Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

Jabbari, Edwin; Holland, Negin; Kobylecki, Christopher; Jones, P. Simon; Lamb, Ruth; Rawlinson, Charlotte; Guo, Tong; Costantini, Alyssa; Tan, Manuela; Heslegrave, Amanda; Roncaroli, Federico; Klein, Johannes; Ansorge, Olaf; Allinson, Kieren; Jaunmuktane, Zane; Holton, Janice L.; Révész, Tamás; Warner, Thomas T.; Lees, Andrew J.; Zetterberg, Henrik; Russell, Lucy L.; Bocchetta, Martina; Rohrer, Jonathan D.; Williams, Nigel; Grosset, Donald; Burn, David J.; Pavese, Nicola; Gerhard, Alexander; Leigh, P. Nigel; Church, Alistair; Hu, Michèle; Woodside, John; Houlden, Henry; Rowe, James B.; Morris, Huw R.

doi:10.1001/jamaneurol.2019.4347

Cited by 113 publications

(151 citation statements)

References 48 publications

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“…It is possible that other neurodegenerative diseases may yet show benefit of salsalate and YP, and given the recent report of key differences in clinical trajectories and biomarker profiles between non-Richardson's subtypes of PSP and corticobasal syndrome, use in other 4R-tau variants is also not precluded. 33 There are a number of important limitations to this approach, including its small sample size and lack of statistical power, and it should be noted that these trials were designed for initial analysis of safety and tolerability and only powered to detect very large differences in efficacy; therefore, statistical comparison should be de-emphasized in favor of a qualitative analysis. Furthermore, the lack of randomization and comparison to a large, untreated, historical clinical cohort allows for overestimation of efficacy by contamination of the placebo effect.…”

Section: Discussionmentioning

confidence: 99%

Open‐Label Phase 1 Futility Studies of Salsalate and Young Plasma in Progressive Supranuclear Palsy

VandeVrede

Dale

Fields

et al. 2020

Movement Disord Clin Pract

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Background Progressive supranuclear palsy (PSP) is a neurodegenerative disease without approved therapies, and therapeutics are often tried off‐label in the hope of slowing disease progression. Results from these experiences are seldom shared, which limits evidence‐based knowledge to guide future treatment decisions. Objectives To describe an open‐label experience, including safety/tolerability, and longitudinal changes in biomarkers of disease progression in PSP‐Richardson's syndrome (PSP‐RS) patients treated with either salsalate or young plasma and compare to natural history data from previous multicenter studies. Methods For 6 months, 10 PSP‐RS patients received daily salsalate 2,250 mg, and 5 patients received monthly infusions of four units of young plasma. Every 3 months, clinical severity was assessed with the Progressive Supranuclear Palsy Rating Scale (PSPRS), and MRI was obtained for volumetric measurement of midbrain. A range of exploratory biomarkers, including cerebrospinal fluid levels of neurofilament light chain, were collected at baseline and 6 months. Interventional data were compared to historical PSP‐RS patients from the davunetide clinical trial and the 4‐Repeat Tauopathy Neuroimaging Initiative. Results Salsalate and young plasma were safe and well tolerated. PSPRS change from baseline (mean ± standard deviation [SD]) was similar in salsalate (+5.6 ± 9.6), young plasma (+5.0 ± 7.1), and historical controls (+5.6 ± 7.1), and change in midbrain volume (cm3 ± SD) did not differ between salsalate (–0.07 ± 0.03), young plasma (–0.06 ± 0.03), and historical controls (–0.06 ± 0.04). No differences were observed between groups on any exploratory endpoint. Conclusions Neither salsalate nor young plasma had a detectable effect on disease progression in PSP‐RS. Focused open‐label clinical trials incorporating historical clinical, neuropsychological, fluid, and imaging biomarkers provide useful preliminary data about the promise of novel PSP‐directed therapies.

