The Resilient Brain. Imaging Biomarkers of Brain Metabolic Reserve
Lead Research Organisation:
Royal Veterinary College
Department Name: Comparative Biomedical Sciences CBS
Abstract
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Technical Summary
The great challenge of ageing research stays in its inherent time-scale where the ideal biomarkers are those that can qualify treatments at baseline without having to wait for the degenerative process to take place. Here we are concerned with brain ageing and focusing on metabolism as the brain has, by far, the highest energy demands of any organ based on its size. Importantly, the brain works at the border of its energy envelope as the majority of this energy is used to support neuronal activity and functional processes and is little affected by task performance. The metabolic reserve theory indeed proposes that a brain that is metabolic efficient is more resilient to declining cognition. It is now established that lifestyle determinants of metabolic reserve promote neuroprotection by increasing brain metabolic efficiency and creating an energetic buffer that can be used by the cell to fight pathology.
Mitochondria are fundamental to the maintenance of cellular health but with age they lose capacity for efficient ATP generation. Damaged mitochondria are generally cleared by mitophagy and protects from ageing-associated degeneration. This leads us to propose two in-vivo measures of brain metabolic reserve:
1) Cerebral Oxygen Metabolic Reserve obtained by measuring oxygen metabolism with quantitative BOLD MRI before and after administration of methylene blue (MB), an inducer of metabolic respiration already approved for use in man. The use of MB will allow us to tap into cellular energetic buffers that would not be otherwise accessed by experimental tasks (e.g. sensory stimulation).
2) Density expression of the 18K Translocator Protein (TSPO). TSPO is a mitochondrial protein with a fundamental role in mitochondrial quality control that in man is visualized using Positron Emission Tomography.
Measures will be validated in a longitudinal setting to determine their potential to predict cognitive resilience in well-characterized models of healthy ageing.
Mitochondria are fundamental to the maintenance of cellular health but with age they lose capacity for efficient ATP generation. Damaged mitochondria are generally cleared by mitophagy and protects from ageing-associated degeneration. This leads us to propose two in-vivo measures of brain metabolic reserve:
1) Cerebral Oxygen Metabolic Reserve obtained by measuring oxygen metabolism with quantitative BOLD MRI before and after administration of methylene blue (MB), an inducer of metabolic respiration already approved for use in man. The use of MB will allow us to tap into cellular energetic buffers that would not be otherwise accessed by experimental tasks (e.g. sensory stimulation).
2) Density expression of the 18K Translocator Protein (TSPO). TSPO is a mitochondrial protein with a fundamental role in mitochondrial quality control that in man is visualized using Positron Emission Tomography.
Measures will be validated in a longitudinal setting to determine their potential to predict cognitive resilience in well-characterized models of healthy ageing.
Planned Impact
This proposal focuses on the validation of two novel measurements of brain metabolic reserve to be used in the study of ageing and neurodegenerative disorders in animal and, in the future, human models. This project, if successful, will have substantial and lasting impact.
The increasingly large ageing population places great pressure on the HEALTH AND SOCIAL CARE SYSTEMS. Currently 16% of the European population is over 65, with this figure to reach 25% by 2030. Effective and predictive biomarkers are key to develop therapies and products aimed at improving lifelong health and wellbeing. Effective biomarkers will allow INDUSTRIES to effectively accelerate the development of products aimed at the ageing population market and enable REGULATORY AGENCIES to test the anti-ageing treatments that are now flooding the market. These include, for example, some poorly validated interventions such as improving antioxidant status and hormone replacement therapies, including growth hormone, testosterone, dehydroepiandrosterone, and melatonin (Butler et al, Journal of Gerontology: Biological Sciences, 2004, Vol. 59A, No. 6, 560-567).
It is easy to predict the immediate translation of these methodologies also to the study of neurodegenerative disorders. These are conditions that result in the progressive degeneration or death of nerve cells. They include Alzheimer's disease and other dementias, Parkinson's disease, Huntington's disease, motor neuron disease and multiple sclerosis. In the UK it has been estimated that dementia alone costs the ECONOMY £17 billion pounds a year, hence any effective development in this area will impact not only patients but also CARERS, HEALTH PROFESSIONALS and SOCIETY AT LARGE.
