| 1. |
- Ashton, Nicholas J., et al.
(författare)
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Plasma and CSF biomarkers in a memory clinic: Head-to-head comparison of phosphorylated tau immunoassays
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:5, s. 1913-1924
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. Methods In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (A beta 42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF A beta 42/p-tau ratio. Results All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF A beta 42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94). Discussion Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD. Highlights Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p-tau) levels than the non-AD CSF profile group. All plasma p-tau biomarkers significantly discriminate patients with an AD CSF profile from the non-AD CSF profile group. Janssen p-tau217, ADx p-tau181, and Lilly p-tau217 in plasma show the highest accuracy to detect biologically defined AD. Janssen p-tau217, ADx p-tau181, Lilly p-tau217, Lilly p-tau181, and UGot p-tau231 in plasma show performances that are comparable to their CSF counterparts.
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| 2. |
- Montoliu-Gaya, Laia, et al.
(författare)
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Plasma and cerebrospinal fluid glial fibrillary acidic protein levels in adults with Down syndrome: a longitudinal cohort study
- 2023
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Ingår i: eBioMedicine. - : Elsevier BV. - 2352-3964. ; 90
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Tidskriftsartikel (refereegranskat)abstract
- Background The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) isa marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome. Methods We performed a three-centre study of adults with Down syndrome, autosomal dominant Alzheimer's disease and euploid individuals enrolled in Hospital Sant Pau, Barcelona (Spain), Hospital Clinic, Barcelona (Spain) and Ludwig-Maximilians-Universitat, Munich (Germany). Cerebrospinal fluid (CSF) and plasma GFAP concentrations were quantified using Simoa. A subset of participants had PET 18F-fluorodeoxyglucose, amyloid tracers and MRI measurements. Findings This study included 997 individuals, 585 participants with Down syndrome, 61 Familial Alzheimer's disease mutation carriers and 351 euploid individuals along the Alzheimer's disease continuum, recruited between November 2008 and May 2022. Participants with Down syndrome were clinically classified at baseline as asymp-tomatic, prodromal Alzheimer's disease and Alzheimer's disease dementia. Plasma GFAP levels were significantly increased in prodromal and Alzheimer's disease dementia compared to asymptomatic individuals and increased in parallel to CSF A beta changes, ten years prior to amyloid PET positivity. Plasma GFAP presented the highest diagnostic performance to discriminate symptomatic from asymptomatic groups (AUC = 0.93, 95% CI 0.9-0.95) and its con-centrations were significantly higher in progressors vs non-progressors (p < 0.001), showing an increase of 19.8% (11.8-33.0) per year in participants with dementia. Finally, plasma GFAP levels were highly correlated with cortical thinning and brain amyloid pathology. Interpretation Our findings support the utility of plasma GFAP as a biomarker of Alzheimer's disease in adults with Down syndrome, with possible applications in clinical practice and clinical trials.
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| 3. |
- Bilgel, M., et al.
(författare)
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Longitudinal changes in Alzheimer's-related plasma biomarkers and brain amyloid
- 2023
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Ingår i: Alzheimers & Dementia. - 1552-5260 .- 1552-5279. ; 19:10, s. 4335-45
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTIONUnderstanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer's progression assessment strategies. METHODSWe examined the temporal order of changes in plasma amyloid-beta ratio (A beta 42/A beta 40${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios (p-tau181/A beta 42$\text{p-tau181}/\mathrm{A}{\beta}_{42}$, p-tau231/A beta 42$\text{p-tau231}/\mathrm{A}{\beta}_{42}$) relative to C-11-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB-/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1-year follow-up. RESULTSPiB groups exhibited different rates of longitudinal change in A beta 42/A beta 40(beta=5.41x10-4,SE=1.95x10-4,p=0.0073)${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}\ ( {\beta \ = \ 5.41 \times {{10}}<^>{ - 4},{\rm{\ SE\ }} = \ 1.95 \times {{10}}<^>{ - 4},\ p\ = \ 0.0073} )$. Change in brain amyloid correlated with change in GFAP (r = 0.5, 95% CI = [0.26, 0.68]). The greatest relative decline in A beta 42/A beta 40${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ (-1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]). DISCUSSIONPlasma A beta 42/A beta 40${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time.
