Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline

Ebenau, Jarith L.; Pelkmans, Wiesje; Verberk, Inge M.W.; Verfaillie, Sander C.J.; Bosch, Karlijn A. van den; Leeuwenstijn, Mardou van; Collij, Lyduine E.; Scheltens, Philip; Prins, Niels D.; Barkhof, Frederik; Berckel, Bart van; Teunissen, Charlotte E.; Flier, Wiesje M. van der

doi:10.1212/wnl.0000000000200035

Cited by 47 publications

(53 citation statements)

References 52 publications

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“…And second, that tau PET is known to not be sensitive to early tau pathology, which may have decreased the power to detect these associations in previous studies. 50–52 On the other hand, recent studies have shown the association between higher levels of plasma GFAP and increased risk of clinical progression and steeper rates of cognitive decline (even after adjusting for amyloid), 53–55 which supports a link with tau pathology given the known strong association between tau and clinical symptoms. Thus, our hypothesis is that plasma GFAP may be associated with AD pathology, but it may primarily relate to early deposited tau tangles.…”

Section: Discussionmentioning

confidence: 92%

Specific associations between plasma biomarkers and post-mortem amyloid plaque and neurofibrillary tau tangle loads

Salvadó

Ossenkoppele

Ashton

et al. 2022

Preprint

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Several promising plasma biomarkers have recently been developed that could serve as diagnostic and/or prognostic tools for Alzheimer's disease (AD). However, their neuropathological correlates have not yet been fully determined. Therefore, we aimed to investigate the independent associations between multiple plasma biomarkers (i.e., phosphorylated tau217 [p-tau217], p-tau181, p-tau231, the amyloid-β42/40 [Aβ42/40] ratio, glial fibrillary acidic protein [GFAP] and neurofilament light [NfL]) and core semi-quantitative measures of AD pathology (i.e., amyloid plaques and tau neurofibrillary tangles) as well as common co-pathologies (i.e., cerebral amyloid angiopathy, Lewy body disease, TAR DNA-binding protein 43, cerebral white matter rarefaction and argyrophilic grain disease). We included 105 participants from the Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program with antemortem collected plasma samples and a post-mortem neuropathological exam (mean(SD) time: 482(355) days), 48 of whom had longitudinal p-tau217 and p-tau181 (mean(SD) follow-up time: 1,378(1,357) days). Participants ranged from cognitively unimpaired to Alzheimer's and non-Alzheimer's dementia. All markers except NfL were associated with plaques (|β|≥0.37, p<0.001) and tangles (|β|≥0.27, p<0.008), in univariable analyses adjusted for age, sex and time between blood sampling and death. In multivariable models, when including both plaques and tangles as independent variables, the Aβ42/40 ratio and p-tau231 were only associated with plaques (βAβ42/40 [95%CI]=-0.59[-0.80,-0.38], R2plaques/R2=77.6%; βp-tau231[95%CI]=0.32[0.09,0.56], R2plaques/R2=45.9%, all p≤0.007), while GFAP was only associated with tangles (βGFAP[95%CI]=0.39[0.19,0.59], p<0.001, R2tangles/R2=30.4%). In contrast, p-tau217 and p-tau181 were associated with both plaques (βp-tau217[95%CI]=0.46[0.30,0.62], R2plaques/R2=40.4%; βp-tau181[95%CI]=0.41[0.22,0.60], R2plaques/R2=35.7%, both p<0.001) and tangles (βp-tau217[95%CI]=0.40[0.24,0.57], p<0.001, R2tangles/R2=30.7%; βp-tau181[95%CI]=0.30[0.10,0.49], p=0.004, R2tangles/R2=17.1%). A parsimonious model predicting plaque load included p-tau217 and Aβ42/40, while a parsimonious model for tangle burden included only p-tau217. Further, combining p-tau217 and Aβ42/40 ratio yielded the highest accuracy for predicting intermediate/high AD neuropathological change ([ADNC], AUC[95%CI]=0.90[0.84,0.96],R2=0.66). High plasma NfL levels were predictive of presence of cerebral white matter rarefaction (AUC[95%CI]=0.76[0.66,0.85],R2=0.25). Finally, p-tau217 (β[95%CI]=0.13[0.02,0.24], p=0.018), but not p-tau181 (β[95%CI]=0.12[-0.05,0.29], p=0.152), levels increased more over time in participants with intermediate/high ADNC compared with those with none/low ADNC. In this relatively large neuropathological study with multiple plasma biomarkers available, we showed that the Aβ42/40 ratio and p-tau231 were specific markers of plaque pathology, and GFAP of tangle pathology, while p-tau181 and, especially, p-tau217 were markers of both plaque and tangle pathologies. Our results suggest that high-performing assays of plasma p-tau217 and Aβ42/40 might be an optimal biomarker combination to detect ADNC in vivo.

