| 1. |
- Mattsson, Niklas, 1979, et al.
(författare)
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The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.
- 2011
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 7:4, s. 386-395.e6
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Tidskriftsartikel (refereegranskat)abstract
- The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
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| 2. |
- Wiltfang, J., et al.
(författare)
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Consensus Paper of the WFSBP Task Force on Biological Markers of Dementia : The role of CSF and blood analysis in the early and differential diagnosis of dementia
- 2009
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Ingår i: Revista de Psiquiatria Clinica. - 0101-6083. ; 36, s. 1-16
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Forskningsöversikt (refereegranskat)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, A beta 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.
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| 3. |
- Wiltfang, J, et al.
(författare)
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Consensus paper of the WFSBP Task Force on Biological Markers of Dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia.
- 2005
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Ingår i: The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. - : Informa UK Limited. - 1562-2975. ; 6:2, s. 69-84
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Forskningsöversikt (refereegranskat)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.
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| 4. |
- Hellwig, K., et al.
(författare)
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Neurogranin and YKL-40: independent markers of synaptic degeneration and neuroinflammation in Alzheimer's disease
- 2015
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Neuroinflammation and synaptic degeneration are major neuropathological hallmarks in Alzheimer's disease (AD). Neurogranin and YKL-40 in cerebrospinal fluid (CSF) are newly discovered markers indicating synaptic damage and microglial activation, respectively. Methods: CSF samples from 95 individuals including 39 patients with AD dementia (AD-D), 13 with mild cognitive impairment (MCI) due to AD (MCI-AD), 29 with MCI not due to AD (MCI-o) and 14 patients with non-AD dementias (non-AD-D) were analyzed for neurogranin and YKL-40. Results: Patients with dementia or MCI due to AD showed elevated levels of CSF neurogranin (p < 0.001 for AD-D and p < 0.05 for MCI-AD) and YKL-40 (p < 0.05 for AD-D and p = 0.15 for MCI-AD) compared to mildly cognitively impaired subjects not diagnosed with AD. CSF levels of neurogranin and YKL-40 did not differ between MCI not due to AD and non-AD dementias. In AD subjects no correlation between YKL-40 and neurogranin was found. The CSF neurogranin levels correlated moderately with tau and p-tau but not with A beta 42 or the MMSE in AD samples. No relevant associations between YKL-40 and MMSE or the core AD biomarkers, A beta 42, t-tau and p-tau were found in AD subjects. Conclusions: Neurogranin and YKL-40 are promising AD biomarkers, independent of and complementary to the established core AD biomarkers, reflecting additional pathological changes in the course of AD.
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| 5. |
- Kvartsberg, Hlin, 1987, et al.
(författare)
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Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer's disease patients and healthy controls
- 2015
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Synaptic dysfunction and degeneration are central events in Alzheimer's disease (AD) pathophysiology that are thought to occur early in disease progression. Synaptic pathology may be studied by examining protein biomarkers specific for different synaptic elements. We recently showed that the dendritic protein neurogranin (Ng), including the endogenous Ng peptide 48 to 76 (Ng(48-76)), is markedly increased in cerebrospinal fluid (CSF) in AD and that Ng48-76 is the dominant peptide in human brain tissue. The aim of this study was to characterize Ng in plasma and CSF using mass spectrometry and to investigate the performance of plasma Ng as an AD biomarker. Methods: Paired plasma and CSF samples from patients with AD (n = 25) and healthy controls (n = 20) were analyzed in parallel using an immunoassay developed in-house on the Meso Scale Discovery platform and hybrid immunoaffinity-mass spectrometry (HI-MS). A second plasma material from patients with AD (n = 13) and healthy controls (n = 17) was also analyzed with HI-MS. High-resolution mass spectrometry was used for identification of endogenous plasma Ng peptides. Results: Ng in human plasma is present as several endogenous peptides. Of the 16 endogenous Ng peptides identified, seven were unique for plasma and not detectable in CSF. However, Ng(48-76) was not present in plasma. CSF Ng was significantly increased in AD compared with controls (P < 0.0001), whereas the plasma Ng levels were similar between the groups in both studies. Plasma and CSF Ng levels showed no correlation. CSF Ng was stable during storage at -20 degrees C for up to 2 days, and no de novo generation of peptides were detected. Conclusions: For the first time, to our knowledge, we have identified several endogenous Ng peptides in human plasma. In agreement with previous studies, we show that CSF Ng is significantly increased in AD as compared with healthy controls. The origin of Ng in plasma and its possible use as a biomarker need to be further investigated. The results suggest that CSF Ng, in particular Ng(48-76), might reflect the neurodegenerative processes within the brain, indicating a role for Ng as a potential novel clinical biomarker for synaptic function in AD.
