Why do nerve cells stop communicating in Lewy body dementias?

Lead Investigator: Professor Paul Francis
Institution: King's College London
Grant type: Project
Amount: £246,415
Start date: January 2011
Completion date: August 2013

Scientific Title: Synaptic dysfunction as a basis for cognitive decline and behavioural symptoms in Lewy body dementia: Molecular mechanisms and novel therapeutic targets.

What was the project, and what did the researchers do?

Dementia with Lewy bodies and the closely related condition of Parkinson's disease dementia are collectively referred to as Lewy body dementias. Individuals with Lewy body dementias usually experience devastating psychiatric symptoms such as depression, hallucinations, delusions, apathy, agitated behaviours, accompanied by progressive cognitive decline.

The main objectives of this project were to explore the underlying synaptic changes (synapses are where nerve cells connect to each other and communicate) driving cognitive decline and psychiatric symptoms in people with Lewy body dementias that will inform the development of new treatments.

The researchers wished to test the hypothesis that such symptoms are related to changes in synaptic function in discrete brain regions and that such alterations in synaptic function are caused by the presence of small alpha-synuclein aggregates within the part of a brain cell that sends out communication.

 

This project used brain tissue that had been donated to our Brains for Dementia Research programme. One hundred and sixteen brain samples were obtained (and twenty eight controls), with up to four regions (frontal, temporal, cingulate and parietal cortices) collected from each case. 

 

This is the first comprehensive study of the neurochemical pathology of Lewy body dementias involving a large number of cases with detailed clinical information. 

What were the key results, and how will this help in the fight against dementia?

Changes in the levels of several proteins were found in the Lewy body dementia cases that weren't found in other samples – these were found to correlate with the presence of Lewy bodies and may help to explain their formation, but more research is needed to confirm this.

 

The study found clinically relevant changes in synapses that may underlie specific changes in behaviour. However, these changes in synapses did not correlate with cognitive decline, indicating that other explanations, including the pathologies seen, are relevant to this symptom.

The presence of both Lewy body and Alzheimer's pathology in some specific brain regions did appear to correlate to cognitive decline. These findings need developing further as they may provide clues to greatly needed new treatment approaches to both cognitive decline and the emergence of behavioural symptoms in Lewy body dementias.

In addition, this knowledge may provide the scientific rationale to drive research to find ways to follow these changes in people living with the condition using imaging or by sampling of available fluids such as blood and cerebrospinal fluid.

What happened next? Future work and additional grants

The huge effort involved in the collection and classification of the samples will not be wasted as the cohort can provide other researchers with a unique collection through which other research relevant to people with Lewy body dementias can be undertaken.

A number of promising leads have been generated in the project and a PhD student linked to the project and funded by the Government of the Kingdom of Saudi Arabia will continue to pursue this area of research.

How were people told about the results? Conferences and publications

Publications

David R. Whitfield, Julie Vallortigara, Amani Alghamdi, David Howlett, Tibor Hortobágyi, Mary Johnson, Johannes Attems, Stephen Newhouse, Clive Ballard, Alan J. Thomas, John T O'Brien, Dag Aarsland and Paul T Francis. Reduced Zinc Transporter 3 is associated with cognitive impairment in Lewy body dementia. Submitted to Neurobiology of Aging.

David R. Whitfield, Julie Vallortigara, Amani Alghamdi, Tibor Hortobágyi, Clive Ballard, Alan J. Thomas, John T O'Brien, Dag Aarsland and Paul T Francis. Depression and synaptic zinc in Alzheimer's disease, dementia with Lewy bodies and Parkinson’s disease dementia. Submitted to The American Journal of Psychiatry.


Conferences

  • Alzheimer's Research UK (ARUK), Leeds 2011.

Impairment of the proteasome in frontal cortex in Lewy body dementias.

Julie Vallortigara, Francis E. Warren, Clive G. Ballard, Frank G. Boess, Dag Aarsland, Marie-Therese Targett, Amani Alghamdi & Paul T. Francis.

  • AAICAD: International Conference on Alzheimer's disease (ICAD), Paris, 16-21 July 2011.

Impairment of the proteasome in prefrontal cortex in Lewy body dementias.

