Title: From neurotransmitters to cognition: The neurochemical mechanism of semantic cognition in frontotemporal dementia
Funder: The Academy of Medical Sciences

Abstract: Semantic cognition refers to our ability to use, manipulate, and generalize knowledge and plays a critical role in verbal and nonverbal communication and daily activities. Therefore, impairments in semantic cognition can have a severe impact on quality of life (e.g. dementia). Frontotemporal dementia (FTD) is the cause of 12.5-16.5% of all degenerative type dementias. FTD defines a heterogeneous group of clinical syndromes marked by the progressive, neurodegeneration of the frontal and temporal lobes – key regions of semantic cognition. However, the clinical and genetic features are heterogeneous and there is still no treatment available for these conditions. Recent changes in the clinical and pathological characterization of the major clinical syndromes caused by FTD give anatomical and pharmacological insights that require to reverse neurotransmitter deficits including glutamate and GABA. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which arise from common deficits of major neurotransmitters such as GABA and glutamate – ‘GABA and glutamate hypothesis of FTD’. My research proposal tackles this hypothesis, by linking GABA and glutamate changes with semantic deficits in patients with FTD. The proposed research has two objectives: 1. To probe how dysfunctional neurotransmitter systems in patients with the FTD is associated with their impaired semantic function 2. To explore the effect of neuromodulation as a potential therapeutic tool in semantic cognition My research contributes to knowledge of the neurotransmitter system as potential imaging biomarkers in diagnosis of FTD and the application of neuomodulation as a potential therapeutic tool for patients with FTD.

Lay abstract: Frontotemporal dementia (FTD) is the second most common form for individuals 65 years and younger characterised by progressive focal neurodegeneration in frontal and temporal lobe. Although FTD are highly variable, they share many behavioural, cognitive and physiological features, which arise from common deficits of major neurotransmitters such as GABA and glutamate. Yet, there is a shortage of research to elucidate its underlying mechanisms and there is no standard pharmacological intervention for the treatment of FTD. GABA and glutamate are major neurotransmitters in the brain, which play a key role in shaping cognitive functions. Therefore, it is paramount to understand the neurotransmitter systems in the FTD and then to use this knowledge to improve pharmacological treatments and clinical management in the FTD. The aim of this award is to use cutting-edge methodologies - multimodal imaging (structural, functional, and neurochemical imaging) and brain stimulation to make significant and fundamental advances in early diagnosis as well as laying the essential foundations for future therapeutic interventions to prevent or mitigate FTD. The research will include two work packages in which I will look at: 1. GABA and glutamate alterations in FTD contributing to behavioural and cognitive impairments 2. the effect of brain stimulation as a potential therapeutic tool to improve cognitive function My proposed research will contribute to knowledge of the neurotransmitter system as potential imaging biomarkers in early diagnosis of FTD and the application of brain stimulation as a potential therapeutic tool for FTD - the development of evidence-based brain stimulation treatment.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL