| 21. |
- Hansson, Oskar, et al.
(författare)
-
The Alzheimer's Association international guidelines for handling of cerebrospinal fluid for routine clinical measurements of amyloid β and tau
- 2021
-
Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:9, s. 1575-1582
-
Tidskriftsartikel (refereegranskat)abstract
- The core cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers amyloid beta (Aβ42 and Aβ40), total tau, and phosphorylated tau, have been extensively clinically validated, with very high diagnostic performance for AD, including the early phases of the disease. However, between-center differences in pre-analytical procedures may contribute to variability in measurements across laboratories. To resolve this issue, a workgroup was led by the Alzheimer's Association with experts from both academia and industry. The aim of the group was to develop a simplified and standardized pre-analytical protocol for CSF collection and handling before analysis for routine clinical use, and ultimately to ensure high diagnostic performance and minimize patient misclassification rates. Widespread application of the protocol would help minimize variability in measurements, which would facilitate the implementation of unified cut-off levels across laboratories, and foster the use of CSF biomarkers in AD diagnostics for the benefit of the patients.
|
|
| 22. |
- Homann, Jan, et al.
(författare)
-
Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset.
- 2022
-
Ingår i: Frontiers in aging neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline.
|
|
| 23. |
- Janelidze, Shorena, et al.
(författare)
-
Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease
- 2021
-
Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:11, s. 1375-1375
-
Tidskriftsartikel (refereegranskat)abstract
- Importance: Blood-based tests for brain amyloid-β (Aβ) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials. Objective: To compare the performance of plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal brain Aβ status in patients with early AD. Design, Setting, and Participants: This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aβ positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aβ42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays. Main Outcomes and Measures: Discriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status. Results: A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aβ42/40 in the whole cohort, plasma IP-MS-WashU Aβ42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc Aβ42/40, IA-EI Aβ42/40, and IA-N4PE Aβ42/40 (AUC range, 0.69-0.78; P <.05). Plasma IP-MS-WashU Aβ42/40 performed significantly better than IP-MS-UGOT Aβ42/40 and IA-Quan Aβ42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P <.001), while there was no difference in the AUCs between IP-MS-WashU Aβ42/40 and IP-MS-Shim Aβ42/40 (0.87 vs 0.83; P =.16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aβ-PET as outcome. Plasma IPMS-WashU Aβ42/40 and IPMS-Shim Aβ42/40 showed highest coefficients for correlations with CSF Aβ42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay. Conclusions and Relevance: The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aβ42/40 when detecting brain Aβ pathology.
|
|
| 24. |
- Momtazmanesh, Sara, et al.
(författare)
-
Neuronal and glial CSF biomarkers in multiple sclerosis : a systematic review and meta-analysis
- 2021
-
Ingår i: Reviews in the Neurosciences. - : Walter de Gruyter GmbH. - 0334-1763 .- 2191-0200. ; 32:6, s. 573-595
-
Forskningsöversikt (refereegranskat)abstract
- Multiple sclerosis (MS) is a neurodegenerative disease associated with inflammatory demyelination and astroglial activation, with neuronal and axonal damage as the leading factors of disability. We aimed to perform a meta-analysis to determine changes in CSF levels of neuronal and glial biomarkers, including neurofilament light chain (NFL), total tau (t-tau), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), and S100B in various groups of MS (MS versus controls, clinically isolated syndrome (CIS) versus controls, CIS versus MS, relapsing-remitting MS (RRMS) versus progressive MS (PMS), and MS in relapse versus remission. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 64 articles in the metaanalysis, including 4071 subjects. For investigation of sources of heterogeneity, subgroup analysis, metaregression, and sensitivity analysis were conducted. Meta-analyses were performed for comparisons including at least three individual datasets. NFL, GFAP, t-tau, CHI3L1, and S100B were higher in MS and NFL, t-tau, and CHI3L1 were also elevated in CIS patients than controls. CHI3L1 was the only marker with higher levels in MS than CIS. GFAP levels were higher in PMS versus RRMS, and NFL, t-tau, and CHI3L1 did not differ between different subtypes. Only levels of NFL were higher in patients in relapse than remission. Meta-regression showed influence of sex and disease severity on NFL and t-tau levels, respectively and disease duration on both. Added to the role of these biomarkers in determining prognosis and treatment response, to conclude, they may serve in diagnosis of MS and distinguishing different subtypes.
|
|
| 25. |
- Pereira, Joana B., et al.
