Brain, Vol. 125, No. 5, 969-975,
May 2002
© 2002 Guarantors of Brain
Pathological, clinical and genetic heterogeneity in progressive supranuclear palsy
1 Department of Molecular Pathogenesis and 2 Queen Square Brain Bank for Neurological Disorders, Institute of Neurology, Queen Square, London, 3 Reta Lila Weston Institute of Neurological Sciences, Windeyer Building, University College London, London, and 4 Department of Neuroscience, Institute of Psychiatry, King’s College London, London, UK
Correspondence to: Tamas Revesz, Division of Neuropathology, Institute of Neurology, Queen Square, London WC1N 3BG, UK E-mail: trevesz{at}ion.ucl.ac.uk
Received April 30, 2001. Revised December 17, 2001. Accepted January 10, 2002.
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We have identified two groups of patients with clinically typical and atypical, pathologically diagnosed progressive supranuclear palsy (PSP), and investigated their genetic and molecular pathological characteristics. Those with clinically typical PSP are more likely to have the PSP susceptibility genotype and to have the deposition of PSP-type hyperphosphorylated tau protein. The clinically atypical PSP group contains a number of different clinical syndromes, including an L-dopa unresponsive bradykinetic syndrome and a clinical syndrome closely resembling idiopathic Parkinson’s disease. The clinically atypical PSP group are less likely to have the PSP susceptibility genotype and often have the deposition of Alzheimer’s disease paired helical filament type hyperphosphorylated tau. This study suggests that the tau PSP susceptibility genotype is most strongly associated with clinically typical PSP. Neurofibrillary tangle parkinsonian disorders, which pathologically resemble PSP but involve the deposition of Alzheimer’s disease-type tau often without involvement of the tau susceptibility genotype, need to be distinguished for diagnostic and research purposes.
Keywords: genotype; immunoblotting; neurofibrillary tangle; progressive supranuclear palsy; tau
Abbreviations: FTDP-17 = frontotemporal dementia with parkinsonism linked to chromosome 17; NFT = neurofibrillary tangle; PHF = paired helical filament; PSP = progressive supranuclear palsy
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Introduction |
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The characteristic pathological and clinical features of progressive supranuclear palsy (PSP) were first delineated by Steele, Richardson and Olszewski in the early 1960s (Steele et al., 1964
). Like Alzheimer’s disease, the pathology of PSP involves the deposition of abnormally hyperphosphorylated tau containing neurofibrillary tangles (NFTs), but the pathological topography and absence of amyloid plaque formation distinguishes the two disorders (Hauw et al., 1994). PSP presents with progressive gait instability with backwards falls, signs of parkinsonism, a vertical supranuclear gaze palsy, frontal dysfunction, axial rigidity and a pseudo-bulbar palsy (Litvan et al., 1996). Subcortical NFT formation with a predilection for the globus pallidus, subthalamic nucleus, substantia nigra and reticular formation of the midbrain and pons is found on pathological examination. The destruction of the midbrain reticular formation includes damage to nuclei thought to be important in the supranuclear control of vertical gaze, and the widespread damage to basal ganglia output pathways may explain L-dopa unresponsiveness and axial parkinsonism (Hauw et al., 1994). The pathologically based clinical features of PSP have been developed into operational research criteria for the diagnosis of definite, probable or possible PSP (Litvan et al., 1996).
A number of authors have reported different clinical syndromes in patients with pathologically diagnosed PSP. Davis and colleagues reported four patients with atypical presentations of PSP (Davis et al., 1985). Two of these patients had prominent cortical dysfunction and two had normal eye movements. A further larger series of patients with pathologically diagnosed PSP and normal eye movements was reported in 1995, raising the possibility of a ‘clinically atypical’ PSP subgroup, with a more benign prognosis (Daniel et al., 1995). Further detailed analysis of the neuropathology of this group has demonstrated that the patients without a supranuclear gaze palsy have less damage to the omnipause neurones located in the pontine nucleus raphe interpositus (Revesz et al., 1996).
