Abstract
Progressive supranuclear palsy (PSP) is an atypical parkinsonian condition characterized by a symmetric akinetic–rigid syndrome, early falls, supranuclear gaze palsy, and a frontotemporal behavioral syndrome. The typical phenotype is termed Richardson’s syndrome, but numerous other phenotypes have been described. The pathophysiology of PSP is not fully understood, but dysfunction of the tau protein seems to play a central role. Despite exciting new knowledge on the pathophysiology of PSP, there is still no highly effective symptomatic or disease-modifying treatment. We review the evidence on pharmacotherapy and experimental therapies in PSP and provide levels of recommendation for the off-label use of commonly used drugs in this disorder.
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References
Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. A Heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol. 1964;10:333–59.
Williams DR, de Silva R, Paviour DC, Pittman A, Watt HC, Kilford L, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Brain. 2005;128(Pt 6):1247–58.
Respondek G, Stamelou M, Kurz C, Ferguson LW, Rajput A, Chiu WZ, et al. The phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases. Mov Disord. 2014;29(14):1758–66.
Ferrer I, Barrachina M, Puig B. Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy and corticobasal degeneration. Acta Neuropathol. 2002;104(6):583–91.
Ingelsson M, Ramasamy K, Russ C, Freeman SH, Orne J, Raju S, et al. Increase in the relative expression of tau with four microtubule binding repeat regions in frontotemporal lobar degeneration and progressive supranuclear palsy brains. Acta Neuropathol. 2007;114(5):471–9.
Albers DS, Augood SJ. New insights into progressive supranuclear palsy. Trends Neurosci. 2001;24(6):347–53.
Ahmed Z, Josephs KA, Gonzalez J, DelleDonne A, Dickson DW. Clinical and neuropathologic features of progressive supranuclear palsy with severe pallido-nigro-luysial degeneration and axonal dystrophy. Brain. 2008;131(Pt 2):460–72.
Stamelou M, Hoeglinger GU. Atypical parkinsonism: an update. Curr Opin Neurol. 2013;26(4):401–5.
Ries V, Oertel WH, Höglinger GU. Mitochondrial dysfunction as a therapeutic target in progressive supranuclear palsy. J Mol Neurosci. 2011;45(3):684–9.
Escobar-Khondiker M, Höllerhage M, Muriel MP, Champy P, Bach A, Depienne C, et al. Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. J Neurosci. 2007;27(29):7827–37.
Höglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011;43(7):699–705.
Zhang H, Zhang YW, Chen Y, Huang X, Zhou F, Wang W, et al. Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration. J Neurosci. 2012;32(44):15565–76.
Zhao Y, Tseng IC, Heyser CJ, Rockenstein E, Mante M, Adame A, et al. Appoptosin-mediated caspase cleavage of tau contributes to progressive supranuclear palsy pathogenesis. Neuron. 2015;87(5):963–75.
Respondek G, Höglinger GU, Stamelou M. From a single nucleotide polymorphism to tau pathology: appoptosin is the missing link. Mov Disord. 2015;30(14):1871–2.
Boxer AL, Lang AE, Grossman M, Knopman DS, Miller BL, Schneider LS, et al. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol. 2014;13(7):676–85.
Tolosa E, Litvan I, Höglinger GU, Burn D, Lees A, Andres MV, et al. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov Disord. 2014;29(4):470–8.
Koros C, Stamelou M. Interventions in progressive supranuclear palsy. Parkinsonism Relat Disord. 2016;22(Suppl 1):S93–5.
Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F. Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci. 1987;84(16):5976–80.
Brandel JP, Hirsch EC, Malessa S, Duyckaerts C, Cervera P, Agid Y. Differential vulnerability of cholinergic projections to the mediodorsal nucleus of the thalamus in senile dementia of Alzheimer type and progressive supranuclear palsy. Neuroscience. 1991;41(1):25–31.
Chinaglia G, Landwehrmeyer B, Probst A, Palacios JM. Serotoninergic terminal transporters are differentially affected in Parkinson’s disease and progressive supranuclear palsy: an autoradiographic study with [3H]citalopram. Neuroscience. 1993;54(3):691–9.