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Section: Discussionmentioning

confidence: 92%

Specific associations between plasma biomarkers and post-mortem amyloid plaque and neurofibrillary tau tangle loads

Salvadó

Ossenkoppele

Ashton

et al. 2022

Preprint

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“…Interestingly, this effect was more pronounced for plasma GFAP than plasma NfL. This could be explained by the fact, that GFAP seems to be a marker of the earliest AD pathology with an association between GFAP levels and amyloid load, while NfL could be more useful in terms of disease monitoring and progression (Verberk et al, 2021 ; Ebenau et al, 2022 ). Unfortunately, for discriminating the disease states of MCI and AD, none of the three biomarker-based panels could add a significant benefit to the age+sex+ APOE4 panel.…”

Section: Discussionmentioning

confidence: 99%

Real-world applicability of glial fibrillary acidic protein and neurofilament light chain in Alzheimer’s disease

Parvizi

König

Wurm

et al. 2022

Front. Aging Neurosci.

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Background: Blood-based biomarkers may add a great benefit in detecting the earliest neuropathological changes in patients with Alzheimer’s disease (AD). We examined the utility of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) regarding clinical diagnosis and differentiation between amyloid positive and negative patients. To evaluate the practical application of these biomarkers in a routine clinical setting, we conducted this study in a heterogeneous memory-clinic population.Methods: We included 167 patients in this retrospective cross-sectional study, 123 patients with an objective cognitive decline [mild cognitive impairment (MCI) due to AD, n = 63, and AD-dementia, n = 60] and 44 age-matched healthy controls (HC). Cerebrospinal fluid (CSF) and plasma concentrations of NfL and GFAP were measured with single molecule array (SIMOA®) technology using the Neurology 2-Plex B kit from Quanterix. To assess the discriminatory potential of different biomarkers, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared.Results: We constructed a panel combining plasma NfL and GFAP with known AD risk factors (Combination panel: age+sex+APOE4+GFAP+NfL). With an AUC of 91.6% (95%CI = 0.85–0.98) for HC vs. AD and 81.7% (95%CI = 0.73–0.90) for HC vs. MCI as well as an AUC of 87.5% (95%CI = 0.73–0.96) in terms of predicting amyloid positivity, this panel showed a promising discriminatory power to differentiate these populations.Conclusion: The combination of plasma GFAP and NfL with well-established risk factors discerns amyloid positive from negative patients and could potentially be applied to identify patients who would benefit from a more invasive assessment of amyloid pathology. In the future, improved prediction of amyloid positivity with a noninvasive test may decrease the number and costs of a more invasive or expensive diagnostic approach.

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“…Neurofilament light and VILIP-1 are biomarkers of neurodegeneration and have been shown to have prognostic value for progression in patients with MCI or dementia due to AD [ 81 , 87 ]. GFAP, a marker of astrogliosis, predicts decline in those with subjective cognitive impairment [ 88 ]. Tau PET offers prognostic information and forecasts MCI and AD dementia progression [ 89 , 90 ].…”

Section: Biomarker Definition and Classificationmentioning

confidence: 99%

Biomarkers for Alzheimer’s Disease: Context of Use, Qualification, and Roadmap for Clinical Implementation

Cummings

Kinney

2022

Medicina

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Background and Objectives: The US Food and Drug Administration (FDA) defines a biomarker as a characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention. Biomarkers may be used in clinical care or as drug development tools (DDTs) in clinical trials. The goal of this review and perspective is to provide insight into the regulatory guidance for the use of biomarkers in clinical trials and clinical care. Materials and Methods: We reviewed FDA guidances relevant to biomarker use in clinical trials and their transition to use in clinical care. We identified instructive examples of these biomarkers in Alzheimer’s disease (AD) drug development and their application in clinical practice. Results: For use in clinical trials, biomarkers must have a defined context of use (COU) as a risk/susceptibility, diagnostic, monitoring, predictive, prognostic, pharmacodynamic, or safety biomarker. A four-stage process defines the pathway to establish the regulatory acceptance of the COU for a biomarker including submission of a letter of intent, description of the qualification plan, submission of a full qualification package, and acceptance through a qualification recommendation. Biomarkers used in clinical care may be companion biomarkers, in vitro diagnostic devices (IVDs), or laboratory developed tests (LDTs). A five-phase biomarker development process has been proposed to structure the biomarker development process. Conclusions: Biomarkers are increasingly important in drug development and clinical care. Adherence to regulatory guidance for biomarkers used in clinical trials and patient care is required to advance these important drug development and clinical tools.

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Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline

Cited by 47 publications

References 52 publications

Specific associations between plasma biomarkers and post-mortem amyloid plaque and neurofibrillary tau tangle loads

Specific associations between plasma biomarkers and post-mortem amyloid plaque and neurofibrillary tau tangle loads

Real-world applicability of glial fibrillary acidic protein and neurofilament light chain in Alzheimer’s disease

Biomarkers for Alzheimer’s Disease: Context of Use, Qualification, and Roadmap for Clinical Implementation

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