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Progressive Supranuclear Palsy New Concepts View and review Arq Neuropsiquiatr 2010;68(6):938-946 Progressive supranuclear palsy New concepts Orlando Graziani Povoas Barsottini, André Carvalho Felício, Camila Catherine Henriques de Aquino, José Luiz Pedroso ABSTRACT Progressive supranuclear palsy (PSP) is a distinctive form of neurodegenerative disease which affects the brainstem and basal ganglia. Patients present supranuclear ophthalmoplegia, postural instability and mild dementia. PSP is defined neuropathologically by the accumulation of neurofibrillary tangles in the subthalamic nucleus, pallidum, red nucleus, substantia nigra, striatum, pontine tegmentum, oculomotor nucleus, medulla and dentate nucleus. Over the last decade many lines of investigations have helped refine PSP in many aspects and it is the purpose of this review to help neurologists identify PSP, to better understand its pathophysiology and to provide a more focused, symptom-based treatment approach. Key words: progressive supranuclear palsy, atypical parkinsonism, tauopathy. Paralisia supranuclear progressiva: conceitos atuais RESUMO A paralisia supranuclear progressiva (PSP) é uma doença neurodegenerativa, que afeta principalmente o tronco cerebral e os núcleos da base. O quadro clínico se caracteriza por oftalmoparesia supranuclear, instabilidade postural e demência . Do ponto de vista anátomo-patológico, a PSP se caracteriza por acúmulo de emaranhados neurofibrilares no núcleo subtalâmico, globo pálido, núcleo rubro, substância negra, estriado, tegumento da ponte, núcleos oculomotores, bulbo e núcleo denteado. Nas últimas décadas, muitas linhas de pesquisa têm colaborado para redefinir a PSP em muitos aspectos. Os objetivos dessa revisão são auxiliar o neurologista geral na identificação da doença, compreensão da sua fisiopatologia, além de apresentar alternativas para seu tratamento sintomático. Palavras-chave: paralisia supranuclear progressiva, parkinsonismo atípico, taupatias. Progressive supranuclear palsy (PSP), the age of 40. The correct diagnosis is usu- also called Steele-Richardson-Olszews- ally made 3.6 to 4.9 years after the onset of ki syndrome, is a distinctive and probably clinical signs2. under diagnosed neurodegenerative syn- In the last few years, we have learned drome. It is the most common cause of de- much about clinical, neuroimaging, mo- generative parkinsonism after Parkinson’s lecular pathology and genetic of PSP. This disease (PD) in most series1,2. The “classic” syndrome is a tauopathy, with deposits of PSP syndrome is characterized by gait dis- neurofibrillay tangles in the brain, which order, ophthalmoparesis (down gaze palsy), are mainly composed of hyperphosphory- cognitive dysfunction and parkinsonism, lated microtubule-associated protein tau. but a number of PSP phenotypic variants Tauopathies refers generally to neurode- Correspondence have been described recently1,2. The prev- generative disorders with prominent tau Orlando G.P. Barsottini alence of PSP is age-dependent and esti- pathology in the neuronal or glial cells. Tau Av. Brigadeiro Luiz Antonio 4454 01402-002 São Paulo SP - Brasil mated at 6% to 10% that of PD, or 6-7 cas- is a microtubule-associated protein ex- E-mail: [email protected] es per 100.000. The disease has a peak on- pressed in neurons, which in tauopathies set at age 63 and no reported cases before forms abnormal, fibrillar structures of ag- Received 7 February 2010 Received in final form 4 May 2010 Accepted 11 May 2010 Federal University of São Paulo, Department of Neurology and Neurosurgery, São Paulo SP, Brazil. 938 Progressive supranuclear palsy: new concepts Arq Neuropsiquiatr 2010;68(6) Barsottini et al. gregated, hyperphosphorylated and ubiquinated tau3,4. There are an increasing number of tauopathies described, including Alzheimer’s disease, corticobasal degeneration, postencephalitic parkinsonism, Parkinson-dementia com- plex of Guam, Guadeloupian parkinsonism, frontotempo- ral dementia with parkinsonism linked to chromosome 17, Pick disease and Niemann-Pick disease type C2-4. PSP is pathologically defined by the accumulation of tau protein and neuropil threads in the subthalamic nu- cleus, pallidum, red nucleus, substantia nigra, striatum, pontine tegmentum, oculomotor nucleus, medulla and dentate nucleus. Similar histopathological findings can be seen in other forms of tauopathies (ex. Guadeloupian parkinsonism), complicating the pathological diagnosis of Fig 1. An illustrative image of a patient with progressive supranu- PSP. The most specific features are star-shaped astrocyt- clear palsy with 5 years of disease duration and retrocollis. Note ic tufts and neurofibrillary tangles that can be seen with that the patient is already in wheelchairs. light microscopy and that immunostain strongly