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| 6. |
- Lewczuk, P., et al.
(författare)
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Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer's disease
- 2018
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10:71
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Tidskriftsartikel (refereegranskat)abstract
- Background: A growing body of evidence suggests that the plasma concentration of the neurofilament light chain (NfL) might be considered a plasma biomarker for the screening of neurodegeneration in Alzheimer's disease (AD). Methods: With a single molecule array method (Simoa, Quanterix), plasma NfL concentrations were measured in 99 subjects with AD at the stage of mild cognitive impairment (MCI-AD; n = 25) or at the stage of early dementia (ADD; n = 33), and in nondemented controls (n = 41); in all patients, the clinical diagnoses were in accordance with the results of the four core cerebrospinal fluid (CSF) biomarkers (amyloid beta (A beta) 1-42, A beta 42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm. The influence of preanalytical storage procedures on the NfL in plasma was tested on samples exposed to six different conditions. Results: NfL concentrations significantly increased in the samples exposed to more than one freezing/thawing cycle, and in those stored for 5 days at room temperature or at 4 degrees C. Compared with the control group of nondemented subjects (22.0 +/- 12.4 pg/mL), the unadjusted plasma NfL concentration was highly significantly higher in the MCI-AD group (38.1 +/- 15.9 pg/mL, p < 0.005) and even further elevated in the ADD group (49.1 +/- 28.4 pg/mL; p < 0.001). A significant association between NfL and age (p = 0.65, p < 0.001) was observed; after correcting for age, the difference in NfL concentrations between AD and controls remained significant (p = 0.044). At the cutoff value of 25.7 pg/mL, unconditional sensitivity, specificity, and accuracy were 0.84, 0.78, and 0.82, respectively. Unadjusted correlation between plasma NfL and Mini Mental State Examination (MMSE) across all patients was moderate but significant (r = -0.49, p < 0.001). We observed an overall significant correlation between plasma NfL and the CSF biomarkers, but this correlation was not observed within the diagnostic groups. Conclusions: This study confirms increased concentrations of plasma NfL in patients with Alzheimer's disease compared with nondemented controls.
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| 7. |
- Mattsson, Niklas, 1979, et al.
(författare)
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CSF biomarker variability in the Alzheimer's Association quality control program
- 2013
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 9:3, s. 251-261
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Tidskriftsartikel (refereegranskat)abstract
- Background The cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1–42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.
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| 8. |
- Blennow, K., et al.
