Abstract: During the last years, several clinical studies have been published trying to elucidate the effect of statin treatment on amyloid precursor protein (APP) processing and metabolism of brain cholesterol in Alzheimer's disease (AD) in humans. We present an open biochemical study where 19 patients with AD have been treated with simvastatin (20 mg/day) for 12 months. The aim was to further investigate the effect of simvastatin treatment on cerebrospinal fluid (CSF) biomarkers of APP processing, AD biomarkers as total tau and tau phosphorylated at threonine 181, brain cholesterol metabolism as well as on cognitive decline in patients with AD. Despite biochemical data suggesting that treatment with 20 mg/day of simvastatin for 12 months does affect the brain cholesterol metabolism, we did not find any change in CSF or plasma levels of beta-amyloid (Abeta)(1-42). However, by analysis of APP isoforms, we found that statin treatment may favor the nonamyloidogenic pathway of APP processing. The relevance and mechanism between statin treatment and AD has to be further elucidated by using statins of different lipophility in different dosages over a longer period of time.

Schoonenboom NS, Mulder C, Vanderstichele H, Van Elk EJ, Kok A, Van Kamp GJ, Scheltens P, Blankenstein MA. · Alzheimer Center and Department of Neurology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands. · Clin Chem. · Pubmed #15539465 links to  free full text

Abstract: BACKGROUND: Reported concentrations of amyloid beta (1-42) (A beta 42) and tau in cerebrospinal fluid (CSF) differ among reports. We investigated the effects of storage temperature, repeated freeze/thaw cycles, and centrifugation on the concentrations of A beta 42 and tau in CSF. METHODS: Stability of samples stored at -80 degrees C was determined by use of an accelerated stability testing protocol according to the Arrhenius equation. A beta 42 and tau concentrations were measured in CSF samples stored at 4, 18, 37, and -80 degrees C. Relative CSF concentrations (%) of the biomarkers after one freeze/thaw cycle were compared with those after two, three, four, five, and six freeze/thaw cycles. In addition, relative A beta 42 and tau concentrations in samples not centrifuged were compared with samples centrifuged after 1, 4, 48, and 72 h. RESULTS: A beta 42 and tau concentrations were stable in CSF when stored for a long period at -80 degrees C. CSF A beta 42 decreased by 20% during the first 2 days at 4, 18, and 37 degrees C compared with -80 degrees C. CSF tau decreased after storage for 12 days at 37 degrees C. After three freeze/thaw cycles, CSF A beta 42 decreased 20%. CSF tau was stable during six freeze/thaw cycles. Centrifugation did not influence the biomarker concentrations. CONCLUSIONS: Repeated freeze/thaw cycles and storage at 4, 18, and 37 degrees C influence the quantitative result of the A beta 42 test. Preferably, samples should be stored at -80 degrees C immediately after collection.

Hampel H, Buerger K, Zinkowski R, Teipel SJ, Goernitz A, Andreasen N, Sjoegren M, DeBernardis J, Kerkman D, Ishiguro K, Ohno H, Vanmechelen E, Vanderstichele H, McCulloch C, Moller HJ, Davies P, Blennow K. · Dementia Research Section and Memory Clinic, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. · Arch Gen Psychiatry. · Pubmed #14706948 links to  free full text

Abstract: BACKGROUND: Abnormal hyperphosphorylation of the microtubule-associated protein tau and its incorporation into neurofibrillary tangles are major hallmarks of the pathogenesis of Alzheimer disease (AD). Different tau phosphoepitopes can be sensitively detected in cerebrospinal fluid (CSF). OBJECTIVE: To compare the diagnostic accuracy of CSF concentrations of tau proteins phosphorylated at 3 pathophysiologically important epitopes (p-tau) to discriminate among patients with AD, nondemented control subjects, and patients with other dementias. DESIGN AND SETTING: Cross-sectional, bicenter, memory clinic-based studies. PARTICIPANTS: One hundred sixty-one patients with a clinical diagnosis of AD, frontotemporal dementia, dementia with Lewy bodies, or vascular dementia and 45 nondemented controls (N = 206). MAIN OUTCOME MEASURES: Levels of tau protein phosphorylated at threonine 231 (p-tau231), threonine 181 (p-tau181), and serine 199 (p-tau199). The CSF p-tau protein levels were measured using 3 different enzyme-linked immunosorbent assays. RESULTS: The mean CSF levels of the studied p-tau proteins were significantly elevated in patients with AD compared with the other groups. Applied as single markers, p-tau231and p-tau181 reached specificity levels greater than 75% between AD and the combined non-AD group when sensitivity was set at 85% or greater. Statistical differences between the assay performances are presented. Particularly, discrimination between AD and dementia with Lewy bodies was maximized using p-tau181at a sensitivity of 94% and a specificity of 64%, and p-tau231 maximized group separation between AD and frontotemporal dementia with a sensitivity of 88% and a specificity of 92%. Combinations of the 3 markers did not add discriminative power compared with the application as single markers. CONCLUSIONS: The p-tau proteins in CSF come closest to fulfilling the criteria of a biological marker of AD. There is a tendency for p-tau proteins to perform differently in the discrimination of primary dementia disorders from AD.

