The PSP Association

Researchers
Dr Huw Morris (Clinical Research Fellow); Supervisors - Professor Nick Wood and Professor Andrew Lees

Institution Institute of Neurology, London

Duration 20.5 months
Start April 1997 End December 1998
(The research continued under a Medical Research Clinical Training Fellowship to January 31st 2001)

Grant

Aim of research
i) To identify PSP patients, obtain DNA samples with a view to identifying genetic risk factors for PSP
ii) To investigate clinical and genetic aspects of the Parkinsonism Dementia Complex of Guam (PDC) with Dr John Steele

About the research
In 1997 when I began my PSP Association Clinical Research Fellowship there was no evidence of any genetic risk factors in PSP. However, during the time of my Fellowship the identification of MAPT (tau) mutations in Fronto-temporal dementia and MAPT (tau) susceptibility to PSP led by Conrad, Hutton and many others, resulted in a great increase in our knowledge of these disorders. I was able to follow up these findings using the resources of the Queen Square Brain Bank with support from The PSP Association.

One of the original authors of the 1964 seminal report on PSP, Dr John Steele, lives and works on the island of Guam and studies the condition known as the Parkinsonism dementia complex of Guam. This condition has close similarities to PSP and part of my work involved the study of this condition.

During my Fellowship I was involved in:
• Assessing PSP patients at home and in the clinic and collecting blood samples for DNA analysis
• Extracting DNA samples from brain bank samples
• Analyzing genetic variation in the tau gene (MAPT) in patients with PSP and the closely related condition Fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP17)
• Working collaboratively with Professor John Hardy at the Mayo Clinic Jacksonville and Dr Jordi Perez-Tur in Guam
• Assessing patients with the Parkinsonism dementia complex (PDC) in Guam in collaboration with Dr. John Steele
• Undertaking a genome wide analysis of PDC in collaboration with Jordi Perez-Tur.

Findings
From this research it was found that:
• One variant of the tau gene is over-represented in patients with PSP and is a risk factor for the disease
• The tau H1 haplotype predisposes to cortico-basal degeneration but not to Pick's disease
• A series of mutations in the tau gene can lead to Fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP17)and in some cases the clinical and pathological features can closely resemble PSP
• There are a number of clinical, pathological and genetic variants of FTDP
• There may be differences in the genetic and pathological characteristics of patients with "typical" and "atypical" PSP.

What does the outcome of this research mean for people with PSP?
This work formed part of a period of intense work around the world into the role of tau in PSP and related disorders. It became clear that tau was of central importance in the pathogenesis of PSP, although the precise mechanisms by which tau leads to nerve cell damage in PSP remains incompletely understood. The research in which I was involved, and that of others, indicates that PSP is not usually a familial condition but there are genetic risk factors present in the general population which can increase the risk of developing the disease.

This work contributed to the focus on tau as the primary agent of PSP and the target for the development of new therapies.

Publications arising from the research
de Silva R, Weiler M, Morris HR, Martin ER, Wood NW, Lees AJ. Strong association of a novel Tau promoter haplotype in progressive supranuclear palsy. Neuroscience Letters 2001; 311:145-148.

Houlden H, Baker M, Morris HR, et al. Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology 2001;56:1702-1706.

Janssen JC, Warrington EK, Morris HR, et al. Clinical features of frontotemporal dementia due to the intronic tau 10(+16) mutation. Neurology 2002; 58:1161-1168.

Lantos PL, Khan N, Cairns NJ, Janssen JC, Morris HR, Rossor MN. The neuropathological classification of familial frontotemporal dementia. Journal of Neuropathology and Experimental Neurology 2001;60:513-513.

Lantos PL, Reyesz T, King A, et al. Phenotypic variations in frontotemporal dementia caused by exon 10+16 splice site tau mutation. Journal of Neuropathology and Experimental Neurology 2000;59:445-445.

Morris HR, Al-Sarraj S, Schwab C, et al. A clinical and pathological study of motor neurone disease on Guam. Brain 2001;124:2215-2222.

Morris HR, Baker M, Yasojima K, et al. Analysis of tau haplotypes in Pick's disease. Neurology 2002;59:443-445.

Morris HR, Gibb G, Katzenschlager R, et al. Pathological, clinical and genetic heterogeneity in progressive supranuclear palsy. Brain 2002; 125:969-975.

Morris HR, Janssen JC, Bandmann O, et al. The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases. Journal of Neurology Neurosurgery and Psychiatry 1999;66:665-667.

Morris HR, Katzenschlager R, Janssen JC, et al. Sequence analysis of tau in familial and sporadic progressive supranuclear palsy. Journal of Neurology Neurosurgery and Psychiatry 2002;72:388-390.

Morris HR, Khan MN, Janssen JC, et al. The genetic and pathological classification of familial frontotemporal dementia. Archives of Neurology 2001; 58:1813-1816.

Morris HR, Lees AJ, Wood NW. Neurofibrillary tangle parkinsonian disorders - Tau pathology and tau genetics. Movement Disorders 1999;14:731-736.

Morris HR, Osaki Y, Holton J, et al. Tau exon 10 +16 mutation FTDP-17 presenting clinically as sporadic young onset PSP. Neurology 2003;61:102-104.

Morris HR, Perez-Tur J, Janssen JC, et al. Mutation in the tau exon 10 splice site region in familial frontotemporal dementia. Annals of Neurology 1999;45:270-271.

Morris HR, Schrag A, Nath U, et al. Effect of ApoE and tau on age of onset of progressive supranuclear palsy and multiple system atrophy. Neuroscience Letters 2001;312:118-120.

Morris HR, Steele JC, Crook R, et al. Genome-wide analysis of the Parkinsonism-dementia complex of Guam. Archives of Neurology 2004; 61:1889-1897.

Morris HR, Vaughan JR, Datta SR, et al. Multiple system atrophy/progressive supranuclear palsy: alpha-Synuclein, synphilin, tau, and APOE. Neurology 2000; 55:1918-1920.

Morris HR, Wood NW, Lees AJ. Progressive supranuclear palsy (Steele-Richardson-Olszewski disease). Postgraduate Medical Journal 1999; 75:579-584.

Nath U, Ben-Shlomo Y, Thomson RG, et al. The prevalence of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) in the UK. Brain 2001;1 24:1438-1449.

Schrag A, Good CD, Miszkiel K, et al. Differentiation of atypical parkinsonian syndromes with routine MRI. Neurology 2000;54:697-702.

How has the research you conducted influenced your career and research direction?
My PSP Association Clinical Research Fellowship led to me receiving a Clinical Training Fellowship from the Medical Research Council and set the foundations for my clinical and research interest in PSP which continues.

I am now a Senior Lecturer in Neurology in Cardiff and am actively engaged in research into tau (supported by The PSP Association), am involved in the therapeutic trials of lithium in PSP, and run a regular PSP clinic.