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Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology.

ABSTRACT: To date, there is no validated fluid biomarker for tau pathology in Alzheimer's disease, with contradictory results from studies evaluating the correlation between phosphorylated tau in CSF with tau PET imaging. Tau protein is subjected to proteolytic processing into fragments before being secreted to the CSF. A recent study suggested that tau cleavage after amino acid 368 by asparagine endopeptidase (AEP) is upregulated in Alzheimer's disease. We used immunoprecipitation followed by mass spectrometric analyses to evaluate the presence of tau368 species in CSF. A novel Simoa® assay for quantification of tau368 in CSF was developed, while total tau (t-tau) was measured by ELISA and the presence of tau368 in tangles was evaluated using immunohistochemistry. The diagnostic utility of tau368 was first evaluated in a pilot study (Alzheimer's disease = 20, control = 20), then in a second cohort where the IWG-2 biomarker criteria were applied (Alzheimer's disease = 37, control = 45), and finally in a third cohort where the correlation with 18F-GTP1 tau PET was evaluated (Alzheimer's disease = 38, control = 11). The tau368/t-tau ratio was significantly decreased in Alzheimer's disease (P < 0.001) in all cohorts. Immunohistochemical staining demonstrated that tau fragments ending at 368 are present in tangles. There was a strong negative correlation between the CSF tau368/t-tau ratio and 18F-GTP1 retention. Our data suggest that tau368 is a tangle-enriched fragment and that the CSF ratio tau368/t-tau reflects tangle pathology. This novel tau biomarker could be used to improve diagnosis of Alzheimer's disease and to facilitate the development of drug candidates targeting tau pathology. Furthermore, future longitudinal studies will increase our understanding of tau pathophysiology in Alzheimer's disease and other tauopathies.

SUBMITTER: Blennow K

PROVIDER: S-EPMC7009597 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology.

Blennow Kaj K Chen Chun C Cicognola Claudia C Wildsmith Kristin R KR Manser Paul T PT Bohorquez Sandra M Sanabria SMS Zhang Zhentao Z Xie Boer B Peng Junmin J Hansson Oskar O Kvartsberg Hlin H Portelius Erik E Zetterberg Henrik H Lashley Tammaryn T Brinkmalm Gunnar G Kerchner Geoffrey A GA Weimer Robby M RM Ye Keqiang K Höglund Kina K

Brain : a journal of neurology 20200201 2

To date, there is no validated fluid biomarker for tau pathology in Alzheimer's disease, with contradictory results from studies evaluating the correlation between phosphorylated tau in CSF with tau PET imaging. Tau protein is subjected to proteolytic processing into fragments before being secreted to the CSF. A recent study suggested that tau cleavage after amino acid 368 by asparagine endopeptidase (AEP) is upregulated in Alzheimer's disease. We used immunoprecipitation followed by mass spectr ...[more]

PMID: 31834365

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Project description: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.

Project description:The two primary molecular pathologies in Alzheimer's disease are amyloid-? plaques and tau-immunoreactive neurofibrillary tangles. Investigations into these pathologies have been restricted to cerebrospinal fluid assays, and positron emission tomography tracers that can image amyloid-? plaques. Tau tracers have recently been introduced into the field, although the utility of the tracer and its relationship to other Alzheimer biomarkers are still unknown. Here we examined tau deposition in 41 cognitively normal and 11 cognitively impaired older adults using the radioactive tau ligand (18)F-AV-1451 (previously known as T807) who also underwent a lumbar puncture to assess cerebrospinal fluid levels of total tau (t-tau), phosphorylated tau181 (p-tau181) and amyloid-?42 Voxel-wise statistical analyses examined spatial patterns of tau deposition associated with cognitive impairment. We then related the amount of tau tracer uptake to levels of cerebrospinal fluid biomarkers. All analyses controlled for age and gender and, when appropriate, the time between imaging and lumbar puncture assessments. Symptomatic individuals (Clinical Dementia Rating > 0) demonstrated markedly increased levels of tau tracer uptake. This elevation was most prominent in the temporal lobe and temporoparietal junction, but extended more broadly into parietal and frontal cortices. In the entire cohort, there were significant relationships among all cerebrospinal fluid biomarkers and tracer uptake, notably for tau-related cerebrospinal fluid markers. After controlling for levels of amyloid-?42, the correlations with tau uptake were r = 0.490 (P < 0.001) for t-tau and r = 0.492 (P < 0.001) for p-tau181 Within the cognitively normal cohort, levels of amyloid-?42, but not t-tau or p-tau181, were associated with elevated tracer binding that was confined primarily to the medial temporal lobe and adjacent neocortical regions. AV-1451 tau binding in the medial temporal, parietal, and frontal cortices is correlated with tau-related cerebrospinal fluid measures. In preclinical Alzheimer's disease, there is focal tauopathy in the medial temporal lobes and adjacent cortices.