The methodologies proposed are destined to be used on MRI and PET scanners for animal and human use. If effective, they will expand their number and their use of these existing technologies in research, industry and in the clinic making them more economically viable. Hence they will have direct impact on MEDICAL DIAGNOSTICS INDUSTRIES (General Electric, Siemens, Phillips, Bruker etc.).
Importantly, by targeting in-vivo biomarkers of mitochondrial function, we are working in a largely un-explored area of the neurosciences. In the recent past, concerns have existed about the growing number of companies disinvesting from neuroscience research in the UK. This has negatively impacted JOBS in this area and the UK ECONOMY at large. The tide has been turning recently with companies with long heritage in brain research such as Lily, Johnson and Johnson, Lundbeck and GSK supporting innovative programmes such as One Mind for research (1mind4research.org) to create a united effort to advance translational research for mental health between GOVERNMENT, ACADEMIA and INDUSTRY. We are already part of one Wellcome supported consortium that unites the organizations above for a strategic award in the area of dementias and mood disorders, all related to ageing, where the need for effective markers of brain bioenergetics is strongly felt.
Finally, it is worth remarking the unique nature of the proposing team with members working in an original setting that stretches from cellular biology to pharmacology, brain energetics, physics, engineering, nuclear imaging and psychology. The scientists and RAs working in this project will have a unique opportunity to expand their KNOWLEDGE BASE from cell biology to cognition, increasing their SKILL-SET in unprecedented fashion. As academics we will be able to communicate the hopefully successful return of this investment to our student population and to the PUBLIC.
The increasingly large ageing population places great pressure on the HEALTH AND SOCIAL CARE SYSTEMS. Currently 16% of the European population is over 65, with this figure to reach 25% by 2030. Effective and predictive biomarkers are key to develop therapies and products aimed at improving lifelong health and wellbeing. Effective biomarkers will allow INDUSTRIES to effectively accelerate the development of products aimed at the ageing population market and enable REGULATORY AGENCIES to test the anti-ageing treatments that are now flooding the market. These include, for example, some poorly validated interventions such as improving antioxidant status and hormone replacement therapies, including growth hormone, testosterone, dehydroepiandrosterone, and melatonin (Butler et al, Journal of Gerontology: Biological Sciences, 2004, Vol. 59A, No. 6, 560-567).
It is easy to predict the immediate translation of these methodologies also to the study of neurodegenerative disorders. These are conditions that result in the progressive degeneration or death of nerve cells. They include Alzheimer's disease and other dementias, Parkinson's disease, Huntington's disease, motor neuron disease and multiple sclerosis. In the UK it has been estimated that dementia alone costs the ECONOMY £17 billion pounds a year, hence any effective development in this area will impact not only patients but also CARERS, HEALTH PROFESSIONALS and SOCIETY AT LARGE.
The methodologies proposed are destined to be used on MRI and PET scanners for animal and human use. If effective, they will expand their number and their use of these existing technologies in research, industry and in the clinic making them more economically viable. Hence they will have direct impact on MEDICAL DIAGNOSTICS INDUSTRIES (General Electric, Siemens, Phillips, Bruker etc.).
Importantly, by targeting in-vivo biomarkers of mitochondrial function, we are working in a largely un-explored area of the neurosciences. In the recent past, concerns have existed about the growing number of companies disinvesting from neuroscience research in the UK. This has negatively impacted JOBS in this area and the UK ECONOMY at large. The tide has been turning recently with companies with long heritage in brain research such as Lily, Johnson and Johnson, Lundbeck and GSK supporting innovative programmes such as One Mind for research (1mind4research.org) to create a united effort to advance translational research for mental health between GOVERNMENT, ACADEMIA and INDUSTRY. We are already part of one Wellcome supported consortium that unites the organizations above for a strategic award in the area of dementias and mood disorders, all related to ageing, where the need for effective markers of brain bioenergetics is strongly felt.
