| 61. |
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| 62. |
- Le Guen, Yann, et al.
(författare)
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Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 120:36
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Tidskriftsartikel (refereegranskat)abstract
- Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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| 63. |
- Lewczuk, Piotr, et al.
(författare)
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Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer's Disease: Analytical and Diagnostic Characterization.
- 2017
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 55:1, s. 159-170
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Tidskriftsartikel (refereegranskat)abstract
- Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF).To establish and analytically and clinically characterize the first assay capable to measure concentrations of Non-P-Tau in human CSF.An antibody (1G2) was developed that selectively binds to the Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method.The 1G2 antibody shows decreasing reactivity to tau peptides containing phosphorylation mainly at positions T175 and T181. Detection limit of the assay is 25 pg/ml; the coefficients of variation (CVs) of the optical densities of the repeated standard curves were between 3.6-15.9%. Median intra-assay imprecision of double measurements was 4.8%; inter-assay imprecision was in the range of 11.2% - 15.3%. Non-P-Tau concentrations are stable in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in patients with Alzheimer's disease in stage of mild cognitive impairment or dementia (AD/MCI, n=58, 109.2±32.0 pg/mL) compared to the non-demented Controls (n=42, 62.1±9.3 pg/mL, p<0.001). At the cut-off of 78.3 pg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively.For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF.
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| 64. |
- Majbour, Nour K, et al.
(författare)
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Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease.
- 2016
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite decades of intensive research, to date, there is no accepted diagnosis for Parkinson's disease (PD) based on biochemical analysis of blood or CSF. However, neurodegeneration in the brains of PD patients begins several years before the manifestation of the clinical symptoms, pointing to serious flaw/limitations in this approach.
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| 65. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Reference measurement procedures for Alzheimer's disease cerebrospinal fluid biomarkers: definitions and approaches with focus on amyloid β42.
- 2012
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Ingår i: Biomarkers in medicine. - : Future Medicine Ltd. - 1752-0371 .- 1752-0363. ; 6:4, s. 409-17
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are increasingly used in clinical settings, research and drug trials. However, their broad-scale use on different technology platforms is hampered by the lack of standardization at the level of sample handling, determination of concentrations of analytes and the absence of well-defined performance criteria for in vitro diagnostic or companion diagnostic assays, which influences the apparent concentration of the analytes measured and the subsequent interpretation of the data. There is a need for harmonization of CSF AD biomarker assays that can reliably, across centers, quantitate CSF biomarkers with high analytical precision, selectivity and stability over long time periods. In this position paper, we discuss reference procedures for the measurement of CSF AD biomarkers, especially amyloid β42 and tau. We describe possible technical approaches, focusing on a selected reaction monitoring mass spectrometry assay as a candidate reference method for quantification of CSF amyloid β42.
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| 66. |
- Miller, Anne-Marie, et al.
(författare)
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Current Approaches and Clinician Attitudes to the Use of Cerebrospinal Fluid Biomarkers in Diagnostic Evaluation of Dementia in Europe.
- 2017
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 60:1, s. 201-210
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Tidskriftsartikel (refereegranskat)abstract
- BIOMARKAPD seeks to diminish the barriers associated with the clinical use of cerebrospinal fluid (CSF) biomarker analysis by reducing variation in CSF laboratory methodologies and generating consensus recommendations on their clinical interpretation and application for dementia diagnosis.To examine the disparity in practitioner attitudes and clinical practice relating to the use of CSF biomarkers for dementia diagnosis across Europe.Clinical dementia experts were surveyed on the prevalence of national consensus guidelines and analytical reimbursement across Europe, their biomarker platform preferences, lumbar puncture methodologies and application of reference values and cut-offs for CSF analysis.74% of respondents (total n=51) use CSF biomarkers in clinical practice and 69% perform lumbar punctures on an outpatient basis. Most use CSF biomarkers to diagnose atypical (84%) and early-onset cases of cognitive impairment (71%) and for the differential diagnosis of other dementias (69%). 82% state they are sufficiently informed about CSF biomarkers yet 61% report a lack of national consensus guidelines on their use for dementia diagnosis. 48% of countries represented do not reimburse clinical CSF analysis costs. 43% report using normal reference ranges derived from publications.Variations in attitude and practice relating to CSF biomarkers, widely recognised as barriers to their clinical acceptance, remain evident within and between countries across Europe, even in expert centres. These shortcomings must be addressed by developing consensus guidelines on CSF-related methodologies and their clinical application, to further their use for the diagnostic evaluation of dementia.
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| 67. |
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| 68. |
- Momtazmanesh, Sara, et al.
(författare)
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Neuronal and glial CSF biomarkers in multiple sclerosis : a systematic review and meta-analysis
- 2021
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Ingår i: Reviews in the Neurosciences. - : Walter de Gruyter GmbH. - 0334-1763 .- 2191-0200. ; 32:6, s. 573-595
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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.
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| 69. |
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| 70. |
- Pereira, Joana B., et al.
(författare)
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Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:11, s. 3505-3516
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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.
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