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| 4. |
- Gonzalez-Ortiz, Fernando, et al.
(författare)
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Preanalytical stability of plasma/serum brain-derived tau
- 2023
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Ingår i: Alzheimers & Dementia. - 1552-5260. ; 19:10, s. 4764-4770
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTIONWe investigated the effects of matrix type and reagent batch changes on diagnostic performances and longitudinal trajectories of brain-derived tau (BD-tau). METHODSWe evaluated (i) Cohort 1: paired EDTA plasma and serum from Alzheimer biomarker-positive older adults versus controls (n = 26); and (ii) Cohort 2: n = 79 acute ischemic stroke patients with 265 longitudinal samples across four time points. RESULTSIn Cohort 1, plasma and serum BD-tau were strongly correlated (rho = 0.96, p < 0.0001) with similar diagnostic performances (AUCs >99%) and correlations with CSF total-tau (rho = 0.93-0.94, p < 0.0001). However, absolute concentrations were similar to 40% higher in plasma versus serum. In Cohort 2, first and repeated BD-tau measurements showed a near-perfect correlation (rho = 0.96, p < 0.0001), with no significant between-batch concentration differences. In longitudinal analyses, substituting similar to 10% of the first-run concentrations for the remeasured values showed overlapping estimated trajectories without significant differences at any time point. DISCUSSIONBD-tau has equivalent diagnostic accuracies, but non-interchangeable absolute concentrations, in plasma versus serum. Furthermore, the analytical robustness is unaffected by batch-to-batch reagent variations. HighlightsBrain-derived tau (BD-tau) is a novel blood-based biomarker that quantifies tau protein of CNS origin.Effects of preanalytical handling procedures on the quality and reproducibility of BD-tau measures are unknown.In two cohorts of n = 105 participants, we compared BD-tau concentrations and diagnostic performances in paired plasma and serum samples, and evaluated impacts of batch-to-batch reagent variations.Paired plasma and serum showed equivalent diagnostic performances to separate amyloid-positive AD from amyloid-negative controls, indicating both can be used independently.Repeated measurements and longitudinal trajectories of plasma BD-tau were unaffected by batch-to-batch reagent variation.
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| 5. |
- Kac, Przemysław R, 1995, et al.
(författare)
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Plasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer's disease neuropathology.
- 2024
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Ingår i: Nature communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer's disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n=388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.
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| 6. |
- Gonzalez-Ortiz, Fernando, et al.
(författare)
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A novel ultrasensitive assay for plasma p-tau217: Performance in individuals with subjective cognitive decline and early Alzheimer's disease.
- 2024
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 20:2, s. 1239-1249
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Tidskriftsartikel (refereegranskat)abstract
- Detection of Alzheimer's disease (AD) pathophysiology among individuals with mild cognitive changesand those experiencing subjective cognitive decline (SCD) remains challenging. Plasma phosphorylated tau 217 (p-tau217) is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited.We employed a novel p-tau217 immunoassay (University of Gothenburg [UGOT] p-tau217) in four independent cohorts (n=308) including a cerebrospinal fluid (CSF) biomarker-classified cohort (Discovery), two cohorts consisting mostly of cognitively unimpaired (CU) and mild cognitively impaired (MCI) participants (MYHAT and Pittsburgh), and a population-based cohort of individuals with SCD (Barcelonaβeta Brain Research Center's Alzheimer's At-Risk Cohort [β-AARC]).UGOT p-tau217 showed high accuracy (area under the curve [AUC]=0.80-0.91) identifying amyloid beta (Aβ) pathology, determined either by Aβ positron emission tomography or CSF Aβ42/40 ratio. In individuals experiencing SCD, UGOT p-tau217 showed high accuracy identifying those with a positive CSF Aβ42/40 ratio (AUC=0.91).UGOT p-tau217 can be an easily accessible and efficient way to screen and monitor patients with suspected AD pathophysiology, even in the early stages of the continuum.
