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Biomarker Development for Postoperative Cognitive Impairment in the Elderly

Periodic Report Summary 2 - BIOCOG (Biomarker Development for Postoperative Cognitive Impairment in the Elderly)

Project Context and Objectives:
Cognitive impairment is increasingly prevalent in our aging society as result of different, interacting medical conditions. It is a consequence of age-associated primary brain disorders (depression, Alzheimer’s dementia (AD), cerebrovascular disease etc.) and/or secondary brain disorders due to medical conditions like diabetes, inflammation or treatment interventions and life style factors. Postoperative Cognitive Impairment is a prime example in this regard and is characterized by the progressive deterioration of sensory and cognitive function following surgery with incidences of up to 20-80%* – particularly in but not limited to elderly patients. The condition often has an acute phase of Postoperative Delirium (POD) which then may be followed by a more chronic phase of Postoperative Cognitive Dysfunction (POCD), which tends to persist over time. Increased age as well as a range of medical conditions may predispose patients to POD/POCD. In older patients, POCD resembles chronic dementia and appears to accelerate the cognitive decline in AD. In our aging society the socioeconomic implications of postoperative cognitive impairments are therefore profound as POD/POCD are associated with longer and more costly hospital treatment, increased mortality and dependency on social transfer payments. Understanding POD/POCD thus constitutes an urgent medical need. Yet, there are hardly any treatments available, partly due to a lack of understanding of the pathomechanisms.
Research aimed at understanding the diverse pathomechanisms of POD/POCD requires a cross-cutting “systems medicine” approach, with different medical disciplines working together: the study of different physiological and molecular mechanisms and the identification of a range of clinically valid biomarkers, whose description is limited at present. Integration of neuroimaging biomarkers, which provide direct information on brain structure/function with high sensitivity, combined with complementary knowledge from molecular biomarkers (cholinergic, inflammatory, metabolic) as obtained from body fluids (plasma, cerebrospinal fluid, CSF) is expected to allow accurate patient stratification (subtyping).
Within BioCog, we will establish valid biomarkers panels for risk and clinical outcome prediction of POD/POCD. The study population will be 1200 patients, aged 65 to 85 undergoing major elective surgery. The resulting expert system is expected:
1) to support clinical decision-making in patient care, e.g. to balance the individual POD/POCD risk against the expected overall clinical outcome of a surgical intervention,
2) to allow the design of more sophisticated and hypothesis-driven clinical studies and drug trials (translational research) in the future to evaluate the role of causality in risk factor associations with POD/POCD.
These challenges can only be met by close collaboration between experienced academic and industrial groups, in a multinational and multidisciplinary network, as realized in the present consortium, BioCog.
Furthermore, a state-of-the art clinical database and biobank will be created to become an integral part of the European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) and will allow to address specific and hypothesis-driven research questions.
We will further analyse the health-economic impact of biomarker-guided strategy.

In summary, our proposed research project is envisaged to improve the way in which medical care and research is conducted in older pre-surgical and surgical patients in the future.
BioCog represents also an opportunity to strengthen the economic competitiveness of the European biomarker research industry: the involved SMEs Immundiagnostik, ATLAS Biolabs, PharmaImage will be provided with a competitive edge in biomarker research simply by having contributed to this project – in particular with regard to future business with research and development (R&D) departments of the pharmaceutical industry.

Project Results:
Neuroimaging biomarkers are expected to allow the detection of relevant aspects of POD/POCD pathophysiology with high sensitivity whereas molecular biomarkers promise high specificity. Developing an expert system on the basis of neuroimaging and molecular biomarkers requires complementary expertise from the fields of clinical (WP1), neuroimaging biomarker (WP2) and molecular biomarker (WP3). For a meaningful integration and interpretation of data from multiple domains, powerful computational tools are needed. The work package bioinformatics (WP4) is critical, as appropriate integration of sufficiently specific and sensitive biomarkers needs to be based on rigorous statistical procedures.
Efficient project management, in synergy with the scientific and business coordination objectives, is a central task within the project (WP5). Dissemination and exploitation strategies have an important role in the BioCog project. They will ensure proper visibility of the project. Strategies will be implemented to target future stakeholders such as the European Commission, clinicians, the academic community, as well as biotech and pharmaceutical companies (WP6).

