Elsevier

The Lancet Neurology

Volume 8, Issue 3, March 2009, Pages 270-279
The Lancet Neurology

Review
Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges

https://doi.org/10.1016/S1474-4422(09)70042-0Get rights and content

Summary

Progressive supranuclear palsy (PSP) is a clinical syndrome comprising supranuclear palsy, postural instability, and mild dementia. Neuropathologically, PSP is defined by the accumulation of neurofibrillary tangles. Since the first description of PSP in 1963, several distinct clinical syndromes have been described that are associated with PSP; this discovery challenges the traditional clinicopathological definition and complicates diagnosis in the absence of a reliable, disease-specific biomarker. We review the emerging nosology in this field and contrast the clinical and pathological characteristics of the different disease subgroups. These new insights emphasise that the pathological events and processes that lead to the accumulation of phosphorylated tau protein in the brain are best considered as dynamic processes that can develop at different rates, leading to different clinical phenomena. Moreover, for patients for whom the diagnosis is unclear, clinicians must continue to describe accurately the clinical picture of each individual, rather than label them with inaccurate diagnostic categories, such as atypical parkinsonism or PSP mimics. In this way, the development of the clinical features can be informative in assigning less common nosological categories that give clues to the underlying pathology and an understanding of the expected clinical course.

Introduction

In 1963, J Clifford Richardson described an “unusual syndrome” of postural instability, supranuclear gaze palsy, mild dementia, and progressive axial rigidity and bulbar palsy.1 His collaborators, Jerzy Olszewski and John Steele, identified consistent pathological findings that were eventually used to establish this unusual syndrome as a new nosological condition: progressive supranuclear palsy (PSP).1 Pathologically, PSP is defined by the accumulation of tau protein and neuropil threads, mainly in the pallidum, subthalamic nucleus, red nucleus, substantia nigra, pontine tegmentum, striatum, oculomotor nucleus, medulla, and dentate nucleus.2, 3 Similar histopathological findings, however, can be seen in patients with postencephalitic parkinsonism (PEP) and the atypical parkinsonian syndromes of Guam and Guadeloupe,4, 5, 6, 7 thus complicating the pathological diagnosis of PSP. The most specific features of PSP pathology are star-shaped astrocytic tufts and neurofibrillary tangles that can be seen with light microscopy and that immunostain strongly with antibodies to tau. These features support the role of tau dysfunction in the pathogenesis of the disorder and the classification of PSP by neuropathologists as a primary tauopathy.8, 9 Despite advances in our understanding of the disease process, there are no reliable diagnostic biomarkers for PSP, and accurate diagnosis depends on clinical acumen.

Although the classic PSP syndrome presents with clear clinical signs in its later stages, several clinical variants have recently been identified that are less distinctive, and many patients with PSP are initially thought to have Parkinson's disease (PD) or multiple system atrophy.10 We refer to the classic clinical picture of PSP as Richardson's syndrome (also known as Steele–Richardson–Olszewski syndrome) to distinguish it from the other clinical variants that fall under pathologically defined PSP.11 These clinicopathological variants can be separated by differences in their severity, regions of pathology, and clinical features, and are linked by the accumulation of neurofibrillary tangles and similar natural histories that lead to death, usually within 6–12 years of diagnosis (figure 1). No accepted guidelines for the clinical diagnosis of these variants have been compiled, and the variants are often labelled as “atypical PSP”. We have termed the commonest of these variants PSP-parkinsonism (PSP-P) and have shown that the associated tau pathology is less severe and presents in a more restricted distribution than the tau pathology seen in patients with Richardson's syndrome (classic PSP).10 Some patients present with early gait disturbance, micrographia, and hypophonia, with eventual gait freezing. This variant has been labelled PSP-pure akinesia with gait freezing (PAGF).12 Patients with PAGF have severe atrophy and neuronal loss only in the globus pallidus, substantia nigra, and subthalamic nucleus.12, 13 Other groups of patients present with progressive, asymmetric dystonia, apraxia, and cortical sensory loss (PSP-corticobasal syndrome [PSP-CBS]) or apraxia of speech (PSP-progressive non-fluent aphasia [PSP-PNFA]) and have more severe cortical tau pathology than the patients with PSP-P.14, 15

