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.
ReviewProgressive supranuclear palsy: clinicopathological concepts and diagnostic challenges
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 (105)
Tau protein and neurodegeneration
Semin Cell Dev Biol
(2004)- et al.
Progressive supranuclear palsy phenotype secondary to CADASIL
Parkinsonism Relat Disord
(2003) - et al.
Blink reflex elicited by auditory stimulation in the rabbit
J Neurol Sci
(1986) - et al.
Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology
Neuron
(2004) - et al.
Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia
Lancet Neurol
(2008) - et al.
Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical supranuclear gaze and pseudobulbar palsy, nuchal dystonia and dementia
Arch Neurol
(1964) - et al.
Preliminary NINDS neuropathologic criteria for Steele–Richardson–Olszewski syndrome (progressive supranuclear palsy)
Neurology
(1994) - et al.
Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders
J Neuropathol Exp Neurol
(1996) - et al.
Atypical unclassifiable parkinsonism on Guadeloupe: an environmental toxic hypothesis
Mov Disord
(2005) - et al.
Parkinsonism, dementia and vertical gaze palsy in a Guamanian with atypical neuroglial degeneration
Acta Neuropathol
(2000)