Investigating the mechanisms of altered cortical excitability in frontotemporal dementia and amyotrophic lateral sclerosis

Award Number
Status / Stage
3 October 2022 -
2 October 2025
Duration (calculated)
02 years 11 months
Wellcome Trust
Funding Amount
Contracted Centre
King's College London
Principal Investigator
Miss Caoimhe Goldrick
WHO Catergories
Understanding risk factors
Understanding Underlying Disease
Disease Type
Frontotemporal Dementia (FTD)

CPEC Review Info
Reference ID283
ResearcherReside Team


Award Number226840/Z/22/Z
Status / StageActive
Start Date20221003
End Date20251002
Duration (calculated) 02 years 11 months
Contracted CentreKing's College London
Funding Amount£0.00


Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are progressive diseases of the central nervous system that form a neurodegenerative spectrum. While seemingly diverse in clinical, pathological, and genetic presentations, there is significant overlap between the diseases, particularly in genetic landscapes. Among the most commonly shared genetic alterations in FTD and ALS are TDP-43 pathology and C9orf72 hexanucleotide repeat expansion (C9orf72RE). Increasingly, abnormal cortical and motor neuron excitability is described here, with such disruptions thought to drive early pre-clinical pathology.

I will investigate pathways driving altered cortical excitability by identifying and examining functional consequences of aberrant splicing events in hiPSC-neuronal circuits models with TDP-43 and C9orf72RE patient genotypes. Our approach is advantageous as we will collate previously published datasets to bioinformatically identify promising candidate abnormal splicing events, like those impacting neuronal excitability. Furthermore, I will establish the functional consequences of altered splicing by assessing neural activity in hiPSC-neuronal networks with electrophysiology and imaging methods.

This research will further our understanding of early pathways leading to altered cortical excitability in FTD and ALS. With no cure and limited therapies, exploring early pathological events, such as abnormal tuning of neural activity, could identify new disease biomarkers and targets for early therapeutic intervention.