Authors: Skillbäck, Tobias | Kornhuber, Johannes | Blennow, Kaj | Zetterberg, Henrik | Lewczuk, Piotr | for the Alzheimer’s Disease Neuroimaging Initiative
Article Type: Research Article
Abstract: Background: To alleviate the interpretation of the core Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers, amyloid β1–42 (Aβ42 ), total tau (T -tau), and phosphorylated tau (P -tau), the Erlangen Score (ES) interpretation algorithm has been proposed. Objective: In this study, we aim to assess the predictive properties of the ES algorithm on cognitive and neuroimaging outcomes in mild cognitive impairment (MCI). Methods: All MCI subjects with an available baseline CSF sample from ADNI-1 were included (n = 193), and assigned an ES between 0 and 4 based on their baseline CSF biomarker profile. Structural magnetic resonance imaging brain scans and …MMSE and ADAS-Cog scores were collected at up to 7 times in follow-up examinations. Results: We observed strong and significant correlations between the ES at baseline and neuroimaging and cognitive results with patients with neurochemically probable AD (ES = 4) progressing significantly (p ≤0.01) faster than those with a neurochemically improbable AD (ES = 0 or 1), and the subjects with neurochemically possible AD (ES = 2 or 3) in-between these two groups. Conclusion: This study further demonstrates the utility of the ES algorithm as a as a tool in predicting cognitive and imaging progression in MCI patients. Show more
Keywords: Aβ1–42, Alzheimer’s disease, biomarkers, cerebrospinal fluid, Erlangen score, P-tau, T-tau
DOI: 10.3233/JAD-190067
Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 551-559, 2019
Authors: Popp, Julius | Lewczuk, Piotr | Frommann, Ingo | Kölsch, Heike | Kornhuber, Johannes | Maier, Wolfgang | Jessen, Frank
Article Type: Research Article
Abstract: In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinical manifestation of the disease. Biomarkers for AD, such as the cerebrospinal fluid (CSF) concentrations of amyloid-β1–42 (Aβ1–42 ) and tau phosphorylated at threonine 181 (pTau181), may reflect these cerebral changes relatively early. Accordingly, cognitively healthy subjects at risk for AD often have altered CSF concentrations of Aβ1–42 and pTau181. In this study, we assessed the effects and interaction of two strong risk factors for AD, aging and the presence of the APOEε4 allele, on the CSF Aβ1–42 and pTau181 concentrations in 280 adults with normal cognition …across the lifespan. For comparison, we further included 152 patients with probable AD. We found significant effects of age on the CSF Aβ1–42 and pTau181, and of the APOEε4 genotype on the Aβ1–42 levels in the cognitively normal participants. Carrying the APOEε4 allele was associated with a significant decrease of the Aβ1–42 concentrations in middle-aged and older participants. In the group of participants with AD, the Aβ1–42 levels were significantly lower in the APOEε4 carriers compared to the non-carriers. These findings demonstrate significant age effects on the CSF Aβ1–42 and pTau181 across lifespan. They also suggest that the decrease of Aβ1–42 , but not the increase of pTau181 CSF levels is accelerated by the APOEε4 genotype in middle-aged and older adults with normal cognition. Show more
Keywords: Alzheimer's disease, amyloid-β, APOEε4, cerebrospinal fluid, hyperphosphorylated tau, normal aging
DOI: 10.3233/JAD-2010-100561
Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 459-468, 2010
Authors: Zimmermann, Rüdiger | Lelental, Natalia | Ganslandt, Oliver | Maler, Juan Manuel | Kornhuber, Johannes | Lewczuk, Piotr
Article Type: Research Article
Abstract: Preanalytical sample handling and storage procedures play an extremely important role in reliably measuring neurochemical dementia diagnostics (NDD) biomarkers: Aβ1-40 , Aβ1-42 , Tau, and pTau181. To test different handling and storage conditions, the following protocols were applied: (a) storage at room temperature for one week, (b) deep-freezing and thawing up to three cycles, (c) deep-freezing, thawing and keeping under +4°C for two days before the analysis, and (d) long-term stability of a deeply frozen sample. Between the first and the seventh day of the storage at room temperature, the percentage of the concentrations (compared to the starting concentrations) fluctuated: …104.3–105.3, 97.6–93.2, 100.6–96.8, and 97.9–90.2 for Aβ1-40 , Aβ1-42 , Tau, and pTau181, respectively. Re-freezing cycles resulted in the percentage fluctuations of the concentrations: 101.1–105.5, 95.4–99.7, 98.3–100.0, and 100.5–101.4 for Aβ1-40 , Aβ1-42 , Tau, and pTau181, respectively. Keeping previously frozen/thawed samples under +4°C for two days resulted in the percentage differences of the concentrations: +15.9, +2.2, −1.1, and −0.1 for Aβ1-40 , Aβ1-42 , Tau, and pTau181, respectively. During long-term stability, the coefficients of linear correlation (R2 ) were: Aβ1-40 , 0.007; Aβ1-42 , 0.02; Tau, 0.011; and pTau181, 0.02, and the corresponding inter-assay coefficients of variation: 13.9%, 13.9%, 11.0%, and 10.7% for Aβ1-40 , Aβ1-42 , Tau, and pTau181, respectively. We conclude that the NDD biomarkers are relatively stable when the cerebrospinal fluid sample is kept at room temperature for about four days; one or two thawing/refreezing cycles do not profoundly affect the biomarkers concentrations, however three cycles result in increased unsystematic variation. The four biomarkers seem to be stable in a sample stored deeply frozen for more than two years. Show more
Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, laboratory quality control, preanalytical sample handling, Tau
DOI: 10.3233/JAD-2011-110212
Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 739-745, 2011
Authors: Lewczuk, Piotr | Popp, Julius | Lelental, Natalia | Kölsch, Heike | Maier, Wolfgang | Kornhuber, Johannes | Jessen, Frank
Article Type: Research Article
Abstract: In this report, we confirm our previous findings of increased concentrations of soluble amyloid-β protein precursor (sAβPP) in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large cohort of patients (n = 314), not overlapping with those of our previous study, and we extend our observations by including a control group of participants with normal cognition. In addition, we investigate the effects of age, the APOEε4 genotype, and the blood-CSF barrier function on the concentrations of sAβPPα and sAβPPβ. The study participants were categorized according to clinical-neuropsychological criteria, supported by CSF neurochemical …dementia diagnostics (NDD) analyses. sAβPPα concentrations in the AD group (132.0 ± 44.8) were significantly higher than in the control group (105.3 ± 37.3, p < 0.0005) but did not differ from the MCI-AD group (138.5 ± 39.5, p = 0.91). The MCI-AD group differed significantly from the MCI-O (97.3 ± 34.3, p < 0.05) group. There was no difference between the control and the MCI-O groups (p = 0.94). Similarly, sAβPPβ concentrations in the AD group (160.2 ± 54.3) were significantly higher than in the control group (129.9 ± 44.6, p < 0.005) but did not differ from the MCI-AD group (184.0 ± 56.4, p = 0.20). The MCI-AD group differed significantly from the MCI-O (127.8 ± 46.2, p < 0.05) group. There was no difference between the control and the MCI-O groups (p > 0.99). We observed highly significant correlation of the two sAβPP forms. Age and the CSF-serum albumin ratio were significant albeit weak predictors of the sAβPPα and sAβPPβ concentrations, while carrying the APOEε4 allele did not influenced the levels of the sAβPP forms. Taken together, the results strongly suggest that CSF sAβPP concentrations may be considered as an extension of already available NDD tools. Show more
Keywords: Alzheimer's disease, amyloid-β protein precursor, biomarkers, cerebrospinal fluid
DOI: 10.3233/JAD-2011-110857
Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 119-125, 2012
Authors: Weih, Markus | Degirmenci, Ümüt | Kreil, Sebastian | Suttner, Gerald | Schmidt, Daniela | Kornhuber, Johannes | Lewczuk, Piotr | Kuwert, Torsten
Article Type: Research Article
Abstract: Nuclear medicine techniques were the first functional imaging techniques used to support the clinical diagnosis of Alzheimer's Disease (AD). Perfusion-SPECT allows registration of regional cerebral blood flow (rCBF) which is altered in a characteristic temporal-parietal pattern in AD. Numerous studies have shown the diagnostic value of reduced CBF and metabolic changes using perfusion-SPECT and FDG-PET in AD diagnosis as well as in differential diagnosis against frontotemporal dementia (FTD), dementia with Lewy-Bodies (DLB), and vascular cognitive disorders. This renders perfusion-SPECT an important piece of the puzzle (together with other diagnostic tests) by the clinician is often faced when making a final …etiologic dementia diagnosis especially between AD and FTD. A similar diagnostic value can be expected when arterial spin labeling (ASL) MRI sequence is used, but the diagnostic value has yet to be confirmed in lager studies. Recently, more pathophysiology-based biomarkers in CSF and Amyloid-PET tracers have been developed that probably have a higher diagnostic accuracy than the more indirect rCBF changes seen in perfusion-SPECT. In the current review, we describe recent advances in AD biomarkers as well as improvements in the SPECT technique. Show more
DOI: 10.3233/JAD-2011-0020
Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 97-103, 2011
Authors: Lewczuk, Piotr | Lelental, Natalia | Spitzer, Philipp | Maler, Juan Manuel | Kornhuber, Johannes
Article Type: Research Article