Olsson A, Vanmechelen E, Vanderstichele H, Davidsson P, Blennow K. · Institute of Clinical Neuroscience, Experimental Neuroscience Section, Göteborg University, Sahlgrenska University Hospital/Mölndal, Mölndal, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #12784033 No free full text.

Abstract: Accumulation of beta-amyloid (Abeta) in the brain is one of the central lesions in Alzheimer's disease (AD). Alternative cleavage of the amyloid precursor protein (APP), occurring in both normal and AD subjects, results in the generation and secretion of soluble APP, Abeta(40) and Abeta(42). Platelets have been regarded as the primary source of circulating APP and Abeta. Plasma levels of Abeta may therefore be dependent on platelet activation. We analysed Abeta(40/42) in plasma in the presence of physiological agonists of platelet activation such as adenosine diphosphate, collagen, thrombin, and a synthetic agonist, thrombin receptor activator peptide 6. We found that the levels of Abeta(40/42) in plasma were not related to platelet activation, suggesting that sampling techniques affecting platelet activation do not confound measurement of Abeta(40/42 )in plasma.

Sáez-Valero J, Fodero LR, Sjögren M, Andreasen N, Amici S, Gallai V, Vanderstichele H, Vanmechelen E, Parnetti L, Blennow K, Small DH. · Department of Pathology, University of Melbourne, Victoria, Australia. · J Neurosci Res. · Pubmed #12704813 No free full text.

Abstract: The identification of biochemical markers of Alzheimer's disease (AD) may help in the diagnosis of the disease. Previous studies have shown that Abeta(1-42) is decreased, and tau and phospho-tau are increased in AD cerebrospinal fluid (CSF). Our own studies have identified glycosylated isoforms of acetylcholinesterase (Glyc-AChE) and butyrylcholinesterase (Glyc-BuChE) that are increased in AD CSF. Glyc-AChE is increased in APP (SW) Tg2576 transgenic mice prior to amyloid plaque deposition, which suggests that Glyc-AChE may be an early marker of AD. The aim of this study was to determine whether Glyc-AChE or Glyc-BuChE is increased in CSF at early stages of AD and to compare the levels of these markers with those of Abeta(1-42), tau and phospho-tau. Lumbar CSF was obtained ante mortem from 106 non-AD patients, including 15 patients with mild cognitive impairment (MCI), and 102 patients with probable AD. Glyc-AChE, tau and phospho-tau were significantly increased in the CSF of AD patients compared to non-neurological disease (NND) controls. Abeta(1-42) was lower in the AD patients than in NND controls. A positive correlation was found between the levels of Glyc-AChE or Glyc-BuChE and disease duration. However, there was no clear correlation between the levels of tau, phospho-tau or Abeta(1-42) and disease duration. The results suggest that Glyc-AChE and Glyc-BuChE are unlikely to be early markers of AD, although they may have value as markers of disease progression.

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.

Skoog I, Davidsson P, Aevarsson O, Vanderstichele H, Vanmechelen E, Blennow K. · Institute of Clinical Neuroscience, Unit of Neuropsychiatric Epidemiology, University of Göteborg, Sahlgrenska University Hospital, Göteborg, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #12584433 No free full text.

Abstract: Deposition of beta-amyloid (Abeta) is an early pathogenic event in Alzheimer's disease (AD). We measured Abeta42 and Abeta40 in cerebrospinal fluid (CSF) in a population-based sample of 85-year-olds, 27 demented and 35 non-demented. During the following 3 years, 7 of the 35 non-demented individuals had developed dementia, while 28 remained non-demented. Reduced CSF levels of both Abeta42 (p = 0.001) and Abeta40 (p = 0.0001) were found in patients with manifest AD and vascular dementia at the age of 85. Non-demented individuals who developed dementia during follow-up had lower levels of CSF- Abeta42 (p = 0.003), but not CSF-Abeta40 (p = 0.96), than those who remained non-demented. The odds ratio for development of dementia was 8.2 (p = 0.027) for individuals in the lower 50th percentile of CSF-Abeta42, while none of those in the highest 33rd percentile of CSF-Abeta42 developed dementia during follow-up. There were no significant differences between carriers and non-carriers of the apolipoprotein E epsilon4 allele regarding CSF-Abeta42 or CSF-Abeta40. Our study suggests that low CSF-Abeta42 is found also in an unselected population-based sample of old demented patients and provides the first evidence of a disturbance in the metabolism of Abeta, specifically involving Abeta42, before the onset of clinical symptoms in AD.

