The PSP Association

Lead researchers Dr David Williams and Dr Rohan de Silva
Co-researchers Professor Tamas Revesz, Dr Janice Holton and Professor Andrew Lees

Institution Institute of Neurology, University College London

Duration 3 years
Start September 2004 End August 2007

Grant £82,733

Aim of research
To compare clinical, pathological and biochemical features of typical PSP cases as defined by Steele, Richardson and Olszewski and ‘atypical' cases that deviate from this description and are often misdiagnosed as Parkinson's disease (PD).

About the research
This project involved a retrospective study of 107 pathologically proven cases of PSP in the brain bank at the Sara Koe PSP Research Centre (SKRC) and involved:
(1) Detailed review of clinical history from clinical notes available for PSP patients whose brains had been donated to the SKRC
(2) Comparative neuropathological assessment of distribution of abnormal tau pathology in these brains and
(3) Comparative biochemical analysis of the precise composition of the abnormal tau protein.

Findings
This project led to the definition of two clinical sub-groups of PSP, PSP - Richardson's syndrome (RS), the classical PSP as first described by Steele, Richardson and Olszewski, and PSP-parkinsonism (PSP-P).

About 54% of the cases examined were RS, with early onset of postural instability and falls, supranuclear gaze palsy and cognitive dysfunction. The second group, about 33%, often misdiagnosed as PD, had asymmetric onset, tremor and a moderate initial response to levodopa. Subsequently, the validity of this classification was supported by biochemical and microscopic, neuropathological analysis of the abnormal tau protein in these brains whereby RS and PSP-P showed significant differences in composition and distribution. This could possibly explain the different clinical features as manifest by the differences in nerve cell loss caused by the defective tau protein.

In this study a third though much less frequent clinical PSP sub-group was identified - pure akinesia with gait freezing (PSP-PAGF) which is clinically distinguishable from RS and PSP-P.

What does the outcome of this research mean for people with PSP?
This research is an important contributor to the refinement of the clinical diagnosis of PSP. In particular, PSP is often misdiagnosed as PD. The findings of this research will help neurologists to distinguish between these clinical entities which will have important consequences for the care and treatment of patients. In due course the ability to distinguish between PSP and PD will have implications for the appropriate testing of new treatments.

Publications arising from the work
Williams,D.R., de Silva,R., Paviour,D.C., Pittman,A., Watt,H.C., Kilford,L., Holton,J.L., Revesz,T., Lees,A.J. (2005). Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism. Brain 128(6), 1247-1258.

Williams,D.R., Holton,J.L., Strand,C., Pittman,A., de Silva,R., Lees,A.J., Revesz,T. (2007). Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain 130(6), 1566-1576

Williams, D.R., Holton, J.L., Strand, K., Revesz, T., Lees, AJ. (2007) Pure akinesia with gait freezing: a third clinical phenotype of progressive supranuclear palsy. Movement Disorders 22(15):2235-2241.

Williams,D.R., Pittman,A.M., Revesz,T., Lees,A.J., de Silva,R. (2007). Genetic variation at the tau locus and clinical syndromes associated with progressive supranuclear palsy. Movement Disorders 22(6), 895-897.

National/international presentations given on this work
Parkinson's disease and Movement Disorders Annual Meeting, New Orleans, 2005
Society for PSP, Annual Scientific Meeting, Virginia, 2005
Society for PSP, Annual Scientific Meeting, Atlanta 2006
Australian and New Zealand Association of Neurologists Scientific Meeting, Alice Springs, 2007
Parkinson's disease and Movement Disorders Annual Meeting, Istanbul, 2007

Awards and prizes received by Dr David Williams for work conducted under this grant
The Queen Square Prize, 2007: Best Research at Institute of Neurology, University College London

Leonard Cox Award 2007: Australian and New Zealand Association of Neurologists, Neuroscience Research Excellence

Queen Square Symposium Prize 2006: Institute of Neurology, University College London

Movement Disorders Society Junior Award for Outstanding Clinical Research, 2004: 8th International Congress of Parkinson's Disease and Movement Disorders, Rome

Web links
Reta Lila Weston Institute of Neurological Studies
Prof David Williams

How has the grant you received influenced your future career and research direction?

Dr David Williams' work on this project formed the bulk of his PhD thesis.
On his return to Australia Dr Williams set up a PSP and movement disorders clinic at the Alfred Hospital, Monash University, Melbourne.

Dr David Williams says,
"This grant allowed me to study PSP in the kind of detail necessary to answer some big questions about the disease. The insight I gained into the condition has been immensely helpful in my subsequent clinical and research work. In particular it provided me with exposure to the leading researchers in movement disorders, and inspired further research in PSP. I have subsequently received grants from CurePSP, National Neuroscience Research Grants (Australia) and Royal Australasian College of Physicians. I am indebted to The PSP Association for supporting this research."