(författare)
-
Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease
- 2021
-
Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:11, s. 3505-3516
-
Tidskriftsartikel (refereegranskat)abstract
- Although recent clinical trials targeting amyloid-β in Alzheimer's disease have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with amyloid-β metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in Alzheimer's disease. However, so far, no studies have assessed whether astrocytosis is independently related to either amyloid-β or tau pathology in vivo. To address this question, we determined the levels of the astrocytic marker GFAP in plasma and CSF of 217 amyloid-β-negative cognitively unimpaired individuals, 71 amyloid-β-positive cognitively unimpaired individuals, 78 amyloid-β-positive cognitively impaired individuals, 63 amyloid-β-negative cognitively impaired individuals and 75 patients with a non-Alzheimer's disease neurodegenerative disorder from the Swedish BioFINDER-2 study. Participants underwent longitudinal amyloid-β (18F-flutemetamol) and tau (18F-RO948) PET as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all amyloid-β-positive groups compared with participants without amyloid-β pathology (P < 0.01). In addition, there were significant associations between plasma GFAP with higher amyloid-β-PET signal in all amyloid-β-positive groups, but also in cognitively normal individuals with normal amyloid-β values (P < 0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict amyloid-β-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, soluble TREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for amyloid-β-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-Alzheimer's disease patients compared to other groups (P < 0.05) and correlated with amyloid-β-PET only in amyloid-β-positive cognitively impaired individuals (P = 0.005). Finally, plasma GFAP was associated with both longitudinal amyloid-β-PET and cognitive decline, and mediated the effect of amyloid-β-PET on tau-PET burden, suggesting that astrocytosis secondary to amyloid-β aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain amyloid-β pathology but not tau aggregation, even in cognitively normal individuals with a normal amyloid-β status. This suggests that plasma GFAP should be incorporated in current hypothetical models of Alzheimer's disease pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to amyloid-β pathology.
|
|
| 26. |
- Reimand, Juhan, et al.
(författare)
-
Why Is Amyloid-β PET Requested After Performing CSF Biomarkers?
- 2020
-
Ingår i: Journal of Alzheimer's disease : JAD. - 1387-2877. ; 73:2, s. 559-569
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Amyloid-β positron emission tomography (PET) and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer's disease. OBJECTIVE: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers. METHODS: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET. RESULTS: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n = 53, 74%), followed by incongruent MRI (n = 16, 22%), unusual clinical presentation (n = 11, 15%) and young age (n = 8, 11%). An amyloid-β PET scan was rarely (n = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET. CONCLUSION: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results.
|
|
| 27. |
- Teunissen, Charlotte E, et al.
(författare)
-
Blood-based biomarkers for Alzheimer's disease: towards clinical implementation.
- 2022
-
Ingår i: The Lancet. Neurology. - 1474-4465 .- 1474-4422. ; 21:1, s. 66-77
-
Tidskriftsartikel (refereegranskat)abstract
- For many years, blood-based biomarkers for Alzheimer's disease seemed unattainable, but recent results have shown that they could become a reality. Convincing data generated with new high-sensitivity assays have emerged with remarkable consistency across different cohorts, but also independent of the precise analytical method used. Concentrations in blood of amyloid and phosphorylated tau proteins associate with the corresponding concentrations in CSF and with amyloid-PET or tau-PET scans. Moreover, other blood-based biomarkers of neurodegeneration, such as neurofilament light chain and glial fibrillary acidic protein, appear to provide information on disease progression and potential for monitoring treatment effects. Now the question emerges of when and how we can bring these biomarkers to clinical practice. This step would pave the way for blood-based biomarkers to support the diagnosis of, and development of treatments for, Alzheimer's disease and other dementias.
|
|
| 28. |
- van Amerongen, Suzan, et al.
