Clinical Trials: Past, Current, and Future for Atypical Parkinsonian Syndromes

 

 Buy Article Permissions and Reprints

Abstract

There are currently no effective Food and Drug Administration-approved treatments for atypical parkinsonian disorders such as progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, or multiple system atrophy. Previous treatment trials for these disorders were focused on symptomatic support and did not affect disease progression. Recent breakthroughs in neuropathology and pathophysiology have allowed a new understanding of these disorders and investigation into potentially disease modifying therapies. Randomized, placebo-controlled clinical trials of these disorders will be reviewed here. Suggestions for future therapeutic targets and clinical trial design (with a focus on progressive supranuclear palsy) will also be provided.

• References

• 1 Wenning GK, Litvan I, Tolosa E. Milestones in atypical and secondary parkinsonisms. Mov Disord 2011; 26 (6) 1083-1095
  CrossrefPubMedGoogle Scholar
• 2 Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brainstem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964; 10: 333-359
  CrossrefPubMedGoogle Scholar
• 3 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 (Pt 6) 1247-1258
  CrossrefPubMedGoogle Scholar
• 4 Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 2009; 8 (3) 270-279
  CrossrefPubMedGoogle Scholar
• 5 Lang AE. Treatment of progressive supranuclear palsy and corticobasal degeneration. Mov Disord 2005; 20 (Suppl. 12) S83-S91
  CrossrefPubMedGoogle Scholar
• 6 Klawans Jr HL, Ringel SP. Observations on the efficacy of L-dopa in progressive supranuclear palsy. Eur Neurol 1971; 5 (2) 115-129
  CrossrefPubMedGoogle Scholar
• 7 Kompoliti K, Goetz CG, Litvan I, Jellinger K, Verny M. Pharmacological therapy in progressive supranuclear palsy. Arch Neurol 1998; 55 (8) 1099-1102
  CrossrefPubMedGoogle Scholar
• 8 Birdi S, Rajput AH, Fenton M , et al. Progressive supranuclear palsy diagnosis and confounding features: report on 16 autopsied cases. Mov Disord 2002; 17 (6) 1255-1264
  CrossrefPubMedGoogle Scholar
• 9 Ruberg M, Javoy-Agid F, Hirsch E , et al. Dopaminergic and cholinergic lesions in progressive supranuclear palsy. Ann Neurol 1985; 18 (5) 523-529
  CrossrefPubMedGoogle Scholar
• 10 Javoy-Agid F. Cholinergic and peptidergic systems in PSP. J Neural Transm Suppl 1994; 42: 205-218
  PubMedGoogle Scholar
• 11 Levy R, Ruberg M, Herrero MT , 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) 127-134
  CrossrefPubMedGoogle Scholar
• 12 Litvan I, Gomez C, Atack JR , et al. Physostigmine treatment of progressive supranuclear palsy. Ann Neurol 1989; 26 (3) 404-407
  CrossrefPubMedGoogle Scholar
• 13 Fabbrini G, Barbanti P, Bonifati V , et al. Donepezil in the treatment of progressive supranuclear palsy. Acta Neurol Scand 2001; 103 (2) 123-125
  CrossrefPubMedGoogle Scholar
• 14 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) 467-473
  CrossrefPubMedGoogle Scholar
• 15 Liepelt I, Gaenslen A, Godau J , 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) 70-74
  CrossrefPubMedGoogle Scholar
• 16 Daniele A, Moro E, Bentivoglio AR. Zolpidem in progressive supranuclear palsy. N Engl J Med 1999; 341 (7) 543-544
  CrossrefPubMedGoogle Scholar
• 17 Poujois A, Vidailhet M, Trocello JM, Bourdain F, Gaymard B, Rivaud-Péchoux S. Effect of gabapentin on oculomotor control and parkinsonism in patients with progressive supranuclear palsy. Eur J Neurol 2007; 14 (9) 1060-1062
  CrossrefPubMedGoogle Scholar
• 18 Rebeiz JJ, Kolodny EH, Richardson Jr EP. Corticodentatonigral degeneration with neuronal achromasia: a progressive disorder of late adult life. Trans Am Neurol Assoc 1967; 92: 23-26
  PubMedGoogle Scholar
• 19 Lee SE, Rabinovici GD, Mayo MC , et al. Clinicopathological correlations in corticobasal degeneration. Ann Neurol 2011; 70 (2) 327-340
  CrossrefPubMedGoogle Scholar
• 20 Ling H, O'Sullivan SS, Holton JL , et al. Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain 2010; 133 (Pt 7) 2045-2057
  CrossrefPubMedGoogle Scholar
