Williams, D.; (2006) Clinical, pathological and biochemical diversity in progressive supranuclear palsy. Doctoral thesis , University of London.

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Abstract

This thesis examines the clinical, pathological and biochemical diversity of progressive supranuclear palsy (PSP). The material and patients used for these studies involved 23 clinically diagnosed living patients and 127 pathologically confirmed cases of PSP, archived at the Queen Square Brain Bank (QSBB). Differences between 'classic' PSP and 'atypical' PSP were identified, and a number of clinical features that separate them from other bradykinetic rigid syndromes were explored. In addition to the clinical phenotype associated with PSP-tau pathology initially described by Richardson in 1963 (Richardson's syndrome, RS) two other distinct clinical syndromes were identified: PSP-Parkinsonism (PSP-P) and pure akinesia with gait freezing (PAGF). The following clinical features, in addition to the operational diagnostic criteria, were supportive of underlying PSP-tau pathology in patients presenting with Parkinsonism: an absence of drug induced dyskinesias, autonomic failure and visual hallucinations the presence of falls within 6 years of disease onset UPSIT scores above the 12th percentile for gender and age and abnormalities in auditory startle response and auditory blink reflex. PSP-tau pathology always involved the subthalamic nucleus (STN), globus pallidus (GP) and substantia nigra (SN), but involvement outside these structures was variable and could be sub-divided into at least three different patterns. Severe tau pathology in PSP-P and PAGF was restricted to the GP, STN and SN. Co-existent pathological diagnoses did not differ between RS, PSP-P and PAGF. The ratio of pathological 4-repeat:3-repeat tau in PSP was variable. In RS the mean ratio was higher than in PSP-P (2.84 vs. 1.63 (p<0.003). Mutations of MAPT did not account for the diversity of clinical features The proposed clinical and pathological sub-classification of PSP will be helpful in clinical practice. Pathological and biochemical correlates raise the possibility that PSP-P and PAGF may represent discrete nosological entities. Further research may ultimately lead to their absolute distinction from Richardson's syndrome and related tauopathies.

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