scholarly journals The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers

2021 ◽  
Author(s):  
N. J. Ashton ◽  
A. Leuzy ◽  
T. K. Karikari ◽  
N. Mattsson-Carlgren ◽  
A. Dodich ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Preliminary Evidence ◽  
Csf Biomarkers ◽  
Phase 2 ◽  
Blood Biomarkers ◽  
Phase 3 ◽  
Development Framework ◽  
Positron Emission ◽  
Phase Development ◽  
Impact Cost

Abstract Purpose The development of blood biomarkers that reflect Alzheimer’s disease (AD) pathophysiology (phosphorylated tau and amyloid-β) has offered potential as scalable tests for dementia differential diagnosis and early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included blood biomarkers in the systematic validation of AD biomarkers. Methods A panel of experts convened in November 2019 at a two-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of blood biomarkers was assessed based on the Biomarker Roadmap methodology and discussed fully during the workshop which also evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Results Plasma p-tau has shown analytical validity (phase 2 primary aim 1) and first evidence of clinical validity (phase 3 primary aim 1), whereas the maturity level for Aβ remains to be partially achieved. Full and partial achievement has been assigned to p-tau and Aβ, respectively, in their associations to ante-mortem measures (phase 2 secondary aim 2). However, only preliminary evidence exists for the influence of covariates, assay comparison and cut-off criteria. Conclusions Despite the relative infancy of blood biomarkers, in comparison to CSF biomarkers, much has already been achieved for phases 1 through 3 – with p-tau having greater success in detecting AD and predicting disease progression. However, sufficient data about the effect of covariates on the biomarker measurement is lacking. No phase 4 (real-world performance) or phase 5 (assessment of impact/cost) aim has been tested, thus not achieved.

scholarly journals Longitudinal Observation of Early-Onset Alzheimer’s Disease Dementia with Positive CSF Biomarkers/Negative Amyloid-β Positron-Emission Tomography

2021 ◽  
Vol 39 (3) ◽  
pp. 214-218
Author(s):  
Min Hye Kim ◽  
Joonho Lee ◽  
Hong Nam Kim ◽  
In Ja Shin ◽  
Keun Lee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Positron Emission Tomography ◽  
Early Onset ◽  
Brain Magnetic Resonance Imaging ◽  
Amyloid Β ◽  
Emission Tomography ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Positron Emission

We report a 61-year-old woman with clinical course for Alzheimer’s disease (AD) dementia and discordant amyloid-β positron-emission tomography (PET) and cerebrospinal fluid biomarkers. Brain magnetic resonance imaging revealed remarkable atrophy in the hippocampus. However, repeated delayed <sup>18</sup>F-flutemetamol brain amyloid PET images with 1 year-interval revealed no amyloid deposition, whereas her CSF revealed low Aβ42, high total tau and p-tau181. This discordant amyloid-β PET and CSF biomarkers in this early-onset AD dementia might be associated with her low resilience or mixed pathology.

scholarly journals Clinical validity of increased cortical binding of tau ligands of the THK family and PBB3 on PET as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

2021 ◽  
Author(s):  
Konstantinos Chiotis ◽  
Alessandra Dodich ◽  
Marina Boccardi ◽  
Cristina Festari ◽  
Alexander Drzezga ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Diagnostic Accuracy ◽  
Preliminary Evidence ◽  
Imaging Biomarkers ◽  
Clinical Validity ◽  
Development Framework ◽  
Phase Development ◽  
Tau Pet ◽  
Target Binding

Abstract Purpose The research community has focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer’s disease (AD). In 2017, the Geneva AD Biomarker Roadmap initiative adapted the framework for the systematic validation of oncological biomarkers to AD, with the aim to accelerate their development and implementation in clinical practice. The aim of this work was to assess the validation status of tau PET ligands of the THK family and PBB3 as imaging biomarkers for AD, based on the Biomarker Roadmap methodology. Methods A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of clinical validity of tau PET ligands of the THK family and PBB3 was assessed based on the 5-phase development framework before the meeting and discussed during the workshop. Results PET radioligands of the THK family discriminate well between healthy controls and patients with AD dementia (phase 2; partly achieved) and recent evidence suggests an accurate diagnostic accuracy at the mild cognitive impairment (MCI) stage of the disease (phase 3; partly achieved). The phases 2 and 3 were considered not achieved for PBB3 since no evidence exists about the ligand’s diagnostic accuracy. Preliminary evidence exists about the secondary aims of each phase for all ligands. Conclusion Much work remains for completing the aims of phases 2 and 3 and replicating the available evidence. However, it is unlikely that the validation process for these tracers will be completed, given the presence of off-target binding and the development of second-generation tracers with improved binding and pharmacokinetic properties.

