In September 2019 in the south of France, 5,800 members of the International Parkinson and Movement Disorder Society convened for the society’s 2019 Congress. The wave of information was tsunamic at times, and in an attempt to disseminate information in tangible tidbits, we focus here on presentations related to atypical parkinsonian disorders. It is glimpse into the wonderful world of movement disorders to digest at your convenience.
Progressive Supranuclear Palsy
Because progressive supranuclear palsy (PSP) is a pure tauopathy, it is reasonable to expect that tau could be a useful biomarker. First-generation tau-PET ligands were limited, however, because of off-target binding. In a late breaking abstract, a new second-generation tau-PET tracer 18F-PI2620, with proven high affinity and little off-target binding,1,2 was shown to have elevated binding levels in the globus pallidus of people with clinically diagnosed PSP-Richardson subtype (PSP-RS) or probable PSP compared with healthy individuals. Elevated tau levels were seen in the globus pallidus even in people with PSP-RS who had low disease severity, suggesting that tau-PET with this tracer could potentially be useful for identifying early PSP.
Several other imaging biomarker studies were also presented. These confirmed the ability of the MRI Parkinsonism index and the pons-to-midbrain ratio to differentiation people with PSP-Richardson syndrome (PSP-RS) from people with Parkinson’s disease (PD) and healthy individuals.3,4 In contrast, these measures differentiate PSP-parkinsonism (PSP-p) subtype from healthy individuals but not other subtypes of PSP or PD.
Antitau Treatments in Development
In the ARISE (NCT02985879) phase 2 clinical trial, the antitau antibody, ABBV-8E12 is being evaluated for treatment of PSP. Because there are known subtypes of PSP that progress at different rates,5 the genetic, biochemical, and volumetric MRI (vMRI) data were obtained from all participants, including neurofilament light chain (NfL) and tau levels in cerebrospinal fluid and plasma and MRI volumes of whole brain, midbrain, and frontal lobe. Biomarkers were compared with baseline disease severity measured with the PSP Rating Scale (PSPRS) for the first 30 participants enrolled. Although there was a trend toward correlation of plasma NfL levels and disease severities, that was not statistically significant in this initial small cohort. However, higher plasma NfL levels did significantly correlate with lower whole brain, midbrain, and frontal lobe volumes as did clinical severity).7 The reduction of brain atrophy is a hopeful sign of the promise antitau antibodies hold and perhaps as more participants complete this study, an effect on clinical progression will be seen.6
There are 2 other antitau antibodies being tested in humans. These are UCB0107, which binds a central tau epitope, and gosuranemab. Both were show to have acceptable safety profiles and tolerability, and both are expected to continue advancing through the clinical trial process.2,7
A few studies built upon a small 2010 study of 40 patients with varying ataxia taking riluzole (100 mg/day for 8 weeks, showing riluzole may improve ataxia symptoms after 8 weeks, proportion of patients with a decrease of at least 5 points in the International Cooperative Ataxia Rating Scale (ICARS) total score after 4 and 8 weeks compared with the baseline score.8
In a small group of children with early-onset ataxia, a home-based ice-skating exercise video game improved the calculated median score on the Scale for Assessment and Rating of Ataxia (SARA) and Pediatric Balance Scale (PBS) but did not result in improvements in muscle force.9 Children in this study were age 4 to 9 years and 30-minute exercise sessions were performed 3 times per week over a 6-week period. Improvements were seen compared with age-matched controls with early-onset ataxia who did perform the exercise program.
Another small study of 22 adults in Pakistan who were randomly assigned to receive a 4-week counseling and rehabilitation program or standard care found that those who received rehabilitation counseling had significantly more improvements on the ataxia impact scale (P = .003).10
Novel Ataxia Gene Identified
Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a novel ataxia that, similarly to Friedrich’s ataxia or spinocerebellar ataxia type 3, is comprised of cerebellar, vestibular, and sensory ataxia. The RFC1 causative gene for CANVAS has now been identified and may account for as much as 22% of late onset ataxias in Europe.11,12 Unfortunately, a test for RFC1 is not widely available. When Friedrich’s ataxia is suspected and genetic testing for frataxin (FTX) is negative, it may be wise to add CANVAS to the differential diagnosis and test for RFC1 when possible.
