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- Cicognola, Claudia, et al.
(författare)
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Cerebrospinal fluid N-224 tau helps discriminate Alzheimer's disease from subjective cognitive decline and other dementias
- 2021
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Elevated cerebrospinal fluid (CSF) concentrations of total tau (T-tau) and phosphorylated tau at Thr181 (P-tau181) protein are typical of Alzheimer's disease (AD). However, the T-tau assay measures only the mid-region of the protein, while tau in CSF is instead composed of a series of fragments. One fragment species in particular, N-224, shows increased levels in AD compared to controls. In this multicentre study, we performed a clinical validation of the N-224 assay in cohorts including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD, non-AD dementias and controls. Methods Cohorts consisted of 30 SCD and 30 probable AD from the Amsterdam Dementia Cohort (cohort 1) and 539 controls, 195 SCD, 232 MCI, 137 AD and 253 non-AD from the Swedish BioFINDER study (cohort 2). All samples had AD core biomarkers (A beta 42, T-tau, P-tau181) measurements. N-224 was measured with an in-house ultrasensitive Simoa assay. Results N-224 levels were significantly higher in AD compared to SCD (cohort 1: p = 0.003) and in AD compared to all other diagnostic groups in cohort 2 (control, SCD, MCI and non-AD, p < 0.0001). Within the non-AD group, N-224 showed significantly lower concentrations compared to AD in Parkinson's disease (PD, p < 0.0001), Parkinson's disease dementia (PDD, p = 0.004), progressive supranuclear palsy (PSP, < 0.0001), multiple system atrophy (MSA, p = 0.002) and parkinsonisms not otherwise specified (NOS, p = 0.007). In cohort 1, higher concentrations of N-224 were associated to lower Mini-Mental State Examination (MMSE) scores (R-2 = 0.318, beta = 0.564, p <= 0.0001) and could accurately identify a pathological (< 24) MMSE score (p < 0.0001, AUC = 0.824). Conclusions N-224 tau can distinguish AD subjects from SCD and can discriminate subgroups of non-AD dementias from AD. Therefore, N-224 may be a useful addition to the tau biomarker toolbox for the study of tau species in CSF and for better understanding disease pathogenesis.
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| 2. |
- Cicognola, Claudia, et al.
(författare)
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Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment
- 2021
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Plasma glial fibrillary acidic protein (GFAP) is a marker of astroglial activation and astrocytosis. We assessed the ability of plasma GFAP to detect Alzheimer’s disease (AD) pathology in the form of AD-related amyloid-β (Aβ) pathology and conversion to AD dementia in a mild cognitive impairment (MCI) cohort. Method: One hundred sixty MCI patients were followed for 4.7 years (average). AD pathology was defined using cerebrospinal fluid (CSF) Aβ42/40 and Aβ42/total tau (T-tau). Plasma GFAP was measured at baseline and follow-up using Simoa technology. Results: Baseline plasma GFAP could detect abnormal CSF Aβ42/40 and CSF Aβ42/T-tau with an AUC of 0.79 (95% CI 0.72–0.86) and 0.80 (95% CI 0.72–0.86), respectively. When also including APOE ε4 status as a predictor, the accuracy of the model to detect abnormal CSF Aβ42/40 status improved (AUC = 0.86, p = 0.02). Plasma GFAP predicted subsequent conversion to AD dementia with an AUC of 0.84 (95% CI 0.77–0.91), which was not significantly improved when adding APOE ε4 or age as predictors to the model. Longitudinal GFAP slopes for Aβ-positive and MCI who progressed to dementia (AD or other) were significantly steeper than those for Aβ-negative (p = 0.007) and stable MCI (p < 0.0001), respectively. Conclusion: Plasma GFAP can detect AD pathology in patients with MCI and predict conversion to AD dementia.
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| 3. |
- Leuzy, Antoine, et al.
(författare)
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Comparing the Clinical Utility and Diagnostic Performance of Cerebrospinal Fluid P-Tau181, P-Tau217 and P-Tau231 Assays
- 2021
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Ingår i: Neurology. - 1526-632X. ; 97:17, s. 1681-1694
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Phosphorylated tau (P-tau) in cerebrospinal fluid (CSF) is considered an important biomarker in Alzheimer's disease (AD) and has been incorporated in recent diagnostic criteria. Several variants exist, including P-tau at threonines 181 (P-tau181), 217 (P-tau217) and 231 (P-tau231). However, no studies have compared their diagnostic performance or association to amyloid-β (Aβ) and Tau positron emission tomography (PET). Understanding which P-tau variant to use remains an important yet answered question. We aimed to compare the diagnostic accuracy of P-tau181, P-tau217 and P-tau231 in CSF for AD and their association with Aβ and Tau-PET.METHODS: 629 subjects from the Swedish BioFINDER-2 study were included (cognitively unimpaired, n=334; Aβ-positive mild cognitive impairment, n=84; AD dementia, n=119; and non-AD disorders, n=92). In addition to P-tau181 and P-tau217 measured using assays with the same detector antibodies from Eli Lilly (P-tau181Lilly, P-tau217Lilly) and P-tau231, we also included P-tau181 measurements from two commonly used assays (Innotest and Elecsys).RESULTS: Though all P-tau variants increased across the AD continuum, P-tau217Lilly showed the greatest dynamic range (13-fold-increase vs 1.9-5.4-fold-increase for other P-tau variants for AD dementia vs non-AD). P-tau217Lilly showed stronger correlations with Aβ- and Tau-PET (P<0.0001). P-tau217Lilly exhibited higher accuracy than other P-tau variants for separating AD dementia from non-AD (AUC, 0.991vs 0.906-0.982, P<0.0001) and for identifying Aβ- (AUC, 0.951 vs 0.816-0.924, P<0.0001) and Tau-PET positivity (AUC, 0.957 vs 0.836-0.938, P<0.0001). Finally, P-tau181Lilly generally performed better than the other P-tau181 assays, (e.g., AD dementia vs non-AD, AUC, 0.976 vs 0.923, P<0.0001).DISCUSSION: CSF P-tau217Lilly seem to be more useful than other included P-tau assays in the work-up of AD. Varied results across P-tau181 assays also highlights the importance of anti-tau antibodies for biomarker performance.CLASSIFICATION OF EVIDENCE: This study provides class II evidence that phosphorylated tau at threonine 217 provides higher diagnostic accuracy for diagnosis of AD dementia than P-tau at threonine 181 or 231.
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