(författare)
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EVOLUTION OF A beta 42 AND A beta 40 LEVELS AND A beta 42/A beta 40 RATIO IN PLASMA DURING PROGRESSION OF ALZHEIMER'S DISEASE: A MULTICENTER ASSESSMENT
- 2009
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Ingår i: Journal Of Nutrition Health & Aging. - 1279-7707. ; 13:3, s. 205-208
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Konferensbidrag (refereegranskat)abstract
- Objective: To better understand the seemingly contradictory plasma beta-amyloid (A beta) results in Alzheimer's disease (AD) patients by using a newly developed plasma A beta assay, the INNO-BIA plasma A beta forms, in a multicenter study. Methods: A combined retrospective analysis of plasma A beta isoforms on mild cognitive impairment (MCI) from three large cross-sectional studies involving 643 samples from the participating German and Swedish centers. Results: Detection modules based on two different amino (N)-terminal specific A beta monoclonal antibodies demonstrated that A beta in plasma could be reliable quantified using a sandwich immunoassay technology with high precision, even for low A beta 42 plasma concentrations. A beta 40 and A beta 42 concentrations varied consistently with the ApoE genotype, while the A beta 42/A beta 40 ratio did not. Irrespective of the decrease of the A beta 42/A beta 40 ratio with age and MMSE, this parameter was strongly associated with AD, as defined in this study by elevated hyperphosphorylated (P-tau181P) levels in cerebrospinal fluid (CSF). Conclusion: A highly robust assay for repeatedly measuring A beta forms in plasma such as INNO-BIA plasma A beta forms might be a useful tool in a future risk assessment of AD.
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| 9. |
- Blennow, Kaj, 1958, et al.
(författare)
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Evolution of Abeta42 and Abeta40 Levels and Abeta42/Abeta40 Ratio in Plasma during Progression of Alzheimer's Disease: A Multicenter Assessment.
- 2009
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Ingår i: The journal of nutrition, health & aging. - 1279-7707. ; 13:3, s. 205-8
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To better understand the seemingly contradictory plasma beta-amyloid (Abeta) results in Alzheimer's disease (AD) patients by using a newly developed plasma Abeta assay, the INNO-BIA plasma Abeta forms, in a multicenter study. Methods: A combined retrospective analysis of plasma Abeta isoforms on mild cognitive impairment (MCI) from three large cross-sectional studies involving 643 samples from the participating German and Swedish centers. Results: Detection modules based on two different amino (N)-terminal specific Abeta monoclonal antibodies demonstrated that Abeta in plasma could be reliable quantified using a sandwich immunoassay technology with high precision, even for low Abeta42 plasma concentrations. Abeta40 and Abeta42 concentrations varied consistently with the ApoE genotype, while the Abeta42/Abeta40 ratio did not. Irrespective of the decrease of the Abeta42/Abeta40 ratio with age and MMSE, this parameter was strongly associated with AD, as defined in this study by elevated hyperphosphorylated (P-tau181P) levels in cerebrospinal fluid (CSF). Conclusion: A highly robust assay for repeatedly measuring Abeta forms in plasma such as INNO-BIA plasma Abeta forms might be a useful tool in a future risk assessment of AD.
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| 10. |
- Boulo, S., et al.
(författare)
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First amyloid β1-42 certified reference material for re-calibrating commercial immunoassays
- 2020
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:11, s. 1493-1503
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Reference materials based on human cerebrospinal fluid were certified for the mass concentration of amyloid beta (Aβ)1-42 (Aβ42). They are intended to be used to calibrate diagnostic assays for Aβ42. Methods: The three certified reference materials (CRMs), ERM-DA480/IFCC, ERM-DA481/IFCC and ERM-DA482/IFCC, were prepared at three concentration levels and characterized using isotope dilution mass spectrometry methods. Roche, EUROIMMUN, and Fujirebio used the three CRMs to re-calibrate their immunoassays. Results: The certified Aβ42 mass concentrations in ERM-DA480/IFCC, ERM-DA481/IFCC, and ERM-DA482/IFCC are 0.45, 0.72, and 1.22 μg/L, respectively, with expanded uncertainties (k = 2) of 0.07, 0.11, and 0.18 μg/L, respectively. Before re-calibration, a good correlation (Pearson's r > 0.97), yet large biases, were observed between results from different commercial assays. After re-calibration the between-assay bias was reduced to < 5%. Discussion: The Aβ42 CRMs can ensure the equivalence of results between methods and across platforms for the measurement of Aβ42. © 2020 the Alzheimer's Association
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