scholarly journals Association of Odor Identification Ability With Amyloid-β and Tau Burden: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 14 ◽  
Author(s):  
Lihui Tu ◽  
Xiaozhen Lv ◽  
Zili Fan ◽  
Ming Zhang ◽  
Huali Wang ◽  
...  
Keyword(s):  
Subgroup Analysis ◽  
Meta Analysis ◽  
Pearson Correlation ◽  
Amyloid Β ◽  
Correlation Coefficients ◽  
Current Evidence ◽  
Csf Biomarkers ◽  
Mild Cognitive Impairment Group ◽  
Positron Emission ◽  
Tau Pet

Background: The associations between olfactory identification (OI) ability and the Alzheimer's disease biomarkers were not clear.Objective: This meta-analysis aimed to examine the associations between OI and Aβ and tau burden.Methods: Electronic databases (PubMed, Embase, PsycINFO, and Google Scholar) were searched until June 2019 to identify studies that reported correlation coefficients or regression coefficients between OI and Aβ or tau levels measured by positron emission tomography (PET) or cerebrospinal fluid (CSF). Pooled Pearson correlation coefficients were computed for the PET imaging and CSF biomarkers, with subgroup analysis for subjects classified into different groups.Results: Nine studies met the inclusion criteria. Of these, five studies (N = 494) involved Aβ PET, one involved tau PET (N = 26), and four involved CSF Aβ or tau (N = 345). OI was negatively associated with Aβ PET in the mixed (r = −0.25, P = 0.008) and cognitively normal groups (r = −0.15, P = 0.004) but not in the mild cognitive impairment group. A similar association with CSF total tau in the mixed group was also observed. No association was found between OI and CSF phosphorylated tau or Aβ42 in the subgroup analysis of the CSF biomarkers. Due to a lack of data, no pooled r value could be computed for the association between the OI and tau PET.Conclusion: The associations between OI ability and Aβ and CSF tau burden in older adults are negligible. While current evidence does not support the association, further studies using PET tau imaging are warranted.

scholarly journals Discordant amyloid-β PET and CSF biomarkers and its clinical consequences

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Arno de Wilde ◽  
Juhan Reimand ◽  
Charlotte E. Teunissen ◽  
Marissa Zwan ◽  
Albert D. Windhorst ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Clinical Syndrome ◽  
Subjective Cognitive Decline ◽  
Csf Biomarkers ◽  
Clinical Progression ◽  
Good Correspondence ◽  
Positron Emission ◽  
Clinical Consequences ◽  
Composite Scores

Abstract Background In vivo, high cerebral amyloid-β load has been associated with (i) reduced concentrations of Aβ42 in cerebrospinal fluid and (ii) increased retention using amyloid-β positron emission tomography. Although these two amyloid-β biomarkers generally show good correspondence, ~ 10–20% of cases have discordant results. To assess the consequences of having discordant amyloid-β PET and CSF biomarkers on clinical features, biomarkers, and longitudinal cognitive trajectories. Methods We included 768 patients (194 with subjective cognitive decline (SCD), 127 mild cognitive impairment (MCI), 309 Alzheimer’s dementia (AD), and 138 non-AD) who were categorized as concordant-negative (n = 315, 41%), discordant (n = 97, 13%), or concordant-positive (n = 356, 46%) based on CSF and PET results. We compared discordant with both concordant-negative and concordant-positive groups on demographics, clinical syndrome, apolipoprotein E (APOE) ε4 status, CSF tau, and clinical and neuropsychological progression. Results We found an increase from concordant-negative to discordant to concordant-positive in rates of APOE ε4 (28%, 55%, 70%, Z = − 10.6, P < 0.001), CSF total tau (25%, 45%, 78%, Z = − 13.7, P < 0.001), and phosphorylated tau (28%, 43%, 80%, Z = − 13.7, P < 0.001) positivity. In patients without dementia, linear mixed models showed that Mini-Mental State Examination and memory composite scores did not differ between concordant-negative (β [SE] − 0.13[0.08], P = 0.09) and discordant (β 0.08[0.15], P = 0.15) patients (Pinteraction = 0.19), while these scores declined in concordant-positive (β − 0.75[0.08] patients (Pinteraction < 0.001). In patients with dementia, longitudinal cognitive scores were not affected by amyloid-β biomarker concordance or discordance. Clinical progression rates from SCD to MCI or dementia (P = 0.01) and from MCI to dementia (P = 0.003) increased from concordant-negative to discordant to concordant-positive. Conclusions Discordant cases were intermediate to concordant-negative and concordant-positive patients in terms of genetic (APOE ε4) and CSF (tau) markers of AD. While biomarker agreement did not impact cognition in patients with dementia, discordant biomarkers are not benign in patients without dementia given their higher risk of clinical progression.

scholarly journals Blood Biomarkers for Alzheimer’s Disease in Down Syndrome

2021 ◽  
Vol 10 (16) ◽  
pp. 3639
Author(s):  
Laia Montoliu-Gaya ◽  
Andre Strydom ◽  
Kaj Blennow ◽  
Henrik Zetterberg ◽  
Nicholas James Ashton
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Amyloid Β ◽  
Detection Methods ◽  
Blood Biomarkers ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Positron Emission ◽  
Diagnosis Of Dementia

