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- Cicognola, Claudia, et al.
(författare)
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Novel tau fragments in cerebrospinal fluid : relation to tangle pathology and cognitive decline in Alzheimer’s disease
- 2019
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 137:2, s. 279-296
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Tidskriftsartikel (refereegranskat)abstract
- Tau is an axonal microtubule-binding protein. Tau pathology in brain and increased tau concentration in the cerebrospinal fluid (CSF) are hallmarks of Alzheimer’s disease (AD). Most of tau in CSF is present as fragments. We immunoprecipitated tau from CSF and identified several endogenous peptides ending at amino acid (aa) 123 or 224 using high-resolution mass spectrometry. We raised neo-epitope-specific antibodies against tau fragments specifically ending at aa 123 and 224, respectively. With these antibodies, we performed immunohistochemistry on brain tissue and designed immunoassays measuring N-123, N-224, and x-224 tau. Immunoassays were applied to soluble brain fractions from pathologically confirmed subjects (81 AD patients, 33 controls), CSF from three cross-sectional and two longitudinal cohorts (a total of 133 AD, 38 MCI, 20 MCI-AD, 31 PSP, 15 CBS patients, and 91 controls), and neuronally- and peripherally-derived extracellular vesicles (NDEVs and PDEVs, respectively) in serum from four AD patients and four controls. Anti-tau 224 antibody stained neurofibrillary tangles and neuropil threads, while anti-tau 123 only showed weak cytoplasmic staining in AD. N-224 tau was lower in the AD soluble brain fraction compared to controls, while N-123 tau showed similar levels. N-224 tau was higher in AD compared to controls in all CSF cohorts (p < 0.001), but not N-123 tau. Decrease in cognitive performance and conversion from MCI to AD were associated with increased baseline CSF levels of N-224 tau (p < 0.0001). N-224 tau concentrations in PSP and CBS were significantly lower than in AD (p < 0.0001) and did not correlate to t-tau and p-tau. In a longitudinal cohort, CSF N-224 tau levels were stable over 6 months, with no significant effect of treatment with AChE inhibitors. N-224 tau was present in NDEVs, while N-123 tau showed comparable concentrations in both vesicle types. We suggest that N-123 tau is produced both in CNS and PNS and represents a general marker of tau metabolism, while N-224 tau is neuron-specific, present in the tangles, secreted in CSF, and upregulated in AD, suggesting a link between tau cleavage and propagation, tangle pathology, and cognitive decline.
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| 2. |
- Martinez-Morillo, Eduardo, et al.
(författare)
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Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer's disease patients and controls
- 2014
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 127:5, s. 633-643
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Tidskriftsartikel (refereegranskat)abstract
- The apolipoprotein E (ApoE) epsilon 4 allele is the strongest risk factor of sporadic Alzheimer's disease (AD), however, the fluid concentrations of ApoE and its different isoforms (ApoE2, ApoE3 and ApoE4) in AD patients and among APOE genotypes (APOE epsilon 2, epsilon 3, epsilon 4) remain controversial. Using a novel mass spectrometry-based method, we quantified total ApoE and specific ApoE isoform concentrations and potential associations with age, cognitive status, cholesterol levels and established AD biomarkers in cerebrospinal fluid (CSF) from AD patients versus non-AD individuals with different APOE genotypes. We also investigated plasma total ApoE and ApoE isoform composition in a subset of these individuals. In total n = 43 AD and n = 43 non-AD subjects were included. We found that CSF and plasma total ApoE levels did not correlate with age or cognitive status and did not differ between AD and non-AD subjects deeming ApoE as an unfit diagnostic marker for AD. Also, whereas CSF ApoE levels did not vary between APOE genotypes APOE epsilon 4 carriers exhibited significantly decreased plasma ApoE levels attributed to a specific decrease in the ApoE4 isoform concentrations. CSF total ApoE concentrations were positively associated with CSF, total tau, tau phosphorylated at Thr181 and A beta 1-42 of which the latter association was weaker and only present in APOE epsilon 4 carriers indicating a differential involvement of ApoE in tau versus A beta-linked neuropathological processes. Future studies need to elucidate whether the observed plasma ApoE4 deficiency is a life-long condition in APOE E > 4 carriers and whether this decrease in plasma ApoE predisposes APOE E > 4 carriers to AD.
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| 5. |
- Yu, Lei, et al.
(författare)
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Plasma p-tau181 and p-tau217 in discriminating PART, AD and other key neuropathologies in older adults
- 2023
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Ingår i: Acta Neuropathologica. - 0001-6322. ; 146:1, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- We examined whether plasma p-tau181 and p-tau217 are specific biomarkers of pathologically confirmed Alzheimer’s disease (AD). In particular, we investigated the utility of plasma p-tau for differentiating AD from primary age-related tauopathy (PART), as well as AD with mixed pathologies. Data came from 269 older adults who participated in the Religious Orders Study or the Rush Memory and Aging Project. Blood samples were collected during annual clinical evaluations. Participants died and underwent brain autopsy. P-tau181 and p-tau217 were quantified in the plasma samples proximate to death (average interval before death: 1.4 years) using Lilly-developed MSD immunoassays. Uniform neuropathologic evaluations assessed AD, PART, and other common degenerative and cerebrovascular conditions. Plasma p-tau217 was more strongly correlated with brain β-amyloid and paired helical filament tau (PHFtau) tangles than p-tau181. Both p-tau markers were associated with greater odds of AD, but p-tau217 had higher accuracy (area under the ROC curve (AUC): 0.83) than p-tau181 (AUC: 0.76). Plasma p-tau markers were almost exclusively associated with AD pathologic indices with the exception of cerebral amyloid angiopathy. Compared to p-tau181, p-tau217 showed a higher AUC (0.82 versus 0.74) in differentiating AD from PART. For either p-tau, we did not observe a level difference between individuals with AD alone and those with mixed AD pathologies. In summary, plasma p-tau181and p-tau217 were specifically associated with AD pathological changes. Further, our data provide initial evidence that p-tau217 may be able to differentiate between AD and PART in individuals with comparable burdens of tau tangle pathology. These results demonstrate the specificity of p-tau217 for AD, supporting its use to identify patients suitable for anti-AD therapies including β-amyloid immunotherapies.
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