In recent years the molecular pathology of tau deposition in PSP, Alzheimer’s disease and related disorders has been studied intensively. In Alzheimer’s disease the microtubule-associated protein tau is deposited as abnormally phosphorylated paired helical filaments (PHFs) and forms a major triplet of bands on immuno-electrophoresis at 59, 64 and 69 kDa, with a weaker band at 71 kDa (Hanger et al., 1991; Goedert, 1993; Mulot et al., 1994). Dephosphorylation of Alzheimer’s disease tau indicates that it consists of all six isoforms of the alternatively spliced tau gene (Goedert et al., 1992). In contrast, in PSP, tau is deposited as a major doublet of hyperphosphorylated tau of 64 and 69 kDa (Flament et al., 1991), predominantly consisting of the four repeat tau protein isoforms, which contain the microtubule binding domain encoded by the alternatively spliced exon 10 (Mailliot et al., 1998; Spillantini and Goedert, 1998). NFTs in PSP ultrastructurally appear as 15–18 nm straight filaments, but filaments with a long periodicity have also been described (Tellez-Nagel and Wisniewski, 1973; Roy et al., 1974; Lee et al., 2001). Thus, PSP and Alzheimer’s disease differ in the type of tau protein deposition, in addition to the differences in topography and amyloid deposition. It is unclear whether these tau protein differences reflect the specific cell types/regions involved, or are global characteristics of the diseases.
The importance of tau in PSP was underlined by the identification of a genetic susceptibility to PSP defined by the tau H1 haplotype (Conrad et al., 1997; Baker et al., 1999). Although this H1 haplotype accounts for 
70% of control haplotypes it makes up 85–95% of PSP tau haplotypes in clinically diagnosed series (Bennett et al., 1998; Higgins et al., 1998; Oliva et al., 1998; Hoenicka et al., 1999; Morris et al., 1999). The functional consequence of this over-representation of the H1 haplotype in PSP is unknown, although one recent study suggested that it has no major influence on the pathological or biochemical phenotype of PSP (Liu et al., 2001). Furthermore, in rare autosomal dominant FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) families, pathogenic mutations in tau may lead to neurodegeneration (Hutton et al., 1998; Poorkaj et al., 1998; Spillantini et al., 1998), and in some cases the clinical and pathological features of affected family members may closely resemble PSP (Murrell et al., 1997; Delisle et al., 1999; Stanford et al., 2000). This emerging information on the pathology, genetics and pathogenesis of tau-related neurodegeneration has led us to re-examine the features of the ‘clinically atypical’ PSP series reported in 1995 and compare them with ‘clinically typical’ cases, in an attempt to further define the nosology of this condition and to provide more evidence for the possible role of the tau H1 haplotype.
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Genetic analysis
DNA was extracted from frozen brain using standard methods. The tau haplotype was assigned by analysis of the tau intronic microsatellite polymorphism and the exon 9i single nucleotide polymorphism as described previously (Baker et al., 1999
).
Pathological diagnosis
Neuropathologically confirmed cases of PSP in which frozen tissue was available were taken from the Queen Square Brain Bank for Neurological Disorders, at the Institute of Neurology (London, UK). After post-mortem the brains were bisected and one half brain immediately frozen and stored at –70°C, while the other half was immersed in 10% (v/v) neutral formalin. Tissue blocks were processed using standard protocols.
