JPND The locus coeruleus: at the crossroad of dementia syndromes
Lead Research Organisation:
King's College London
Department Name: Forensic and Neurodevelopmental Science
Abstract
The locus coeruleus (LC) is a brain area involved in important brain functions, including attention, memory, and wakefulness. It contains neurons (nerve cells) that use noradrenaline (Norepinephrine) as transmitter that are connected to other brain areas. These are often affected by brain diseases that result in neuronal loss, such as Alzheimer's disease, Down syndrome and Parkinson's disease. Loss of LC neurons may underlie similarities in symptoms between these diseases.
Our consortium have found that early markers of dementia in Down syndrome (which is due to an extra chromosome 21) and in other dementias may relate to LC cell loss.
Building on previous work, the goal of our project is now to uncover the common mechanisms and pathways associated with LC cell loss that is caused by dementias due to Down syndrome, Parkinson's disease, and Alzheimer's disease.
We will use state-of-the-art technologies to
(i) explore cell degeneration and cell function alterations in the LC of post-mortem brain material, stem cells derived from patients, and in mouse models of these diseases
(ii) Better understand the noradrenaline system in patients with and without dementia using blood and spinal fluid biomarkers and PET brain scan studies, and relate this to established biomarkers
(iii) analyze the involvement of specific genes on chromosome 21 in Alzheimer's disease, Parkinson's disease, and Down syndrome and explore their role as common risk or protective mechanisms for dementia.
The work will provide better knowledge of biomarkers related to LC degeneration, and their relationship to other dementia biomarkers and to dementia status across patient groups. This will help to improve clinical diagnosis, and also provide important information on biomarkers of dementia progression that will be valuable for prognosis and future clinical studies. The work will also provide improved knowledge of common causes and pathways of cell degeneration across patient groups, which could help to identify new treatment strategies.
Our consortium have found that early markers of dementia in Down syndrome (which is due to an extra chromosome 21) and in other dementias may relate to LC cell loss.
Building on previous work, the goal of our project is now to uncover the common mechanisms and pathways associated with LC cell loss that is caused by dementias due to Down syndrome, Parkinson's disease, and Alzheimer's disease.
We will use state-of-the-art technologies to
(i) explore cell degeneration and cell function alterations in the LC of post-mortem brain material, stem cells derived from patients, and in mouse models of these diseases
(ii) Better understand the noradrenaline system in patients with and without dementia using blood and spinal fluid biomarkers and PET brain scan studies, and relate this to established biomarkers
(iii) analyze the involvement of specific genes on chromosome 21 in Alzheimer's disease, Parkinson's disease, and Down syndrome and explore their role as common risk or protective mechanisms for dementia.
The work will provide better knowledge of biomarkers related to LC degeneration, and their relationship to other dementia biomarkers and to dementia status across patient groups. This will help to improve clinical diagnosis, and also provide important information on biomarkers of dementia progression that will be valuable for prognosis and future clinical studies. The work will also provide improved knowledge of common causes and pathways of cell degeneration across patient groups, which could help to identify new treatment strategies.
Technical Summary
Noradrenergic projection neurons from the locus coeruleus (LC) mediate attention, memory, and arousal and their loss occurs early in neurodegenerative conditions, such as Alzheimer's disease (AD), Down syndrome (DS) and even more in Parkinson's disease (PD). Consequently, LC neuronal loss affects the function of target areas such as the hippocampus and the cerebral cortex. Evidence from our consortium and others, suggests that AD, DS and PD may share key mechanisms of LC degeneration, affecting early onset and/or progression of neurodegenerative process.
Our consortium has been successful in identifying new biomarkers of AD in DS, some of which have already been validated in sporadic AD and are also common to PD. Specifically, alterations in the endo-lysosomal system (within which amyloid-beta processing occurs) and changes in noradrenaline and its main metabolite (3-methoxy-4-hydroxyphenylglycol, MHPG) due to LC degeneration were found to be early markers of dementia in DS and also in other dementias.
The goal of this project is now to uncover the common mechanisms and pathways related to dementia associated with LC degeneration among these three neurodegenerative diseases (AD, DS and PD). By using state-of-the-art technologies we will (i) characterize noradrenergic neurodegeneration and endo-lysosomal alterations in the LC of post-mortem brain material, iPSC-derived neurons/cerebral organoids from AD, DS and PD patients, and mouse models (WP1/2); (ii) characterize the noradrenergic system functionality in patients with and without dementia using biomarkers and PET studies (WP1); (iii) analyze the involvement of specific chromosome 21 genes (such as DYRK1A and APP) in AD, DS and PD pathways and their role as common risk or protective mechanisms for dementia (WP3); and (iv) identify common genes and pathways using transcriptomic studies (RNAseq) in the LC and validate new targets in post-mortem material from AD, DS and PD patients (WP4).