with an- tibodies to tau3,4. In adult human brain tau has six alternatively spliced sentation. The National Institute of Neurological Disor- isoforms that are derived from a single gene. Disordered ders and Stroke/ Society for PSP (NINDS/SPSP) crite- regulation of exon 10 splicing may therefore explain tau ria detect only 50-70% of patients within 3 years of dis- aggregation into neurofibrillary tangles in PSP and oth- ease onset2. Several clinical variants have recently been er tauopathies.The microtubule-binding domain contains identified and a new nosology is emerging. These clinic- either three 31 amino acids repeats (3R) or four 31 amino pathological variants can be separated by differences in acids repeats (4R) and in normal adults brains the propor- their severity, regions of pathology involvement and clin- tion of 3R and 4R tau are similar. In PSP the ratio of hu- ical features. man brain tau isoforms is at least 3:1 in favor of 4R tau4. Richardson’s syndrome (RS): Starting after the age PSP has traditionally been considered a sporadic dis- 40, this is the “classical” and more common picture of PSP. ease, but its consistent genetic association with markers A lurching gait and unexplained fall backwards without in chromosome 17q21 and reports of familial PSP cas- loss of consciousness are the commonest presentations es suggest a familial aggregation. A linkage study on a of PSP. Patients have more axial than appendicular rigid- large Spanish family with typical autosomal dominant ity and retrocollis is a common form of dystonia (Fig 1). PSP mapped a candidate gene in a 3.4-cM region in chro- Early ocular symptoms include blurred vision, slow sac- mosome 1q31.1. Several families with PSP-like presenta- cades, photophobia, slowing of vertical saccades and in- tion have been described. MAPT (microtubule-associat- voluntary eyelid closure due to blepharospasm. Vertical ed protein tau) and PARK-2 mutations may cause a PSP- supranuclear gaze palsy is the definitive diagnostic feature like phenotype. Mutations in the LRRK2 gene cause an but this commonly develops many years after disease on- autosomal dominant parkinsonism and may present as a set. In RS, apathy, intellectual slowing and impairment of PSP-like parkinsonism. Rajput and coworkers described executive functions are also consistent findings, and may a family, with parkinsonism and LRRK2 (G2019S muta- include the “applause sign”, a test of impaired motor con- tion), where the affected proband had tau-immunopos- trol leading to perseveration due to frontal dysfunction. itive neurofibrillary tangles at autopsy rather than Lewy Apraxia of eyelid opening, a slow and slurred speech and body disease5. Santos-Rebouças and colleagues reported difficulties in swallowing are other typical features. Limb- the co-occurrence of sporadic parkinsonism and late-on- kinetic apraxia, or difficulty performing simple gesture set Alzheimer’s disease in a Brazilian male with mutations and the fine movements, although most often associat- in the LRRK2 gene6. TheMAPT H1 haplotype is probably ed with corticobasal syndrome, also occurs in PSP. Most a genetic risk locus for PSP, but the haplotype H2 plays a patients become dependent on others for care within 3 protective role7-9. to 4 years of diagnosis and the common causes of death are aspiration pneumonia, primary neurogenic respira- Clinical subtypes tory failure and pulmonary emboli. RS consists of diffuse PSP is frequently misdiagnosed, most commonly as tau pathology and the most severely affected regions are PD, and less than a half of patients with pathologically- subthalamic nucleus and substantia nigra3,4,7,10. proven PSP will have received the diagnosis of PSP at pre- PSP-parkinsonism (PSP-P): The PSP-P phenotype 939 Progressive supranuclear palsy: new concepts Barsottini et al. Arq Neuropsiquiatr 2010;68(6) comprises about one-third of the cases and is a more in- CBS have pathology that is typical of corticobasal degen- dolent form with a PD-like presentation. The features in- eration and the PSP-CBS seems to be a rare presentation clude bradykinesia and rigidity, tremor, asymmetric onset, of PSP-tau pathology. For instance, in neuropathologically normal eye movements and a clear, but transient levodo- studied cases, a “corticobasal syndrome” was observed in pa response. Parkinsonism dominates the early clinical PSP, Pick disease, Alzheimer’s disease, frontotemporal de- picture and a jerky postural tremor and even a 4-6 HZ mentia with parkinsonism and frontotemporal lobar de- rest tremor are common in PSP-P patients. Falls and cog- generation with ubiquitin-positive inclusions 3,7,10. nitive impairment occur later in PSP-P than in RS. These syndromes can be distinguished by their clinical pictures Clinical criteria for the diagnosis
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