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Alzheimer's Disease Fluid Biomarkers: Highlights from AAT-AD/PD 2018 Meeting

The Alzheimer's and Parkinson's Diseases scientific and medical community gathered at the AAT-AD/PD Focus Meeting in March to share the latest research and clinical advances. The event, a new joint meeting between the International Geneva/Springfield Symposium on Advances in Alzheimer Therapy (AAT) and AD/PDTM, brought new insights on how fluid biomarkers can contribute to Alzheimer's Disease (AD) understanding and diagnosis. Here are some of the key highlights.

Certified Reference Material for Aβ1-42: a milestone for standardization

The first immunoassays to quantify CSF Amyloid-beta 1-42 (Aβ1-42), tau and p-tau181 were developed around 20 years ago (INNOTEST, Fujirebio). These assays allowed us to define the now very well-known AD profile, characterized by a decrease in CSF Aβ1-42 and an increase in both CSF total-tau and p-tau181.

Since then, different teams and organizations have developed their own assays to quantify these biomarkers. Despite their high diagnostic accuracy and correlation with amyloid PET, studies showed a marked difference in the reported biomarkers absolute concentrations. This variability is clearly highlighted by the data generated by the Alzheimer's Association quality control (QC) program 1. This between-laboratories and between-assays variability is particularly pronounced for Aβ1-42, compared to total tau and p-tau181.

Standardization is needed for this tricky biomarker in order to define a uniform cut-off -- the major step before implementation in clinical routine. Thus, the International Federation of Clinical Chemistry and Laboratory Medicine Group for CSF proteins (IFCC WG-CSF) and the Alzheimer's Association Global Biomarker Standardization Consortium decided to establish a Certified Reference Material (CRM) for Aβ1-42 quantification. Three certified CSF CRM have been established with respectively low, medium and high concentrations of Aβ1-42, determined by using the mass spectrometry method approved as a Reference Measurement Procedure 2,3. These CRM will be used as calibrators or quality controls to harmonize the results between assays, batches and laboratories. The establishment of these CRMs is an important step for the implementation in clinics.  If the CRM are now defined, much work must be done to standardize the using procedure between laboratories. Moreover, CRM will certainly be applied to other CSF analytes, for which further development is required.

Rise of Synaptic proteins

Regarding CSF biomarker reflecting other AD molecular aspects than amyloid plaques and tangles, neurogranin confirms its promises as a marker of synaptic degeneration, specific to AD. Indeed, Kaj Blennow presented data confirming, in a large cohort study, the specific increase of CSF neurogranin levels in AD dementia and prodromal AD, but not in other neurodegenerative disorders such as frontotemporal dementia or Parkinson’s Disease (unpublished data). Recently, high CSF neurogranin levels have been shown to associate with poor memory scores and executive functions in patients with MCI 4. Neurogranin proven useful in the Phase Ib/IIa clinical study for Elayta, the lead product candidate of Cognition Therapeutics. Susan Catalano presented data where mild-to-moderate AD patients showed significantly reduced CSF neurogranin levels – and synaptotagmin-1, another synaptic protein – compared to placebo, after four weeks of Elyata treatment. These reductions in treated patients were greater and occurred more rapidly than those reported for other AD drug candidates, Catalano said.

Moving from CSF to blood – new promises

Compared to CSF, blood matrix has everything to be attractive: more accessible, less invasive for the patient and is less costly to handle. However, blood turned out to be a difficult matrix to measure the levels of amyloid species, presenting a high risk of interference and degradation by proteases. Until recently, plasma Aβ studies led to contradictory results and showed weak or no correlation with CSF Aβ and hardly allowed the discrimination between amyloid positive and amyloid negative subjects 5–7. In the last months, research teams developed two immunoprecipitation-mass spectrometry (IP-MS) techniques and one ELISA to quantify Aβ peptides in plasma more accurately. These studies reported significant changes in Aβ1-40 and Aβ1-42 plasma levels in amyloid positive patients -̶  allowing their discrimination from cognitively normal subjects -̶  along with a high correlation between plasma amyloid species and Aβ PET and CSF Aβ1-42 8–10. All these assays are quantifying Aβ monomers while oligomers are known to be the major toxic form found in AD pathologies, thus explaining the increasing number of therapeutic drugs targeting Aβ oligomers. SangYun Kim and colleagues presented a promising assay, based on the Multimer Detection System, to quantify Aβ oligomers in blood samples. The MDS assay, originally developed to detect prion oligomers in blood, has a principle very close to ELISA and uses antibodies specific to Aβ oligomers. Kim showed that plasma Aβ oligomer levels are higher in AD patients than in cognitively normal subjects, and correlate with CSF Aβ1-42, total-tau, p-tau181 and amyloid PET 11. Even if plasma Aβ oligomers allow discriminating between AD and normal control groups, the AUC of 0.844 could certainly be improved by optimizing the method, Kim said.

