Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome
1Queen Square Brain Bank for Neurological Disorders, 2Sara Koe PSP Research Centre, 3Reta Lila Weston Institute of Neurological Studies, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK and 4Faculty of Medicine (Neurosciences), Monash University (Alfred Hospital Campus), Melbourne, Australia
Correspondence to: Prof. Tamas Revesz, Queen Square Brain Bank for Neurological Disorders, 1 Wakefield St, London, WC1N 1PJ, UK E-mail: t.revesz{at}ion.ucl.ac.uk
Clinical syndromes associated with progressive supranuclear palsy-tau pathology now include progressive supranuclear palsy-parkinsonism (PSP-P), in addition to classic Richardson's syndrome (RS) and pure akinesia with gait freezing (PAGF). Although pathological heterogeneity of progressive supranuclear palsy (PSP) has also been established, attempts to correlate this with clinical findings have only rarely provided conclusive results. The aim of this study was to investigate whether regional variations in the types of tau lesions or differences in overall tau load may explain the clinical differences between the RS, PSP-P and PAGF. Quantitative tau pathology assessment was performed in 17 brain regions in 42 cases of pathologically diagnosed PSP (22 RS, 14 PSP-P and 6 PAGF). Neurofibrillary tangles, tufted astrocytes, coiled bodies and thread pathology were quantitated and a grading system was developed separately for each region. Using these grades the overall tau load was calculated in each case. To establish a simplified system for grading the severity of tau pathology, all data were explored to identify the minimum number of regions that satisfactorily summarized the overall tau severity. The subthalamic nucleus, substantia nigra and globus pallidus were consistently the regions most severely affected by tau pathology. The mean severity in all regions of the RS group was higher than in PSP-P and PAGF, and the overall tau load was significantly higher in RS than in PSP-P (P = 0.002). Using only the grade of coiled body + thread lesions in the substantia nigra, caudate and dentate nucleus, a reliable and repeatable 12-tiered grading system was established (PSP-tau score: 0, mild tau pathology, restricted distribution; >7, severe, widespread tau pathology). PSP-tau score was negatively correlated with disease duration (Spearman's rho –0.36, P = 0.028) and time from disease onset to first fall (Spearman's rho –0.49, P = 0.003). The PSP-tau score in PSP-P (median 3, range 0–5) was significantly lower than in RS (median 5, range 2–10, Mann–Whitney U, P < 0.001). The two cases carrying the tau-H2 protective allele had the two lowest PSP-tau scores. We have identified significant pathological differences between the major clinical syndromes associated with PSP-tau pathology and the restricted, mild tau pathology in PSP-P supports its clinical distinction from RS. The grading system we have developed provides an easy-to-use and sensitive tool for the morphological assessment of PSP-tau pathology and allows for consideration of the clinical diversity that is known to occur in PSP.
Key Words: progressive supranuclear palsy; PSP; Richardson's syndrome; PSP-parkinsonism; tau
Abbreviations: CB, coiled body; NFT, neurofibrillary tangle; PAGF, pure akinesia with gait freezing; PSP, progressive supranuclear palsy; PSP-P, progressive supranuclear palsy-parkinsonism; RS, Richardson's syndrome; TA, tufted astrocyte
Received February 19, 2007. Revised March 27, 2007. Accepted April 5, 2007.
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