"Finding tools to assess synaptic health in frontotemporal dementia will be key to helping in its diagnosis and the development of clinical trials. With the backing of the UK DRI, I will be able to develop a method to measure synaptic health during life that will help us to better understand and treat this devastating disease." Aitana Sogorb-Esteve
UK DRI Emerging Leader
Dr Aitana Sogorb-Esteve is a UK DRI Emerging Leader with a prestigious Race Against Dementia (RAD) Fellowship – jointly sponsored by Prof Jonathan Rohrer (Dementia Research Centre, UCL) and Group Leader Prof Henrik Zetterberg (UK DRI at UCL). Dr Sogorb-Esteve completed a degree in biology at the University of Alicante, her hometown in Spain; followed by a masters and a PhD in neuroscience at the University Miguel Hernandez de Elche (Spain). She has worked at the UK DRI at UCL for the past three years where she has mainly focused on the study of novel fluid biomarkers for Alzheimer’s Disease, such as those related to pathology or neuroinflammation. Most recently, Dr Sogorb-Esteve has been working as a postdoctoral researcher in Prof Jonathan Rohrer's lab at the Dementia Research Centre at UCL studying fluid biomarkers in Frontotemporal Dementia (FTD) as part of the Genetic FTD Initiative (GENFI). In her RAD Fellowship project, Dr Sogorb-Esteve will work to identify biomarkers to assess synaptic dysfunction in FTD, with the aim of developing a method to measure these synaptic markers in blood samples and improve diagnostics for the disease.
1. At a glance
Frontotemporal dementia (FTD) is a condition affecting the brain that can result in changes in behaviour, language, and/or movement. These symptoms are caused by nerve cells in the brain becoming dysfunctional and dying over the course of the disease. Synapses are the connections between nerve cells which are essential for electrical messages to travel and the brain to function correctly. However, little is known about how synapses are affected in FTD.
Dr Aitana Sogorb-Esteve is investigating what goes wrong in synapses during FTD by studying the proteins that are found within them. As well as measuring these proteins in cerebrospinal fluid that surrounds the brain, using a method called mass spectrometry, she is developing a new protocol to measure these proteins in the blood, which is more easily acquired. This involves extracting particles called extracellular vesicles that enter the blood from the brain and using mass spectrometry to measure the level of synaptic proteins inside them.
Dr Sogorb-Esteve’s UK DRI programme is using a large set of samples from the Genetic FTD Initiative, allowing a greater understanding of how synapses change from the pre-symptomatic through to the symptomatic stages of the disease. Beyond providing important insight into the mechanisms of disease, developing such markers will be useful for future trials, potentially indicating if synaptic function has been restored after treatment.
2. Scientific goals
Frontotemporal dementia (FTD) is a heterogeneous disorder associated with dysfunction and neuronal loss in the frontal and temporal lobes of the brain. Approximately a third of FTD is genetic with the most common causes being mutations in the C9orf72, GRN or MAPT genes. Whilst there are different symptoms and biological pathways associated with the different mutations, synaptic dysfunction is a common mechanism observed across all forms.
Fluid biomarkers from cerebrospinal fluid (CSF) or blood could help identify synaptic dysfunction in people with FTD, but, so far, the markers used have not been deeply studied or validated. Developing synaptic measures has the potential to improve the diagnostic accuracy in FTD, as well as provide a readout of cellular dysfunction during therapeutic trials.
In this UK DRI programme, Dr Aitana Sogorb-Esteve is identifying synaptic proteins in CSF and blood samples. She is isolating these proteins from extracellular vesicles released from neurons and immune cells in the brain, including microglia and astrocytes. Dr Sogorb-Esteve will then identify which of these synaptic proteins can be detected in a large fluid biomarker sample from the Genetic FTD Initiative (GENFI), a cohort study of people with pre-symptomatic and symptomatic genetic FTD, with the aim of developing a diagnostic tool. Any biomarkers identified could be used as outcome measures that indicate if synaptic function has been restored in clinical trials.
Main objectives and research goals:
1. Develop and optimise a protocol for the extraction, enrichment and characterisation of neuronal-, astrocytic- and microglial-derived extracellular vesicles from CSF and blood.
2. Screen the proteins in extracellular vesicles using mass spectrometry.
3. Analyse the same mass spectrometry panel using a large fluid biomarker sample set from GENFI.
4. Develop individual or multiplexed immune-based assays for translation to the clinical laboratory.
3. Team members
Imogen Swift (PhD candidate)
Katie Thompson (Research assistant)
Within UK DRI:
- Prof Chris Shaw, UK DRI at King’s College London
- Prof Adrian Isaacs, UK DRI at UCL
Beyond UK DRI:
- Prof Matthis Synofzik, Hertie-Institute for Clinical Brain Research & Center for Neurology, University of Tübingen, Germany.
- Prof Markus Otto, Universitätsklinik und Poliklinik für Neurologie am Universitätsklinikum Halle, Germany.
- Prof John van Swieten, Erasmus University Medical Centre Rotterdam, Netherlands.
- Prof Caroline Graff, Karolinska Instituet, Sweden.
- Prof James Rowe, Cambridge Centre for Frontotemporal Dementia, UK.
- Prof Jesmond Dalli, The William Harvey Research Institute – Barts and The London, Queen Mary University of London, UK.
Frontotemporal Dementia (FTD), genetic FTD, fluid biomarkers, exosomes, clinical trials
Exosome extraction development, proteomics, mass spectrometry, immunoassays
7. Key publications
Sogorb-Esteve A, Colas RA, Dalli J, Rohrer JD. Differential Lipid Mediator Involvement in the Different Forms of Genetic Frontotemporal Dementia: Novel Insights into Neuroinflammation. J Alzheimers Dis. 2021 Sep 15. doi: 10.3233/JAD-210559. Epub ahead of print. PMID: 34542074.
Swift IJ, Sogorb-Esteve A, Heller C, Synofzik M, Otto M, Graff C, Galimberti D, Todd E, Heslegrave AJ, van der Ende EL, Van Swieten JC, Zetterberg H, Rohrer JD. Fluid biomarkers in frontotemporal dementia: past, present and future. J Neurol Neurosurg Psychiatry. 2021 Feb;92(2):204-215. doi: 10.1136/jnnp-2020-323520. Epub 2020 Nov 13. PMID: 33188134.