Project description:BACKGROUND:Cerebrospinal fluid biomarker profiles characterized by decreased amyloid-beta peptide levels and increased total and phosphorylated tau levels at threonine 181 (pT181) are currently used to discriminate between Alzheimer's disease and other neurodegenerative diseases. However, these changes are not entirely specific to Alzheimer's disease, and it is noteworthy that other phosphorylated isoforms of tau, possibly more specific for the disease process, have been described in the brain parenchyma of patients. The precise detection of these isoforms in biological fluids remains however a challenge. METHODS:In the present study, we used the latest quantitative mass spectrometry approach, which achieves a sensitive detection in cerebrospinal fluid biomarker of two phosphorylated tau isoforms, pT181 and pT217, and first analyzed a cohort of probable Alzheimer's disease patients and patients with other neurological disorders, including tauopathies, and a set of cognitively normal controls. We then checked the validity of our results on a second cohort comprising cognitively normal individuals and patients with mild cognitive impairments and AD stratified in terms of their amyloid status based on PiB-PET imaging methods. RESULTS:In the first cohort, pT217 but not pT181 differentiated between Alzheimer's disease patients and those with other neurodegenerative diseases and control subjects much more specificity and sensitivity than pT181. T217 phosphorylation was increased by 6.0-fold in patients with Alzheimer's disease whereas T181 phosphorylation was only increased by 1.3-fold, when compared with control subjects. These results were confirmed in the case of a second cohort, in which the pT217 cerebrospinal fluid levels marked out amyloid-positive patients with a sensitivity and a specificity of more than 90% (AUC 0.961; CI 0.874 to 0.995). The pT217 concentrations were also highly correlated with the PiB-PET values (correlation coefficient 0.72; P?<?0.001). CONCLUSIONS:Increased cerebrospinal fluid pT217 levels, more than those of pT181, are highly specific biomarkers for detecting both the preclinical and advanced forms of Alzheimer's disease. This finding should greatly improve the diagnosis of Alzheimer's disease, along with the correlations found to exist between pT217 levels and PiB-PET data. It also suggests that pT217 is a promising potential target for therapeutic applications and that a link exists between amyloid and tau pathology.

Project description:ImportanceFluid and imaging biomarkers of Alzheimer disease (AD) are often used interchangeably, but some biomarkers may reveal earlier stages of disease.ObjectiveTo characterize individuals with tau abnormality indicated by cerebrospinal fluid (CSF) assay or positron emission tomography (PET).Design, setting, and participantsBetween 2010 and 2019, 322 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent CSF and PET assessments of tau pathology. Data-driven, clinically relevant thresholds for CSF phosphorylated tau (P-tau) (≥26.64 pg/mL) and flortaucipir-PET meta-regions of interest (ROI) (standard uptake value ratio ≥1.37) indicated participants' tau status as CSF-/PET-, CSF+/PET-, CSF-/PET+, and CSF+/PET+. Of 1659 ADNI participants with a CSF or flortaucipir assessment, 588 had both measures (1071 were excluded). Among these, 266 were further excluded because they did not have flortaucipir and CSF testing within less than 25 months, leaving 322 for analysis. Of these, 213 were cognitively unimpaired (CU); 98 had mild cognitive impairment (MCI); and 11 had AD dementia.Main outcomes and measuresWe compared tau-positive vs tau-negative groups as indicated by either modality or demographic and clinical variables, amyloid β-PET burden, and flortaucipir-PET binding across Braak stage-related ROIs. We also compared 5-year rates of CSF P-tau accumulation and cognitive decline prior to flortaucipir-PET scanning.ResultsAmong the 322 study participants, 180 were women (56%), and the mean (SD) age was 73.08 (7.37) years. Two hundred ten participants were CSF-/PET- (65%); 63 were CSF+/PET- (19.5%); 15 were CSF-/PET+ (4.6%); and 34 were CSF+/PET+ (10.5%). Most CSF-/PET+ participants had measures near CSF or PET tau thresholds. The CSF+/PET- participants showed faster 5-year accrual of P-tau and increased flortaucipir-PET binding in early Braak ROIs but similar memory decline compared with CSF-/PET- participants. Tau-positive individuals by either measure showed increased amyloid β-PET burden. All CSF+/PET+ individuals were amyloid-positive, and 26 had MCI or AD dementia (76%). Compared with the CSF-/PET- group, CSF+/PET+ individuals had experienced faster 5-year accrual of CSF P-tau and decline in memory and executive function, resulting in reduced cognitive abilities at the time of flortaucipir-PET assessment.Conclusions and relevanceSuprathreshold CSF P-tau without flortaucipir-PET abnormality may indicate a stage of AD development characterized by early tau abnormality without measurable loss in cognitive performance. Persons with both tau CSF and PET abnormality appear to have reduced cognitive capacities resulting from faster antecedent cognitive decline. Elevation of CSF P-tau appears to precede flortaucipir-PET positivity in the progression of AD pathogenesis and related cognitive decline.

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Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology.

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Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology.

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