Our consortium has been successful in identifying new biomarkers of AD in DS, some of which have already been validated in sporadic AD and are also common to PD. Specifically, alterations in the endo-lysosomal system (within which amyloid-beta processing occurs) and changes in noradrenaline and its main metabolite (3-methoxy-4-hydroxyphenylglycol, MHPG) due to LC degeneration were found to be early markers of dementia in DS and also in other dementias.
The goal of this project is now to uncover the common mechanisms and pathways related to dementia associated with LC degeneration among these three neurodegenerative diseases (AD, DS and PD). By using state-of-the-art technologies we will (i) characterize noradrenergic neurodegeneration and endo-lysosomal alterations in the LC of post-mortem brain material, iPSC-derived neurons/cerebral organoids from AD, DS and PD patients, and mouse models (WP1/2); (ii) characterize the noradrenergic system functionality in patients with and without dementia using biomarkers and PET studies (WP1); (iii) analyze the involvement of specific chromosome 21 genes (such as DYRK1A and APP) in AD, DS and PD pathways and their role as common risk or protective mechanisms for dementia (WP3); and (iv) identify common genes and pathways using transcriptomic studies (RNAseq) in the LC and validate new targets in post-mortem material from AD, DS and PD patients (WP4).
Planned Impact
The main results expected by the project will fall mostly under the following categories:
New knowledge about common molecular, cellular and pathophysiological mechanisms in DS, AD and PD;
New molecular, neuroimaging and cognitive biomarkers across our target diseases;
Bio repositories (human samples and iPSCs) for further research;
New molecular targets for common therapy for patients affected by DS, AD and PD.
Anticipated impacts include:
1. Improved knowledge of biomarkers related to locus coeruleus degeneration and their relationship to other dementia biomarkers and to dementia status across patient groups will impact on clinical diagnosis, and also provide important information on biomarkers of dementia progression that will be valuable for prognosis and future clinical studies.
2. Improved knowledge of common mechanisms and pathways of degeneration across patient groups, which could help to identify new treatment strategies.
New knowledge about common molecular, cellular and pathophysiological mechanisms in DS, AD and PD;
New molecular, neuroimaging and cognitive biomarkers across our target diseases;
Bio repositories (human samples and iPSCs) for further research;
New molecular targets for common therapy for patients affected by DS, AD and PD.
Anticipated impacts include:
1. Improved knowledge of biomarkers related to locus coeruleus degeneration and their relationship to other dementia biomarkers and to dementia status across patient groups will impact on clinical diagnosis, and also provide important information on biomarkers of dementia progression that will be valuable for prognosis and future clinical studies.
2. Improved knowledge of common mechanisms and pathways of degeneration across patient groups, which could help to identify new treatment strategies.
Organisations
- King's College London (Lead Research Organisation)
- Karolinska Institute (Collaboration)
- University of Gothenburg (Collaboration)
- Ludwig Maximilian University of Munich (LMU Munich) (Collaboration)
- Fondation Jérôme Lejeune (Collaboration)
- University of Barcelona (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- EU Health Programme (Collaboration)
Publications
Alic I
(2021)
Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.
in Molecular psychiatry
Antonarakis SE
(2020)
Down syndrome.
in Nature reviews. Disease primers
Aschenbrenner AJ
(2021)
Markers of early changes in cognition across cohorts of adults with Down syndrome at risk of Alzheimer's disease.
in Alzheimer's & dementia (Amsterdam, Netherlands)
Ashton NJ
(2021)
A multicentre validation study of the diagnostic value of plasma neurofilament light.
in Nature communications
Aslam AA
(2022)
Diabetes and Obesity in Down Syndrome Across the Lifespan: A Retrospective Cohort Study Using U.K. Electronic Health Records.
in Diabetes care
Baksh RA
(2024)
Toward the right treatment at the right time: Modeling the trajectory of cognitive decline to identify the earliest age of change in people with Alzheimer's disease.
in Alzheimer's & dementia (Amsterdam, Netherlands)
Baksh RA
(2022)
Susceptibility to COVID-19 Diagnosis in People with Down Syndrome Compared to the General Population: Matched-Cohort Study Using Primary Care Electronic Records in the UK.