Tau protein analysis
Whenever it was available the globus pallidus was selected for protein analysis (23 cases). In eight cases the pons was also used for additional studies, and in the three cases in which these areas were not available, the putamen was selected. Insoluble tau was extracted using a previously described method (Hanger et al., 1998). In brief, 0.1–0.2 g of brain tissue was hand-homogenized in 50 mM MES (2-[N-morpholino]ethanesulfonic acid) buffer, pH 6.5, containing 1 M NaCl, 50 mM imidazole, 0.1 mM phenylmethylsulphonyl fluoride (PMSF), 20 mM NaF, 10 mM Na+ pyrophosphate and 25 mM Naß-glycerophosphate, and the homogenate was centrifuged at 27 000 g for 30 min at 4°C. The supernatant was retained and re-centrifuged at 100 000 g for 60 min at 4°C. The pellet of the second centrifugation step was solubilized in Laemmli sample buffer and analysed on sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS–PAGE) using a discontinuous buffer system (Laemmli, 1970). Western blotting with the rabbit polyclonal antiserum TP70 (Brion et al., 1993), which recognizes all forms of tau, and with the phosphorylation-dependent monoclonal antibody PHF-1 (a kind gift from P. Davies) was subsequently carried out on the resolved proteins using enhanced chemiluminesence (Amersham Biosciences, Little Chalfont, UK).
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The results presented below are summarized in Tables 1 and 2.
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Clinical features
Among 26 pathologically diagnosed cases of PSP we identified 15 clinically atypical and 11 clinically typical cases. The clinical features were identified on the basis of retrospective notes review and the cases were referred from a variety of sources between 1987 and 1998. In some case records there was incomplete recording of eye movement examination, onset symptoms and onset of balance disturbance. The clinically typical cases all met the Tolosa criteria for PSP with slow vertical saccades or a more severe vertical eye movement disorder, falls/postural instability and additional supportive features (Tolosa et al., 1994
). Five of these cases did not have falls in the first year following symptom onset, and in one case the presence or absence of falls was not documented; therefore, only five of these clinically typical cases met the more rigorous NINDS criteria for the diagnosis of PSP, which specify falls in the first year of symptoms (Litvan et al., 1996). The clinically atypical group had a variety of clinical syndromes. Four clinically atypical cases had idiopathic Parkinson’s disease-like presentations with an asymmetrical onset and a good response to L-dopa treatment. Four cases had non-L-dopa-responsive parkinsonism, and three of these four cases were documented to have normal eye movements. Two cases had an eye movement disorder with relatively preserved balance and some response to L-dopa. One case had a corticobasal degeneration syndrome with asymmetrical dystonia and apraxia. The remaining four cases had insufficient clinical documentation for confident clinical diagnosis, but three of these cases had significant postural instability, raising the possibility that they had an unrecognized eye movement disorder and were in fact typical PSP cases.
Pathological features
The distribution of NFTs in the cases identified was consistent with the diagnosis of PSP. Some cases had more prominent cortical involvement, in particular the mesial temporal cortex, and some cases had sparing of one of the areas typically affected in PSP, usually the basis pontis. These atypical features were more common in the clinically atypical groups (pathologically atypical features 7/15 versus 2/11). In order to determine whether concurrent Alzheimer-type pathology could account for the differences in tau deposition, we examined the cases for Alzheimer-type pathology. The majority of the cases with Alzheimer-type pathology had mesial temporal NFTs with or without mesial temporal and in some cases also with neocortical, mainly diffuse, plaques. Such cases were defined as showing pathological ageing. In two cases the number of neuritic plaques was such that, using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria, they met the diagnostic criteria of possible Alzheimer’s disease (Mirra et al., 1991). The average age at death of cases with extra-hippocampal plaque formation cases was greater than those without (80 versus 72 years).