Finally, it is worth remarking the unique nature of the proposing team with members working in an original setting that stretches from cellular biology to pharmacology, brain energetics, physics, engineering, nuclear imaging and psychology. The scientists and RAs working in this project will have a unique opportunity to expand their KNOWLEDGE BASE from cell biology to cognition, increasing their SKILL-SET in unprecedented fashion. As academics we will be able to communicate the hopefully successful return of this investment to our student population and to the PUBLIC.
People |
ORCID iD |
Michelangelo Campanella (Principal Investigator) |
Publications
Beffagna G
(2017)
Circulating Cell-Free DNA in Dogs with Mammary Tumors: Short and Long Fragments and Integrity Index.
in PloS one
Casbolt H
(2022)
Ca2+ Signalling is a Conserved Game of Contact.
in Contact (Thousand Oaks (Ventura County, Calif.))
D'Ambrosio EM
(2017)
Clinical Features and Complications of the HLA-B27-associated Acute Anterior Uveitis: A Metanalysis.
in Seminars in ophthalmology
D'Eletto M
(2018)
Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75.
in Cell reports
Desai R
(2018)
MitoCPR: Meticulous Monitoring of Mitochondrial Proteostasis.
in Molecular cell
Desai R
(2019)
Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions.
in British journal of pharmacology
Desai R
(2020)
Mitochondria form contact sites with the nucleus to couple prosurvival retrograde response.
in Science advances
Di Rita A
(2018)
HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKa
in Nature Communications
Draper ACE
(2020)
Species-specific consequences of an E40K missense mutation in superoxide dismutase 1 (SOD1).
in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Description | The major findings from the work developed till now regard the parallel between mitochondrial import of cholesterol and oxysterols which are involved in neurodegenerative phenotypes. The work developed in the past year lead to a revolution in our understanding of intracellular pathways of communications based on the priming by cholesterol fluxes. Specifically it has been corroborated how the lipid, trafficked by TSPO, may become a signalling molecule key for the communication with the nucleus and hence by framing the retrograde response at the basis of cellular adaption to pathological cues. This is therefore applicable not just to the homeostasis of neuronal cells but to other cell types undergoing metabolic stress of hormonal nature leading to uncontrolled proliferation. Nonetheless cholesterol accumulates on specific points of contact between mitochondria and nucleus which establish a physical interaction between the two organelles which has never been reported before. To further characterize the impact of this novel signalling cascade on neuronal metabolic reservoir, we generated a TSPO KO SH-SY5Y cell line via CRISPR/Cas9-mediated genome editing, and carried out an RNAseq analysis to identify alterations in pathways regulating metabolic stress sensing and adaptation. Relevant infomations are now published. |
Exploitation Route | These are likely to deliver both an academic and applicative outcome. One major research paper is currently being finalised with the hope to see it published in this academic year and discussions with companies are currently ongoing to learn how to translate this into a deliverable bearing a positive impact to the society. |
Sectors | Chemicals Education Healthcare Pharmaceuticals and Medical Biotechnology |
URL | https://pubmed.ncbi.nlm.nih.gov/33664474/ |
Description | The understanding developed in bio-marking cellular aberration proved useful to inform novel approaches to detect early damage in mammalian cells.This is being refined to implement a method useful on large scale to detect toxicity and therefore to reduce attrition of medicinal products. |
First Year Of Impact | 2021 |
Sector | Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
Impact Types | Cultural Economic |
Description | 3i Case Panel Memmbership BBSRC London Interdisciplinary Biosciences PhD Consortium |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | BBSRC London Interdisciplinary Biosciences PhD Consortium |
Amount | £100,000 (GBP) |
Funding ID | Flirting In The Little Space: Homeostatic Regulation of The Mitochondria and Cytoskeleton Interplay via The Tubulin--Vdac--Tspo Pathway |
Organisation | Bloomsbury Colleges |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2016 |
End | 10/2020 |
Description | BBSRC Project Grant |
Amount | £450,000 (GBP) |
Funding ID | BB/N007042/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2016 |