• 21 Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002; 125 (Pt 4) 861-870
  CrossrefPubMedGoogle Scholar
• 22 Mathew R, Bak TH, Hodges JR. Diagnostic criteria for corticobasal syndrome: a comparative study. J Neurol Neurosurg Psychiatry 2012; 83 (4) 405-410
  CrossrefPubMedGoogle Scholar
• 23 Armstrong MJ, Litvan I, Lang AE , et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013; 29 (80) 498-503
  PubMedGoogle Scholar
• 24 Maruyama M, Shimada H, Suhara T , et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 2013; 79 (6) 1094-1108
  CrossrefPubMedGoogle Scholar
• 25 Xia CF, Arteaga J, Chen G , et al. [(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease. Alzheimers Dement 2013; 9 (6) 666-676
  CrossrefPubMedGoogle Scholar
• 26 Drechsel DN, Hyman AA, Cobb MH, Kirschner MW. Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell 1992; 3 (10) 1141-1154
  CrossrefPubMedGoogle Scholar
• 27 Khlistunova I, Biernat J, Wang Y , et al. Inducible expression of tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem 2006; 281 (2) 1205-1214
  CrossrefPubMedGoogle Scholar
• 28 Van der Jeugd A, Hochgräfe K, Ahmed T , et al. Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human tau. Acta Neuropathol 2012; 123 (6) 787-805
  CrossrefPubMedGoogle Scholar
• 29 Bramblett GT, Goedert M, Jakes R, Merrick SE, Trojanowski JQ, Lee VM. Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron 1993; 10 (6) 1089-1099
  CrossrefPubMedGoogle Scholar
• 30 Brunden KR, Trojanowski JQ, Lee VM. Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies. Nat Rev Drug Discov 2009; 8 (10) 783-793
  CrossrefPubMedGoogle Scholar
• 31 Roberson ED, Scearce-Levie K, Palop JJ , et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 2007; 316 (5825) 750-754
  CrossrefPubMedGoogle Scholar
• 32 Abbondante S, Baglietto-Vargas D, Rodriguez-Ortiz CJ, Estrada-Hernandez T, Medeiros R, Laferla FM. Genetic ablation of tau mitigates cognitive impairment induced by type 1 diabetes. Am J Pathol 2014; 184 (3) 819-826
  CrossrefPubMedGoogle Scholar
• 33 Morris M, Hamto P, Adame A, Devidze N, Masliah E, Mucke L. Age-appropriate cognition and subtle dopamine-independent motor deficits in aged tau knockout mice. Neurobiol Aging 2013; 34 (6) 1523-1529
  CrossrefPubMedGoogle Scholar
• 34 Wischik CM, Harrington CR, Storey JM. Tau-aggregation inhibitor therapy for Alzheimer's disease. Biochem Pharmacol 2014; 88 (4) 529-539
  CrossrefPubMedGoogle Scholar
• 35 US National Institute of Health Clinical Trials Registry. 2010. Available at: http://clinicaltrials.gov/show/NCT00703677 . Accessed February 21, 2014
  PubMed
• 36 Höglinger GU, Huppertz HJ, Wagenpfeil S , et al; TAUROS MRI Investigators. Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial. Mov Disord 2014; 29 (4) 479-487
  CrossrefPubMedGoogle Scholar
• 37 Tolosa E, Litvan I, Höglinger GU , et al; TAUROS Investigators. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov Disord 2014; 29 (4) 470-478
  CrossrefPubMedGoogle Scholar
• 38 Min SW, Cho SH, Zhou Y , et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 2010; 67 (6) 953-966
  CrossrefPubMedGoogle Scholar
• 39 DeVos SL, Goncharoff DK, Chen G , et al. Antisense reduction of tau in adult mice protects against seizures. J Neurosci 2013; 33 (31) 12887-12897
  CrossrefPubMedGoogle Scholar
• 40 Pride M, Seubert P, Grundman M, Hagen M, Eldridge J, Black RS. Progress in the active immunotherapeutic approach to Alzheimer's disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis 2008; 5 (3-4) 194-196
  CrossrefPubMedGoogle Scholar
• 41 Boimel M, Grigoriadis N, Lourbopoulos A, Haber E, Abramsky O, Rosenmann H. Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice. Exp Neurol 2010; 224 (2) 472-485
  CrossrefPubMedGoogle Scholar
• 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) 9115-9129
  CrossrefPubMedGoogle Scholar
• 43 Boutajangout A, Quartermain D, Sigurdsson EM. Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci 2010; 30 (49) 16559-16566
  CrossrefPubMedGoogle Scholar
