Cholinergic Neurochemistry of Progressive Supranuclear Palsy
Lead researcher Dr Naomi Warren
Co-researchers Dr Margaret Piggott and Professor David Burn
Institution Institute for Ageing and Health, Newcastle General Hospital
Duration 2 years
Start October 2003 End June 2006 (end date delayed due to maternity leave)
Grant £60,000
Aim of research
To investigate the status of the cholinergic receptors in the basal ganglia, thalamus and frontal cortex in PSP.
About the research
There are specific areas of the brain involved in the production of smooth movement, memory and behavior. Some areas are deep inside the brain (e.g., the basal ganglia and thalamus) while others are on the surface (e.g., the frontal cortex). This research was seeking to determine if there are any changes in specific receptors (cholinergic) to which chemicals attach in these key areas of the brain. The research involved attaching radioactive material to the receptors and measuring how much or little change there was compared to healthy brains. In the frontal cortex the number of receptors and whether they were functioning correctly was examined.
Findings
In the basal ganglia there is loss of specific sub types of cholinergic receptors, M4 and M2, which suggests damage to the cholinergic nerve cells and to some of the nerves which project to the thalamus. In the thalamus there was a reduction in M2 and M4 receptors in key areas which may be involved in behavioural and memory changes. In the frontal cortex the cholinergic receptors appeared normal in number and function.
The findings of this research suggests that the cholinergic system, which uses a specific neurotransmitter called acetylcholine, is damaged in PSP. There are key changes in deep brain structures which may be involved in cognitive and behavioural problems and possibly in the mobility problems experienced by many PSP patients.
What does the outcome of this research mean for people with PSP?
Knowing which chemical systems are damaged in PSP has the potential to help in the development of a treatment. The fact that the frontal cortex receptors are functioning normally suggests a potential target for drugs. There is also some (albeit limited) suggestion that targeting these receptors may slow the disease process although there is the added complication that there are probably other neurotransmitter systems which also contribute to the symptoms of PSP. This research does however provide some possible targets and offers hope that drug treatment(s) can be developed to help manage the symptoms of PSP and slow its progression.
Publications arising from the work
NM Warren, MA Piggott, EK Perry and DJ Burn. Cholinergic systems in Progressive Supranuclear Palsy. Brain 2005: 128; 239-249
NM Warren, MA Piggott, AJ Lees and DJ Burn. The basal ganglia cholinergic neurochemistry of progressive supranuclear palsy and other neurodegenerative diseases. J Neurol Neurosurg Psychiatry. 2007. 78(6);571-5.
NM Warren, MA Piggott, AJ Lees and DJ Burn. Muscarinic receptors in the thalamus in progressive supranuclear palsy and other neurodegenerative disorders. J Neuropathol Exp Neurol. 2007. 66(5); 399-404.
NM Warren, MA Piggott, Greally E, Lake M, AJ Lees and DJ Burn.
Basal ganglia cholinergic and dopaminergic function in progressive supranuclear palsy. Mov Disord. 2007. 15;22(11); 1594-600
NM Warren, MA Piggott, AJ Lees, EK Perry and DJ Burn. Intact coupling of M1 receptors and preserved M2 and M4 receptors in the cortex in progressive supranuclear palsy: contrast with other dementias. J Chem Neuroanat. 2008. 35(3); 268-74.
National/international presentations given on this work
‘Basal Ganglia Cholinergic and Dopaminergic function in Progressive Supranuclear Palsy'. Poster presentation at the ABN, April 2004.
Awards and prizes received for work conducted under this grant
MD thesis with commendation
How has the grant you received influenced your future career and research direction?
Undertaking this research developed my interest in movement disorders - and particularly in PSP and Parkinson's disease. When I become a consultant I hope to continue with specialist clinics in this area. I am grateful to The PSP Association for supporting this research and for giving me the opportunity to develop my knowledge of PSP.