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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - BBDiag (Blood Biomarker-based Diagnostic Tools for Early Stage Alzheimerâ€™s Disease)

Teaser

Summary

BBDiag project aims to train a new generation of ESRs for early AD diagnosis based on blood biomarkers.

Dementia is one of the major causes of severe cognitive deficits, disability and dependency in daily living, and eventual death in old people. It affects approx.10 million people in Europe and poses a heavy burden to individuals and societies with an estimated European cost of over â‚¬300 billion for 2018. AD is one of the major forms of dementia. Despite of the notable recent advances in AD biomarkers and diagnostics, currently there is still no definitive diagnostic markers, disease-modifying treatments or preventive strategies are clinically available. It is one of the Societal Challenges listed by the UN Sustainable Development Goals and EU H2020.

BBDiag responds to such a need and establishes a much-needed ETN for blood based early-AD diagnostics to address these challenges. It brings together leading academic and industrial experts from five major consortia in Europe and uses their synergies to build a triple-i research & training platform with the required multidisciplinary expertise and cutting-edge technologies. BBDiag Fellows will be trained under the Vitae Researcher Development Framework innovatively combined with the BBDiag platform for gaining interdisciplinary scientific and transferable skills as well as personal quality, creative thinking and business mind-set. The ETN has a highly innovative research programme for the discovery of AD biomarkers, development of novel biosensing techniques and point of care tools, and for technological exploitation of the diagnostics. These advances will strongly support improved care provision and development of disease-modifying treatments and preventive strategies for AD patients. More importantly, BBDiag will deliver its first generation of 13 highly-skilled, creative and entrepreneurial Fellows, setting them on a path to successful careers in academia or industry to ensure that the medical and societal challenges imposed by AD are met.

The scientific objectives of the project are:

To develop novel graphene and ELISA barcoding based multiplexed biosensing techniques with embedded electronics for the detection of a panel of blood-based AD biomarkers at clinically relevant concentrations.
To discover a panel of most reliable early-AD blood biomarkers by employing innovative techniques.
To develop a fully integrated prototype point of care (PoC) diagnostic tool for early-stage AD.
To carry out preclinical and clinical validation for assessment of reliability & pathologies of biomarkers.
To carry out clinical trials for evaluation of diagnostic accuracy of the BBDiag PoC tool.
To develop an innovative business model and exploitation strategies for early-AD diagnostics, and to explore novel commercial and clinical applications of the technology.

Work performed

Work package 1 focuses on the development of biosensing techniques (digital ELISA and graphene biosensors) and point of care devices for the detection of blood based AD biomarkers.
For Digital ELISA, a robust way to divide the droplet array slides has been achieved thorough the optimisation of the procedure for fabricating the microfluidic systems. The surface chemistry for probe immobilisation and the procedure for fabricating hydrophilic-in-hydrophobic spot arrays are being optimized while other strategies for fabricating chips outside the cleanroom are under investigation. Once the optimized, multiplexed assays for cross-biomarker class testing will be carried out. For graphene biosensors, a number of sensor types together with their surface chemical functionalisation and detection protocols have been developed and the detection of typical AD blood biomarkers have been carries out and linearity of the detections have been demonstrated. For PoC devices, packaging design and prototyping of a device have been completed and successful moulding of both the microfluidics channels and the inlets/outlets for integration with graphene-based multi-analyte sensors and digital ELISA droplet arrays have been achieved.

In WP2, novel blood-based assays are in the pipeline, which will allow determination of whether brain-derived extracellular matrix are useful as biomarkers of AD. Furthermore, a novel sensitive platform is being implemented to help address one of the major challenges, namely the low circulating levels of brain-derived molecules. AD biomarker discovery from exosome research has been carried out.Initial biomarker panels for early and clinical disease detection have been produced by machine learning and recommend them for testing on the BBDiag biosensors and further validations.
Work Package 3:

The clinical research of thee WP3 builds on an international platform for the AD diagnosis and treatment at UniRoma1, UoP, and URos. This platform provides training opportunities for the BBDiag ESRs such as novel designs for diagnostic trials, the biostatistical analysis and the strategy of recruitment, the patient characterization, and the stakeholder involvement.

WP4 has clearly positioned itself within BBDiag project from its value chain perspective. By strategically positioning at the downstream of the value chain, WP4 has so far focused its scientific work on the following in relation to the three tasks: identifying opportunities to access to markets and establishing links to the industry, developing ICT app to look into the links of peopleâ€™s lifestyle such as smoking with AD, and building a business model that is market-oriented, resilient and robust for the exploitation of BBDiag platform.

Final results

Controlled deposition of 1,5-diaminonaphthalene (DAN) has been achieved on CVD graphene surfaces. The experimental results evidence that the electrochemical sensing efficiency increases, owing to the synergistic effects of better electron transfer as well as higher enzyme loading on DAN modified electrodes. Detection of typical protein AD biomarkers using graphene biosensors have also bee demonstrated.

A main limitation of AD mouse models is their current wide application in late disease stage. Little is known about the early phase of signs onset in these mice. We performed work in this direction, finding the right timeline for blood collection in search of early biomarkers, to be then possibly translated to humans. Also in this sense, we have decided to focus on MCI patients, an early phase of dementia.

Validity of an in vivo amyloid staging model is evaluated in an independent cohort of older people with subjective memory complaints (SMC) and further examined its potential association with subtle cognitive impairments in this population at elevated risk for Alzheimerâ€™s disease (AD). Our results showed that neither in vivo amyloid stage nor conventional binary amyloid status4 was significantly associated with cognitive performance in this preclinical cohort.

The biomarker detection techniques will be applied to the detection of blood AD biomarkers in clinical samples. New blood biomarkers will be discovered from the two bimolecular labs. Further clinical validation of the biomarkers and their detection techniques will be carried out. The BBDiag business model will be developed. Potentially patentable results may result in spin-outs. Collaborations with other project consortium and institutions outside BBDiag may result in new research grants/projects for the early AD diagnostic field.