Sjögren M, Vanderstichele H, Agren H, Zachrisson O, Edsbagge M, Wikkelsø C, Skoog I, Wallin A, Wahlund LO, Marcusson J, Nägga K, Andreasen N, Davidsson P, Vanmechelen E, Blennow K. · Institute of Clinical Neuroscience, Psychiatry Section, Göteborg University, SE 431 80 Mölndal, Sweden. · Clin Chem. · Pubmed #11568086 links to  free full text

Abstract: BACKGROUND: Tau protein and the 42-amino acid form of beta-amyloid (Abeta42) measured in cerebrospinal fluid (CSF) have been proposed as potential biochemical diagnostic markers for Alzheimer disease. For the introduction of these assays in clinical practice, adequate reference values are of importance. METHODS: CSF samples were obtained from 231 neurologically and psychiatrically healthy individuals, 21-93 years of age, all with a MiniMental State examination score of 28 or above. Standardized ELISAs were used to measure tau and Abeta42 in CSF. Following IFCC recommendations, we used a rank-based method; the 0.90 and 0.10 fractiles were estimated to establish reference values for CSF-tau and CSF-Abeta42, respectively. Putative confounding factors, such as the influence of the passage of proteins from peripheral blood to CSF, influence of dysfunction of the blood-brain barrier, and freezing and thawing of CSF, were investigated. RESULTS: A correlation with age was found for CSF-tau (r = 0.60; P <0.001). Therefore, separate reference values for different age groups were established for CSF-tau: <300 ng/L in the group 21-50 years of age, <450 ng/L in the group 51-70 years of age, and <500 ng/L in the group 71-93 years of age. CSF-Abeta42 did not correlate with age (r = -0.045), and the reference value was set to >500 ng/L. No correlation was found between blood-brain barrier function and CSF-tau or CSF-Abeta42. CONCLUSIONS: These reference values can be applied when using CSF-tau and CSF-Abeta42 in clinical practice.

Sjögren M, Davidsson P, Gottfries J, Vanderstichele H, Edman A, Vanmechelen E, Wallin A, Blennow K. · Institute of Clinical Neuroscience, Göteborg University, Sahlgrenska University Hospital, Mölndal, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #11351137 No free full text.

Abstract: Cerebrospinal fluid (CSF) levels of tau (total tau), growth-associated protein-43 (GAP-43), soluble amyloid precursor protein (sAPP; i.e. total sAPP), and beta-amyloid(42) (Abeta(42)) were studied in patients with frontotemporal dementia (FTD; n = 14), Alzheimer's disease (AD; n = 47) and vascular dementia (VAD; n = 16), and in age-matched controls (n = 12). CSF-tau was increased in AD compared to controls and FTD (p < 0.001 for both). CSF-GAP-43 was increased in AD compared to controls (p < 0.05), and both CSF-GAP-43 and CSF-sAPP were increased in AD compared to FTD (p < 0.01). Positive and highly significant correlations were found between CSF-tau and CSF-GAP-43 in all groups and between CSF-tau, CSF-GAP-43 and CSF-sAPP in AD. The correlations found may reflect a common pathophysiologic process such as axonal degeneration.

Sjögren M, Davidsson P, Tullberg M, Minthon L, Wallin A, Wikkelso C, Granérus AK, Vanderstichele H, Vanmechelen E, Blennow K. · Institute of Clinical Neuroscience, Göteborg University, Sahlgrenska University Hospital / SE 431 80 Mölndal, Sweden. · J Neurol Neurosurg Psychiatry. · Pubmed #11309456 links to  free full text

Abstract: BACKGROUND: [corrected] Pathological tau protein concentrations in CSF are found in both Alzheimer's disease (AD) and frontotemporal dementia (FTD), but studies on brain tissue have suggested that the tau pathology in AD differs from that in FTD and that the difference may be related to the degree of phosphorylation. As CSF tau protein is increased after stroke, tau may also be implicated in the pathophysiology of vascular dementia, of which subcortical arteriosclerotic encephalopathy (SAE) is a putative subtype. OBJECTIVES: To investigate the nature of tau protein in CSF and the involvement of total CSF tau and phosphorylated CSF tau (phosphotau) in various types of dementia. METHODS: Using ELISAs for total tau and tau phosphorylated at Thr181 (phosphotau), the CSF concentrations of total tau and phosphotau were determined in patients with probable and possible AD (n=41 and 19, respectively), FTD (n=18), SAE (n=17), and Parkinson's disease (PD; n=15) and in age matched controls (n=17). All the antibodies stained the lower molecular weight bands, whereas only the antibodies that recognise phosphorylated tau stained the higher molecular bands. RESULTS: Both CSF tau and CSF phosphotau were increased in probable AD compared with FTD (p<0.001), SAE (p<0.001), PD (p<0.001), and controls (p<0.001). CSF phosphotau was increased in possible AD compared with FTD (p<0.001) and SAE (p<0.001). CSF tau and CSF phosphotau were positively correlated in all the groups. Molecular weight forms of tau ranging from 25 kDa to 80 kDa were found in the CSF CONCLUSION: Both phosphorylated and unphosphorylated tau isoforms were present in the CSF, and tau protein appeared in both truncated and full length forms. The results suggest that the CSF concentrations of tau and phosphotau are increased in about two thirds of patients with probable AD and in half of those with possible AD but are normal in FTD, SAE, and PD compared with normal aging. Values in the normal range do not exclude AD.