The specific main activities performed so far are:

WP1: The screening of patients started in Charité Berlin, Campus Virchow on 20/10/2014 and in Campus Mitte on 08/06/2015. In Utrecht screening started on 12/01/2015. As of 31/01/2017, a total of 6577 patients were screened (4614 patients were screened in Berlin and 1963 patients were screened in Utrecht). 919 patients have been included: 681 patients in Berlin, 238 patients in Utrecht. In addition, 60 control subjects (Subjects with no surgical intervention) have been included (24 subjects in Berlin and 36 subjects in Utrecht).
In total: N = 979 patients/controls have been included. Target N = 1200.

Regarding the 3-month follow-up visit, 311 patients did not complete all study visits due to drop out, loss to follow-up or death: N = 267 in Berlin and 44 patients in Utrecht.
The follow-up visit T3 (i.e. 3 months postoperative) was completed for 459 patients (309 patients in Berlin and 150 patients in Utrecht).
The recruitment of the POCD control group has been started on 13/06/2015 in Berlin and is in progress. Remark: we have decided to reduce the target N of 1200 surgical patients to be included into the study down to N = 1100 and to investigate instead N = 100 control subjects (with no surgical intervention). By January 31 2017, 60 control subjects have been included (24 subjects in Berlin and 36 subjects in Utrecht).
All drawn blood samples have been collected under the directive protocol of the MDC (WP3). Every patient has received neuropsychological testing via CANTAB battery, geriatric assessment, delirium screening and further examination (EEG, heart rate variability) per protocol. Transthoracic echocardiography (TTE) has been performed in 41 patients in Berlin according to the availability of certified examiners.
In addition to the previous reporting period, the Standard Operating Procedure (SOP) concerning drop-out criteria was updated.
Applications for ethical approval have been submitted to the relevant ethics committees in Berlin and Utrecht and encompass the work within WP1, 2, 3 (for details, please see “Description of the work performed during the first 36 months of the project”).
For further analysis of study data, we will continue to work together with the KKS-Charité.
WP2: The MRI protocol has been finalized and harmonized between the Charité Berlin and the UMC Utrecht with support from the Cambridge University Hospital and Pharmaimage GmbH (Berlin). The MRI contract/agreement was available on 17/11/2014 (start of neuroimaging data collection). A standard operating procedure (SOP) for data collection as well as a protocol for data handling has been developed with central (raw) data storage in a secured research PACS at the UMC Utrecht. In addition, the Extensible Neuroimaging Archive Toolkit (XNAT) for the management of raw and processed neuroimaging data (and related clinical and molecular data) is implemented at PharmaImage (Berlin). First analyses based on the MRI data were presented at the 2015 Biocog Annual Meeting in June, the Biocog winterschool in 2016 and the Biocog Annual Meeting in September 2016 in Sienna. First results presented included pilot analyses (interim analyses) of local or global brain volume relations with POD and POCD. Furthermore, analyses were presented with the collected resting state functional MRI data and diffusion tensor imaging data. In addition to POD and POCD the relation between anatomical and functional MRI data and other clinical parameter such as frailty were analysed. Until 31/1/2017, a total of neuroimaging data sets was successfully collected in 363 patients in Berlin (incl. 17 control participants) and 192 patients in Utrecht (incl. 22 control participants). Follow-up neuroimaging data collection (after three months) was conducted in 206 patients in Berlin and 135 in Utrecht.

WP3: procedures (incl. SOPs) for the smooth, efficient and secure shipping of samples, for biomarker analysis and for biobanking in a central biorepository have been successfully implemented. By February 2017, blood samples (≥1 of the three time points) for N=282 patients of the N=400 interim sample (‘training set’) as well as for around 200 patients of the N=800 ‘test set’ had been received, processed and shipped on to partner labs by MDC Berlin. Aliquoted samples of these patients have additionally been stored at the central biorepository on MDC campus. WP3 partners have provided MDC with data on the parameters measured at their respective laboratories. ATLAS Biolabs received in total 1512 whole blood samples in PaxGene tubes (A + B samples). 807 of them were converted into total RNA samples including both mRNA and microRNA. 5 x 95 samples have already been processed for expression analysis using Affymetrix’ Clariom™ S and miRNA array plates. CNR examined the serum levels of ten inflammation-related factors of the IL-1 family in 137 patients at all three time points. For the N=400 interim sample, all data received back by MDC Berlin from partner laboratories have been integrated with patients’ clinical and cognitive data. Analyses of parameters of metabolic function and inflammation began at MDC Berlin in November 2016 and will be brought to completion by March 2017. Finally, to prepare its own statistical analyses of BioCog data, WP3 has conducted four systematic reviews and meta-analyses on metabolic and cognitive predictors of POCD since project start. All have been published in peer-reviewed journals and have added to the international visibility of the BioCog consortium. Overall, with exception of biobanking of biomaterial of the total N=1200 sample, which has not been possible due to delays with patient recruitment, WP3 is on track with its assigned tasks and is ready to begin dissemination of findings on the interim sample.

