MES-CoBraD Scientific Objectives progress

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During the first 18 months of the MES-CoBraD project, we have collectively defined a harmonized multidisciplinary precision medicine protocol for assessing CoBraD, the parameters to verify quality control in the acquisition of RWD, their abstract representation, verified quality of obtained data through protocol test runs, and obtained IRB approvals and registered the study within, under the regular feedback of an Expert Advisory Board and local Stakeholder engagement meetings, while also accounting for Sex and Gender sensitive requirements within our consortium. Through this process, we have collectively acquired prospective data through this comprehensive assessment protocol from 171 participants in these first 18 months, far surpassing the KPI of 120 participants by the M18 mark. Individual partners have leveraged these additional data and their own expertise to produce scientific results related to CoBraD, while also collaborating through specialty Work Groups across types of RWD, CoBraD, and SciSci that define novel hypotheses and methodologies to test their hypotheses.

Scientific Objective 1: Improvement of early, accurate, and comprehensive diagnosis of CoBraD through the multisource-multidisciplinary MES-CoBraD Assessment Protocol

During the first 18 months of the study we have established a novel time-effective, and probably cost-effective diagnostic protocol for assessing CoBraD across domains of cognitive, sleep, and seizure disorders, ranging from daily RWD applied in clinic or at home. This already indicates a faster and earlier process of diagnosing people with CoBraD and allowing for deep phenotyping their presentation in a comprehensive manner. Published results from group members funded through the MES-CoBraD project have already revealed a number of findings in CoBraD. Specifically, (a) different episodic memory measures are associated with cortical atrophy in specific brain regions in adults with Down syndrome and Alzheimer’s disease, (b) MRI cortical mean diffusivity is a promising and sensitive biomarker for assessing neurodegeneration-related microstructural changes in primary progressive aphasia, (c) there are 577 genes whose expression is associated with the spatial spreading of tau in neurodegenerative disorders (topological vulnerability), including APOE and glutamatergic synaptic genes, such as SLC1A2, supporting specific drug development strategies targeting the gradient expression of this set of genes.

Scientific Objective 2: Improve clinical and social outcomes prognostic accuracy of CoBraD through the MES-CoBraD Advanced Analytic deep-phenotyping algorithms

With regards to prognostic objectives, (a) members of the MES-CoBraD Consortium have identified that pGFAP and pNfL levels differ in Frontotemporal Dementia and Alzheimer’s Disease, and their combination is useful for distinguishing between the two. Importantly, also, pGFAP is helpful to track disease severity and predict greater cognitive decline during follow-up in patients with FTD, a marker we have been lacking until now. Additionally, (b) our members identified that MRI-based cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration, and clinical progression, a feature that can be useful in real world trials. Finally, (c) analyzing cognitive data from people with Down syndrome, scientific analyses support the need for population health plans to screen for AD-related cognitive decline from the fourth decade of life and provide longitudinal data to inform clinical trials in adults with DS to prevent AD.

Scientific Objective 3: Identify novel purposes and evaluate safety and efficacy of approved therapies in CoBraD through the MES-CoBraD Platform’s Advanced Analytics modules

With regards to protocols that assess therapeutic intervention efficacy and safety in CoBraD, we have identified that (a) Cognitive Behavioral Therapy for Insomnia is helpful in improving insomnia in people with Mild Cognitive Impairment, while at the same time allowing for tapering of central nervous system sedatives. We are actively pursuing in follow up assessments whether it also helps in delaying cognitive decline over time.

Scientific Objective 4: Implement an effective clinical management Expert System algorithm for CoBraD that is well-tolerated and accepted by patients and their caregivers

During the first 18 months of the project, we have provided technical partners with the scientific operations that an Expert System is required to perform for guiding the Assessment and Management of CoBraD. This is a representation of methodological operations identified in our hypothesis testing protocols (D4.2, D4.3) and whose high-level outputs are assessed through a defined validation framework and end-user feedback, including test-case executions, to examine if Platform modules are assessed as-intended. We anticipate, as planned from the start of the project, to start assessing this key objective from M24 onwards.