Associations of the A/T/N profiles in PET, CSF, and plasma biomarkers with Alzheimer's disease neuropathology at autopsy

Wang, Zhibo; Tan, Lan; Gao, Pei-Yang; Ma, Ya‐Hui; Fu, Yan; Sun, Yan; Yu, Jin‐Tai

doi:10.1002/alz.13413

Cited by 9 publications

(2 citation statements)

References 45 publications

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“…Currently, plasma assays have not received regulatory approval, but a few assays based on standalone amyloid or tau biomarkers have received the FDA breakthrough device designation (Table 1). However, recent studies have shown substantial variation in accuracy of plasma-related A/T/N biomarker assays with respect to PET visual reads or CSF reference standard (60-90%) [22][23][24][25].…”

Section: Taumentioning

confidence: 99%

Label-free and reference region-free X-ray cross-β index for quantifying protein aggregates of neurodegenerative diseases

Suresh,

Dahal,

Badano

2024

Preprint

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Background and objectivesRecent advancements in therapies targeting various protein aggregates, ranging from oligomers to fibrils, in neurodegenerative diseases exhibit considerable promise. This underscores the imperative for robust quantitative methods capable of accurately detecting and quantifying these biomarker aggregates across different structural states, even when present in sparse quantities during the early stages of the disease continuum. In response to this exigency, we propose and assess an X-ray-based quantitative metric designed for the global and region-specific detection and quantification of oligomers and fibrils within tissues. This methodology proves applicable to a broad spectrum of neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Notably, unlike positron emission tomography (PET)-based biomarker quantification methods, our approach obviates the need for a contrast agent or a reference region.MethodsWe assessed the proposed metric, termed X-ray cross-β aggregate index (XβAI), in a sheep brain model and brain tissue phantoms, incorporating synthetic oligomers and fibrils characterized against amyloid β-42 and α-synuclein aggregates. Detection of these biomarkers utilized laboratory-based monochromatic, and polychromatic X-ray sources, specifically targeting the cross-β substructure of protein aggregates. We employed a peak-location, knowledge-based material decomposition approach to extract target signals from the complex X-ray scattering spectrum originating from a mixture of tissue, water, and aggregate signals.ResultsClinically relevant quantities of oligomers and fibrils were detected in tissues from different brain regions using the laboratory-based X-ray scattering method, without the need for a contrast agent. The signals from protein aggregates were successfully recovered from composite X-ray scattering spectra through material decomposition, eliminating the need for a reference region. The area under the peak of the decomposed inter-β-strand signal correlated well with aggregate burden in synthetically diseased brain tissues. The X-ray cross-β aggregate index (XβAI) accurately quantified aggregate burden in heterogeneous tissues across various brain regions and effectively tracked the deposition increments in specific tissue regions.ConclusionOur study introduces a novel metric, for both regional and global quantification of protein aggregates linked to various protein misfolding diseases, including synucleinopathies.

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Section: Taumentioning

confidence: 99%

Label-free and reference region-free X-ray cross-β index for quantifying protein aggregates of neurodegenerative diseases

Suresh,

Dahal,

Badano

2024

Preprint

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“…Compared to necropsy as the gold standard, PET and CSFrelated biomarkers in combination showed high concordance with the pathological stage; alone, they showed high accuracy in discriminating autopsy-confirmed AD. However, the plasma-related biomarkers alone showed better discriminative performance only when combined with the apolipoprotein E (APO) Eε4 genotype [40]. In this context, biomarkers that accurately reflect disease progression and have prognostic capabilities are also needed.…”

Section: Markers In Biological Fluids (Cerebrospinal Fluid and Plasma)mentioning

confidence: 99%

Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

Santillán-Morales,

Rodriguez-Espinosa,

Muñoz-Estrada

et al. 2024

Brain Sciences

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Alzheimer’s disease (AD), as the main cause of dementia, affects millions of people around the world, whose diagnosis is based mainly on clinical criteria. Unfortunately, the diagnosis is obtained very late, when the neurodegenerative damage is significant for most patients. Therefore, the exhaustive study of biomarkers is indispensable for diagnostic, prognostic, and even follow-up support. AD is a multifactorial disease, and knowing its underlying pathological mechanisms is crucial to propose new and valuable biomarkers. In this review, we summarize some of the main biomarkers described in AD, which have been evaluated mainly by imaging studies in cerebrospinal fluid and blood samples. Furthermore, we describe and propose neuronal precursors derived from the olfactory neuroepithelium as a potential resource to evaluate some of the widely known biomarkers of AD and to gear toward searching for new biomarkers. These neuronal lineage cells, which can be obtained directly from patients through a non-invasive and outpatient procedure, display several characteristics that validate them as a surrogate model to study the central nervous system, allowing the analysis of AD pathophysiological processes. Moreover, the ease of obtaining and harvesting endows them as an accessible and powerful resource to evaluate biomarkers in clinical practice.

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Amyloid PET detects the deposition of brain Aβ earlier than CSF fluid biomarkers

Lowe,

Mester,

Lundt

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONUnderstanding the relationship between amyloid beta (Aβ) positron emission tomography (PET) and Aβ cerebrospinal fluid (CSF) biomarkers will define their potential utility in Aβ treatment. Few population‐based or neuropathologic comparisons have been reported.METHODSParticipants 50+ years with Aβ PET and Aβ CSF biomarkers (phosphorylated tau [p‐tau]181/Aβ42, n = 505, and Aβ42/40, n = 54) were included from the Mayo Clinic Study on Aging. From these participants, an autopsy subgroup was identified (n = 47). The relationships of Aβ PET and Aβ CSF biomarkers were assessed cross‐sectionally in all participants and longitudinally in autopsy data.RESULTSCross‐sectionally, more participants were Aβ PET+ versus Aβ CSF− than Aβ PET− versus Aβ CSF+ with an incremental effect when using Aβ PET regions selected for early Aβ deposition. The sensitivity for the first detection of Thal phase ≥ 1 in longitudinal data was higher for Aβ PET (89%) than p‐tau181/Aβ42 (64%).DISCUSSIONAβ PET can detect earlier cortical Aβ deposition than Aβ CSF biomarkers. Aβ PET+ versus Aβ CSF− findings are several‐fold greater using regional Aβ PET analyses and in peri‐threshold‐standardized uptake value ratio participants.Highlights Amyloid beta (Aβ) positron emission tomography (PET) has greater sensitivity for Aβ deposition than Aβ cerebrospinal fluid (CSF) in early Aβ development. A population‐based sample of participants (n = 505) with PET and CSF tests was used. Cortical regions showing early Aβ on Aβ PET were also used in these analyses. Neuropathology was used to validate detection of Aβ by Aβ PET and Aβ CSF biomarkers.

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Associations of the A/T/N profiles in PET, CSF, and plasma biomarkers with Alzheimer's disease neuropathology at autopsy

Cited by 9 publications

References 45 publications

Label-free and reference region-free X-ray cross-β index for quantifying protein aggregates of neurodegenerative diseases

Label-free and reference region-free X-ray cross-β index for quantifying protein aggregates of neurodegenerative diseases

Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

Amyloid PET detects the deposition of brain Aβ earlier than CSF fluid biomarkers

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