title: Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism.
abstract: The clinical diagnosis of progressive supranuclear palsy (PSP) relies on the identification of characteristic signs and symptoms. A proportion of pathologically diagnosed cases do not develop these classic features, prove difficult to diagnose during life and are considered as atypical PSP. The aim of this study was to examine the apparent clinical dichotomy between typical and atypical PSP, and to compare the biochemical and genetic characteristics of these groups. In 103 consecutive cases of pathologically confirmed PSP, we have identified two clinical phenotypes by factor analysis which we have named Richardson's syndrome (RS) and PSP-parkinsonism (PSP-P). Cases of RS syndrome made up 54% of all cases, and were characterized by the early onset of postural instability and falls, supranuclear vertical gaze palsy and cognitive dysfunction. A second group of 33 (32%) were characterized by asymmetric onset, tremor, a moderate initial therapeutic response to levodopa and were frequently confused with Parkinson's disease (PSP-P). Fourteen cases (14%) could not be separated according to these criteria. In RS, two-thirds of cases were men, whereas the sex distribution in PSP-P was even. Disease duration in RS was significantly shorter (5.9 versus 9.1 years, P < 0.001) and age at death earlier (72.1 versus 75.5 years, P = 0.01) than in PSP-P. The isoform composition of insoluble tangle-tau isolated from the basal pons also differed significantly. In RS, the mean four-repeat:three-repeat tau ratio was 2.84 and in PSP-P it was 1.63 (P < 0.003). The effect of the H1,H1 PSP susceptibility genotype appeared stronger in RS than in PSP-P (odds ratio 13.2 versus 4.5). The difference in genotype frequencies between the clinical subgroups was not significant. There were no differences in apolipoprotein E genotypes. The classic clinical description of PSP, which includes supranuclear gaze palsy, early falls and dementia, does not adequately describe one-third of cases in this series of pathologically confirmed cases. We propose that PSP-P represents a second discrete clinical phenotype that needs to be clinically distinguished from classical PSP (RS). The different tau isoform deposition in the basal pons suggests that this may ultimately prove to be a discrete nosological entity.
authors.affiliation: The Queen Square Brain Bank for Neurological Disorders, University College London, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Williams
authors.forename: Rohan
authors.initials: R
authors.lastname: de Silva
authors.forename: Dominic C
authors.initials: DC
authors.lastname: Paviour
authors.forename: Alan
authors.initials: A
authors.lastname: Pittman
authors.forename: Hilary C
authors.initials: HC
authors.lastname: Watt
authors.forename: Linda
authors.initials: L
authors.lastname: Kilford
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lees
mesh_terms: D017668:Age of Onset; D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020734:Parkinsonian Disorders / Q000145:classification / Q000175:diagnosis / Q000235:genetics; D010641:Phenotype; D011149:Pons / Q000737:chemistry; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics; D013494:Supranuclear Palsy, Progressive / Q000145:classification / Q000175:diagnosis* / Q000235:genetics; D013577:Syndrome; D016875:tau Proteins / Q000032:analysis / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D020033:Protein Isoforms; D016875:tau Proteins