End | 08/2019 |
Description | BBSRC iCase Studentship |
Amount | £150,000 (GBP) |
Funding ID | Bioactive targets of mitochondrial quality control and function. |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2016 |
End | 09/2020 |
Description | BBSRC-LiDo Studentship |
Amount | £105,000 (GBP) |
Funding ID | Imaging the Ageing Brain: Cellular and PET Tracing of the Neuroinflammatory Protein TSPO |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2014 |
End | 09/2018 |
Description | BBSRC-iCase Studentship |
Amount | £150,000 (GBP) |
Funding ID | Focusing on the mitochondrial expression of TSPO as a marker and promoter of neuroinflammation |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2015 |
End | 09/2019 |
Description | Form and Function of the Mitochondrial Retrograde Response |
Amount | £1,400,000 (GBP) |
Funding ID | European Research Council Consolidator Grant |
Organisation | European Research Council (ERC) |
Sector | Public |
Country | Belgium |
Start | 11/2019 |
End | 11/2024 |
Description | Is the Epigenetic clock accelerated by mitochondrial reprogramming via mtDNA heteroplasmy and deemed quality control? |
Amount | £120,000 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2019 |
End | 09/2023 |
Description | MedTech SuperConnector (MTSC) award cohort 3 |
Amount | £78,000 (GBP) |
Organisation | MedTech SuperConnector |
Sector | Private |
Country | United Kingdom |
Start | 11/2019 |
End | 05/2021 |
Description | MedTech SuperConnector (MTSC) award cohort 6 |
Amount | £5,400 (GBP) |
Organisation | MedTech SuperConnector |
Sector | Private |
Country | United Kingdom |
Start | 11/2021 |
End | 05/2022 |
Description | Research Grant |
Amount | £87,000 (GBP) |
Funding ID | Chemo-targeting of TSPO to validate Endocrine Therapy in Canine Mammary Tumours |
Organisation | Petplan Charitable Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2019 |
Title | Cancer Biomarker |
Description | We are devising a way via which we can score tumor stages in animals by checking TSPO expression |
Type Of Material | Biological samples |
Provided To Others? | No |
Impact | A potential way to image diagnostically tumor stage and progression via TSPO |
Title | Mitophagy Inducer |
Description | A new tool to physiologically activate mitophagy which we called PMI as working via the p62 pathway. |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | Mitochondrial quality control is a fundamental process in cellular homeostasis, and its deficiency is linked to several neurodegenerative diseases and cancers. Despite this, the discrete mechanisms, regulatory pathways, and impact oncellular physiology are still far from being elucidated. The current canonical methods to trigger mitophagy in vitro typically involve the abrupt depolarization of mitochondrial membrane potential (DYm) using ionophores such as carbonyl cyanide m-chlorophenyl hydraz |
Title | TSPO marking to detect mito-nuclear contact sites |
Description | TSPO is found to be required for the establishment of contact sites between mitochondria and nucleus, This has allowed us to enrol the protein to assess the frequency of these contacts. |
Type Of Material | Model of mechanisms or symptoms - in vitro |
Year Produced | 2018 |
Provided To Others? | No |
Impact | Impact is potentially multiple given the ground-breaking nature of the discovery and ability gained to map this interaction which bears implications for inter-organelles communication and core functions regulation. |
Description | Concept Development Parntership |
Organisation | Merck |
Department | Merck UK |
Country | United Kingdom |
Sector | Private |
PI Contribution | We designed the science and driving the project. |
Collaborator Contribution | Contribution of feasibility in the formation of the most suitable experimental plan to deliver impact. |
Impact | Hitherto the outcome refers on teh advacned understanding of neuronal cell signalling. |
Start Year | 2020 |
Description | Elucidate the Neuronal Cell Biology of the Neuroimaging Tool TSPO |
Organisation | King's College London |
Department | Brain Bank |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Coordination of the research work on functional role of the PET tracer TSPO in neuronal cell physiology and toxicity determination. |
Collaborator Contribution | Research Grant Share to support a PDRA and consumable. |
Impact | A manuscript is now submitted for final revision which will outline TSPO role in neurotoxicity besides characterising its function in cell signalling homeostasis. |
Start Year | 2014 |
Description | TSPO role in Hormonal Chemotherapy Resistance |
