Cycle 1 project 5

Identifying biomarkers for age-associated and neurodegenerative diseases


PhD student: Jordan McAfoose, United States of America
Home Institute: Neuroscience Center Zürich; Principle Investigator: Roger Nitsch
Host Institute: Amsterdam Neuroscience; Principle Investigator: Philip Scheltens

Executive Summary
Rapid progress towards understanding the molecular and cellular pathology of neurodegenerative disorders, such as Alzheimer’s disease, is revolutionizing drug discovery and clinical diagnosis/prognosis[1][2]. However, there is still an urgent need for biomarkers to diagnose neurodegenerative disorders, especially early in their course, when therapy is likely to be most effective, and to monitor responses of patients to new therapies. Immune and inflammatory factors are important biomarker candidates as accumulating evidence indicates that immune/inflammatory processes contribute to, or at least influence, the pathogenesis and progression of neurodegenerative diseases[3]; the central scientific aim of (Jordan McAfoose’s) PhD research that combines both clinical screening and translational animal experimentation. This project, therefore, represents the clinical part of his PhD which also integrates mechanistic research using an AD animal model.

The use of human brain tissue from brain banking centres remains a crucial aspect of brain research that promises to provide new insight into the still many open questions in neuroscience; especially in light of the increasing incidence of brain diseases associated with the global aging population[4]. The opportunity to collaborate with Professor Scheltens – director of the Alzheimer center and codirector of the Programme Neurodegeneration – in association with the Neuroscience campus Amsterdam, Vrije Universiteit Amsterdam will allow Jordan to expand his PhD project (preliminary data discussed below) and represents one aspect by which the EU Erasmus Mundus Joint Doctoral Program is creating opportunities for early career neuroscientists to conduct essential research on topical neuroscience questions using state-of-the-art facilities with access to precious human samples and clinical resources. Equally important, this program will provide him with the opportunity to work alongside leading researchers/programs in neuroscience throughout Europe, along with, the opportunity to develop further competency in neurodegenerative diseases, translational medicine and neuroscience.

This unique clinical screening approach, that combines both human postmortem brain tissue analysis and serum/CSF analysis, directly addresses the global effort to identify and develop successful biomarkers for age-associated and neurodegenerative diseases. Moreover, the outcomes of this project would significantly contribute to the understanding of immune and inflammatory processes underlying aging, MCI and AD; which based on several points of evidence is of high biomedical importance, including
1. the increasing realization that neuro-immune processes serve essential roles in brain development, function, plasticity and repair;
2. discoveries that naturally occurring immune responses against brain-resident misfolded proteins in human subjects serve a protective function, along with, the advent of immune-therapies for the treatment and prevention of neurodegenerative diseases, and
3.  that with age, mechanisms of immune senescence progressively impair functions of immunity and tolerance, possibly leading to decreased ability to protect against neurotoxicity along with a heightened inflammatory response to toxic misfolded proteins.

Lastly, by combining this clinical screening project and the cognitive-behavioral assessment and molecular and cellular characterization of an AD mouse model, we take an indispensable step in the translational research processes to bring information from the clinic to the lab and back again.

[1] Perrin RJ, Fagan AM and Holtzman DM (2009). Multimodal techniques for diagnosis and prognosis of Alzheimer’s disase. Nature. 461, 916-922.
[2] Shaw LM, Korecka M, Clark CM et al., (2007). Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics. Nature Reviews Drug Discovery. 6, 295-303.
[3] McAfoose J, Hock C and Nitsch RM (in submission). Role of Immunity against Misfolded Proteins in Neurodegeneration. Trends in Neuroscience.
[4] Kretzschmar, H. (2009). Brain banking: opportunities, challenges and meaning for the future. Nature Reviews Neuroscience. 10, 70-77

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