Update on Progressive Supranuclear Palsy
By Lawrence I. Golbe, MD
Professor of Neurology, UMDNJ-Robert Wood Johnson Medical School
New Brunswick, NJ
Progressive supranuclear palsy would be one of the last examples of "diagnose and adios" neurology but for the fact that the "diagnose" task has been as elusive as the treatment. Recent advances, however, are bringing this tau aggregation disorder into the modern era of both diagnosis and therapy.
The search for a diagnostic marker for PSP - and its cause - has been advanced by a whole-genome analysis using 288 pooled, autopsy-proven DNA samples.1 It revealed the long-known association at the MAPT (tau) locus on chromosome 17 and a significant lod score on chromosome 11 at a locus with at least two candidate genes. A follow-up whole-genome analysis using 1,106 individual autopsy-proven samples is in progress. One goal will be to confirm or refute recent evidence that the cause of tau aggregation in PSP is excessive tau protein production caused by a defect in the MAPT promoter.2
A CSF marker shows promise for early diagnosis of PSP.3 The ratio of the 33-kDa form of tau to a 55-kDa form is significantly lower in PSP than in controls, in Parkinson's disease and even in the tauopathies Alzheimer's disease and corticobasal degeneration.
Another readily available clinical modality, MRI, shows atrophy of the superior cerebellar peduncle and a 24% median elevation in the apparent diffusion coefficient in that area.4 For individual ADC values, sensitivity and specificity were perfect in distinguishing PSP from controls and from PD. For distinguishing PSP from multiple system atrophy of the parkinsonian type, a separation that has confounded most previous diagnostic markers, the sensitivity was 96% and the specificity 93%.
Experimental neuroprotective treatment of PSP is directed primarily at its mitochondrial energy defect and its tau aggregation. A promising result comes from a small double-blind trial of coenzyme Q-10.5 The six weeks of treatment in 10 patients stabilized or slowed decline as measured by the PSP Rating Scale, the Frontal Assessment Battery and two magnetic resonance spectroscopy-based measures of basal ganglia energy metabolism. Clinicians await confirmation before advising patients to pay for this expensive treatment not covered by prescription insurance.
An ambitious European trial of riluzole in PSP found no neuroprotective benefit.6 That compound, which modestly delays clinical milestones in amyotrophic lateral sclerosis, has protein antiaggregant and other properties suggesting it may do at least as well for PSP. The Neuroprotection and Natural History of Parkinson-Plus Syndromes (NNIPPS) trial of 362 patients with PSP and 398 with multiple system atrophy gave treatment for three years and used death as its primary endpoint. It did succeed in gathering valuable data on the course of those disorders along with DNA samples for future study.
A biochemically different approach to slowing the progression of PSP may be provided by lithium, the old treatment for mood disorders that inhibits glycogen synthase kinase-3 beta (GSK-3β), which abnormally phosphorylates tau in PSP. A multi-center trial powered principally to assess tolerability has been initiated by the NINDS. Lithium has been found to slow progression in amyotrophic lateral sclerosis.7
Conventional physical therapy for gait retraining in PSP has been disappointing. A new study8 recognizes that during gait, patients often fix their gaze on an inappropriate target rather than using visual feedback to aid balance. Combining gait training with a program teaching patients to improve gaze control partly redressed this problem. The technique can be incorporated into routine clinical practice.
Perhaps aiding, perhaps confounding the search for a cause and treatment of PSP is the 2005 delineation of "PSP-parkinsonism."9 This variant comprises about a third of PSP cases, while the classic "Richardson's syndrome" type comprises half. PSP-P progresses more slowly than RS and features more levodopa responsiveness, tremor, asymmetry, bradykinesia and dystonia and less postural instability, dementia, vertical gaze palsy and saccadic abnormalities. Three other variants featuring, respectively, pure akinesia with gait freezing, corticobasal syndrome and speech apraxia have been described more recently and comprise small percentages.10-12 At autopsy, all of these variants have the classic pathologic features of PSP but emphasize different anatomic areas.13
The first clinical rating scale for PSP was published in 2007.14 The "PSP Rating Scale" rates 28 items, with a total score range of 100 points and requires about 10 minutes to administer. No floor or ceiling effects occur and patients progress an average of 11.3 points per year. Validated by its ability to track and predict clinical decline, the scale requires little training to administer. It has been adopted internationally in interventional and observational studies.
- Melquist S, Craig DW, Huentelman MJ, et al. Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms. Am J Hum Genet 2007; 80: 769-778.
- Rademakers R, Melquist S, Cruts M, et al. High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet 2005; 14: 3281-3292.
- Borroni B, Malinverno M, Gardoni F, et al. Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy. Neurology 2008; 71: 1796-1803.
- Nicoletti G, Tonon C, Lodi R, et al. Apparent diffusion coefficient of the superior cerebellar peduncle differentiates progressive supranuclear palsy from Parkinson's disease. Mov Disord 2008; 23: 2370-2376.
- Stamelou M, Reuss A, Pilatus U, et al. Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial. Mov Disord 2008; 23:942-949.
- Bensimon G, Ludolph A, Agid Y, Vidailhet M, Payan C, Leigh PN; NNIPPS Study Group. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study. Brain 2009; 132: 156-171.
- Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2008;105: 2052-2057.
- Zampieri C, Di Fabio RP. Improvement of gaze control after balance and eye movement training in patients with progressive supranuclear palsy: a quasi-randomized controlled trial. Arch Phys Med Rehabil 2009; 90: 263-270.
- Williams DR, de Silva R, Paviour DC, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism. Brain 2005; 128: 1247-1258.
- Williams DR, Holton JL, Strand K, Revesz T, Lees AJ. Pure akinesia with gait freezing: a third clinical phenotype of progressive supranuclear palsy. Mov Disord 2007; 22:2235-2241.
- Josephs KA, Boeve BF, Duffy JR, et al. Atypical progressive supranuclear palsy underlying progressive apraxia of speech and nonfluent aphasia. Neurocase 2005; 11: 283-296.
- Cordato NJ, Halliday GM, McCann H., et al. Corticobasal syndrome with tau pathology. Mov Disord 2001; 16; 656-667.
- Williams DR, Holton JL, Strand C, et al. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain 2007; 130: 1566-1576.
- Golbe LI, Ohman-Strickland PA. A clinical rating scale for progressive supranuclear palsy. Brain 2007; 130: 1552-1565.