in Journal of general internal medicine
Cannavo C
(2020)
Using mouse models to understand Alzheimer's disease mechanisms in the context of trisomy of chromosome 21.
in Progress in brain research
Carmona-Iragui M
(2021)
Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study.
in The Lancet. Neurology
Description | COVID-19 vaccination prioritisation for people with Down syndrome |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
Impact | Based upon our recommendation, most people with Down syndrome now have access to COVID-19 vaccination and we have subsequently demonstrated that vaccination is safe, and also resulted in a significant decrease in mortality following infection |
URL | https://www.t21rs.org/covid_vaccination/ |
Description | Implementation of the Down syndrome Act |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
Impact | Helping to inform guidance on implementation fo the Down syndrome Act by providing expert input on the specific helath needs of people with Down syndrome |
Description | Inform policy in the USA on use guidance for new amyloid immune therapies in people with Down syndrome |
Geographic Reach | North America |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | People with Down syndrome are now seen as eligible for these new teratments |
Description | Clinical and trial outcome measures for dementia in individuals with Down syndrome |
Amount | £180,000 (GBP) |
Organisation | LuMind Research Down Syndrome Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 08/2018 |
End | 12/2020 |
Description | Multi-professional Clinical Training Partnership - Aarsland, D., Sleeman, K., Strydom, A. |
Amount | £225,000 (GBP) |
Organisation | Alzheimer's Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2019 |
End | 12/2021 |
Description | Neuropathological and amyloid peptide differences between DS and familial AD with duplications and missense mutations in APP gene |
Amount | £105,352 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 03/2020 |
Description | GO-DS21 |
Organisation | EU Health Programme |
Country | European Union (EU) |
Sector | Public |
PI Contribution | The work on HEROES led to the formation of a subsequent collaboration, including most of the HEROES partners with addition of new partners. This is called GO-DS21 and led to a successful application to teh EU's Horizon2020 programme. |
Collaborator Contribution | See above |
Impact | Multi-disciplinary collaboration; impacts to follow |
Start Year | 2020 |
Description | Horizon21 consortium: Down syndrome and Alzheimer's disease |
Organisation | Fondation Jérôme Lejeune |
Country | France |
Sector | Charity/Non Profit |
PI Contribution | Lead - established and coordinates the consortium |
Collaborator Contribution | Contributing to development of new cognitive and clinical assessment tools, and to validate these, as well as to establish a clinical trials network |
Impact | Ongoing |
Start Year | 2020 |
Description | Horizon21 consortium: Down syndrome and Alzheimer's disease |
Organisation | Karolinska Institute |
Department | Stockholm Brain Institute |
Country | Sweden |
Sector | Academic/University |
PI Contribution | Lead - established and coordinates the consortium |
Collaborator Contribution | Contributing to development of new cognitive and clinical assessment tools, and to validate these, as well as to establish a clinical trials network |
Impact | Ongoing |
Start Year | 2020 |
Description | Horizon21 consortium: Down syndrome and Alzheimer's disease |
Organisation | Ludwig Maximilian University of Munich (LMU Munich) |
Country | Germany |
Sector | Academic/University |
PI Contribution | Lead - established and coordinates the consortium |
Collaborator Contribution | Contributing to development of new cognitive and clinical assessment tools, and to validate these, as well as to establish a clinical trials network |
Impact | Ongoing |
Start Year | 2020 |
Description | Horizon21 consortium: Down syndrome and Alzheimer's disease |
Organisation | University of Barcelona |
Department | Faculty of Medicine |
Country | Spain |
Sector | Academic/University |
PI Contribution | Lead - established and coordinates the consortium |
Collaborator Contribution | Contributing to development of new cognitive and clinical assessment tools, and to validate these, as well as to establish a clinical trials network |
Impact | Ongoing |
Start Year | 2020 |
Description | Horizon21 consortium: Down syndrome and Alzheimer's disease |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Lead - established and coordinates the consortium |
Collaborator Contribution | Contributing to development of new cognitive and clinical assessment tools, and to validate these, as well as to establish a clinical trials network |
Impact | Ongoing |
Start Year | 2020 |
Description | Horizon21 consortium: Down syndrome and Alzheimer's disease |
Organisation | University of Gothenburg |
Department | Sahlgrenska Academy |
Country | Sweden |
Sector | Academic/University |
PI Contribution | Lead - established and coordinates the consortium |
Collaborator Contribution | Contributing to development of new cognitive and clinical assessment tools, and to validate these, as well as to establish a clinical trials network |
Impact | Ongoing |
Start Year | 2020 |
Title | Industry sponsored clinical trial protocols |