• 44 FierceBiotech. AC Immune begins first trial of a tau-targeting Alzheimer's vaccine. 2014. Available at: http://www.fiercevaccines.com/story/ac-immune-begins-first-trial-tau-targeting-alzheimers-vaccine/2014-01-13 . Accessed February 21, 2014
  PubMedGoogle Scholar
• 45 Chai X, Wu S, Murray TK , 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) 34457-34467
  CrossrefPubMedGoogle Scholar
• 46 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) 658-667
  CrossrefPubMedGoogle Scholar
• 47 Yanamandra K, Kfoury N, Jiang H , et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 2013; 80 (2) 402-414
  CrossrefPubMedGoogle Scholar
• 48 Higuchi M, Lee VM, Trojanowski JQ. Tau and axonopathy in neurodegenerative disorders. Neuromolecular Med 2002; 2 (2) 131-150
  CrossrefPubMedGoogle Scholar
• 49 Brunden KR, Ballatore C, Lee VM, Smith III AB, Trojanowski JQ. Brain-penetrant microtubule-stabilizing compounds as potential therapeutic agents for tauopathies. Biochem Soc Trans 2012; 40 (4) 661-666
  CrossrefPubMedGoogle Scholar
• 50 Barten DM, Fanara P, Andorfer C , et al. Hyperdynamic microtubules, cognitive deficits, and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027. J Neurosci 2012; 32 (21) 7137-7145
  CrossrefPubMedGoogle Scholar
• 51 US National Institute of Health Clinical Trials Registry. 2014. Available at: http://clinicaltrials.gov/ct2/show/NCT01966666?term=tpi+287&rank . Accessed February 21, 2014
  PubMedGoogle Scholar
• 52 Stamelou M, de Silva R, Arias-Carrión O , et al. Rational therapeutic approaches to progressive supranuclear palsy. Brain 2010; 133 (Pt 6) 1578-1590
  CrossrefPubMedGoogle Scholar
• 53 Stamelou M, Pilatus U, Reuss A , et al. In vivo evidence for cerebral depletion in high-energy phosphates in progressive supranuclear palsy. J Cereb Blood Flow Metab 2009; 29 (4) 861-870
  CrossrefPubMedGoogle Scholar
• 54 Swerdlow RH, Golbe LI, Parks JK , et al. Mitochondrial dysfunction in cybrid lines expressing mitochondrial genes from patients with progressive supranuclear palsy. J Neurochem 2000; 75 (4) 1681-1684
  CrossrefPubMedGoogle Scholar
• 55 Albers DS, Swerdlow RH, Manfredi G , et al. Further evidence for mitochondrial dysfunction in progressive supranuclear palsy. Exp Neurol 2001; 168 (1) 196-198
  CrossrefPubMedGoogle Scholar
• 56 Chirichigno JW, Manfredi G, Beal MF, Albers DS. Stress-induced mitochondrial depolarization and oxidative damage in PSP cybrids. Brain Res 2002; 951 (1) 31-35
  CrossrefPubMedGoogle Scholar
• 57 Caparros-Lefebvre D, Elbaz A ; Caribbean Parkinsonism Study Group. Possible relation of atypical parkinsonism in the French West Indies with consumption of tropical plants: a case-control study. Lancet 1999; 354 (9175) 281-286
  CrossrefPubMedGoogle Scholar
• 58 Abdin AA, Hamouda HE. Mechanism of the neuroprotective role of coenzyme Q10 with or without L-dopa in rotenone-induced parkinsonism. Neuropharmacology 2008; 55 (8) 1340-1346
  CrossrefPubMedGoogle Scholar
• 59 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 (7) 942-949
  CrossrefPubMedGoogle Scholar
• 60 US National Institute of Health Clinical Trials Registry. 2013. Available at: http://clinicaltrials.gov/show/NCT00382824. Accessed February 21, 2014
  PubMedGoogle Scholar
• 61 US National Institute of Health Clinical Trials Registry. 2009. http://clinicaltrials.gov/show/NCT00605930 . Accessed February 21, 2014
  PubMedGoogle Scholar
• 62 McKeith IG, Dickson DW, Lowe J , et al; Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005; 65 (12) 1863-1872
  CrossrefPubMedGoogle Scholar
• 63 Piggott MA, Marshall EF, Thomas N , et al. Striatal dopaminergic markers in dementia with Lewy bodies, Alzheimer's and Parkinson's diseases: rostrocaudal distribution. Brain 1999; 122 (Pt 8) 1449-1468
  CrossrefPubMedGoogle Scholar
• 64 Klein JC, Eggers C, Kalbe E , et al. Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology 2010; 74 (11) 885-892
  CrossrefPubMedGoogle Scholar
• 65 Tiraboschi P, Hansen LA, Alford M , et al. Early and widespread cholinergic losses differentiate dementia with Lewy bodies from Alzheimer disease. Arch Gen Psychiatry 2002; 59 (10) 946-951
  CrossrefPubMedGoogle Scholar