Organisation | Imperial College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are defining the link between cholesterol mediated resistance to hormonal chemotherapy and TSPO triggered expression in mammary cancer models. |
Collaborator Contribution | The main goal is trap the definition of pro-survival genes transcription mediated by TSPO and its potential intracellular relocation from mitochondrial outer membrane when pathologically overexpressed. Concomitantly TSPO ligands are being tested as pharmacological means to facilitate/promote chemotherapy induced cell death and prevent long-term resistance. |
Impact | Grants is being drafted |
Start Year | 2016 |
Description | Testing mitochondrial mechanisms as early marker of Drugs Attrition |
Organisation | Royal Veterinary College (RVC) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | The Royal Veterinary, University of London |
Collaborator Contribution | By the work on TSPO we succeeded in devising a suitable protocol via which we could detect mitochondrial toxicity and therefore provide early detection of pharmaceuticals which might reveal in vivo toxicity. |
Impact | We hope to gain sufficient evidences to secure valuable Intellectual Property. |
Start Year | 2018 |
Description | Testing of the antipsychotic drugs on TSPO |
Organisation | King's College London |
Department | Brain Bank |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Research Group of Dr. Anthony Vernon (King's College London Institute of Psychiatric) |
Collaborator Contribution | Expertise in clinical pharmacology, sharing of reagents. |
Impact | Clarification of TSPO role in trafficking neuro specific drugs, affecting their performance and outcome. |
Start Year | 2017 |
Description | Invited Seminar Talk at specialised audience |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Invited Seminar at the Beatson Institute for Cancer Research on September the 6th 2018 |
Year(s) Of Engagement Activity | 2018 |
Description | Invited Talk |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited Talk to deliver updates on our work of TSPO in neuronal models. |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.biophysics.org/Membership/Subgroups/Bioenergetics/tabid/506/Default.aspx |
Description | Invited Talk at Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Audience of industrial experts in the field of drug discovery. |
Year(s) Of Engagement Activity | 2018 |
Description | Invited Talk at the Redox Society of Medicine and Biology Annual Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Update on our work on the interpay between stress response mecchanims and redox stress |
Year(s) Of Engagement Activity | 2019 |
Description | Invited Talk in conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Invited presentation on mitochondrial regulation of inflammation and new regulatory mechanisms we have unveiled. |
Year(s) Of Engagement Activity | 2018 |
Description | Lay article |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Blog articles in Connected Health Quarterly |
Year(s) Of Engagement Activity | 2015,2016,2017 |
URL | http://www.connectedhealthquarterly.com/category/dr-radha-desai/ |
Description | Meeting with experts |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Chairing a focused workshop session on the meaning in Physiology and Pathology of Mitochondrial Biology |
Year(s) Of Engagement Activity | 2017 |
Description | New Scientist Live |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Participation in New Scientist Live as part of the Society of Biology's 'Ask a Biologist' initiative |
Year(s) Of Engagement Activity | 2017 |
URL | https://www.youtube.com/watch?v=d9K5r4j2PcY&t=5s |
Description | Oral Presentation on mito-nuclear contact sites at the EMBO workshop on on Membranes Contact Sites in Health and Diseases |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Oral presentation on our original research in energy balance and cross-organelles communication. |
Year(s) Of Engagement Activity | 2018 |
Description | Presentation to a group of patients |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Illustrate how our activities could inform new ways of treatments and handling of neurodegenerative conditions. |
Year(s) Of Engagement Activity | 2018 |
Description | Special Interest Group on Mitochondrial Biology |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Bring together postdocs and PhD students from RVC groups working on mitochondria to talk about common research interests, new ideas, problems, external fellowships and set internal collaborative projects. |
Year(s) Of Engagement Activity | 2020,2021 |