Cycle 5 project 4

Synaptic biomarkers for early diagnosis and monitoring of AD


P04-MadhurimaPhD student: Chatterjee Madhurima, India
Home Institute: Amsterdam Neuroscience; Principle Investigator: Charlotte Teunissen
Host Institute: European Neuroscience Institute Göttingen; Principle Investigator: Detlev Schild

Executive Summary

Alzheimer’s disease (AD) is the most common form of dementia, which imposes an increasing burden to society due to the aging population. Early diagnosis of AD is as yet hampered by the lack of sensitive and cost-effective tools. The cerebrospinal fluid (CSF) biomarkers amyloid beta(Abeta)1-42 protein, combined with tau and phosphorylated tau proteins are well established biomarkers for diagnosis of Alzheimer’s disease (AD) and have some value in early diagnosis of this disease (Blennow et al, Nat Rev Neurology 2010). However, blood-based tests are a prerequisite for repeated collection that is needed during screening and monitoring of progression and therapy responses. No such biomarkers are available yet for use in clinical practice of Alzheimer’s disease.

Novel discovery-based technologies, such as proteomics, can identify and quantify large numbers of peptides and proteins simultaneously. In a recent proteomics study comparing CSF of controls, MCI and AD patients, we successfully identified up to 30 several discriminatory biomarkers for early stages of AD [Chiasserini, submitted]. A specific subset of these biomarkers has a relation with synaptic function, which is of interest as synaptic dysfunction is the pathological correlate of the earliest changes in cognition in AD, and maybe even the earliest neuronal deficit in AD brain tissue (Selkoe, Science 2012).
Several of the identified proteins are neurospecific, such as Bri2, Nell-2 proteins ed and are therefore interesting as potential neurospecific blood-based biomarkers. However, ultra-sensitive detection methods are an requirement for analysis of these biomarkers in blood, since the levels will likely be low, due to dilution effects inferred by peripheral organs. Fluorescence correlation spectroscopy (FCS)-based methods are ultra-sensitive technologies and hold great promise for brain-derived low abundant proteins in body fluids.
The aim of the current project is to further establish whether these synaptic biomarkers in body fluids reflect the earliest clinical of AD, and can be used for early diagnosis and monitoring of AD.

The FCS method, although extensively used in cell cultures studies but due to its high sensitivity potentially very powerful for biomarker detection, have not yet been applied for biomarker studies in body fluids. The study will provide a starting point for a novel, high sensitive, approach in the biomarker area. Moreover, we will study novel biomarker candidates, which were not yet related to AD or synaptic dysfunction so far.

Rationale of collaboration:
We will take advantage of expertise and available resources at the Alzheimer Center VUmc and the state of the art technological expertise at Gottingen. Specifically, the collaboration provides a unique opportunity for VUmc to gain access to FCS expertise necessary for the project aims. Furthermore, Uni Gottingen to obtain access to novel identified candidate biomarkers and clinical cohorts available in Amsterdam. Therefore, the project would not be possible by one of the centers separately.

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