Progressive Supranuclear Palsy: Clinicopathological Concepts and Diagnostic Challenges
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Review Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges David R Williams, Andrew J Lees Lancet Neurol 2009; 8: 270–79 Progressive supranuclear palsy (PSP) is a clinical syndrome comprising supranuclear palsy, postural instability, and Faculty of Medicine mild dementia. Neuropathologically, PSP is defi ned by the accumulation of neurofi brillary tangles. Since the fi rst (Neurosciences), Monash description of PSP in 1963, several distinct clinical syndromes have been described that are associated with PSP; this University, Melbourne, discovery challenges the traditional clinicopathological defi nition and complicates diagnosis in the absence of a reliable, Australia (D R Williams FRACP); Reta Lila Weston Institute of disease-specifi c biomarker. We review the emerging nosology in this fi eld and contrast the clinical and pathological Neurological Studies, characteristics of the diff erent disease subgroups. These new insights emphasise that the pathological events and University College London, processes that lead to the accumulation of phosphorylated tau protein in the brain are best considered as dynamic London, UK (A J Lees FRCP, processes that can develop at diff erent rates, leading to diff erent clinical phenomena. Moreover, for patients for whom D R Williams); and Queen Square Brain Bank for the diagnosis is unclear, clinicians must continue to describe accurately the clinical picture of each individual, rather Neurological Disorders, than label them with inaccurate diagnostic categories, such as atypical parkinsonism or PSP mimics. In this way, the University College London, development of the clinical features can be informative in assigning less common nosological categories that give clues London, UK (A J Lees) to the underlying pathology and an understanding of the expected clinical course. Correspondence to: David R Williams, Faculty of 4–7 Medicine (Neurosciences), Introduction parkinsonian syndromes of Guam and Guadeloupe, thus Monash University, In 1963, J Cliff ord Richardson described an “unusual complicating the pathological diagnosis of PSP. The most Alfred Hospital Campus, syndrome” of postural instability, supranuclear gaze palsy, specifi c features of PSP pathology are star-shaped astrocytic Commercial Road, Melbourne mild dementia, and progressive axial rigidity and bulbar tufts and neurofi brillary tangles that can be seen with light 3004, Australia 1 [email protected]. palsy. His collaborators, Jerzy Olszewski and John Steele, microscopy and that immunostain strongly with antibodies edu identifi ed consistent pathological fi ndings that were to tau. These features support the role of tau dysfunction eventually used to establish this unusual syndrome as a in the pathogenesis of the disorder and the classifi cation new nosological condition: progressive supranuclear palsy of PSP by neuropathologists as a primary tauopathy.8,9 (PSP).1 Pathologically, PSP is defi ned by the accumulation Despite advances in our understanding of the disease of tau protein and neuropil threads, mainly in the pallidum, process, there are no reliable diagnostic biomarkers for subthalamic nucleus, red nucleus, substantia nigra, PSP, and accurate diagnosis depends on clinical acumen. pontine tegmentum, striatum, oculomotor nucleus, Although the classic PSP syndrome presents with clear medulla, and dentate nucleus.2,3 Similar histopathological clinical signs in its later stages, several clinical variants fi ndings, however, can be seen in patients with have recently been identifi ed that are less distinctive, and postencephalitic parkinsonism (PEP) and the atypical 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 Postencephalitic parkinsonism pathology syndrome (also known as Steele–Richardson–Olszewski Parkinsonism dementia complex Progressive supranuclear syndrome) to distinguish it from the other clinical variants of Guam pathology palsy-parkinsonism that fall under pathologically defi ned PSP.11 These clinico- pathological variants can be separated by diff erences in Corticobasal Progressive non-fluent Pure akinesia with gait freezing their severity, regions of pathology, and clinical features, degeneration aphasia pathology and are linked by the accumulation of neurofi brillary Corticobasal syndrome Richardson’s syndrome tangles and similar natural histories that lead to death, usually within 6–12 years of diagnosis (fi gure 1). No accepted guidelines for the clinical diagnosis of these bvFTD Progressive supranuclear palsy pathology variants have been compiled, and the variants are often FTDP-17 pathology labelled as “atypical PSP”. We have termed the commonest PiD pathology