Here, we review recent advances in the understanding of the pathological heterogeneity of PSP subtypes and highlight the similarities and differences between PSP and other tauopathies. Our aim is to integrate these findings into the emerging picture of the range of clinical subtypes of PSP and to discuss the implications for the diagnosis of this complex and devastating disorder.

Section snippets

Pathological heterogeneity

The operational diagnostic criteria for the pathological diagnosis of PSP are derived from the first detailed studies made by Olszewski and Steele in 1964.1 Although they found “no pathological evidence of frontal, cortical, or white matter involvement of consequence”, more recent reports that have used up-to-date staining techniques have shown cortical tau pathology to be a common finding in PSP.1, 9 The pathological heterogeneity of PSP has recently been examined in detail in two post-mortem

Clinical heterogeneity

The early clinical features of PSP are often subtle and can be difficult to discern from those of other physical or psychological disorders.42 Early diagnosis is a challenge in primary health-care settings, and the definitive clinical diagnosis is commonly delayed for many months. Fewer than half of patients with pathologically diagnosed PSP will have received a diagnosis of PSP at presentation, and 20% will have had a different diagnosis at the time of death.43, 44, 45, 46, 47 However, in most

Conclusions

The classic Richardson's syndrome is the most distinctive clinical disorder related to PSP-tau pathology. As with other neurodegenerative conditions, including Alzheimer's disease,30 idiopathic Parkinson's disease,98 and even among patients with monogenetic parkinsonism99 and frontotemporal dementias,100 there is clinical variability among patients with PSP-tau pathology. The identification of PSP-P, PAGF, PSP-CBS, and PNFA indicate that there are other related but distinct clinical syndromes

Search strategy and selection criteria

References for this Review were identified through searches of PubMed from 1966 until October, 2008, with the terms “progressive supranuclear palsy” and “corticobasal syndrome”. Articles were also identified through searches of the authors' own files. We selected papers in which clinicopathological correlations had been made, and relied less on phenomenological descriptions from clinically defined cases. Only papers published in English were reviewed.

References (105)

  • K Oyanagi et al.

    Substantia nigra in progressive supranuclear palsy, corticobasal degeneration, and parkinsonism–dementia complex of Guam: specific pathological features

    J Neuropathol Exp Neurol

    (2001)
  • M Yamazaki et al.

    Progressive supranuclear palsy on Guam

    Acta Neuropathol

    (2001)
  • R de Silva et al.

    Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies

    Neuropathol Appl Neurobiol

    (2003)
  • DW Dickson
  • DR Williams et al.

    Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism

    Brain

    (2005)
  • DR Williams et al.

    Clifford Richardson and 50 years of progressive supranuclear palsy

    Neurology

    (2008)
  • DR Williams et al.

    Pure akinesia with gait freezing: A third clinical phenotype of progressive supranuclear palsy

    Mov Disord

    (2007)
  • Z Ahmed et al.

    Clinical and neuropathologic features of progressive supranuclear palsy with severe pallido–nigro–luysial degeneration and axonal dystrophy

    Brain

    (2008)
  • Y Tsuboi et al.

    Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome

    Mov Disord

    (2005)
  • KA Josephs et al.

    Atypical progressive supranuclear palsy underlying progressive apraxia of speech and nonfluent aphasia

    Neurocase

    (2005)
  • DR Williams et al.

    Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome

    Brain

    (2007)
  • KA Jellinger

    Different tau pathology pattern in two clinical phenotypes of progressive supranuclear palsy

    Neurodegenerative Dis

    (2008)
  • DR Williams et al.