Abstract: Background: The increasing role of cerebrospinal fluid (CSF) biomarkers in the early diagnosis of Alzheimer's disease (AD) is reflected in recently published diagnostic and/or research criteria. A growing body of evidence suggests better diagnostic performance of the amyloid-β (Aβ)42/40 CSF concentration ratio compared to the Aβ42 concentration alone. Objective: (a) to analytically validate two novel ELISAs capable to measure Aβ1-40 and Aβ1-42 in the CSF, and (b) to compare the diagnostic accuracies of Aβ1-42 and Aβ42/40 ratio. Methods: In this study, (a) the novel Aβ1-40 and Aβ1-42 ELISAs (IBL International GmbH, Hamburg, Germany) have been analytically validated, and (b) a …clinical study has been performed comparing the diagnostic performance of the CSF Aβ42/40 concentration ratio and the CSF Aβ42 concentration. Results: In the analytical part of the study, only marginal cross-reactivity (Aβ1-42 versus Aβ1-40 ) was observed; recoveries were in the range of 85–100% for the samples diluted 1 : 20–1 : 640 (Aβ1-40 ), and 92–104% for the samples diluted 1 : 20–1 : 320 (Aβ1-42 ). For Aβ1-40 , the intra-assay imprecision was 2.1%, the inter-assay imprecision was 4.4%, and the inter-lot imprecision was 5.4 %. For Aβ1-42 , the numbers were 3.1%, 6.2%, and 6.9%, respectively. The goodness of the fit of the average standard curves was >0.99 for both assays, and the imprecision of the optical densities in ten repetitions of the standard curves was ≤5% for all standards. In the clinical part, at the cut off value 691 pg/mL, Aβ1-42 showed sensitivity and specificity of 69.3% and 88.9%, respectively, whereas at the cut off value 0.06, the Aβ42/40 ratio showed significantly improved performance with sensitivity and specificity of 93.3% and 100%, respectively. The area under the ROC curve for Aβ42/40 (0.974) was highly significantly larger compared to Aβ1-42 concentration ROC curve (0.827, p < 0.0001). Conclusions: (a) the novel Aβ1-40 and Aβ1-42 ELISA assays characterize with very good analytical performance; (b) we reconfirm that the CSF Aβ42/40 concentration ratio shows significantly better diagnostic performance compared to the CSF Aβ1-42 concentration alone. Show more
Keywords: Alzheimer's disease, Aβ42/40 ratio, amyloid-β, biomarkers, cerebrospinal fluid, validation
DOI: 10.3233/JAD-140771
Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 183-191, 2015
Authors: Zimmermann, R. | Beck, Georg | Knispel, Sabine | Maler, Juan Manuel | Weih, Markus | Wiltfang, Jens | Kornhuber, Johannes | Lewczuk, Piotr
Article Type: Research Article
Abstract: Neurochemical Dementia Diagnostics (NDD), i.e., analysis of the cerebrospinal fluid (CSF) concentrations of amyloid-β peptides and tau/phospho-tau proteins plays important role in the diagnosis of neurodegeneration and dementias. Several studies show alterations of these biomarkers in Alzheimer's disease (AD), however, only a few reports address alterations of other CSF biomarkers (albumin and immunoglobulins' quotients, cell count, lactate concentration, etc.) in the pathophysiology and diagnostic procedures of dementias. Therefore, we analyzed these biomarkers in patients diagnosed for dementia syndromes and carefully characterized with the state-of-the-art NDD analysis: Aβ1–42 , Aβx–42 , Aβx–42/x–40 ratio, tau, and ptau181. We found intrathecal IgG synthesis …in 5 out of 112 patients showing alterations of the NDD biomarkers, and in four out of these five subjects, we could not find any satisfying reason for the intrathecal humoral response. In 25.9% of the patients with altered NDD biomarkers, we found an increased albumin quotient indicating a dysfunction of the blood-CSF barrier; however a similar figure of 25.2% was found in the group of patients without alterations in the NDD. Our findings suggest that at least some patients with increased CSF concentrations of tau/ptau proteins and decreased concentrations of Aβ42 peptides show simultaneously CSF alterations found otherwise in neuroinflammatory processes. This, in turn, suggests that extended diagnosis should be performed in patients with “isolated” alterations of NDD biomarkers or intrathecal immunoglobulin synthesis. Show more
Keywords: Amyloid-β, cerebrospinal fluid, dementia, neurodegeneration, neuroimmunology, tau
DOI: 10.3233/JAD-2010-1313
Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1199-1203, 2010
Authors: Brandner, Sebastian | Thaler, Christian | Lelental, Natalia | Buchfelder, Michael | Kleindienst, Andrea | Maler, Juan Manuel | Kornhuber, Johannes | Lewczuk, Piotr
Article Type: Research Article