Epidemiological evidence suggests that by the age of 40 years, all individuals with Down syndrome (DS) have Alzheimer’s disease (AD) neuropathology. Clinical diagnosis of dementia by cognitive assessment is complex in these patients due to the pre-existing and varying intellectual disability, which may mask subtle declines in cognitive functioning. Cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, although accurate, are expensive, invasive, and particularly challenging in such a vulnerable population. The advances in ultra-sensitive detection methods have highlighted blood biomarkers as a valuable and realistic tool for AD diagnosis. Studies with DS patients have proven the potential blood-based biomarkers for sporadic AD (amyloid-β, tau, phosphorylated tau, and neurofilament light chain) to be useful in this population. In addition, biomarkers related to other pathologies that could aggravate dementia progression—such as inflammatory dysregulation, energetic imbalance, or oxidative stress—have been explored. This review serves to provide a brief overview of the main findings from the limited neuroimaging and CSF studies, outline the current state of blood biomarkers to diagnose AD in patients with DS, discuss possible past limitations of the research, and suggest considerations for developing and validating blood-based biomarkers in the future.

Predictive Accuracy of Blood-Derived Biomarkers for Amyloid-β Brain Deposition Along with the Alzheimer’s Disease Continuum: A Systematic Review

2021 ◽  
pp. 1-15
Author(s):  
Alessandra Cianflone ◽  
Luigi Coppola ◽  
Peppino Mirabelli ◽  
Marco Salvatore
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Predictive Accuracy ◽  
Amyloid Β ◽  
Normal Subjects ◽  
Bibliographic Databases ◽  
Blood Biomarkers ◽  
Prognostic Accuracy ◽  
Positron Emission

Background: An amyloid-β (Aβ) positron emission tomography (Aβ-PET) scan of the human brain could lead to an early diagnosis of Alzheimer’s disease (AD) and estimate disease progression. However, Aβ-PET imaging is expensive, invasive, and rarely applicable to cognitively normal subjects at risk for dementia. The identification of blood biomarkers predictive of Aβ brain deposition could help the identification of subjects at risk for dementia and could be helpful for the prognosis of AD progression. Objective: This study aimed to analyze the prognostic accuracy of blood biomarkers in predicting Aβ-PET status along with progression toward AD. Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched bibliographic databases from 2010 to 2020. The quality of the included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Results: A total of 8 studies were retrieved. The prognostic accuracy of Aβ-PET status was calculated by obtaining ROCs for the following biomarkers: free, total, and bound Aβ 42 and Aβ 40; Aβ 42/40 ratio; neurofilaments (NFL); total tau (T-tau); and phosphorylated-Tau181 (P-tau181). Higher and lower plasma baseline levels of P-tau181 and the Aβ 42/40 ratio, respectively, showed consistently good prognostication of Aβ-PET brain accumulation. Only P-tau181 was shown to predict AD progression. Conclusion: In conclusion, the Aβ 42/40 ratio and plasma P-tau181 were shown to predict Aβ-PET status. Plasma P-tau181 could also be a preclinical biomarker for AD progression.

scholarly journals Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Henrik Zetterberg ◽  
Kaj Blennow
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Practice ◽  
Diagnostic Tests ◽  
Amyloid Β ◽  
Research Field ◽  
Clinical Diagnostics ◽  
Csf Biomarkers ◽  
Neurofilament Light ◽  
Positron Emission

AbstractFour fluid-based biomarkers have been developed into diagnostic tests for Alzheimer’s disease (AD) pathology: the ratio of 42 to 40 amino acid-long amyloid β, a marker of plaque pathology; total-tau and phosphorylated tau, markers of AD-related changes in tau metabolism and secretion; and neurofilament light, a marker of neurodegeneration. When measured in cerebrospinal fluid, these biomarkers can be used in clinical practice to support a diagnosis of mild cognitive impairment or dementia due to AD. Recently, technological breakthroughs have made it possible to measure them in standard blood samples as well. Here, we give an updated account of the current state of the fluid-based AD biomarker research field. We discuss how the new blood tests may be used in research and clinical practice, and what role they may play in relation to more established diagnostic tests, such as CSF biomarkers and amyloid and tau positron emission tomography, to facilitate the effective implementation of future disease-modifying therapies.

scholarly journals 2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

2021 ◽  
Author(s):  
A. Leuzy ◽  
N. J. Ashton ◽  
N. Mattsson-Carlgren ◽  
A. Dodich ◽  
M. Boccardi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Large Degree ◽  
Preliminary Evidence ◽  
Diagnostic Tools ◽  
Clinical Implementation ◽  
Development Framework ◽  
The Impact

Abstract Purpose In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer’s disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers—encompassing the 42 amino-acid isoform of amyloid-β (Aβ42), phosphorylated-tau (P-tau), and Total-tau (T-tau)—with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology. Methods A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop. Results By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for Aβ42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability. Conclusions Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy.

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