Landwehrmeyer B, Palacios JM. Alterations of neurotransmitter receptors and neurotransmitter transporters in progressive supranuclear palsy. J Neural Transm Suppl. 1994;42:229–46.
Blin J, Mazetti P, Mazoyer B, Rivaud S, Ben Ayed S, Malapani C, et al. Does the enhancement of cholinergic neurotransmission influence brain glucose kinetics and clinical symptomatology in progressive supranuclear palsy? Brain. 1995;118(Pt 6):1485–95.
Kasashima S, Oda Y. Cholinergic neuronal loss in the basal forebrain and mesopontine tegmentum of progressive supranuclear palsy and corticobasal degeneration. Acta Neuropathol. 2003;105(2):117–24.
Warren NM, Piggott MA, Perry EK, Burn DJ. Cholinergic systems in progressive supranuclear palsy. Brain. 2005;128(Pt 2):239–49.
Stamelou M, Matusch A, Elmenhorst D, Hurlemann R, Eggert KM, Zilles K, et al. Nigrostriatal upregulation of 5-HT2A receptors correlates with motor dysfunction in progressive supranuclear palsy. Mov Disord. 2009;24(8):1170–5.
Hazrati LN, Wong JC, Hamani C, Lozano AM, Poon YY, Dostrovsky JO, et al. Clinicopathological study in progressive supranuclear palsy with pedunculopontine stimulation. Mov Disord. 2012;27(10):1304–7.
Stamelou M, Schöpe J, Wagenpfeil S, Del Ser T, Bang J, Lobach IY, et al. Power calculations and placebo effect for future clinical trials in progressive supranuclear palsy. Mov Disord. 2016;31(5):742–7.
Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology. 1996;47(1):1–9.
Nieforth KA, Golbe LI. Retrospective study of drug response in 87 patients with progressive supranuclear palsy. Clin Neuropharmacol. 1993;16(4):338–46.
Collins SJ, Ahlskog JE, Parisi JE, Maraganore DM. Progressive supranuclear palsy: neuropathologically based diagnostic clinical criteria. J Neurol Neurosurg Psychiatry. 1995;58(2):167–73.
Litvan I, Mangone CA, McKee A, Verny M, Parsa A, Jellinger K, et al. Natural history of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) and clinical predictors of survival: a clinicopathological study. J Neurol Neurosurg Psychiatry. 1996;60(6):615–20.
Litvan I. The clinical and pathologic hallmarks of progressive supranuclear palsy. Curr Opin Neurol. 1997;10(4):346–50.
Kompoliti K, Goetz CG, Litvan I, Jellinger K, Verny M. Pharmacological therapy in progressive supranuclear palsy. Arch Neurol. 1998;55(8):1099–102.
Defazio G, De Mari M, De Salvia R, Lamberti P, Giorelli M, Livrea P. “Apraxia of eyelid opening” induced by levodopa therapy and apomorphine in atypical parkinsonism (possible progressive supranuclear palsy): a case report. Clin Neuropharmacol. 1999;22(5):292–4.
Litvan I. Diagnosis and management of progressive supranuclear palsy. Semin Neurol. 2001;21(1):41–8.
Birdi S, Rajput AH, Fenton M, Donat JR, Rozdilsky B, Robinson C, et al. Progressive supranuclear palsy diagnosis and confounding features: report on 16 autopsied cases. Mov Disord. 2002;17(6):1255–64.
Carrilho PE, Barbosa ER. Progressive supranuclear palsy in a sample of Brazilian population: clinical features of 16 patients. Arq Neuropsiquiatr. 2002;60(4):917–22.
Diroma C, Dell’Aquila C, Fraddosio A, Lamberti S, Mastronardi R, Russo I, et al. Natural history and clinical features of progressive supranuclear palsy: a clinical study. Neurol Sci. 2003;24(3):176–7.
Marra M, Toni V, Trianni G, Coppola G. Progressive supranuclear palsy: analysis of six cases. Neurol Sci. 2003;24(3):186–7.
Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Burn DJ. Clinical features and natural history of progressive supranuclear palsy: a clinical cohort study. Neurology. 2003;60(6):910–6.
Lang AE. Treatment of progressive supranuclear palsy and corticobasal degeneration. Mov Disord. 2005;20(Suppl 12):S83–91.
van Balken I, Litvan I. Current and future treatments in progressive supranuclear palsy. Curr Treat Options Neurol. 2006;8(3):211–23.
Chung EJ, Kim SJ. Levodopa-induced facial dystonia in a case of progressive supranuclear palsy. J Mov Disord. 2012;5(1):28–32.
Arena JE, Weigand SD, Whitwell JL, Hassan A, Eggers SD, Höglinger GU, et al. Progressive supranuclear palsy: progression and survival. J Neurol. 2016;263(2):380–9.
Neophytides A, Lieberman AN, Goldstein M, Gopinathan G, Leibowitz M, Bock J, et al. The use of lisuride, a potent dopamine and serotonin agonist, in the treatment of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 1982;45(3):261–3.
Jackson JA, Jankovic J, Ford J. Progressive supranuclear palsy: clinical features and response to treatment in 16 patients. Ann Neurol. 1983;13(3):273–8.
Weiner WJ, Minagar A, Shulman LM. Pramipexole in progressive supranuclear palsy. Neurology. 1999;52(4):873–4.
van Balken I, Litvan I. Current and future therapeutic approaches in progressive supranuclear palsy. Handb Clin Neurol. 2008;89:493–508.
Moccia M, Picillo M, Erro R, Allocca R, Barone P, Vitale C. Diagnosis and treatment of restless legs syndrome in progressive supranuclear palsy. J Neurol Sci. 2015;350(1–2):103–4.
Poewe W, Mahlknecht P, Krismer F. Therapeutic advances in multiple system atrophy and progressive supranuclear palsy. Mov Disord. 2015;30(11):1528–38.
Paulson GW, Lowery HW, Taylor GC. Progressive supranuclear palsy: pneumoencephalography, electronystagmography and treatment with methysergide. Eur Neurol. 1981;20(1):13–6.
Rafal RD, Grimm RJ. Progressive supranuclear palsy: functional analysis of the response to methysergide and antiparkinsonian agents. Neurology. 1981;31(12):1507–18.
Duncombe AS, Lees AJ. Methysergide in progressive supranuclear palsy. Neurology. 1985;35(6):936–7.
Schneider LS, Gleason RP, Chui HC. Progressive supranuclear palsy with agitation: response to trazodone but not to thiothixine or carbamazepine. J Geriatr Psychiatry Neurol. 1989;2(2):109–12.
Di Trapani G, Stampatore P, La Cara A, Azzoni A, Vaccario ML. Treatment of progressive supranuclear palsy with methysergide. A clinical study. Ital J Neurol Sci. 1991;12(2):157–61.
Watanabe H, Arahata Y, Tadokoro M, Kato T, Sobue G. Effects of tandospirone citrate on frozen gait in patients with early stage of progressive supranuclear palsy, investigated by walk-induced activation single photon emission computed tomography method. Rinsho Shinkeigaku. 2000;40(11):1130–2.
Fujino Y, Nakajima M, Tsuboi Y, Baba Y, Yamada T. Clinical effectiveness of tandospirone citrate (5-HT1A agonist) on patients with progressive supranuclear palsy. Rinsho Shinkeigaku. 2002;42(1):42–4.
Miyaoka T, Seno H, Inagaki T, Horiguchi J. Fluvoxamine for the treatment of depression and parkinsonism in progressive supranuclear palsy. Int J Psychiatry Clin Pract. 2002;6(1):45–7.
Ghika J, Tennis M, Hoffman E, Schoenfeld D, Growdon J. Idazoxan treatment in progressive supranuclear palsy. Neurology. 1991;41(7):986–91.
Rascol O, Sieradzan K, Peyro-Saint-Paul H, Thalamas C, Brefel-Courbon C, Senard JM, et al. Efaroxan, an alpha-2 antagonist, in the treatment of progressive supranuclear palsy. Mov Disord. 1998;13(4):673–6.
