CSF Aβ1–42 – an excellent but complicated Alzheimer's biomarker – a route to standardisation

Kuhlmann, Julia; Andréasson, Ulf; Pannee, Josef; Bjerke, Maria; Portelius, Erik; Leinenbach, Andreas; Bittner, Tobias; Korecka, Magdalena; Jenkins, Rand; Vanderstichele, Hugo; Stoops, Erik; Lewczuk, Piotr; Shaw, Leslie M.; Zegers, Ingrid; Schimmel, Heinz; Zetterberg, Henrik; Blennow, Kaj

doi:10.1016/j.cca.2016.05.014

Cited by 113 publications

(99 citation statements)

References 24 publications

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“…Soluble Aβ levels in the hippocampus and CSF are similarly decreased in IL-17A-overexpressing mice. Contrary to this observation, a decrease in CSF Aβ, especially Aβ42, is accompanied by an increase in brain Aβ deposition in the early stages of AD patients (Kuhlmann et al , 2016; Maia et al , 2013). Therefore, CSF Aβ levels do not always reflect Aβ load in the brain.…”

Section: Discussioncontrasting

confidence: 59%

Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

Yang

Kou

Lalonde

et al. 2017

Brain, Behavior, and Immunity

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Neuroinflammation is a pervasive feature of Alzheimer’s disease (AD) and characterized by activated microglia, increased proinflammatory cytokines and/or infiltrating immune cells. T helper 17 (Th17) cells are found in AD brain parenchyma and interleukin-17A (IL-17A) is identified around deposits of aggregated amyloid β protein (Aβ). However, the role of IL-17A in AD pathogenesis remains elusive. We overexpressed IL-17A in an AD mouse model via recombinant adeno-associated virus serotype 5 (rAAV5)-mediated intracranial gene delivery. AD model mice subjected to injection of a vehicle (PBS) or rAAV5 carrying the lacZ gene served as controls. IL-17A did not exacerbate neuroinflammation in IL-17A-overexpressing mice. We found that IL-17A overexpression markedly improved glucose metabolism, decreased soluble Aβ levels in the hippocampus and cerebrospinal fluid, drastically reduced cerebral amyloid angiopathy, and modestly but significantly improved anxiety and learning deficits. Moreover, the ATP-binding cassette subfamily A member 1 (ABCA1), which can transport Aβ from the brain into the blood circulation, significantly increased in IL-17A-overexpressing mice. In vitro treatment of brain endothelial bEnd.3 cells with IL-17A induced a dose-dependent increase in protein expression of ABCA1 through ERK activation. Our study suggests that IL-17A may decrease Aβ levels in the brain by upregulating ABCA1 in blood-brain barrier endothelial cells.

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Section: Discussioncontrasting

confidence: 59%

Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

Yang

Kou

Lalonde

et al. 2017

Brain, Behavior, and Immunity

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“…Factors that had been recognized but incompletely understood, such as the effect of tube type and CSF volume involved in transfer steps, were recently described and will help to clarify the potential impact of such factors on CSF AD biomarker measurements [386]. The International Federation of Clinical Chemistry Working Group for CSF proteins (IFCC WG-CSF) is an international joint effort to develop reference measurement procedures (RMP) and certified reference materials (CRM) with the aim of standardizing CSF biomarkers and harmonizing read-outs between assay formats [185]. To date, two Joint Committee for Traceability in Laboratory Medicine (JCTLM) -approved RMPs and three CRMs for CSF Aβ42 are available, and work on Aβ40 and tau proteins is ongoing.…”

Section: Discussionmentioning

confidence: 99%

Current state of Alzheimer’s fluid biomarkers

et al. 2018

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

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“…This problem stems from differences in analytical procedures for the manual ELISA methods between laboratories and from variability in reagent quality and manufacturing procedures for the kits. Standardization efforts to control for and resolve these issues include development of a fully validated mass spectrometry-based Reference Measurement Procedures (RMP) for CSF Aβ42 to serve as the “gold standard” for Aβ42 measurement [11], and Certified Reference Materials (CRM) for the core AD CSF biomarkers [12]. In addition, novel assays have been developed on fully automated laboratory analyzers, resulting in very precise and stable measurements, also between many reagents and laboratories [13].…”

Section: The Core Csf Biomarkers For Alzheimer’s Diseasementioning

confidence: 99%

A Review of Fluid Biomarkers for Alzheimer’s Disease: Moving from CSF to Blood

2017

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A set of core cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) includes total tau (T-tau), phosphorylated tau (P-tau) and β-amyloid 42 (Aβ42). These biomarkers reflect some of the key aspects of AD pathophysiology, including neuronal degeneration, tau phosphorylation with tangle formation, and Aβ aggregation with deposition of the peptide into plaques. The core AD CSF biomarkers have been validated clinically in numerous studies, and found to have a very high diagnostic performance to identify AD, both in the dementia and in the mild cognitive impairment stages of the disease. CSF Aβ42 has also been found to show very high concordance with amyloid PET to identify brain amyloid deposition. The synaptic protein neurogranin is a novel candidate CSF biomarker for AD and prodromal AD. High CSF neurogranin predicts future cognitive decline and seems to be more specific for AD than, for example, T-tau. Importantly, technical developments have given ultrasensitive measurement techniques that allow measurement of brain-specific proteins such as tau and neurofilament light (NFL) in blood samples. Both plasma tau and NFL are increased in AD, and a recent study showed that plasma NFL has a diagnostic performance comparable to the core AD CSF biomarkers, and predicted future cognitive decline. Future large longitudinal clinical studies are warranted to determine the potential for plasma tau and NFL to serve as first-in-line screening tools for neurodegeneration in primary care.

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CSF Aβ1–42 – an excellent but complicated Alzheimer's biomarker – a route to standardisation

Cited by 113 publications

References 24 publications

Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

Current state of Alzheimer’s fluid biomarkers

A Review of Fluid Biomarkers for Alzheimer’s Disease: Moving from CSF to Blood

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