Julie Vallortigara, Amani Alghamdi, Francis E. Warren, Clive G. Ballard, Tibor Hortobágyi, Johannes Attems, Dag Aarsland, Frank G. Boess, Marie-Therese Targett & Paul T. Francis.

Correlations between clinico-pathological features and biochemistry in Lewy body dementia and Parkinson's Disease dementia.

David Whitfield, Julie Vallortigara, Tibor Hortobágyi, Dag Aarsland, Clive Ballard, John O'Brien, David Howlett & Paul Francis.

  • SFN: Society for Neuroscience (SFN), Washington D.C., 12-16 November 2011.

Synaptic dysfunction and correlations between clinico-pathological features and biochemistry in Lewy body dementia and Parkinson's Disease dementia.

David Whitfield, Julie Vallortigara, Tibor Hortobágyi, Dag Aarsland, Clive Ballard, John O'Brien, David Howlett & Paul Francis.

  • ARUK: Alzheimer's Research UK conference, Birmingham, 27-28 March 2012

Alterations of SNARE proteins and synaptic regulators in frontal cortex in Lewy Body dementias

Julie Vallortigara, Tibor Hortobágyi, Johannes Attems, Clive G. Ballard, Dag Aarsland, John O'Brien, & Paul T. Francis

Synaptic dysfunction in dementia with Lewy bodies and Parkinson's disease dementia

David Whitfield, Dag Aarsland, Tibor Hortobágyi & Paul T. Francis

Effect of proteasome and p62 protein impairment on frontal cortex and anterior cingulate in Lewy body dementias

Amani Alghamdi, Tibor Hortobágyi, Clive G. Ballard, Johannes Attems, John O’Brien, Dag Aarsland & Paul T. Francis

  • ECNP: 10th European Congress of Neuropathology EICC, Edinburgh, 6 - 9 June 2012.

Synaptic dysfunction in Lewy body dementia and Parkinson's disease dementia.

David Whitfield, Tibor Hortobágyi, Dag Aarsland, Clive Ballard, John O'Brien & Paul Francis

  • AAICAD: Alzheimer's Association International Conference (AAIC) 2012 in Vancouver, British Columbia, Canada, July 14-19, 2012.

Proteasome and p62 protein impairment on frontal cortex and anterior cingulate in Lewy body dementias
Amani Alghamdi, Tibor Hortobágyi, Clive G. Ballard, Johannes Attems, John O'Brien, Dag Aarsland & Paul T. Francis

Biochemical correlates of clinical symptoms in dementia with Lewy bodies and Parkinsons' disease dementia.
David Whitfield, Julie Vallortigara, Dag Aarsland, Tibor Hortobágyi  and Paul T Francis

  • SFN: Society for Neuroscience (SFN), New Orleans, 13-17 October 2012.

Correlations between synaptic proteins expression and clinico-pathological features in Dementia with Lewy bodies, Parkinson's Disease Dementia and Alzheimer's Disease.

Julie Vallortigara, Tibor Hortobágyi, Johannes Attems, Clive G. Ballard, Dag Aarsland, & Paul T. Francis. Abstract selected for oral communication.

  • ESN conference: 5th conference on Advances in molecular mechanisms underlying neurological disorders, Bath, 23-26 June.

Synaptic dysfunction and Correlations with clinico-pathological features in Dementia with Lewy bodies and Parkinson's Disease Dementia

Julie Vallortigara, William Quelch, Tibor Hortobágyi, Johannes Attems, John O'Brien, Alan Thomas, Clive G. Ballard, Dag Aarsland, & Paul T. Francis
(Award of best poster presentation)

Reduction of Rpt6/S8 (a Proteasome component) is associated with cognitive decline in LBD & AD.

Amani Alghamdi, Tibor Hortobágyi , Clive G. Ballard, David Howlett, Dag Aarsland, John O'Brien, Johannes Attems, Paul T Francis

  • Life beyond the PhD: a residential conference. Cumberland Lodge, Windsor, 12-14 August 2013

Julie Vallortigara. Synaptic dysfunction as a basis for cognitive decline and behavioural symptoms in Lewy Body dementias: Molecular mechanisms and novel therapeutic targets. (Awarded to attend the conference, funded by the Graduate School KCL).

This project was jointly funded by Alzheimer's Society and the Bupa foundation