Newman GC. Treatment of progressive supranuclear palsy with tricyclic antidepressants. Neurology. 1985;35:1189–93.
Frattali CM, Sonies BC, Chi-Fishman G, Litvan I. Effects of physostigmine on swallowing and oral motor functions in patients with progressive supranuclear palsy: a pilot study. Dysphagia. 1999;14(3):165–8.
Fabbrini G, Barbanti P, Bonifati V, Colosimo C, Gasparini M, Vanacore N, et al. Donepezil in the treatment of progressive supranuclear palsy. Acta Neurol Scand. 2001;103(2):123–5.
Litvan I, Phipps M, Pharr VL, Hallett M, Grafman J, Salazar A. Randomized placebo-controlled trial of donepezil in patients with progressive supranuclear palsy. Neurology. 2001;57(3):467–73.
Liepelt I, Gaenslen A, Godau J, Di Santo A, Schweitzer KJ, Gasser T, et al. Rivastigmine for the treatment of dementia in patients with progressive supranuclear palsy: clinical observations as a basis for power calculations and safety analysis. Alzheimers Dement. 2010;6(1):70–4.
Levy R, Ruberg M, Herrero MT, Villares J, Javoy-Agid F, Agid Y, et al. Alterations of GABAergic neurons in the basal ganglia of patients with progressive supranuclear palsy: an in situ hybridization study of GAD67 messenger RNA. Neurology. 1995;45(1):127–34.
Daniele A, Moro E, Bentivoglio AR. Zolpidem in progressive supranuclear palsy. N Engl J Med. 1999;341(7):543–4.
Poujois A, Vidailhet M, Trocello JM, Bourdain F, Gaymard B, Rivaud-Pechoux S. Effect of gabapentin on oculomotor control and parkinsonism in patients with progressive supranuclear palsy. Eur J Neurol. 2007;14(9):1060–2.
Polo KB, Jabbari B. Botulinum toxin-A improves the rigidity of progressive supranuclear palsy. Ann Neurol. 1994;35(2):237–9.
Piccione F, Mancini E, Tonin P, Bizzarini M. Botulinum toxin treatment of apraxia of eyelid opening in progressive supranuclear palsy: report of two cases. Arch Phys Med Rehabil. 1997;78(5):525–9.
Lepore V, Defazio G, Acquistapace D, Melpignano C, Pomes L, Lamberti P, et al. Botulinum A toxin for the so-called apraxia of lid opening. Mov Disord. 1995;10(4):525–6.
Krack P, Marion MH. “Apraxia of lid opening,” a focal eyelid dystonia: clinical study of 32 patients. Mov Disord. 1994;9(6):610–5.
Gómez-Caravaca MT, Cáceres-Redondo MT, Huertas-Fernández I, Vargas-González L, Carrillo F, Carballo M, Mir P. The use of botulinum toxin in the treatment of sialorrhea in parkinsonian disorders. Neurol Sci. 2015;36(2):275–9.
Bergmann KJ, Salak VL. Subthalamic stimulation improves levodopa responsive symptoms in a case of progressive supranuclear palsy. Parkinsonism Relat Disord. 2008;14(4):348–52.
Doshi PK, Desai JD, Karkera B, Wadia PM. Bilateral pedunculopontine nucleus stimulation for progressive supranuclear palsy. Stereotact Funct Neurosurg. 2015;93(1):59–65.
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(Pt 1):156–71.
Leclair-Visonneau L, Rouaud T, Debilly B, Durif F, Houeto JL, Kreisler A, et al. Randomized placebo-controlled trial of sodium valproate in progressive supranuclear palsy. Clin Neurol Neurosurg. 2016;146:35–9.
Höglinger GU, Huppertz HJ, Wagenpfeil S, Andres MV, Belloch V, Leon T, et al. Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial. Mov Disord. 2014;29(4):479–87.
Albers DS, Beal MF. Mitochondrial dysfunction in progressive supranuclear palsy. Neurochem Int. 2002;40(6):559–64.