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| 7. |
- Gonzalez-Ortiz, Fernando, et al.
(författare)
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A novel ultrasensitive assay for plasma p-tau217: performance in individuals with subjective cognitive decline and early Alzheimer's disease.
- 2023
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Ingår i: medRxiv : the preprint server for health sciences.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Detection of Alzheimer's disease (AD) pathophysiology among cognitively unimpaired individuals and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma p-tau217 is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited.We employed a novel p-tau217 immunoassay (UGOT p-tau217) in four independent cohorts (n=308) including a cerebrospinal fluid (CSF) biomarker-classified cohort (Discovery), two cohorts consisting mostly of cognitively unimpaired participants (MYHAT and Pittsburgh), and a population-based cohort of individuals with SCD (β-AARC).UGOT p-tau217 showed high accuracy (AUC= 0.80-0.91) identifying Aβ pathology, determined either by Aβ positron emission tomography or CSF Aβ42/40 ratio. In individuals experiencing SCD, UGOT p-tau217 showed high accuracy identifying those with a positive CSF Aβ42/40 ratio (AUC= 0.91).UGOT p-tau217 can be an easily accessible and efficient way to screen and monitor patients with suspected AD pathophysiology, even in the early stages of the continuum.
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| 8. |
- Gonzalez-Ortiz, Fernando, et al.
(författare)
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Association of Serum Brain-Derived Tau With Clinical Outcome and Longitudinal Change in Patients With Severe Traumatic Brain Injury.
- 2023
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Ingår i: JAMA network open. - 2574-3805. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- Blood-based measurements of total tau (T-tau) are commonly used to examine neuronal injury in patients with traumatic brain injury (TBI), but current assays do not differentiate between brain-derived tau (BD-tau) and tau produced in peripheral tissues. A novel assay for BD-tau has recently been reported that selectively quantifies nonphosphorylated tau of central nervous system origin in blood samples.To examine the association of serum BD-tau with clinical outcomes in patients with severe TBI (sTBI) and its longitudinal changes over 1 year.This prospective cohort study was conducted at the neurointensive unit at the Sahlgrenska University Hospital, Gothenburg, Sweden, between September 1, 2006, and July 1, 2015. The study included 39 patients with sTBI followed up for up to 1 year. Statistical analysis was performed between October and November 2021.Serum BD-tau, T-tau, phosphorylated tau231 (p-tau231), and neurofilament light chain (NfL) measured on days 0, 7, and 365 after injury.Associations of serum biomarkers with clinical outcome and longitudinal change in sTBI. Severity of sTBI was evaluated using the Glasgow Coma Scale at hospital admission, while clinical outcome was assessed with the Glasgow Outcome Scale (GOS) at 1-year follow-up. Participants were classified as having a favorable outcome (GOS score, 4-5) or unfavorable outcome (GOS score, 1-3).Among the 39 patients (median age at admission, 36 years [IQR, 22-54 years]; 26 men [66.7%]) in the study on day 0, the mean (SD) serum BD-tau level was higher among patients with unfavorable outcomes vs those with favorable outcomes (191.4 [190.8] pg/mL vs 75.6 [60.3] pg/mL; mean difference, 115.9 pg/mL [95% CI, 25.7-206.1 pg/mL]), while the other markers had smaller between-group mean differences (serum T-tau, 60.3 pg/mL [95% CI, -22.0 to 142.7 pg/mL]; serum p-tau231, 8.3 pg/mL [95% CI, -6.4 to 23.0 pg/mL]; serum NfL, -5.4 pg/mL [95% CI, -99.0 to 88.3 pg/mL]). Similar results were recorded on day 7. Longitudinally, baseline serum BD-tau concentrations showed slower decreases in the whole cohort (42.2% on day 7 [from 138.6 to 80.1 pg/mL] and 93.0% on day 365 [from 138.6 to 9.7 pg/mL]) compared with serum T-tau (81.5% on day 7 [from 57.3 to 10.6 pg/mL] and 99.0% on day 365 [from 57.3 to 0.6 pg/mL]) and p-tau231 (92.5% on day 7 [from 20.1 to 1.5 pg/mL] and 95.0% on day 365 [from 20.1 to 1.0 pg/mL]). These results did not change when considering clinical outcome, where T-tau decreased twice as fast as BD-tau in both groups. Similar results were obtained for p-tau231. Furthermore, the biomarker levels on day 365 were lower, compared with day 7, for BD-tau but not T-tau or p-tau231. Serum NfL had a different trajectory to the tau biomarkers, with levels increasing by 255.9% on day 7 compared with day 0 (from 86.8 to 308.9 pg/mL) but decreasing by 97.0% by day 365 vs day 7 (from 308.9 to 9.2 pg/mL).This study suggests that serum BD-tau, T-tau, and p-tau231 have differential associations with clinical outcome and 1-year longitudinal change in patients with sTBI. Serum BD-tau demonstrated utility as a biomarker to monitor outcomes in sTBI and can provide valuable information regarding acute neuronal damage.
