Authors: Sjölander, Annica | Minthon, Lennart | Nuytinck, Lieve | Vanmechelen, Eugeen | Blennow, Kaj | Nilsson, Staffan
Article Type: Research Article
Abstract: Mannan-Binding lectin (MBL) is a serum lectin and an important constituent of the innate immune system. Processes linked to the innate immune response have previously been implicated in Alzheimer's disease (AD). MBL is associated with blood vessels in the brain and AD patients demonstrate lower MBL levels in the cerebrospinal fluid compared to controls. We investigated six single nucleotide polymorphisms, linked to MBL deficiency, in the corresponding MBL2 gene in AD patients and controls. Two MBL2 haplotypes, LXP and LYQ, were significantly associated with AD risk (OR = 1.6, p = 0.01 and OR = 1.5, p = 0.02, respectively). …The present study is the first investigating MBL2 genotypes and haplotypes in relation to AD. Our findings support that the MBL2 gene impact the disease risk. Show more
Keywords: Alzheimer's disease, cerebrospinal fluid, gene, immune response, Mannan-Binding lectin, single nucleotide polymorphism
DOI: 10.3233/JAD-122044
Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 121-127, 2013
Authors: Hertze, Joakim | Minthon, Lennart | Zetterberg, Henrik | Vanmechelen, Eugeen | Blennow, Kaj | Hansson, Oskar
Article Type: Research Article
Abstract: In this study, we determined the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers to predict development of Alzheimer's disease (AD) within five years in patients with mild cognitive impairment (MCI). To do so, the levels of tau, phosphorylated tau, Aβ42 , Aβ40 , Aβ38 , sAβPPα, and sAβPPβ were analyzed in 327 CSF samples obtained at baseline from patients with AD (n= 94), MCI (n= 166), depressive disorder (n= 29), and cognitively healthy controls (n= 38). In the cohort with MCI at baseline, 33% subsequently developed AD and 16% developed other types of dementia; however, 51% were still cognitively stable …after a follow-up of 4.7 years (range 3.0–7.2). Optimal cut-offs for each biomarker or combinations of biomarkers were defined in the AD, control, and depressive disorder groups. Several combinations resulted in sensitivity and specificity levels > 85% for differentiation of AD from controls and depressive disorder. Using the previously established cut-offs, a combination of Aβ42 and tau could predict future development of AD in MCI patients with a sensitivity of 88%, specificity 82%, positive predictive value 71%, and negative predictive value 94%. MCI patients with both low Aβ42 and high tau levels had a substantially increased risk of developing AD (OR 20; 95% CI 6–58), even after adjustment for confounding factors. Ultimately, CSF biomarkers can stratify MCI patients into those with very low or high risk for future development of AD. However, the specificities and positive predictive values are still too low to be able to diagnose AD before the patients fulfill the clinical criteria. Show more
Keywords: Alzheimer's disease, amyloid-β, biomarkers, cerebrospinal fluid, early diagnosis, mild cognitive impairment
DOI: 10.3233/JAD-2010-100207
Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1119-1128, 2010
Authors: Le Bastard, Nathalie | Coart, Els | Vanderstichele, Hugo | Vanmechelen, Eugeen | Martin, Jean-Jacques | Engelborghs, Sebastiaan
Article Type: Research Article
Abstract: Combined analysis of the Alzheimer's disease (AD) biomarkers amyloid-β1-42 (Aβ1-42 ), total tau (T-tau), and hyperphosphorylated tau (P-tau181P ) in cerebrospinal fluid (CSF) reduces the uncertainty associated with clinical dementia diagnosis. The present study evaluated the diagnostic accuracy of the CSF biomarker concentrations obtained with a multi-analyte Luminex assay (INNO-BIA AlzBio3) in comparison to single-analyte ELISA tests (INNOTEST). Data from 66 pathologically-confirmed dementia patients (51 AD and 15 non-AD) and 95 controls were included. Cut-off values were determined for each individual biomarker determined using both methods for different diagnostic challenges (dementia-controls; AD-controls; AD-non-AD). Comparing the diagnostic accuracy of individual cut-off …values between INNO-BIA and INNOTEST, no relevant differences could be identified. Logistic regression was used in addition to identify the best combination of predictor variables (biomarkers). Discrimination of dementia patients from controls using Aβ1-42 and T-tau yielded a diagnostic accuracy of 0.87 and 0.90 for INNO-BIA and INNOTEST, respectively. Discriminating AD patients from controls, the diagnostic accuracy was 0.90 and 0.93 for INNO-BIA and INNOTEST, respectively. Optimal discrimination of AD and non-AD patients was achieved by combining Aβ1-42 and P-tau181P (diagnostic accuracy = 0.86). In conclusion, which AD biomarkers or combination thereof are most informative is dependent on the differential diagnosis, but the clinical value of these markers in each of the differential diagnoses is independent of the method by which concentrations are determined. Since the clinical value of the ELISA (INNOTEST) and Luminex (INNO-BIA) tests is comparable, further research to select the most suitable analytical platform for routine CSF biomarker measurements is needed. Show more
Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, immunoassay
DOI: 10.3233/JAD-2012-121246
Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 117-131, 2013
Authors: Hesse, Camilla | Rosengren, Lars | Vanmechelen, Eugeen | Vanderstichele, Hugo | Jensen, Christer | Davidsson, Pia | Blennow, Kaj
Article Type: Research Article
Abstract: Potential cerebrospinal fluid (CSF) markers for Alzheimer's disease (AD) include tau protein, the 42 amino-acid form of amyloid ß (amyloid ß(1-42)) and apolipoprotein E (apoE). To study new aspects of these protein markers, we examined consecutive CSF samples from 26 patients with acute ischemic stroke. CSF samples were taken on day 0–1, day 2–3, day 7–9, 3 weeks and 3–5 months after the stroke. CSF-tau showed a marked increase day 2–3, which peaked after 1 week and returned to normal after 3–5 months. CSF-tau also showed correlation (r = 0.95; p < 0.01) with the size of the infarct. In contrast, CSF-amyloid ß(1-42) and …CSF-apoE showed no significant changes during the period. The marked increase in CSF-tau levels after acute ischemic stroke indicate that CSF-tau reflect the degree of neuronal damage. The reason for unchanged levels of CSF-amyloid ß(1-42) and CSF-apoE after ischemic stroke remains unclear. Show more
Keywords: apolipoprotein E, amyloid ß(1-42), tau, cerebrospinal fluid (CSF), stroke, cerebral infarction, Alzheimer's disease
DOI: 10.3233/JAD-2000-23-402
Citation: Journal of Alzheimer's Disease, vol. 2, no. 3-4, pp. 199-206, 2000
Authors: Hansson, Oskar | Stomrud, Erik | Vanmechelen, Eugeen | Östling, Svante | Gustafson, Deborah R | Zetterberg, Henrik | Blennow, Kaj | Skoog, Ingmar
Article Type: Research Article
Abstract: Amyloid-β (Aβ) pathology is a major component in the mechanisms behind Alzheimer's disease (AD). Measurement of Aβ42 in cerebrospinal fluid predicts cognitive decline in patients with mild cognitive impairment and identifies AD in patients with dementia. However, studies on Aβ in plasma are contradictory. In this prospective population-based study, plasma Aβ42 and Aβ40 were measured at baseline in 730 adults aged 70 years or older and without dementia. After five years, plasma levels were analyzed again and participants were assessed for development of dementia. During follow-up, 53 individuals (7%) developed dementia of which 37 (5%) were classified as AD. No …difference in baseline plasma Aβ42 , Aβ40 , or Aβ42 /Aβ40 ratio levels were observed between converters to dementia or AD compared to the cognitively stable individuals. However, individuals with plasma Aβ40 levels above the median level for the group at baseline had an increased risk of developing dementia and AD during the follow-up, even after adjustment for age, gender, APOE genotype, and educational level (odds ratio = 2.2, 95% confidence interval = 1.0–4.7, p < 0.05). Neither plasma Aβ42 nor the Aβ42 /Aβ40 ratio influenced the risk of developing dementia or AD. Moreover, Aβ42 and Aβ40 levels increased over the 5 years, whereas the Aβ42 /Aβ40 ratio decreased (p < 0.001). In conclusion, this study suggests that measurement of plasma Aβ should not be used clinically to predict dementia or AD. However, plasma Aβ40 may possibly be regarded as a moderate risk marker comparable to other risk markers for AD such as first-degree family history of dementia. Show more
Keywords: Alzheimer's disease, amyloid-β 40, amyloid-β 42, biological markers, cohort studies, dementia, plasma
DOI: 10.3233/JAD-2011-111418
Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 231-238, 2012
Authors: De Vos, Ann | Struyfs, Hanne | Jacobs, Dirk | Fransen, Erik | Klewansky, Tom | De Roeck, Ellen | Robberecht, Caroline | Van Broeckhoven, Christine | Duyckaerts, Charles | Engelborghs, Sebastiaan | Vanmechelen, Eugeen
Article Type: Research Article