Further Reading and Reviews
Reviews by Zesiewicz et al. and Novak et al. were highlighted as good practical foundations for ataxia.13,14
Treatments for multisystem atrophy (MSA) in the pipeline can be found at www.Multisystematrophy.org
The most recent news is of a novel compound, verdiperstat, for which a first participant was enrolled in a phase 3 clinical trial in July 2019. Verdiperstat is a first-in-class, oral, brain-penetrant, irreversible inhibitor of myeloperoxidase, an enzyme that acts as a key driver of oxidative stress and inflammation in the brain. Approximately 250 healthy volunteers and patients were treated with verdiperstat in phase 1 and 2 clinical trials. Results from a phase 2 trial in participants with MSA showed evidence of target engagement and favorable trends over 12 weeks on the Unified MSA Rating Scale (UMSARS), an exploratory clinical outcome measure. Verdiperstat received orphan drug designation from the Food and Drug Association (FDA) because of unmet medical need in MSA. Verdiperstat also has potential to be developed in a number of other diseases associated with oxidative stress, inflammation, and neurodegeneration.
A small study of 16 patients with cognitive impairment in PD and MSA showed the use of intranasal insulin as a potentially safe intervention for functional clinical improvement.15
Reducing α-synuclein aggregation continues to be a therapeutic target. In a novel approach, active vaccine immunotherpay is aimed at disease modification. In a phase 1 study, the vaccine PD01A induced a significant and sustained immune response against α-synuclein and could be reactivated by a booster injection. Antibodies induced by PD01A recognize an α-synuclein target epitope and a phase 2 study is pending.16
Unfortunately, as presented in a late breaking abstract,17 antiaggregative epigallocatechin gallate (EGCG) treatment of individuals with MSA did not slow disease progression and did lead to hepatotoxicity. However, striatal volume loss was slowed in those treated with EGCG vs controls. In another presentation18 PBT434—a small molecule that inhibits synuclein aggregation—was found safe when administered to 8 healthy volunteers. Dose-dependent pharmacokinetics and transport into the central nervous system (CNS) were also confirmed. In preclinical trials, PBT434 preserved neurons, improved motor function, and reduced glial cell inclusions in a mouse MSA model.
A small group of 4 people with possible or probable MSA-p treated with safinamide had improvement of motor function and freezing of gait. The Hoehn-Yahr scale score improved from 3 to 2 in 3 of the 4 individuals. A single person developed nontroublesome orofacial dyskinesia; no symptomatic orthostatic hypotension or hallucinations occurred.19 Although this is a small sample, it suggests that people with MSA-p patients may experience some benefit from safinamide.
1. Brendel M, van Eimeren T, Barthel H, et al. Tau PET in Progressive Supranuclear Palsy. Multi-Center Evaluation of [18F]PI-2620. Abstract LBA 2. Presented at the International Congress on Parkinson’s Disease and Movement Disorders, September 22-26, 2019, Nice, France. https://www.mdscongress.org/Congress-Branded/Congress-2019-Files/2019Late-BreakingAbstractsPublicationFile.pdf. Accessed November 4, 2019.
2. T. Buchanan, S. De Bruyn, T. Fadini, et al. A randomised, placebo-controlled, first-in-human study with a central tau epitope antibody –UCB0107. Abstract LBA 3. Presented at the International Congress on Parkinson’s Disease and Movement Disorders, September 22-26, 2019, Nice, France. https://www.mdscongress.org/Congress-Branded/Congress-2019-Files/2019Late-BreakingAbstractsPublicationFile.pdf. Accessed November 4, 2019.
3. Picillo M, Tepedino MF, Abate F, et al. Midbrain MRI assessments in progressive supranuclear palsy subtypes. J Neurol Neurosurg Psychiatry. 2019 Sep 16. pii: jnnp-2019-321354. doi: 10.1136/jnnp-2019-321354. [Epub ahead of print].