Blood tau assays are not that advanced but have known breakthrough in the last few months. Michelle Mielke from the Mayo Clinic, in collaboration with Eli Lilly and Co., developed an assay to detect plasma p-tau181 on the Meso Scale Discovery (MSD) platform. As it has been demonstrated for CSF p-tau181, Mielke findings showed that plasma p-tau181 is a more accurate predictor of elevated brain Aβ than total-tau and is more strongly associated with Aβ and tau PET 12. These results highlight the potential use of plasma p-tau181 as a non-invasive screener of AD pathophysiology, Mielke said. Meanwhile, Charles S.Y. Yang and team, from the MagQu biotech, described an innovative and ultra-sensitive technology for the measurement of p-tau181 in plasma 13. Using an ImmunoMagnetic Reduction (IMR) assay, Yang and colleagues discriminated AD and MCI due to AD subjects to healthy controls according to plasma p-tau181 levels. As demonstrated by Mielke and colleagues, Yang showed that plasma p-tau181 is more correlated to AD severity than total-tau. These promising results are currently repeated in a Swedish cohort, in collaboration with Blennows’ team.

Bioclinica Lab

This is indeed exciting work for our team and me at Bioclinica Lab and we're fortunate to play a role in helping advance research in Alzheimer's and Parkinson's Diseases. Here at Bioclinica Lab, our team of biomarker experts:

  • Developed standardized methods for CSF sample collection, handling and storage to improve the reproducibility of your data;
  • Established an efficient, quality-driven, fit-for-purpose approach to analyze CSF biomarkers in clinical trials;
  • Takes part in the AAQC program for CSF biomarkers and is part of the ADNI biomarker initiative.

Bioclinica Lab offers to our clients fully-validated assays to measure core biomarkers of AD (Aβ1-40, Aβ1-42, total tau and p-tau181) along with markers of neuropathological processes such as synaptic and neuronal dysfunctions (e.g. neurogranin, BACE1, NFL, VILIP-1), or neuroinflammation (e.g. YKL-40, inflammatory cytokines) in human CSF and blood samples.  More information about our services and capabilities can be found online here.

If you have any questions about Bioclinica Lab and our biomarker services, feel free to reach out to me at melanie.bodnar-wachtel@bioclinicalab.com.

Bibliography

  1. Alzheimer's Association QC Program. Göteborgs universitet Available at: http://neurophys.gu.se/sektioner/psykiatri_och_neurokemi/neurokem/TheAlz....
  2. Leinenbach, A. et al. Mass Spectrometry–Based Candidate Reference Measurement Procedure for Quantification of Amyloid-β in Cerebrospinal Fluid. Clin. Chem. 60, 987–994 (2014).
  3. Kuhlmann, J. et al. CERTIFICATION REPORT: The certification of Amyloid β1-42 in CSF in ERM®-DA480/IFCC, ERM®-DA481/IFCC and ERM®-DA482/IFCC - EU Science Hub - European Commission. EU Science Hub (2017). Available at: https://ec.europa.eu/jrc/en/publication/eur-scientific-and-technical-res....
  4. Headley, A. et al. Neurogranin as a predictor of memory and executive function decline in MCI patients. Neurology 90, e887–e895 (2018).
  5. Olsson, B. et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 15, 673–684 (2016).
  6. Hanon, O. et al. Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers. Alzheimers Dement. J. Alzheimers Assoc. 0, (2018).
  7. Janelidze, S. et al. Plasma β-amyloid in Alzheimer's disease and vascular disease. Sci. Rep. 6, 26801 (2016).
  8. Ovod, V. et al. Amyloid β concentrations and stable isotope labeling kinetics of human plasma to central nervous system amyloidosis. Alzheimers Dement. J. Alzheimers Assoc. 13, 841–849 (2017).
  9. Nakamura, A. et al. High performance plasma amyloid-β biomarkers for Alzheimer's disease. Nature 554, 249–254 (2018).
  10. Fandos, N. et al. Plasma amyloid β 42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals. Alzheimers Dement. Diagn. Assess. Dis. Monit. 8, 179–187 (2017).
  11. Wang, M. J. et al. Oligomeric forms of amyloid-β protein in plasma as a potential blood-based biomarker for Alzheimer's disease. Alzheimers Res. Ther. 9, (2017).
  12. Mielke, M. M. et al. Plasma phospho-tau181 increases with Alzheimer's disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement. J. Alzheimers Assoc. 0, (2018).
  13. Yang, C.-C. et al. Assay of Plasma Phosphorylated Tau Protein (Threonine 181) and Total Tau Protein in Early-Stage Alzheimer's Disease. J. Alzheimers Dis. JAD 61, 1323–1332 (2018).

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