Abstract: Background: In diagnosing Alzheimer’s disease (AD), ratios of cerebrospinal fluid (CSF) biomarkers, such as CSF Aβ1-42 /tau, have an improved diagnostic performance compared to the single analytes, yet, still a limited value to predict cognitive decline. Since synaptic dysfunction/loss is closely linked to cognitive impairment, synaptic proteins are investigated as candidate CSF AD progression markers. Objective: We studied CSF levels of the postsynaptic protein neurogranin and protein BACE1, predominantly localized presynaptically, and their relation to CSF total-tau, Aβ1-42 , Aβ1-40 , and Aβ1-38 . All six analytes were considered as single parameters as well as ratios. Methods: Every ELISA involved …was based on monoclonal antibodies, including the BACE1 and neurogranin immunoassay. The latter specifically targets neurogranin C-terminally truncated at P75, a more abundant species of the protein in CSF. We studied patients with MCI due to AD (n = 38) and 50 dementia due to AD patients, as well as age-matched cognitively healthy elderly (n = 20). A significant subset of the patients was followed up by clinical and neuropsychologically (MMSE) examinations for at least one year. Results: The single analytes showed statistically significant differences between the clinical groups, but the ratios of analytes indeed had a higher diagnostic performance. Furthermore, only the ratio of CSF neurogranin trunc P75/BACE1 was significantly correlated with the yearly decline in MMSE scores in patients with MCI and dementia due to AD, pointing toward the prognostic value of the ratio. Conclusion: This is the first study demonstrating that the CSF neurogranin trunc P75/BACE1 ratio, reflecting postsynaptic/presynaptic integrity, is related to cognitive decline. Show more
Keywords: Alzheimer’s disease, BACE1 protein, biomarkers, cerebrospinal fluid, ELISA, mild cognitive impairment, neurogranin, prognostic, ratio
DOI: 10.3233/JAD-160227
Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1523-1538, 2016
Authors: Roeben, Benjamin | Maetzler, Walter | Vanmechelen, Eugeen | Schulte, Claudia | Heinzel, Sebastian | Stellos, Konstantinos | Godau, Jana | Huber, Heiko | Brockmann, Kathrin | Wurster, Isabel | Gaenslen, Alexandra | Grüner, Eva | Niebler, Raphael | Eschweiler, Gerhard W. | Berg, Daniela | the TREND study team
Article Type: Research Article
Abstract: Background/Objective: Plasma levels of amyloid-beta (Aβ) 1-40 peptide have been proposed to be associated with cardiovascular mortality in patients with coronary artery disease (CAD). Therefore, we aimed to investigate the association of plasma Aβ levels with CAD, cardiovascular risk factors (CVRF), and APOE genotype in non-demented elderly individuals. Methods: Plasma Aβ1 - 40 and Aβ1 - 42 levels of 526 individuals (mean age of 63.0±7.3 years) were quantified with the INNO-BIA plasma Aβ forms assay based on multiplextrademark technique. APOE genotype was determined with an established protocol. Presence of CAD and CVRFs were ascertained using a questionnaire and/or medical records. Results: Plasma Aβ1 - 40 levels …were significantly higher in individuals with CAD (p = 0.043) and, independently, in individuals with diabetes mellitus (DM) type 2 (p = 0.001) while accounting for age- and gender-effects. Plasma Aβ1 - 42 levels were higher in APOE ɛ 4 carriers (p = 0.004), but were neither relevantly associated with CAD nor with any CVRF. Plasma Aβ1 - 40 showed no association with APOE genotype. Discussion: Our findings argue for an association of circulating plasma Aβ1 - 40 peptides with incident CAD and DM. Further investigations are needed to entangle the role of Aβ1 - 40 role in the pathophysiology of cardiovascular disease independent of its known role in Alzheimer’s disease. Show more
Keywords: Alzheimer’s disease, amyloid-beta, APOE genotype, coronary artery disease, diabetes mellitus, vascular
DOI: 10.3233/JAD-150575
Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 161-169, 2016
Authors: Zetterberg, Henrik | Pedersen, Mona | Lind, Karin | Svensson, Maria | Rolstad, Sindre | Eckerström, Carl | Syversen, Steinar | Mattsson, Ulla-Britt | Ysander, Christina | Mattsson, Niklas | Nordlund, Arto | Vanderstichele, Hugo | Vanmechelen, Eugeen | Jonsson, Michael | Edman, Åke | Blennow, Kaj | Wallin, Anders
Article Type: Research Article
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-tau181 (P-tau181 ) and amyloid-β1–42 (Aβ1–42 ). 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-tau181 levels were elevated in the MCI-AD group …as compared to the stable MCI patients and the control group (p < 0.01 ), while baseline Aβ1–42 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. Show more
Keywords: Mild cognitive impairment, Alzheimer's disease, cerebrospinal fluid, biomarkers, longitudinal study, tau, amyloid-β (Aβ), stability
DOI: 10.3233/JAD-2007-12307
Citation: Journal of Alzheimer's Disease, vol. 12, no. 3, pp. 255-260, 2007
Authors: Bolsewig, Katharina | Hok-A-Hin, Yanaika S. | Sepe, Federica N. | Boonkamp, Lynn | Jacobs, Dirk | Bellomo, Giovanni | Paoletti, Federico Paolini | Vanmechelen, Eugeen | Teunissen, Charlotte E. | Parnetti, Lucilla | Willemse, Eline A. J.
