In vivo neuroimaging of synaptic density in Lewy body diseases and its relationship to structural, functional, and molecular markers

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Lewy body diseases refers collectively to are a highly heterogenous group of neurodegenerative disorders that include Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). The pathological hallmark of such diseases are intracellular proteinaceous inclusions formed primarily of misfolded and aggregated forms of α-synuclein, thus these diseases are primarily classified as synucleiopathies. Progress over the last two decades has disclosed compelling evidence that synapse loss and dysfunction is a key feature in Lewy body diseases, thus they have also been termed ‘synaptopathies’. However, until relatively recently, all approaches for synapse quantification in the human brain have relied heavily on the examination of brain tissue from autopsy or surgical resection. The recent development of the novel positron emission tomography (PET) radioligand [11C]UCB-J has now made it feasible to quantify synaptic density in vivo since [11C]UCB-J is a synapse-specific radioligand that binds to ubiquitously expressed synaptic vesicle glycoprotein 2A (SV2A).

Recent studies have demonstrated that both PD and Lewy body dementia exhibit a reduction of SV2A as measured by [11C]UCB-J PET. However, further investigation is required to determine whether SV2A is sensitive to disease chronicity and whether this marker of synaptic density is related to alterations in grey matter volume and brain perfusion. Furthermore, whilst localised alterations of SV2A provides useful information about the spatial location of such alterations, the potential neurophysiological mechanisms underlying these observations is currently unexplored in Lewy body disease.

In this thesis, a series of cross-sectional studies were performed in modestly sized cohorts of drug-naïve PD patients, medicated PD patients and healthy controls (Chapter 3) and medicated PD, PDD and DLB patients and healthy controls (Chapter 4). [11C]UCB-J PET was employed with high resolution PET to evaluate localised alterations of synaptic density in these subjects. Quantitative measures of T1-weighted Magnetic Resonance Imaging (MRI) and Arterial Spin Labelling (ASL) within the same participants allowed for an assessment of grey matter volume and perfusion alterations and how these measures relate to synaptic density. The clinical relevance of [11C]UCB-J was evaluated by delineating its associations with motor and non-motor symptoms, as well as cognitive performance. To gain an insight into the potential biological mechanisms contributing to alterations in SV2A, spatial correlation analyses were conducted between the spatial distribution pattern of group-level alterations in SV2A expression and the canonical distribution of neuromodulatory neuroreceptors and transporters derived from healthy control PET and SPECT maps. The spatial distribution patterns of group-level grey matter volume and perfusion alterations were also integrated in these analyses.

Here, synaptic density was clearly reduced in early, symptomatic stages of PD, concomitant with negligible reductions in grey matter volume. On the other hand, and consistent with the notion that dopamine replacement therapies may promote neuroplasticity, medicated PD patients exhibited comparable SV2A concentrations to healthy controls and increased compared to drug- naïve PD patients. In Lewy body dementia, more extensive reductions of SV2A were present in PDD, characterised predominately by frontal and parietal involvement, whilst DLB exhibited a more widespread reduction of SV2A across the cortex and subcortex. Notably, synaptic density reductions were not simply explained by volumetric reductions as demonstrated in the dementia cohorts, although volumetric alterations exhibited limited confounding effects. Across all Lewy body disease cohorts, there was a general discordance between hypoperfusion and synaptic density reductions. Finally, the spatial distribution pattern of SV2A alterations were explained, in part, by discrete neurophysiological markers at each stage of the disease, with the dopaminergic system predominately most consonant at early stages but becoming less consistent with SV2A distribution as the disease progressed to dementia where instead grey matter volume was more closely associated.

Overall, this thesis provides some preliminary insight regarding synaptic density alterations across Lewy body diseases, and the potential neurophysiological properties that may be contributing to these alterations at different stages of the disease. These findings also contribute, albeit in an indirect manner, to the utility of [11C]UCB-J as a specific marker of synaptic protein SV2A.
Date of Award1 Oct 2022
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorMitul Mehta (Supervisor) & Owen O'Daly (Supervisor)

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