(författare)
-
Rationale and design of the “NEurodegeneration : Traumatic brain injury as Origin of the Neuropathology (NEwTON)” study: a prospective cohort study of individuals at risk for chronic traumatic encephalopathy
- 2022
-
Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Repetitive head injury in contact sports is associated with cognitive, neurobehavioral, and motor impairments and linked to a unique neurodegenerative disorder: chronic traumatic encephalopathy (CTE). As the clinical presentation is variable, risk factors are heterogeneous, and diagnostic biomarkers are not yet established, the diagnostic process of CTE remains a challenge. The general objective of the NEwTON study is to establish a prospective cohort of individuals with high risk for CTE, to phenotype the study population, to identify potential fluid and neuroimaging biomarkers, and to measure clinical progression of the disease. The present paper explains the protocol and design of this case-finding study. Methods: NEwTON is a prospective study that aims to recruit participants at risk for CTE, with features of the traumatic encephalopathy syndrome (exposed participants), and healthy unexposed control individuals. Subjects are invited to participate after diagnostic screening at our memory clinic or recruited by advertisement. Exposed participants receive a comprehensive baseline screening, including neurological examination, neuropsychological tests, questionnaires and brain MRI for anatomical imaging, diffusion tensor imaging (DTI), resting-state functional MRI (rsfMRI), and quantitative susceptibility mapping (QSM). Questionnaires include topics on life-time head injury, subjective cognitive change, and neuropsychiatric symptoms. Optionally, blood and cerebrospinal fluid are obtained for storage in the NEwTON biobank. Patients are informed about our brain donation program in collaboration with the Netherlands Brain Brank. Follow-up takes place annually and includes neuropsychological assessment, questionnaires, and optional blood draw. Testing of control subjects is limited to baseline neuropsychological tests, MRI scan, and also noncompulsory blood draw. Results: To date, 27 exposed participants have finished their baseline assessments. First baseline results are expected in 2023. Conclusions: The NEwTON study will assemble a unique cohort with prospective observational data of male and female individuals with high risk for CTE. This study is expected to be a primary explorative base and designed to share data with international CTE-related cohorts. Sub-studies may be added in the future with this cohort as backbone.
|
|
| 29. |
- van Maurik, Ingrid S., et al.
(författare)
-
Biomarker testing in MCI patients—deciding who to test
- 2021
-
Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to derive an algorithm to define the optimal proportion of patients with mild cognitive impairment (MCI) in whom cerebrospinal fluid (CSF) testing is of added prognostic value. Methods: MCI patients were selected from the Amsterdam Dementia Cohort (n = 402). Three-year progression probabilities to dementia were predicted using previously published models with and without CSF data (amyloid-beta1-42 (Abeta), phosphorylated tau (p-tau)). We incrementally augmented the proportion of patients undergoing CSF, starting with the 10% patients with prognostic probabilities based on clinical data around the median (percentile 45–55), until all patients received CSF. The optimal proportion was defined as the proportion where the stepwise algorithm showed similar prognostic discrimination (Harrell’s C) and accuracy (three-year Brier scores) compared to CSF testing of all patients. We used the BioFINDER study (n = 221) for validation. Results: The optimal proportion of MCI patients to receive CSF testing selected by the stepwise approach was 50%. CSF testing in only this proportion improved the performance of the model with clinical data only from Harrell’s C = 0.60, Brier = 0.198 (Harrell’s C = 0.61, Brier = 0.197 if the information on magnetic resonance imaging was available) to Harrell’s C = 0.67 and Brier = 0.190, and performed similarly to a model in which all patients received CSF testing. Applying the stepwise approach in the BioFINDER study would again select half of the MCI patients and yielded robust results with respect to prognostic performance. Interpretation: CSF biomarker testing adds prognostic value in half of the MCI patients. As such, we achieve a CSF saving recommendation while simultaneously retaining optimal prognostic accuracy.
|
|
| 30. |
- Verberk, Inge M.W., et al.
(författare)
-
Characterization of pre-analytical sample handling effects on a panel of Alzheimer's disease–related blood-based biomarkers : Results from the Standardization of Alzheimer's Blood Biomarkers (SABB) working group
- 2022
-
Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:8, s. 1484-1497
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Pre-analytical sample handling might affect the results of Alzheimer's disease blood-based biomarkers. We empirically tested variations of common blood collection and handling procedures. Methods: We created sample sets that address the effect of blood collection tube type, and of ethylene diamine tetraacetic acid plasma delayed centrifugation, centrifugation temperature, aliquot volume, delayed storage, and freeze–thawing. We measured amyloid beta (Aβ)42 and 40 peptides with six assays, and Aβ oligomerization-tendency (OAβ), amyloid precursor protein (APP)699-711, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), total tau (t-tau), and phosphorylated tau181. Results: Collection tube type resulted in different values of all assessed markers. Delayed plasma centrifugation and storage affected Aβ and t-tau; t-tau was additionally affected by centrifugation temperature. The other markers were resistant to handling variations. Discussion: We constructed a standardized operating procedure for plasma handling, to facilitate introduction of blood-based biomarkers into the research and clinical settings.
|
|
