The PSP Association

Lead researchers Dr Margaret Piggott and Professor David Burn
Co-researchers Professor Andrew J Lees, Dr David R Williams, Professor Tamas Revesz, Professor Robert Perry, Professor Philip Winn

Institution Institute for Ageing and Health, Newcastle University

Duration 27 months
Start April 2006 End June 2008

Grant £89,400

Aim of research
• To test the hypothesis that falls, slowness, rigidity, and poor response to levodopa in PSP may be caused by degeneration of the cholinergic projections in the pedunculopontine nucleus (PPN).
• To test the hypothesis that there are differences in acetylcholine neurotransmission between patients with PSP-Parkinson (PSP-P) and the more typical PSP-Richardson's syndrome (PSP-R) and with patients with Parkinson's disease.

About the research
Many PSP patients can be subdivided into two groups, PSP-P which resembles Parkinson's disease in the early stages and PSP-R, which does not (Williams DR et al, 2005). In ‘Richardson's syndrome' falls and eye movement problems are prominent and early features, while in ‘PSP-P' falls and eye movement problems tend to occur later, or not at all. This research is aimed at elucidating the underlying reasons for these differences which may help in the development of an effective treatment for PSP.

The pedunculopontine nucleus (PPN) is a small area in the midbrain (at the upper end of the brainstem) which produces acetylcholine and releases it in the thalamus. It consists of a compact part (PPNc) with a higher density of cholinergic neurons, and a diffuse part (PPNd) which has glutamatergic and other neuron types as well as cholinergic. The PPN has an influence on the movement control circuits in the brain, and is a potential target for deep brain stimulation in Parkinson's disease and PSP.

The midbrain just below the PPN also has the cholinergic laterodorsal tegmental nucleus - of interest in PSP as it is involved in sleep. The substantia nigra lies at the rostral end of the PPN and is a target for PPN neurons. The SN produces dopamine, which is reduced in PSP and PD.

We collected frozen midbrain samples donated to the Queen Square Brain Bank from 9 cases of PSP-P, 10 cases of PSP-R, 10 cases of PD and 10 normal elderly control cases, supplemented with 6 cases of PSP (not clinically classified), 5 PD and 10 controls from the Newcastle Brain Tissue Resource. For further disease comparison we sampled cases of Parkinson's disease dementia and dementia with Lewy bodies, which have some attributes in common with PSP, e.g. poor response to levodopa and a tendency to falls.

Midbrains were sectioned and at intervals stained and assessed to visualize and map the anatomy and indicate acetylcholinesterase activity. Cholinergic receptors were measured by radioactively labelled drugs which bind to receptors and can be shown up by sensitive film autoradiography. We examined several areas in the midbrain as well as the PPN. Cholinergic muscarinic M1, M2, M4, and M3/M5 receptors were measured, and the relative preservation or degree of atrophy of the midbrain nuclei assessed by acetylcholinesterase staining and cross-sectional area in the autoradiographs. Nicotinic cholinergic receptors were also measured, giving an additional parameter of cholinergic loss.

Findings
Currently, we are analyzing the results and preparing them for publication.

We have confirmed our initial hypothesis, finding reduced acetylcholinesterase staining density in PPNc in both PSP-R and PSP-P compared to controls, while staining density in PD was not significantly reduced compared to controls. PSP-R cases tended to have lower acetylcholinesterase than PSP-P.

The hope of assessing PPN cholinergic neurons by quantifying urotensin receptors, reported to be uniquely expressed in cholinergic neurons in rat PPN, was not fulfilled; urotensin binding in the human PPN proved elusive.

For muscarinic receptors, the midbrain has mostly M2, then M3/M5, at higher density than M1 or M4. There were no significant changes between groups for either M1 or M4 receptors. Preliminary results for the M2 receptors show they were significantly higher (20-30%) in PSP cases compared to either controls or PD in the PPNd, but there was not a difference between PSP-P and PSP-R subgroups. Comparison of M3/M5 binding density is not yet complete.

We will correlate our findings with the results of our completed and published investigations of cholinergic systems, particularly in the thalamus, but also in striatum and cortex of PSP (Warren NM et al 2005; 2007a and b; 2008).

What does the outcome of this research mean for people with PSP?
The research aim was to assist development of treatments designed to protect, restore or stimulate the PPN and thus hopefully relieve some of the most disabling symptoms of PSP. We have shown that muscarinic receptors are present and hence available, but that as there are differences in cholinergic parameters between PSP and PD the response to deep brain stimulation of the PPN in PSP may differ from PD. It has been suggested that in PSP DBS of the PPN will give greater benefit if combined with DBS of the STN, as in advanced PD (Stefani A et al 2007; Benatru I et al 2008). Our results indicate that cholinergic modulation in the midbrain may show positive effect combined with pro-dopaminergic medication.

Publications arising directly from the research
Piggott MA, Wright Muelas M, Burn DJ
British Neuroscience Association Abstracts 2007 Cholinergic neurons in human midbrain labelled with 125I Urotensin II in post-mortem tissue in Progressive Supranuclear Palsy and normal elderly.

Weblinks

Institute for Ageing and Health

Professor David Burn

References

Benatru I, Vaugoyeau M, Azulay JP. Postural disorders in Parkinson's disease. Neurophysiologie Clinique/Clinical Neurophysiology In Press.

Stefani A, Lozano AM, Peppe A, Stanzione P, Galati S, Tropepi D, Pierantozzi M, Brusa L, Scarnati E, Mazzone P. 2007. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease. Brain 130(Pt 6):1596-1607.

Warren NM, Piggott MA, Lees AJ, Burn DJ. 2007a. The basal ganglia cholinergic neurochemistry of progressive supranuclear palsy and other neurodegenerative diseases. Journal of Neurology, Neurosurgery, and Psychiatry 78(6):571-575.

Warren NM, Piggott MA, Lees AJ, Burn DJ. 2007b. Muscarinic receptors in the thalamus in progressive supranuclear palsy and other neurodegenerative disorders. J Neuropathology and Experimental Neurology 66(5):399-404.

Warren NM, Piggott MA, Lees AJ, Perry EK, Burn DJ. 2008. Intact coupling of M1 receptors and preserved M2 and M4 receptors in the cortex in progressive supranuclear palsy: Contrast with other dementias. Journal of Chemical Neuroanatomy 35(3):268-274.

Warren NM, Piggott MA, Perry EK, Burn DJ. 2005. Cholinergic systems in progressive supranuclear palsy. Brain 128(Pt 2):239-249.

Williams DR, de Silva R, Paviour DC, Pittman A, Watt HC, Kilford L, Holton JL, Revesz T, Lees AJ. 2005. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism. Brain 128(Pt 6):1247-1258.