Samra, Kiran; (2025) Defining the stages of frontotemporal dementia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Frontotemporal dementia (FTD) is a heterogeneous disorder characterised by progressive changes in behaviour, language, cognition and motor function. Autosomal dominant inheritance is seen in over a third of individuals, including chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) and microtubule-associated protein tau (MAPT) mutations. This group was studied to detect early changes in symptom severity, neuropsychometry, MRI and neurofilament light chain (NfL), to define the FTD phenotype and disease progression. This informed selection of items into an FTD scale able to stage disease, monitor progression and provide outcome measures for clinical trials. Results highlighted that, of the genetic groups, GRN was most affected by the language variant, Primary Progressive Aphasia (PPA) and shared features with sporadic PPA. A distinct GRN PPA subtype was also identified. Additionally, language features were seen in behavioural variant (bv) FTD, and before overt FTD. Early neuropsychiatric and motor features were identified and subsequently incorporated into an existing FTD severity scale to capture the whole phenotypic spectrum. This led to the reclassification of unaffected individuals, including those with an FTD diagnosis inappropriately classed as asymptomatic, as affected. Key differences between genetic groups were identified in all the FTD measures so disease progression modelling using Event-Based Modelling (EBM) and Ordinal Subtype and Stage Inference (SuStaIn) to order biomarker changes focused on each genetic group. Ordinal SuStaIn identified phenotypes based on symptom severity scores, supported by the EBM and work in prior chapters: C9orf72 bvFTD, bulbar and limb amyotrophic lateral sclerosis subtypes; GRN PPA and bvFTD-parkinsonian subtypes; and a MAPT semantic-behavioural-parkinsonian subtype. Accounting for key findings, Rasch analysis was used to develop a FTD-specific clinimetric symptom rating scale, to improve measures both clinically and in clinical trials. Untangling the heterogeneity of this disorder and providing a way to accurately measure change are crucial steps towards individualised care.

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