Description | Immune therapy using an amyloid vaccine to prevent/ delay Alzheimer's disease in Down syndrome, currently stage 2A trial |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2023 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Industry sponsored; I helped to make the case for the trial in Down syndrome, and to develop the research protocol to be suitable for the population. |
URL | https://www.alzheimer-europe.org/research/clinical-trials/abate?language_content_entity=en |
Description | COVID and Down Syndrome Webinar |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | An update on the Trisomy 21 Research Society COVID and Down Syndrome Survey and discussed the DSMIG-USA Vaccination Position Statement. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.youtube.com/watch?v=9WKB90zua-o |
Description | COVID-19 is 10 times deadlier for people with Down syndrome, raising calls for early vaccination |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Impact of Covid-19 on down syndrome patients |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.science.org/content/article/covid-19-10-times-deadlier-people-down-syndrome-raising-call... |
Description | Covid-19 and Down Syndrome on-line survey: results and perspective |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | EDSA (European Down syndrome association) - Organized webinar with Dr. Andre Strydom and Prof. Mara Dierssen about Covid-19 and Down Syndrome. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.youtube.com/watch?v=97-UyBUbkaQ |
Description | International study finds increased mortality in adults with Down syndrome |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Research led by King's College London in collaboration with the Centre for Genomic Regulation (CRG) and the Trisomy 21 Research Society (T21RS) finds increased COVID-19 mortality among adults with Down syndrome compared to the general population, emphasizing the need to prioritise vaccinations for those with the genetic disorder. https://thedaily.case.edu/international-study-finds-increased-covid-19-mortality-among-adults-with-down-syndrome/ https://news.emory.edu/stories/2021/02/coronavirus_inreased_mortality_down_syndrome/index.html |
Year(s) Of Engagement Activity | 2021 |
URL | https://eu.usatoday.com/story/news/2021/03/08/covid-19-vaccine-many-adults-down-syndrome-cant-get-sh... |
Description | Keynote at Trisomy 21 Research Society international conference |
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 | Keynote speaker at Trisomy 21 Research Society international conference |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.t21rs.org/news-meetings |
Description | LDID SIG chair |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | I am the founding chair of the London Dementia in Intellectual Disabilities Special Interest Group, which has membership from clinicians across London. It is a forum for regular discussion and dissemination of research results related to the treatment and management of Dementia in individuals with Down Syndrome (DS) or other Intellectual Disabilities (ID). We have formed a new research collaboration to collect anonymised clinical data from dementia assessments on adults with DS and ID, which will be used to seek answers to clinically driven research questions. We have also developed generic care pathway guides which can be used by clinicians to improve services, and are in the process of organising a conference in 2012 that will be used as platform for a Intellectual Disabilities Dementia Care Alliance. |
Year(s) Of Engagement Activity | 2011,2012,2013,2014,2015,2016,2017,2018,2019,2020 |
URL | https://www.kcl.ac.uk/ioppn/depts/fans/research/dementia-in-intellectual-disabilities-special-intere... |
Description | Medical vulnerability of individuals with Down syndrome to severe COVID-19-data from the Trisomy 21 Research Society and the UK ISARIC4C survey |
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 | Researcher chat via facebook organised by a family organisation to support uptake of covid vaccination for people with Down syndrome |
Year(s) Of Engagement Activity | 2021 |
Description | Multimorbidity in Down syndrome press release |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Press release for Lancet Public Health publication on multimorbidity in Down syndrome |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.kcl.ac.uk/news/tracking-multiple-morbidities-across-the-lifespan-in-people-with-down-syn... |
Description | The COVID-19 pandemic should be last orders for poor care of people with neurodevelopmental disorders |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Editorial - Explored whether the needs of individuals with neurodevelopmental disorders have been overlooked during the COVID-19 pandemic and set out the issues that need to be considered in response to future health crises and pandemics. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/covid19-pandemic-s... |
Description | The Down Syndrome Medical Interest Group Annual Winter Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | The impact of COVID-19 on children & adults with Down Syndrome |
Year(s) Of Engagement Activity | 2020 |
Description | World Down Syndrome day |
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 | Talking about research to people with Down syndrome and their carers |
Year(s) Of Engagement Activity | 2019,2020,2021 |