4. Quattrone A, Morelli M, Vescio B, et al. Refining initial diagnosis of Parkinson’s disease after follow-up: A 4-year prospective clinical and magnetic resonance imaging study. Mov Disord. 2019;34(4):487-495.
5. Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Mov Disord. 2017;32(6):853-864.
6. Soares H, Jin Z, Fisseha N, Gold M, et al. Clinical correlates of genetic and biomarker profiles in patients with progressive supranuclear palsy: data from the ARISE [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/clinical-correlates-of-genetic-and-biomarker-profiles-in-patients-with-progressive-supranuclear-palsy-data-from-the-arise-study/. Accessed November 4, 2019.
7. Kupferman J, Boxer A, Grundman L, et al. Safety results of an open-label, long-term treatment study of gosuranemab (formerly BIIB092) in participants with PSP. Abstract LBA 11. Presented at the International Congress on Parkinson’s Disease and Movement Disorders, September 22-26, 2019, Nice, France. https://www.mdscongress.org/Congress-Branded/Congress-2019-Files/2019Late-BreakingAbstractsPublicationFile.pdf. Accessed November 4, 2019.
8. Ristori G, Romano S, Visconti A, et al. Riluzole in cerebellar ataxia. Neurology. 2010;74(10):839-845.
9. Brandsma R, Ganzevoort I, Berg M, et al. Exergame training in early onset ataxia patients [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/exergame-training-in-early-onset-ataxia-patients/. Accessed November 1, 2019.
10. Arain MIA. Supportive treatments for ataxia, a randomized control trial [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/supportive-treatments-for-ataxia-a-randomized-control-trial/. Accessed November 1, 2019.
11. Houlden H, Reilly M, Zuchner S, et al. A recessive repeat expansion causes CANVAS and is a common cause of late-onset ataxia [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/a-recessive-repeat-expansion-causes-canvas-and-is-a-common-cause-of-late-onset-ataxia/. Accessed November 1, 2019.
12. Cortese A, Simone R, Sullivan R, et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019;51(4):649-658. Erratum in: Nat Genet. 2019 May;51(5):920.
13. de Silva RN, Vallortigara J, Greenfield J, Hunt B, Giunti P, Hadjivassiliou M. Diagnosis and management of progressive ataxia in adults. Pract Neurol. 2019;19(3):196-207.
14. Zesiewicz TA, Wilmot G, Kuo SH, et al. Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(10):464-471.
15. Novak P, Pimentel Maldonado DA, Novak V. Safety and preliminary efficacy of intranasal insulin for cognitive impairment in Parkinson disease and multiple system atrophy: a double-blinded placebo-controlled pilot study. PLoS One. 2019;14(4):e0214364.
16. Meissner W, Pavy-Le Traon A, Foubert-Samier A, et al. Specific active immunotherapy (SAIT) against alpha-synuclein with AFFITOPE® PD01A and PD03A: Results from the AFF009 phase I trial [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/specific-active-immunotherapy-sait-against-alpha-synuclein-with-affitope-pd01a-and-pd03a-results-from-the-aff009-phase-i-trial/. Accessed November 3, 2019.
17. Levin J, Giese A, Oertel W, et al. Safety and efficacy of treatment with the anti-aggregative epigallocatechin gallate in patients with multiple system atrophy tested in a multicentric interventional double blinded placebo-controlled trial. [abstract]. Mov Disord. 2019; 34 (S2). https://www.movementdisorders.org/Congress-Branded/Congress-2019-Files/2019Late-BreakingAbstractsPublicationFile1.pdf. Accessed October 30, 2019.
18. Stamler D, Bradbury M, Wong C, Offman E. A first in human study of PBT434, a novel small molecule inhibitor of alpha-synuclein aggregation [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/a-first-in-human-study-of-pbt434-a-novel-small-molecule-inhibitor-of-alpha-synuclein-aggregation/. Accessed October 30, 2019.
19. Simões R, Gonçalves A, Ferreira JJ. Is safinamide helpful in multiple system atrophy? [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/is-safinamide-helpful-in-multiple-system-atrophy/. Accessed October 29, 2019