Di Monte DA, Harati Y, Jankovic J, Sandy MS, Jewell SA, Langston JW. Muscle mitochondrial ATP production in progressive supranuclear palsy. J Neurochem. 1994;62(4):1631–4.
Albers DS, Swerdlow RH, Manfredi G, Gajewski C, Yang L, Parker WD Jr, et al. Further evidence for mitochondrial dysfunction in progressive supranuclear palsy. Exp Neurol. 2001;168(1):196–8.
Park LC, Albers DS, Xu H, Lindsay JG, Beal MF, Gibson GE. Mitochondrial impairment in the cerebellum of the patients with progressive supranuclear palsy. J Neurosci Res. 2001;66(5):1028–34.
Swerdlow RH, Golbe LI, Parks JK, Cassarino DS, Binder DR, Grawey AE, et al. Mitochondrial dysfunction in cybrid lines expressing mitochondrial genes from patients with progressive supranuclear palsy. J Neurochem. 2000;75(4):1681–4.
Stamelou M, Pilatus U, Reuss A, Magerkurth J, Eggert KM, Knake S, et al. In vivo evidence for cerebral depletion in high-energy phosphates in progressive supranuclear palsy. J Cereb Blood Flow Metab. 2009;29(4):861–70.
Stamelou M, Reuss A, Pilatus U, Magerkurth J, Niklowitz P, Eggert KM, et al. Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial. Mov Disord. 2008;23(7):942–9.
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11(7):909–13.
Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci. 2013;110(23):9535–40.
Clavaguera F, Grueninger F, Tolnay M. Intercellular transfer of tau aggregates and spreading of tau pathology: Implications for therapeutic strategies. Neuropharmacology. 2014;76 Pt A:9–15.
Asuni AA, Boutajangout A, Scholtzova H, Knudsen E, Li YS, Quartermain D, et al. Vaccination of Alzheimer’s model mice with Abeta derivative in alum adjuvant reduces Abeta burden without microhemorrhages. Eur J Neurosci. 2006;24(9):2530–42.
Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci. 2007;27(34):9115–29.
Wisniewski T, Boutajangout A. Vaccination as a therapeutic approach to Alzheimer’s disease. Mt Sinai J Med. 2010;77(1):17–31.
Boutajangout A, Ingadottir J, Davies P, Sigurdsson EM. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem. 2011;118(4):658–67.
Chai X, Wu S, Murray TK, Kinley R, Cella CV, Sims H, et al. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J Biol Chem. 2011;286(39):34457–67.
Boutajangout A, Wisniewski T. Tau-based therapeutic approaches for Alzheimer’s disease: a mini-review. Gerontology. 2014;60(5):381–5.
Gotkine M, Rozenstein L, Einstein O, Abramsky O, Argov Z, Rosenmann H. Presymptomatic treatment with acetylcholinesterase antisense oligonucleotides prolongs survival in ALS (G93A-SOD1) mice. Biomed Res Int. 2013;2013:845345.
Riboldi G, Zanetta C, Ranieri M, Nizzardo M, Simone C, Magri F, et al. Antisense oligonucleotide therapy for the treatment of C9ORF72 ALS/FTD diseases. Mol Neurobiol. 2014;50(3):721–32.
Xu H, Rosler TW, Carlsson T, de Andrade A, Fiala O, Hollerhage M, et al. Tau Silencing by siRNA in the P301S Mouse model of Tauopathy. Curr Gene Ther. 2014;14(5):343–51.
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Dr. Maria Stamelou and Professor Günter Höglinger have participated in clinical trials evaluating davunetide (Allon Therapeutics Inc.), tideglusib (Noscira Inc.), and co-enzyme Q10 (MSE Pharmazeutika) in PSP.
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Stamelou, M., Höglinger, G. A Review of Treatment Options for Progressive Supranuclear Palsy. CNS Drugs 30, 629–636 (2016). https://doi.org/10.1007/s40263-016-0347-2
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DOI: https://doi.org/10.1007/s40263-016-0347-2
Keywords
- Levodopa
- CoQ10
- Progressive Supranuclear Palsy
- Rasagiline
- Progressive Supranuclear Palsy