• 66 Lippa CF, Duda JE, Grossman M , et al; DLB/PDD Working Group. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology 2007; 68 (11) 812-819
  CrossrefPubMedGoogle Scholar
• 67 Guo JL, Lee VM. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med 2014; 20 (2) 130-138
  CrossrefPubMedGoogle Scholar
• 68 Masliah E, Rockenstein E, Mante M , et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS ONE 2011; 6 (4) e19338
  CrossrefPubMedGoogle Scholar
• 69 Halliday GM, Holton JL, Revesz T, Dickson DW. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol 2011; 122 (2) 187-204
  CrossrefPubMedGoogle Scholar
• 70 McKeith I, Del Ser T, Spano P , et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356 (9247) 2031-2036
  CrossrefPubMedGoogle Scholar
• 71 Wesnes KA, McKeith IG, Ferrara R , et al. Effects of rivastigmine on cognitive function in dementia with Lewy bodies: a randomised placebo-controlled international study using the cognitive drug research computerised assessment system. Dement Geriatr Cogn Disord 2002; 13 (3) 183-192
  CrossrefPubMedGoogle Scholar
• 72 Beversdorf DQ, Warner JL, Davis RA, Sharma UK, Nagaraja HN, Scharre DW. Donepezil in the treatment of dementia with lewy bodies. Am J Geriatr Psychiatry 2004; 12 (5) 542-544
  CrossrefPubMedGoogle Scholar
• 73 Mori E, Ikeda M, Kosaka K ; Donepezil-DLB Study Investigators. Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Ann Neurol 2012; 72 (1) 41-52
  CrossrefPubMedGoogle Scholar
• 74 Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I ; Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291 (3) 317-324
  CrossrefPubMedGoogle Scholar
• 75 Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ ; Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003; 348 (14) 1333-1341
  CrossrefPubMedGoogle Scholar
• 76 Aarsland D, Ballard C, Walker Z , et al. Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol 2009; 8 (7) 613-618
  CrossrefPubMedGoogle Scholar
• 77 Emre M, Tsolaki M, Bonuccelli U , et al; 11018 Study Investigators. Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010; 9 (10) 969-977
  CrossrefPubMedGoogle Scholar
• 78 Cummings JL, Street J, Masterman D, Clark WS. Efficacy of olanzapine in the treatment of psychosis in dementia with Lewy bodies. Dement Geriatr Cogn Disord 2002; 13 (2) 67-73
  CrossrefPubMedGoogle Scholar
• 79 Kurlan R, Cummings J, Raman R, Thal L ; Alzheimer's Disease Cooperative Study Group. Quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Neurology 2007; 68 (17) 1356-1363
  CrossrefPubMedGoogle Scholar
• 80 Cummings J, Isaacson S, Mills R , et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 2014; 383 (9916) 533-540
  CrossrefPubMedGoogle Scholar
• 81 Stefanova N, Bücke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol 2009; 8 (12) 1172-1178
  CrossrefPubMedGoogle Scholar
• 82 Freeman R, Landsberg L, Young J. The treatment of neurogenic orthostatic hypotension with 3,4-DL-threodihydroxyphenylserine: a randomized, placebo controlled crossover trial. Neurology 1999; 53: 2151-2157
  CrossrefPubMedGoogle Scholar
• 83 US National Institute of Health Clinical Trials Registry. 2013. Available at: http://clinicaltrials.gov/show/NCT00782340 . Accessed February 21, 2014
  PubMedGoogle Scholar
• 84 MedScape. FDA Clears Droxidopa for Neurogenic Orthostatic Hypotension. 2014. Available at: http://www.medscape.com/viewarticle/820786 . Accessed February 21, 2014
  PubMedGoogle Scholar
• 85 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) 156-171
  PubMedGoogle Scholar
• 86 Dodel R, Spottke A, Gerhard A , et al. Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial). Mov Disord 2010; 25 (1) 97-107
  CrossrefPubMedGoogle Scholar
• 87 Schwid SR, Cutter GR. Futility studies: spending a little to save a lot. Neurology 2006; 66 (5) 626-627
  CrossrefPubMedGoogle Scholar
• 88 Schoenfeld DA, Cudkowicz M. Design of phase II ALS clinical trials. Amyotroph Lateral Scler 2008; 9 (1) 16-23
  CrossrefPubMedGoogle Scholar
• 89 Collins B, Constant J, Kaba S, Barclay CL, Mohr E. Dementia with Lewy bodies: implications for clinical trials. Clin Neuropharmacol 2004; 27 (6) 281-292
  CrossrefPubMedGoogle Scholar