of these variants PSP-parkinsonism (PSP-P) and have shown that the associated tau pathology is less severe and Predominant pathological distribution presents in a more restricted distribution than the tau pathology seen in patients with Richardson’s syndrome Cortical Brainstem (classic PSP).10 Some patients present with early gait disturbance, micrographia, and hypophonia, with eventual Figure !: Distribution of tau pathology in clinical and pathological nosological syndromes of progressive gait freezing. This variant has been labelled PSP-pure supranuclear palsy 12 Dashed boxes=clinical syndromes. Solid boxes=pathologically defi ned diseases. PiD=Pick’s disease. akinesia with gait freezing (PAGF). Patients with PAGF FTDP-17=frontotemporal dementia with parkinsonism-17. bvFTD=behavioural variant of frontotemporal have severe atrophy and neuronal loss only in the globus dementia.3,6,45,60,65 pallidus, substantia nigra, and subthalamic nucleus.12,13 270 www.thelancet.com/neurology Vol 8 March 2009 Review Other groups of patients present with progressive, Richardson’s syndrome, although the pattern of asymmetric dystonia, apraxia, and cortical sensory loss distribution between both groups was similar: the (PSP-corticobasal syndrome [PSP-CBS]) or apraxia of subthalamic nucleus and substantia nigra were the regions speech (PSP-progressive non-fl uent aphasia [PSP-PNFA]) that were most severely aff ected (fi gure 2).16–18 The regions and have more severe cortical tau pathology than the where the diff erences in severity were greatest were the patients with PSP-P.14,15 cerebral cortex, pons, caudate, cerebellar dentate nucleus, Here, we review recent advances in the understanding and cerebellar white matter. Although the substantia nigra of the pathological heterogeneity of PSP subtypes and pars compacta and ventrotegmental areas are aff ected in highlight the similarities and diff erences between PSP Richardson’s syndrome and PD, the severity of the and other tauopathies. Our aim is to integrate these pathology is substantially higher in the former.19 The fi ndings into the emerging picture of the range of clinical dopamine cell groups in the substantia nigra pars subtypes of PSP and to discuss the implications for the compacta and ventrotegmental areas innervate the motor diagnosis of this complex and devastating disorder. and limbic cortical and thalamic regions, infl uencing motor function and executive and other cognitive and Pathology behavioural features. The destruction of these cell groups Pathological heterogeneity is likely to contribute to levodopa non-responsiveness and The operational diagnostic criteria for the pathological frontostriatal cognitive dysfunction in patients with PSP.20 diagnosis of PSP are derived from the fi rst detailed studies Although the substantia nigra is severely aff ected in PSP-P, made by Olszewski and Steele in 1964.1 Although they the clinical features that distinguish PSP-P from found “no pathological evidence of frontal, cortical, or Richardson’s syndrome, including tremor and moderate white matter involvement of consequence”, more recent levodopa responsiveness, might be due to less severe reports that have used up-to-date staining techniques have depletion of dopamine in the extranigral midbrain in shown cortical tau pathology to be a common fi nding in PSP-P.10 PSP.1,9 The pathological heterogeneity of PSP has recently The distribution and severity of pathological changes in been examined in detail in two post-mortem series, in patients with PAGF have been investigated in several which the extent of tau pathology was used as a surrogate small clinicopathological series. In one detailed study, marker for pathological severity in patients with patients with pathologically diagnosed PSP who also had Richardson’s syndrome and PSP-P.16,17 The patients with severe atrophy, neuronal loss, and gliosis in the globus PSP-P had less severe tau pathology than those with pallidus, substantia nigra, and subthalamic nucleus were A Key to anatomical structures B PSP-P or PAGF C Richardson’s syndrome, PSP-P, or PAGF Frontal lobe Caudate Parietal GPi lobe STN Putamen GPe Substantia nigra Griseum pontis Dentate nucleus Cerebellar white matter D Richardson’s syndrome, PSP-P, or PAGF E Richardson’s syndrome F Richardson’s syndrome Figure ": Severity of PSP tau pathology varies according to distribution Brown=mild severity. Purple=moderate severity. Red=severe. Green=very severe. PSP=progressive supranuclear palsy. PSP-P=PSP-parkinsonism. PAGF=pure akinesia with gait freezing. STN=subthalamic nucleus. GPi=globus pallidus interna. GPe=globus pallidus externa. Reproduced with permission from Oxford University Press.18 www.thelancet.com/neurology Vol 8 March 2009 271 Review selected from a large autopsy