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| 9. |
- Gonzalez-Ortiz, Fernando, et al.
(författare)
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Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration.
- 2022
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 146:3, s. 1152-1165
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Tidskriftsartikel (refereegranskat)abstract
- Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies and agreements with their corresponding CSF and neuroimaging biomarkers in the amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer's disease. However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer's disease while total-tau shows lack of correlation with CSF total-tau. Recent studies suggest that blood total-tau originates principally from peripheral, non-brain sources. We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed 'big tau' isoform. We applied this antibody to develop an ultrasensitive blood-based assay for brain-derived tau, and validated it in five independent cohorts (n = 609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts and memory clinic cohorts. In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P < 0.0001), while serum and CSF total-tau were not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau showed equivalent diagnostic performance as CSF total-tau and CSF brain-derived tau to separate biomarker-positive Alzheimer's disease participants from biomarker-negative controls. Furthermore, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer's disease from other neurodegenerative diseases (area under the curve = 86.4%) while neurofilament light did not (area under the curve = 54.3%). These performances were independent of the presence of concomitant pathologies. Plasma brain-derived tau (rho = 0.52-0.67, P = 0.003), but not neurofilament light (rho = -0.14-0.17, P = 0.501), was associated with global and regional amyloid plaque and neurofibrillary tangle counts. These results were further verified in two memory clinic cohorts where serum brain-derived tau differentiated Alzheimer's disease from a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%). Notably, plasma/serum brain-derived tau correlated with neurofilament light only in Alzheimer's disease but not in the other neurodegenerative diseases. Across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function. Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer's disease-type neurodegeneration. Thus, brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer's disease-dependent neurodegenerative processes for clinical and research purposes.
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| 10. |
- Gonzalez-Ortiz, Fernando, et al.
(författare)
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Levels of plasma brain-derived tau and p-tau181 in Alzheimer's disease and rapidly progressive dementias.
- 2024
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 20:1, s. 745-751
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Tidskriftsartikel (refereegranskat)abstract
- Rapidly progressive dementias (RPDs) are a group of neurological disorders characterized by a rapid cognitive decline. The diagnostic value of blood-based biomarkers for Alzheimer's disease (AD) in RPD has not been fully explored.We measured plasma brain-derived tau (BD-tau) and p-tau181 in 11 controls, 15 AD patients, and 33 with RPD, of which 19 were Creutzfeldt-Jakob disease (CJD).Plasma BD-tau differentiated AD from RPD and controls (p=0.002 and p=0.03, respectively), while plasma and cerebrospinal fluid (CSF) p-tau181 distinguished AD from RPD (p<0.001) but not controls from RPD (p>0.05). The correlation of CSF t-tau with plasma BD-tau was stronger (r=0.78, p<0.001) than the correlation of CSF and plasma p-tau181 (r=0.26, p=0.04). The ratio BD-tau/p-tau181 performed equivalently to the CSF t-tau/p-tau181 ratio, differentiating AD from CJD (p<0.0001).Plasma BD-tau and p-tau181 mimic their corresponding cerebrospinal fluid (CSF) markers. P-tau significantly increased in AD but not in RPD. Plasma BD-tau, like CSF t-tau, increases according to neurodegeneration intensity.
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