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Boston Children's Hospital

Judith Steen, PhD | Massachusetts, United States

Boston Children's Hospital

Judith Steen, PhD | Massachusetts, United States

Quantitative Profiling of Proteopathy-associated Proteins and their Fragments in Blood to Diagnose AD and FTD and to Monitor Treatment Response

Clinical diagnosis of various dementias including Alzheimer’s Disease (AD) and FrontotemporalDementia (FTD) often occurs late during the progression of disease andrelies on the clinical documentation of cognitive decline. However,neurodegeneration starts decades prior to diagnosis. Thus, the earlierdetection of these diseases could lead to better assessments of therapeutics inclinical trials and outcome for patients. Many clinical trials have failedpartly because the patient population participating in clinical trials haveadvanced dementia and do not respond at this late stage, and/or the treatmentresponse cannot be well quantified using existing methods. While CSF is aproximal body fluid, this fluid is not collected routinely. Focusing on accessiblebody fluids such as blood would be ideal as such samples are collected duringan annual physical.

The objectiveof this proposal is to provide blood-based diagnostic biomarkers to diagnose ADand FTD to enable objective evaluation of therapeutic approaches. Suchperipheral biomarkers will have a major impact on diagnosing, managing andtreating these diseases as: i) better differentiation of various neurodegenerativedisease to guide clinicians into appropriate treatment strategies; ii) aidingin the development of efficacious drugs as treatment effectiveness can bemonitored; and iii) providing clinicians with critically needed tools to stageAD and FTD and to follow individual treatment response.

In this proposal, we will focus on blood-based fragments ofTau and TDP43 – two proteins implicated in proteopathic neurodegenerations suchas AD or FTD. The choice of such protein fragments is supported by three observations:firstly, we detected such fragments only in the fractions from tauopathysamples. Secondly, we identified disease-specific increased abundances of severalproteases, which give rise to these fragments, in samples from tauopathypatients. Thirdly, several of these proteolytic events were also observed on Tauin CSF.