WP4: several options for effective communication were evaluated by the Bioinformatics Center Luxembourg. Together with the other partners of the consortium, it was decided to build the extension into the project web site (internal data exchange platform).
In Luxembourg, the first draft of the knowledge map was realized by text-mining and manual curation and published in the form of review focussing on the systemic effects of POD and POCD. The extensive text mining for the POD-, POCD-associated molecules improved the initial knowledge map.
The second revision included results from the updated in-house textmining tool, that together with the manual curation provided a revised version of the POD and POCD knowledge maps.

WP6: development of the project visual identity and logo, web site, flyers by Alta together with the coordinator (Charité), Health and Technology Assessment(HTA) by Cellulogic GmbH together with the Depts. of Anesthesiology (Charité/Utrecht).

Potential Impact:
The BioCog project will have a deep impact on the development of effective imaging tools for diagnosis, monitoring and management of mental disorders, in particular on POD/POCD. Given the tremendous unmet need for clinical management of POD/POCD, particularly in patients with multimorbidity, the improvement of clinical management would constitute a glimmer of hope for all those who are afflicted, their family members and society as a whole.
The multivariate expert system based on neuroimaging and molecular biomarkers is expected to allow the identification of patients at risk for POD/POCD with high sensitivity. At the same time, molecular biomarkers will allow stratification of patients at risk for POD/POCD with regard to specific molecular pathologies.
As a direct consequence, clinical management could be improved by supporting decision-making before a surgical intervention: i.e. balancing the risks (incl. POD/POCD) against the benefits of a surgical intervention, particularly in older patients. If a surgical intervention is unavoidable, subtyping of risk patients would enable clinicians to minimize risk factors for developing POD/POCD, for instance by avoiding or replacing drug treatments/anesthetics with anticholinergic side-effects (older patients often receive multiple treatments with anticholinergic components) or by moderate perioperative glucose control, should these risk factors be identified as predictive of POD/POCD in BioCog.
In addition, development of new drugs would be facilitated: in clinical drug development, biomarker-based stratification of patients would improve testing of drugs with specific mechanisms of action. Predictive biomarkers could also be translated back to pre-clinical studies and facilitate the development of animal models for drug testing.
Accordingly, a successful expert system for POD/POCD accompanied by a solid reference database could become a software-based “medical device” with great market potential.
The study is also expected to promote our knowledge on the pathophysiology and molecular basis of POD/POCD, in particular on the role of the cholinergic-inflammatory pathway, glucose control and vascular disease in POD/POCD patients. Along this line, we also expect that our project will help clarify the intimate relationship between AD and POD/POCD.
A highly valuable database of POD/POCD patients incl. biobank will be created that will be unique in the world. This database could also be used to address scientifically and clinically relevant questions that are not directly related to but go far beyond the role of the cholinergic-inflammatory system or glucose control in POD/POCD patients.
Additional value is generated for both the involved SMEs and academia: the newly established biomarkers can be used by scientists to address research questions more accurately and future drug development can be greatly supported. This is because the proven capability to conduct high-end, biomarker-enhanced clinical studies is a major asset when it comes to attracting clinical trials with novel compounds from the major players in R&D pharmaceutical industry. The development of an infrastructure for using biomarkers in clinical studies creates a clinical research environment which is truly “translational” and which is therefore attractive to all R&D departments for testing novel drug candidates, in particular when this kind of infrastructure is combined with a (professional) clinical phase-I/IIa set-up. At present, only few places in Europe display this kind of infrastructure. Sophisticated biomarker-enhanced clinical studies should therefore help to provide Europe with a competitive edge in attracting clinical studies/trials and also in the biomarker industry which is one of the most rapidly growing market segments in biopharmaceutical industry: biomarker industry was worth over $13 billion in 2011 and its value is expected to double over the next 5 years.

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