Genetic and molecular features
The majority of the clinically typical PSP cases had the normal PSP tau protein electrophoretic pattern (Flament et al., 1991) as compared with about one-third of the clinically atypical cases (73% versus 33%). This pattern of the insoluble tau-enriched protein fraction labelled with TP70 contains the upper two bands of PHF-tau plus a fourth, faint, slowest migrating protein band (Fig. 1, lanes 1 and 2). However, abnormal PSP tau protein profiles could be divided into two types of pattern: the first banding pattern was very similar to PHF-tau in that there were three major protein species that aligned with the three major tau bands in PHF-tau (Fig. 1, lanes 1 and 3), as well as the fourth, faint protein species, which is present in both PHF-tau and PSP-tau. The second abnormal PSP tau protein array demonstrated six to eight protein bands, which migrated similarly to the six recombinant tau isoforms (Fig. 1, lanes 4 and 5). Interestingly, when the normal and abnormal PSP samples were probed with the phosphorylation-dependent antibody PHF-1, they showed a similar tau protein staining pattern (Fig. 1, lanes 6–8), although the relative intensity of staining of the tau bands varied between cases. The fourth uppermost weak band was more readily observed with the PHF-1 antibody (Fig. 1, lanes 6–8). The occurrence of abnormal western blot profiles did not correlate with the presence of Alzheimer-type pathology (9/19 versus 3/7) or of pathologically atypical features (5/9 versus 8/17).
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All clinically typical, pathologically typical PSP cases were homozygous for the PSP susceptibility genotype H1H1, compared with 73% of the clinically atypical cases. Conversely, the majority of all cases with the deposition of the normal PSP-type tau possessed the PSP susceptibility genotype (12/13, 92%).
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Discussion |
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This study suggests that there may be a clinically atypical PSP subgroup in which a classical distribution of PSP pathology occurs, but with the deposition of Alzheimer’s disease-type tau protein rather than PSP-type tau. The atypical PSP subgroup, which is defined on the basis of an atypical clinical presentation, is less likely to have the PSP susceptibility genotype and more likely to have an Alzheimer’s disease tau deposition pattern. Some of these cases are likely to correspond to the pathologically atypical PSP subgroup defined in the preliminary NINDS criteria for the pathological diagnosis of PSP. The pathologically atypical subgroup was defined by more marked cortical involvement and sparing of some subcortical areas, including the basis pontis (Hauw et al., 1994
). The differences in tau protein deposition in this series cannot be explained by regional differences in tau pathology, since the same brain areas were studied, and is not explained by concurrent Alzheimer-type pathology associated with ageing. Previous studies have shown that in PSP cases a PHF-type tau triplet electrophoretic migration pattern may be seen on immunoblots from tissue samples of the mediotemporal region when it is affected by NFT formation related to ageing. In such cases, however, a PSP-type tau doublet pattern is seen when tissue samples from areas other than the mediotemporal region are used for immunoblotting (Vermersch et al., 1994; Schmidt et al., 1996). There are a number of arguments supporting the notion that pathological ageing alone does not explain the abnormal tau protein patterns seen in our atypical groups. (i) There was no difference in the involvement by senile plaques and Alzheimer’s disease-type NFTs between the disease groups. (ii) In this study the globus pallidus and pontine base were used for immunoblotting in all but three cases, as these structures are not usually affected by Alzheimer’s disease-type neurofibrillary pathology (Braak and Braak, 1994). The value of this approach is supported by our finding of a normal PSP-type tau doublet pattern on the immunoblots of the two (one clinically typical and one atypical) PSP cases, in which the diagnosis of possible Alzheimer’s disease was established, in addition to PSP.
This combination of molecular and topographical pathology in these Caucasian cases is most similar to the pathology seen in the parkinsonism dementia complex of Guam (PDC), the FTDP-17 family with the tau R406W mutation and post-encephalitic parkinsonism (PEP) (Geddes et al., 1993; Reed et al., 1997). In these conditions subcortical deposition of PHF-type tau occurs (Buee-Scherrer et al., 1997; Reed et al., 1997; Perez-Tur et al., 1999). However, in these conditions mesial temporal involvement may be more extensive than is seen in PSP, and this is usually accompanied by clinical amnesia, in PDC and FTDP-17. PDC, PEP and R406W cases do not usually have an idiopathic Parkinson’s disease-type clinical presentation. There are three further conditions in which subcortical tau NFT deposition occurs with parkinsonism. These are autosomal recessive parkinsonism linked to chromosome 6 in one reported case (Mori et al., 1998), NFT parkinsonism as described by Rajput et al. (1989) and Alzheimer’s disease-associated parkinsonism (Daniel and Lees, 1991). Detailed molecular studies of these conditions are not available, and it is not clear how closely they resemble the atypical PSP cases described in this series. However, although the neuropathology of parkin mutation cases may include NFT deposition, the atypical PSP cases in this series present at an older age (Lucking et al., 2000). NFT parkinsonism as described by Rajput et al. (1989) predominantly involves the substantia nigra and locus coeruleus, but not other subcortical sites such as the subthalamic nucleus, which are characteristically involved in PSP. The atypical PSP cases described in this series had a more widespread subcortical NFT deposition. Unlike the atypical PSP cases, the Alzheimer’s disease-associated parkinsonism cases were associated with sufficient amyloid plaque formation to be classified as Alzheimer’s disease (Daniel and Lees, 1991).