    Pathological tau burden and distribution distinguishes PSP-P from Richardson's syndrome

    Brain

    (2007)
  • KE Murphy et al.

    Excessive dopamine neuron loss in progressive supranuclear palsy

    Mov Disord

    (2008)
  • MA Sanchez-Gonzalez et al.

    The primate thalamus is a key target for brain dopamine

    J Neurosci

    (2005)
  • HK Park et al.

    Functional brain imaging in pure akinesia with gait freezing: [(18)F] FDG PET and [(18)F] FP-CIT PET analyses

    Mov Disord

    (2008)
  • DR Williams et al.

    The auditory startle response in parkinsonism may reveal the extent but not type of pathology

    J Neurol

    (2008)
  • JJ Hauw et al.
  • J Olszewski et al.

    Pathological report on six cases of heterogeneous system degeneration

    J Neuropathol Exp Neurol

    (1963)
  • I Wakayama et al.

    Rare neuropil threads in amyotrophic lateral sclerosis and parkinsonism-dementia on Guam and in the Kii Peninsula of Japan

    Dementia

    (1993)
  • K Oyanagi et al.

    Distinct pathological features of the gallyas- and tau-positive glia in the Parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam

    J Neuropathol Exp Neurol

    (1997)
  • M Yamazaki et al.

    Tau-positive fine granules in the cerebral white matter: a novel finding among the tauopathies exclusive to parkinsonism-dementia complex of Guam

    J Neuropathol Exp Neurol

    (2005)
  • D Caparros-Lefebvre et al.

    Guadeloupean parkinsonism: a cluster of progressive supranuclear palsy-like tauopathy

    Brain

    (2002)
  • DW Dickson et al.

    Office of Rare Diseases neuropathologic criteria for corticobasal degeneration

    J Neuropathol Exp Neurol

    (2002)
  • T Mizuno et al.

    Discrepancy between clinical and pathological diagnoses of CBD and PSP

    Journal of Neurology

    (2005)
  • AM Pittman et al.

    Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration

    J Med Genet

    (2005)
  • DR Williams

    Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau

    Intern Med J

    (2006)
  • P Poorkaj et al.

    An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype

    Ann Neurol

    (2002)
  • DR Williams et al.

    Genetic variation at the tau locus and clinical syndromes associated with progressive supranuclear palsy

    Mov Disord

    (2007)
  • HR Morris et al.

    Sequence analysis of tau in familial and sporadic progressive supranuclear palsy

    JNNP

    (2002)
  • P Pastor et al.

    Familial atypical progressive supranuclear palsy associated with homozigosity for the delN296 mutation in the tau gene

    Ann Neurol

    (2001)
  • R Ros et al.

    Genetic linkage of autosomal dominant progressive supranuclear palsy to 1q31.1

    Ann Neurol

    (2005)
  • HR Morris et al.

    Tau exon 10 +16 mutation FTDP-17 presenting clinically as sporadic young onset PSP

    Neurology

    (2003)
  • PM Stanford et al.

    Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations

    Brain

    (2000)
  • RP Friedland et al.

    NIH conference. Alzheimer disease: clinical and biological heterogeneity

    Annals of Internal Medicine

    (1988)
  • DR Williams et al.

    How do patients with parkinsonism present? A clinicopathological study

    Internal Medicine Journal

    (2008)
  • Y Osaki et al.

    Accuracy of clinical diagnosis of progressive supranuclear palsy

    Mov Disord

    (2004)
  • AJ Hughes et al.

    The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service

    Brain

    (2002)
  • HR Morris et al.

    Pathological, clinical and genetic heterogeneity in progressive supranuclear palsy

    Brain

    (2002)
  • SE Daniel et al.

    The clinical and pathological spectrum of Steele–Richardson–Olszewski syndrome (progressive supranuclear palsy): a reappraisal

    Brain

    (1995)
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