Article Type: Research Article
Abstract: Background: The differential diagnosis of frontotemporal dementia (FTD) is still a challenging task due to its symptomatic overlap with other neurological diseases and the lack of biofluid-based biomarkers. Objective: To investigate the diagnostic potential of a combination of novel biomarkers in cerebrospinal fluid (CSF) and blood. Methods: We included 135 patients from the Center for Memory Disturbances, University of Perugia, with the diagnoses FTD (n = 37), mild cognitive impairment due to Alzheimer’s disease (MCI-AD, n = 47), Lewy body dementia (PDD/DLB, n = 22), and cognitively unimpaired patients as controls (OND, n = 29). Biomarker levels of neuronal pentraxin-2 (NPTX2), neuronal pentraxin receptor, …neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were measured in CSF, as well as NfL and GFAP in serum. We assessed biomarker differences by analysis of covariance and generalized linear models (GLM). We performed receiver operating characteristics analyses and Spearman correlation to determine biomarker associations. Results: CSF NPTX2 and serum GFAP levels varied most between diagnostic groups. The combination of CSF NPTX2, serum NfL and serum GFAP differentiated FTD from the other groups with good accuracy (FTD versus MCI-AD: area under the curve (AUC) [95% CI] = 0.89 [0.81–0.96]; FTD versus PDD/DLB: AUC = 0.82 [0.71–0.93]; FTD versus OND: AUC = 0.80 [0.70–0.91]). CSF NPTX2 and serum GFAP correlated positively only in PDD/DLB (ρ = 0.56, p < 0.05). NPTX2 and serum NfL did not correlate in any of the diagnostic groups. Serum GFAP and serum NfL correlated positively in all groups (ρ = 0.47–0.74, p < 0.05). Conclusion: We show the combined potential of CSF NPTX2, serum NfL, and serum GFAP to differentiate FTD from other neurodegenerative disorders. Show more
Keywords: Biomarker, differential diagnosis, frontotemporal dementia, glial fibrillary acidic protein, neurofilament light, NPTX2, NPTXR
DOI: 10.3233/JAD-220318
Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 363-380, 2022
Authors: Zhang, Min | Zhong, Xiaomei | Shi, Haishan | Vanmechelen, Eugeen | De Vos, Ann | Liu, Sen | Chen, Ben | Mai, Naikeng | Peng, Qi | Chen, Xinru | Wu, Zhangying | Hou, Le | Zhou, Huarong | Ouyang, Cong | Zhang, Weiru | Liang, Wanyuan | Dai, Chunying | Ning, Yuping
Article Type: Research Article
Abstract: Background: Patients with spirochetal infection, which causes neurosyphilis (NS) and at a later stage general paresis of the insane (GPI), present with brain pathology features of Alzheimer’s disease (AD). However, the relationships among these illnesses regarding biomarker levels are still unclear. Objective: To explore biomarker levels in NS and GPI compared with those in AD and the relationship between biomarker levels and cognitive function in NS and GPI. Methods: Levels of neurogranin (NGRN) and β-amyloid precursor protein cleaving enzyme (BACE1) in cerebrospinal fluid (CSF)/plasma, together with amyloid-β 1–40 (Aβ40 ), Aβ42 , and total tau in the CSF of 23 …AD patients, 55 GPI patients, and 13 NS patients were measured. Patients were classified into none-to-mild, moderate, and severe stages of cognitive impairment. Results: Levels of CSF NGRN, BACE1, and tau as well as plasma BACE1 levels were significantly different among groups. In the none-to-mild stage, plasma BACE1 levels correlated with the protein levels in CSF and were significantly increased in AD patients versus GPI patients. The CSF tau levels in AD patients were significantly increased versus GPI patients in the moderate and severe stages. Pooling data from GPI and NS patients, both CSF tau and plasma NGRN levels correlated with cognitive scale scores. Conclusion: GPI and NS patients might have different biomarker level patterns compared to AD patients. While plasma BACE1 could be a promising early biomarker for distinguishing AD from GPI, CSF tau and plasma NGRN levels might be valuable in indications of cognitive function in pooled NS populations. Show more
Keywords: Alzheimer’s disease, BACE1, general paresis of insane, neurogranin, neurosyphilis
DOI: 10.3233/JAD-200362
Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 313-322, 2020