Abstract: Background: Little information is available on the rostro-caudal concentration gradient of Alzheimer’s disease (AD) biomarkers. Objective: We studied the concentrations of amyloid-β (Aβ) peptides 1-42 and 1-40 as well as the Tau and pTau proteins in simultaneously collected ventricular and lumbar cerebrospinal fluid (CSF) samples. Methods: The samples were simultaneously collected from the ventricle and the lumbar spinal canal in two groups of patients: 10 subjects being treated for normal pressure hydrocephalus (NPH) by the placement of a ventriculo-peritoneal shunt and 5 patients treated simultaneously with an external ventricular drain and a lumbar CSF drain due to posttraumatic hydrocephalus (PTH). …Results: The ventricular-lumbar (V/L) concentration ratio for Aβ1-40 was 0.81 in NPH patients and 0.71 in PTH patients. The V/L-ratio for Aβ1-42 was 0.84 in NPH, reflecting significantly higher concentrations in lumbar CSF than in ventricular CSF, and 1.02 in PTH patients. The V/L-ratios for Tau and pTau differed significantly depending on the diagnostic group: the median V/L-ratio for Tau was 6.83 in NPH patients but only 0.97 in PTH patients. The median V/L-ratio for pTau was 2.36 in NPH patients and 0.91 in PTH patients. Conclusions: We conclude that the rostro-caudal concentration gradient for brain-derived proteins (Tau and pTau in this study) depends on the diagnosis and clinical status of the patient, which were largely neglected in the previously postulated models. Show more
Keywords: Amyloid-β, biomarker, cerebrospinal fluid, rostro-caudal gradient, tau
DOI: 10.3233/JAD-132708
Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1057-1062, 2014
Authors: Mroczko, Barbara | Groblewska, Magdalena | Zboch, Marzena | Kulczyńska, Agnieszka | Koper, Olga M. | Szmitkowski, Maciej | Kornhuber, Johannes | Lewczuk, Piotr
Article Type: Research Article
Abstract: Background: A growing body of evidence shows the involvement of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in neurodegeneration processes, but reports of their concentrations in the cerebrospinal fluid (CSF) are inconsistent. Objective: Therefore, the aim of our study was to evaluate the CSF concentrations of MMP-2, MMP-3, MMP-9, and their inhibitors (TIMP-1 and TIMP-2) in carefully selected groups of patients with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and non-demented controls, whose clinical and neuropsychological diagnoses were confirmed by the corresponding CSF biomarkers of neurochemical dementia diagnostics: decreased concentrations of Aβ1-42 and/or Aβ42/40 ratio, and increased concentrations of …Tau and pTau181 proteins. Methods: The study included 33 AD patients, 15 subjects with MCI, and 18 elderly individuals without cognitive deficits. The CSF concentrations of MMPs and TIMPs were determined with ELISAs. Results: CSF concentrations of MMP-9 were significantly lower, and the concentrations of MMP-3 significantly higher in AD patients compared to the controls. Neither MMP-2 nor TIMPs showed significant changes among the groups investigated. Conclusion: Altered concentrations of two out of three MMPs investigated in this study suggest that this family of biomolecules may play a role in the AD pathophysiology. Further studies are needed to establish their potential diagnostic utility. Show more
Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases
DOI: 10.3233/JAD-131634
Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 351-357, 2014
Authors: Popp, Julius | Lewczuk, Piotr | Linnebank, Michael | Cvetanovska, Gabriela | Smulders, Yvo | Kölsch, Heike | Frommann, Ingo | Kornhuber, Johannes | Maier, Wolfgang | Jessen, Frank
Article Type: Research Article
Abstract: Disturbed homocysteine metabolism is a risk factor for Alzheimer's disease (AD) and may contribute to the disease pathophysiology by increasing both amyloid-β (Aβ) production and phosphorylated tau (P-tau) accumulation. Here, we evaluated the relationship between the cerebrospinal fluid (CSF) concentrations of homocysteine (Hcys), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and 5-methyltetrahydrofolate (5-MTHF), and the markers for AD pathology, Aβ1-42 and P-tau181, in 98 cognitively healthy subjects aged 16-81 years and 54 AD patients. In multivariate regression tests including age, gender, creatinine, and presence of the apolipoprotein E ε4 allele, P-tau181 was associated with SAH (β = 0.490; p < 0.001), 5-MTHF (β …= -0.273; p = 0.010) levels, and SAM/SAH ratio (β = -0.319; p = 0.013) in controls, and with SAH (β = 0.529; p = 0.001) in AD patients. The levels of Aβ1-42 were not associated with the CSF concentrations of Hcys, SAM, SAH, or 5-MTHF neither in the AD nor in the control group. The results suggest that alteration of the homocysteine metabolism is related to increased accumulation of phosphorylated tau and may contribute to the neurofibrillary pathology in normal aging and in AD. Show more
Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, homocysteine, phosphorylated tau
DOI: 10.3233/JAD-2009-1187
Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 819-828, 2009