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.

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).

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.

Publications

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Antonarakis S (2020) Down syndrome in Nature Reviews Disease Primers

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Firth NC (2018) Aging related cognitive changes associated with Alzheimer's disease in Down syndrome. in Annals of clinical and translational neurology

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Hithersay R (2020) Optimal age and outcome measures for Alzheimer's disease prevention trials in people with Down syndrome. in Alzheimer's & dementia : the journal of the Alzheimer's Association

 
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 09/2018 
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 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 2018
 
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 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