| 1. |
- Ashton, Nicholas J., et al.
(författare)
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An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders.
- 2020
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Ingår i: Nature Reviews Neurology. - : Springer Science and Business Media LLC. - 1759-4766 .- 1759-4758. ; 16, s. 265-284
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Forskningsöversikt (refereegranskat)abstract
- Cerebrospinal fluid analyses and neuroimaging can identify the underlying pathophysiology at the earliest stage of some neurodegenerative disorders, but do not have the scalability needed for population screening. Therefore, a blood-based marker for such pathophysiology would have greater utility in a primary care setting and in eligibility screening for clinical trials. Rapid advances in ultra-sensitive assays have enabled the levels of pathological proteins to be measured in blood samples, but research has been predominantly focused on Alzheimer disease (AD). Nonetheless, proteins that were identified as potential blood-based biomarkers for AD, for example, amyloid-β, tau, phosphorylated tau and neurofilament light chain, are likely to be relevant to other neurodegenerative disorders that involve similar pathological processes and could also be useful for the differential diagnosis of clinical symptoms. This Review outlines the neuropathological, clinical, molecular imaging and cerebrospinal fluid features of the most common neurodegenerative disorders outside the AD continuum and gives an overview of the current status of blood-based biomarkers for these disorders.
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| 2. |
- Ashton, Nicholas J., et al.
(författare)
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Effects of pre-analytical procedures on blood biomarkers for Alzheimer's pathophysiology, glial activation, and neurodegeneration.
- 2021
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Ingår i: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- We tested how tube types (ethylenediaminetetraacetic acid [EDTA], serum, lithium heparin [LiHep], and citrate) and freeze-thaw cycles affect levels of blood biomarkers for Alzheimer's disease (AD) pathophysiology, glial activation, and neuronal injury.Amyloid beta (Aβ)42, Aβ40, phosphorylated tau181 (p-tau181), glial fibrillary acidic protein, total tau (t-tau), neurofilament light, and phosphorylated neurofilament heavy protein were measured using single molecule arrays.LiHep demonstrated the highest mean value for all biomarkers. Tube types were highly correlated for most biomarkers (r>0.95) but gave significantly different absolute concentrations. Weaker correlations between tube types were found for Aβ42/40 (r=0.63-0.86) and serum t-tau (r=0.46-0.64). Freeze-thaw cycles highly influenced levels of serum Aβ and t-tau (P<.0001), and minor decreases in EDTA Aβ40 and EDTA p-tau181 were found after freeze-thaw cycle 4 (P<.05).The same tube type should be used in research studies on blood biomarkers. Individual concentration cut-offs are needed for each tube type in all tested biomarkers despite being highly correlated. Serum should be avoided for Aβ42, Aβ40, and t-tau. Freeze-thaw cycles>3 should be avoided for p-tau181.
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| 3. |
- 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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| 4. |
- 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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| 5. |
- Gonzalez-Ortiz, Fernando, 1990, et al.
(författare)
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Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer's disease.
- 2024
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Ingår i: Nature communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n=1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.
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| 6. |
- Karikari, Thomas, et al.
(författare)
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Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer's Disease Neuroimaging Initiative.
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26, s. 429-442
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Tidskriftsartikel (refereegranskat)abstract
- Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans show little increase but plasma p-tau181 is increased if CSF Aβ has already changed prior to Aβ PET changes. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC=85.3%; 95% CI, 81.4-89.2%), as well as to distinguish between Aβ- and Aβ+ individuals along the Alzheimer's continuum (AUC=76.9%; 95% CI, 74.0-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.
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| 7. |
- Lantero Rodriguez, Juan, et al.
(författare)
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P-tau235: a novel biomarker for staging preclinical Alzheimer's disease.
- 2021
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Ingår i: EMBO molecular medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p-tau) species such as p-tau217 and p-tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p-tau235 is a prominent feature of AD pathology. In addition, p-tau235 seemed to be preceded by p-tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p-tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p-235 increases early in AD continuum, and (ii) changes in CSF p-tau235 and p-tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p-tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment.
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| 8. |
- Lantero Rodriguez, Juan, et al.
(författare)
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Plasma p-tau181 accurately predicts Alzheimer's disease pathology at least 8years prior to post-mortem and improves the clinical characterisation of cognitive decline.
- 2020
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 140:3, s. 267-278
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Tidskriftsartikel (refereegranskat)abstract
- The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis of Alzheimer's disease (AD). Nowadays, the in vivo diagnosis of AD is greatly aided by both cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation is restricted by high cost, limited accessibility and invasiveness. We recently developed a high-performance, ultrasensitive immunoassay for the quantification of tau phosphorylated at threonine-181 (p-tau181) in plasma, which identifies AD pathophysiology with high accuracy. However, it remains unclear whether plasma p-tau181, measured years before the death, can predict the eventual neuropathological confirmation of AD, and successfully discriminates AD from non-AD dementia pathologies. We studied a unique cohort of 115 individuals with longitudinal blood collections with clinical evaluation at 8, 4 and 2years prior to neuropathological assessment at death. The results demonstrate that plasma p-tau181 associates better with AD neuropathology and Braak staging than a clinical diagnosis 8years before post-mortem. Moreover, while all patients had a diagnosis of AD dementia during life, plasma p-tau181 proved to discriminate AD from non-AD pathologies with high accuracy (AUC=97.4%, 95% CI=94.1-100%) even 8years before death. Additionally, the longitudinal trajectory of plasma p-tau181 was assessed in all patients. We found that the main increases in plasma p-tau181 occurred between 8 and 4years prior to death in patients with AD neuropathology and later plateauing. In contrast, non-AD pathologies and controls exhibited minor, albeit significant, increases in p-tau181 up until death. Overall, our study demonstrates that plasma p-tau181 is highly predictive and specific of AD neuropathology years before post-mortem examination. These data add further support for the use of plasma p-tau181 to aid clinical management in primary care and recruitment for clinical trials.
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| 9. |
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| 10. |
- Rial, Alexis Moscoso, et al.
(författare)
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Longitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain With Neurodegeneration in Alzheimer Disease.
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 78:4, s. 396-406
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Tidskriftsartikel (refereegranskat)abstract
- Plasma phosphorylated tau at threonine 181 (p-tau181) has been proposed as an easily accessible biomarker for the detection of Alzheimer disease (AD) pathology, but its ability to monitor disease progression in AD remains unclear.To study the potential of longitudinal plasma p-tau181 measures for assessing neurodegeneration progression and cognitive decline in AD in comparison to plasma neurofilament light chain (NfL), a disease-nonspecific marker of neuronal injury.This longitudinal cohort study included data from the Alzheimer's Disease Neuroimaging Initiative from February 1, 2007, to June 6, 2016. Follow-up blood sampling was performed for up to 8 years. Plasma p-tau181 measurements were performed in 2020. This was a multicentric observational study of 1113 participants, including cognitively unimpaired participants as well as patients with cognitive impairment (mild cognitive impairment and AD dementia). Participants were eligible for inclusion if they had available plasma p-tau181 and NfL measurements and at least 1 fluorine-18-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) or structural magnetic resonance imaging scan performed at the same study visit. Exclusion criteria included any significant neurologic disorder other than suspected AD; presence of infection, infarction, or multiple lacunes as detected by magnetic resonance imaging; and any significant systemic condition that could lead to difficulty complying with the protocol.Plasma p-tau181 and NfL measured with single-molecule array technology.Longitudinal imaging markers of neurodegeneration (FDG PET and structural magnetic resonance imaging) and cognitive test scores (Preclinical Alzheimer Cognitive Composite and Alzheimer Disease Assessment Scale-Cognitive Subscale with 13 tasks). Data were analyzed from June 20 to August 15, 2020.Of the 1113 participants (mean [SD] age, 74.0 [7.6] years; 600 men [53.9%]; 992 non-Hispanic White participants [89.1%]), a total of 378 individuals (34.0%) were cognitively unimpaired (CU) and 735 participants (66.0%) were cognitively impaired (CImp). Of the CImp group, 537 (73.1%) had mild cognitive impairment, and 198 (26.9%) had AD dementia. Longitudinal changes of plasma p-tau181 were associated with cognitive decline (CU: r=-0.24, P<.001; CImp: r=0.34, P<.001) and a prospective decrease in glucose metabolism (CU: r=-0.05, P=.48; CImp: r=-0.27, P<.001) and gray matter volume (CU: r=-0.19, P<.001; CImp: r=-0.31, P<.001) in highly AD-characteristic brain regions. These associations were restricted to amyloid-β-positive individuals. Both plasma p-tau181 and NfL were independently associated with cognition and neurodegeneration in brain regions typically affected in AD. However, NfL was also associated with neurodegeneration in brain regions exceeding this AD-typical spatial pattern in amyloid-β-negative participants. Mediation analyses found that approximately 25% to 45% of plasma p-tau181 outcomes on cognition measures were mediated by the neuroimaging-derived markers of neurodegeneration, suggesting links between plasma p-tau181 and cognition independent of these measures.Study findings suggest that plasma p-tau181 was an accessible and scalable marker for predicting and monitoring neurodegeneration and cognitive decline and was, unlike plasma NfL, AD specific. The study findings suggest implications for the use of plasma biomarkers as measures to monitor AD progression in clinical practice and treatment trials.
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