Progressive Supranuclear Palsy (PSP) is an adult-onset neurodegenerative disorder with cerebral 4R-tau pathology leading to an akinetic-rigid syndrome with oculomotor dysfunction, postural instability, frontal lobe and bulbar dysfunction. The PSP study group also has an active interest in corticobasal degeneration (CBD). New consensus research criteria have recently been published to facilitate studies of CBD (Armstrong, et al. Neurology 2013; 80: 496-503). Like PSP, CBD is a primary four repeat (4R) tauopathy with strong genetic links to the tau gene (MAPT). Because pathological CBD often overlaps with clinical PSP, and vice versa, both disorders are often considered in parallel, particularly in biomarker and imaging studies. As specific tau-directed therapies are developed for PSP, it is predicted that such agents may also be useful to treat CBD, possibly leading to combined clinical trials in both disorders.
No curative treatment options for PSP and CBD are available at present. Clinical research into these rare disorders is limited in power due to its fragmentation.
Our overall aim is to stimulate research to improve diagnostic and therapeutic options for PSP and CBD. Specifically, we aim to improve the early diagnosis for PSP and CBD, to create clinical research networks, and to facilitate clinical therapeutic trials in PSP and CBD.
Aim 1: To improve the clinical diagnosis of PSP and CBD.
The diagnostic gold standard is pathological diagnosis (Hauw et al., Neurology. 1994;44:2015-9). Clinical diagnosis remains a challenge. The National Institute of Neurological Disorders and Stroke and the Society for PSP (NINDS-SPSP) criteria had been proposed for the clinical diagnosis (Litvan et al., Neurology 1996; 46:922-930). Validation of these criteria in independent sets of patients demonstrated a high positive predictive value, albeit low sensitivity particularly during the early course of the disease and for variant clinical presentations (Osaki et al., Mov Disord. 2004;19;181–189; Respondek et al., Mov Disord. 2013 doi: 10.1002/mds.25327). Particularly, the NINDS-SPSP criteria did not allow the recognition of the recently described variable phenotypic PSP presentations and the very early clinical manifestations.
A very important aspect is the differential diagnosis vs. corticobasal degeneration (CBD).
Therefore, the MDS-PSP study group established new MDS-criteria for the clinical diagnosis of PSP on the basis of a systematic screen of more than 6000 published original research articles and focused consensus meeting with ~40 international experts (Höglinger et al., for the Movement Disorder Society-endorsed PSP Study Group. Clinical Diagnosis of Progressive Supranuclear Palsy - The Movement Disorder Society Criteria. Movement Disorders, 2017;32(6):853-864.
A validation of the MDS-PSP criteria in independent retrospective clinico-pathological cases is currently ongoing.
A collaborative prospective validation of the of the MDS-PSP criteria is also ongoing (see aim 2).
Aim 2: To promote cooperative clinical research into PSP and CBD.
We aim to create clinical research networks to improve the quality of clinical natural history data, neuroimaging data and biomaterials. Therefore, clinical research networks have been initiated in
- France (NS-PARK/FCRIN network PIs: Jean-Christoph Corvol, Olivier Rascol)
- Germany (Describe-PSP / ProPSP Studies: PI: Günter Höglinger)
- Italy (Italian PSP Registry: PIs: Paolo Barone / Angelo Antonini)
- Japan (JALPAC Study, PI: Takahiko Tokuda, Ikuko Aiba, Kenji Nakashima)
- UK (PROSPECT-UK Study, PI: Huw Morris),
- USA (4RTNI / ARTFL Studies, PI: Adam Boxer),
We continue our efforts to harmonize protocols for the national cohort studies to maximize the scientific output. There is particular need to generate natural history data for the variant clinical manifestations of PSP, as operationalized now for the first time in the MDS-PSP criteria, as a basis for future therapeutic trials.
Aim 3: To promote clinical trials aiming to cure PSP and CBD.
Presently available treatment options are limited to symptomatic interventions with low efficacy. No protective or curative treatment options are available at present. Therefore, we aim to initiate measures facilitating therapeutic clinical trials in PSP.
Basic science continues to identify molecular targets and corresponding interventions. Translation into clinical trials to evaluate their safety and efficacy lags behind. The reasons therefore lie partly in the limited repertoire of study designs specific for PSP. For this purpose we need to develop and optimize clinical scores and scales to quantify disease-specific target symptoms, and to identify surrogate markers for disease progression. Acquisition of the natural history data needed for power calculation is particularly challenging in PSP because of its broad clinical spectrum, absence of commonly accepted clinical sub-classification criteria, and geographical fragmentation of clinical research.
The MDS-PSP study group is actively involved in optimizing the clinical trial methodology, e.g.
- Stamelou M, Schöpe J, Wagenpfeil S, del Ser T, Antonelou RCh, Oertel WH, Boxer AL, Höglinger GU. Power Calculations and Placebo Effect Estimation for Clinical Trials in Progressive Supranuclear Palsy. Movement Disorders, 2016;31(5):742-7.
- Höglinger GU, Schöpe J, Stamelou M., Kassubek J., Del Ser T, Boxer AL, Wagenpfeil S, Huppertz HJ, Longitudinal MRI volumetry as a read-out for clinical trials in progressive supranuclear palsy: new combined score. Movement Disorders. 2017;32(6):842-852.
The MDS-PSP study group members have proven expertise to professionally run clinical trials in PSP, e.g.:
- Stamelou M, Reuss A, Pilatus U, Magerkurth J, Niklowitz P, Eggert KM, Krisp A, Menke T, Schade-Brittinger C, Oertel WH, Höglinger GU. Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial. Movement Disorders, 2008;23:942-9.
- Tolosa E, Litvan I, Höglinger GU, Burn D, Lees A, Andrés MV, Gómez-Carrillo B, León T, Del Ser T; TAUROS Investigators. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov Disord. 2014 Apr;29(4):470-8.
- Höglinger GU, Huppertz HJ, Wagenpfeil S, Andrés MV, Belloch V, León T, Del Ser T; TAUROS MRI Investigators. Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial. Mov Disord. 2014 Apr;29(4):479-87.
- Boxer AL, Lang AE, Grossman M, Knopman DS, Miller BL, Schneider LS, Doody RS, Lees A, Golbe LI, Williams DR, Corvol JC, Ludolph A, Burn D, Lorenzl S, Litvan I, Roberson ED, Höglinger GU, Koestler M, Jack CR Jr, Van Deerlin V, Randolph C, Lobach IV, Heuer HW, Gozes I, Parker L, Whitaker S, Hirman J, Stewart AJ, Gold M, Morimoto BH; AL-108-231 Investigators. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol. 2014 Jul;13(7):676-85.
Thus, the MDS-PSP study group members are actively engaged in planning and conducting phase II/III trials with tau-targeting interventions.
Aim 4: To disseminate knowledge about PSP and CBD.
The European section of the group has conducted Continuing Medical Education Course ‘50 years of Progressive Supranuclear Palsy’ in October 2014 in Munich. Due to the high interest and positive feed-back, we aim to prepare a second course for 2019.
The group aims to prepare a website tool and a video-based tutorial for the broad implementation of the new MDS-diagnostic criteria in clinical routine.
In summary, the MDS PSP Study Group has set up studies and initiatives to improve awareness, early diagnosis and treatment of PSP and CBD.