Analysis of Mitochondrial Imaging Biomarkers in Neurodegenerative Disease

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Neurodegenerative disorders affect millions of people in the UK and it is estimated that dementia alone costs the economy £23 billion a year1. The heterogeneous aetiologies and differing clinical courses of these disorders have rendered the clinical evaluations of the effects of existing drugs largely inadequate for successfully monitoring treatment response. These difficulties are compounded by the fact that the underlying pathophysiology of neurodegenerative disease is multifaceted and varies across disease types. A growing body of evidence suggests that cellular stress induced mitochondrial and endoplasmic reticulum (ER) dysfunction is a common denominator that contributes to synaptic abnormalities and, ultimately, to selective neuronal degeneration across all neurodegenerative diseases. A more comprehensive understanding of the mitochondrial/ER/synapse pathophysiology can be accomplished by developing molecular imaging tools that will serve as markers of progression, in turn enabling early diagnosis and monitoring of disease progression.

There are three molecular targets within the mitochondrial/ER/Synapse axis that have been identified to play a role in neurodegenerative disease pathophysiology. Novel PET radioligands are available to quantify the density of each of these molecular markers, making them an attractive target system for neuroimaging studies of disease progression. Mitochondrial Complex 1 (MC1) is the largest enzyme supercomplex in the mitochondrial electron transport chain (ETC), and has been shown to have impaired function in neurodegenerative disease leading to cell damage and accelerated aging2,3,4,5. Another mitochondrion-associated molecule of interest, Sigma 1 receptor, is a non-opioid receptor that is a molecular marker for the mitochondrion-associated ER membrane (MAM) 6. It plays a significant role in enabling Ca2+ flow from the ER to mitochondria during ATP production, and is associated with dendritic spin arborisation6,7. Importantly, rodent studies have shown o1R increases to predate the appearance of plaques8. The third molecular marker,
synaptic vesicle protein 2a (SV2A), is a transmembrane protein that is critical to synaptic function and has been established as an excellent molecular target for measuring synaptic loss in neurodegenerative disease.

In conjunction with Dr Ilan Rabiner (Imanova and Kings College), I have secured funding (>£1M) through a consortium including the MRC, Imperial College and pharmaceutical companies to acquire human PET & MRI data in in normal ageing, Parkinson's and Alzheimer's disease with these three tracers as part of the MIND MAPS program (Molecular Imaging of Neurodegenerative Disease - Mitochondria, Associated Proteins & Synapses).

Data acquisition will commence in Q1 2017 and will enable the measurement of signal in normal ageing, Parkinson's and Alzheimer's disease. This study will complete by Q4 2019 and will provide a proof-of-principle for the utility of this approach to monitor neurodegenerative pathophysiology. However, what is not yet funded is a PhD student to develop appropriate analytical methods and apply them to the MIND MAPS clinical imaging data. The EPSRC PhD studentship would provide the ideal opportunity to deliver the required analytical advances and their application to these data. This project provides a high degree of novelty and forms an ideal PhD.

Publications

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Mansur A (2020) Test-retest variability and reference region-based quantification of F-BCPP-EF for imaging mitochondrial complex I in the human brain. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Mansur A (2020) Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: F-BCPP-EF, C-SA-4503, and C-UCB-J. in Journal of nuclear medicine : official publication, Society of Nuclear Medicine

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Wilson H (2020) Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease. in Movement disorders : official journal of the Movement Disorder Society

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509486/1 01/10/2016 31/03/2022
1965868 Studentship EP/N509486/1 02/05/2017 31/10/2020 Ayla Mansur