A high-resolution assessment of human Motor Neuron Disease and its association with clinical presentation

  • Anna Sanchez Avila

    Student thesis: Doctoral ThesisDoctor of Philosophy


    Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease and affects up to 5000 people a year in the UK. Unfortunately, it is a fatal neurodegenerative disease, with an average lifespan of 3 years after diagnosis. Even though ALS is characterised by its progressive paralysis, half of people with ALS also develop cognitive impairment. Those who are cognitively impaired tend to have a worse prognosis and a faster developing disease. The mechanisms underlying cognitive impairment are still not known, but unravelling the drivers of this dysfunction could prove crucial to the people living with ALS. Previously, factors such as synapse loss, presence of protein aggregates and inflammation have been associated with cognitive decline, but their regional specificity and correlation with the presence of symptoms remains to be assessed.

    The main aim of this project was to generate a database of comprehensive patient information including detailed clinical cognitive profiling, post-mortem high-resolution synapse density measurements as well as pathology presence and astrocytic and microglial burden. I believe this study is the first of its kind, given all these factors have been assessed in the same group.

    Moreover, molecular biology techniques as well as high-resolution and super-resolution microscopy techniques have been used to assess the synaptic localisation of ALS-associated proteins TDP-43 and FUS. I believe this study provides the first evidence of the synaptic presence of TDP-43 and FUS in the human synapse in post-mortem tissue.

    In summary, this project provides a unique human dataset combining detailed cognitive assessment, regional neuropathology, and single synapse analysis to try and uncover the underlying pathology associated with cognitive decline in ALS. It also provides evidence of the physiological synaptic presence of ALS-associated proteins, which could be crucial for the field, highlighting them as potential therapeutic targets.
    Date of Award2023
    Original languageEnglish
    SponsorsEuan MacDonald Centre for Motor Neurone Disease & Alzheimer's Research UK
    SupervisorChristopher Henstridge (Supervisor), Calum Sutherland (Supervisor) & Tara L Spires-Jones (Supervisor)

    Cite this