The initial description of the tau genotype–PSP association was based on a pathologically defined series and indicated a 95% A0/A0 frequency among PSP patients. Subsequent series that have included clinically diagnosed cases have indicated a lesser association between A0/A0 and PSP, with the homozygote genotype frequency at 70–80%. Our data indicate that when the strictest criteria for PSP diagnosis are used, and this includes pathological, biochemical and clinical information, the associated H1/H1 genotype frequency is 100%.
Although a relatively small number of cases have been studied in this series, the fact that there is an association between the tau H1H1 genotype and the deposition of normal PSP-type tau, regardless of the clinical presentation, may give some further indication of the role of the H1 haplotype in the pathogenesis of PSP. In FTDP-17 families PSP-type tau protein deposition occurs either in families with a coding mutation of exon 10 or in families with a splice-site mutation, which increases the splicing in of exon 10 at the RNA level (Hutton et al., 1998). By extension, the pathogenesis of PSP may involve similar mechanisms, and some data support a change in the splicing of exon 10 in RNA analysis from post-mortem PSP tissue (Chambers et al., 1999). This may be related in some way to the H1 haplotype.
The molecular pathological data in this series argue against a region-specific tau deposition response, as has been suggested may occur in Pick’s disease (Delacourte et al., 1998). In this study, tissue from the same area may contain either Alzheimer’s disease-type tau or PSP-type tau, and in cases where both the brainstem and basal ganglia have been examined this has been found to be consistent. This argues that the type of tau deposited is disease- rather than region-specific. However, since the protein analysis is performed on homogenized brain areas we cannot exclude the possibility of involvement of different cellular populations within these areas, and this can only be properly examined by techniques such as in situ mRNA hybridization.
In summary, our data indicate that several discrete clinico-pathological entities may lie within the spectrum of pathologically diagnosed PSP. However, the presence of the doublet PSP-tau deposition is correlated with a typical clinical presentation and the presence of the PSP susceptibility genotype. This study reinforces NFT diseases as an occasional pathological basis for a clinical Parkinson’s disease-type syndrome and suggests possible pathways by which the susceptibility genotype may increase the likelihood of PSP development.
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Acknowledgements |
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We wish to thank Linda Elliott and Hardev Sangha for technical assistance, and the many UK neurologists who allowed us to study their cases. H.R.M. was an MRC Clinical Training Fellow and this work was supported by the PSP (Europe) Association and the Wellcome Trust.
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D. R. Williams, R. de Silva, D. C. Paviour, A. Pittman, H. C. Watt, L. Kilford, J. L. Holton, T. Revesz, and A. J. Lees Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism Brain, June 1, 2005; 128(6): 1247 - 1258. [Abstract] [Full Text] [PDF]
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D. C. Paviour, A. J. Lees, K. A. Josephs, T. Ozawa, M. Ganguly, C. Strand, A. Godbolt, R. S. Howard, T. Revesz, and J. L. Holton Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes: broadening the clinical picture to include progressive supranuclear palsy Brain, November 1, 2004; 127(11): 2441 - 2451. [Abstract] [Full Text] [PDF]
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