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Section: Discussionmentioning

confidence: 99%

Open‐Label Phase 1 Futility Studies of Salsalate and Young Plasma in Progressive Supranuclear Palsy

VandeVrede

Dale

Fields

et al. 2020

Movement Disord Clin Pract

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“…This study does not include cases from the full phenotypic range of corticobasal syndromes, or syndromes caused by corticobasal degeneration ( Alexander et al , 2014 ). The current study was not designed to resolve the issue of heterogeneity, but rather to highlight methodological considerations, and best practice, which we hope can be carried forward to identify robust biomarkers of a wide range of phenotypic expressions of the pathologies of Parkinson’s disease, PSP and corticobasal degeneration ( Jabbari et al , 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Although we have addressed four key methodological issues, several limitations remain. This was a single centre study, resulting in a modest sample size when compared to recent multi-centre studies ( Huppertz et al , 2016 ; Nigro et al , 2017 ; Jabbari et al , 2020 ). This limits the generalisation of our results to different clinical sites with potentially different scanning practices, scanner manufacturers and sequence parameters.…”

Section: Discussionmentioning

confidence: 99%

“…Biomarkers should be objective and observer-independent, reproducible, informative about the underlying biology and ideally non-invasive. Candidate biomarkers for parkinsonian disorders have included cognitive tests ( Pillon et al , 1995 ; Aarsland, 2003 ; Rittman et al , 2013 ) and assays of cerebrospinal fluid, serum or urine such as neurofilament light chain ( Jabbari et al , 2017 ; Constantinescu et al , 2019 ; Jabbari et al , 2020 ), supplementing those clinical features that have high clinicopathological correlations ( Alexander et al , 2014 ; Respondek et al , 2017 ; Gazzina et al , 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Towards accurate and unbiased imaging-based differentiation of Parkinson’s disease, progressive supranuclear palsy and corticobasal syndrome

Correia

Rittman

Barnes

et al. 2020

Brain Communications

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The early and accurate differential diagnosis of parkinsonian disorders is still a significant challenge for clinicians. In recent years, a number of studies have used magnetic resonance imaging data combined with machine learning and statistical classifiers to successfully differentiate between different forms of Parkinsonism. However, several questions and methodological issues remain, to minimize bias and artefact-driven classification. In this study, we compared different approaches for feature selection, as well as different magnetic resonance imaging modalities, with well-matched patient groups and tightly controlling for data quality issues related to patient motion. Our sample was drawn from a cohort of 69 healthy controls, and patients with idiopathic Parkinson’s disease (n = 35), progressive supranuclear palsy Richardson’s syndrome (n = 52) and corticobasal syndrome (n = 36). Participants underwent standardized T1-weighted and diffusion-weighted magnetic resonance imaging. Strict data quality control and group matching reduced the control and patient numbers to 43, 32, 33 and 26, respectively. We compared two different methods for feature selection and dimensionality reduction: whole-brain principal components analysis, and an anatomical region-of-interest based approach. In both cases, support vector machines were used to construct a statistical model for pairwise classification of healthy controls and patients. The accuracy of each model was estimated using a leave-two-out cross-validation approach, as well as an independent validation using a different set of subjects. Our cross-validation results suggest that using principal components analysis for feature extraction provides higher classification accuracies when compared to a region-of-interest based approach. However, the differences between the two feature extraction methods were significantly reduced when an independent sample was used for validation, suggesting that the principal components analysis approach may be more vulnerable to overfitting with cross-validation. Both T1-weighted and diffusion magnetic resonance imaging data could be used to successfully differentiate between subject groups, with neither modality outperforming the other across all pairwise comparisons in the cross-validation analysis. However, features obtained from diffusion magnetic resonance imaging data resulted in significantly higher classification accuracies when an independent validation cohort was used. Overall, our results support the use of statistical classification approaches for differential diagnosis of parkinsonian disorders. However, classification accuracy can be affected by group size, age, sex and movement artefacts. With appropriate controls and out-of-sample cross validation, diagnostic biomarker evaluation including magnetic resonance imaging based classifiers may be an important adjunct to clinical evaluation.

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“…In the classical form, PSP-Richardson syndrome (PSP-RS), patients develop imbalance and frequent falls, bulbar failure and dementia, and survive a mean of 6.9 years from symptom onset [1]. More recently defined PSP subtypes, such as PSP-Parkinsonism and PSP-Progressive Gait Freezing, are associated with a slower rate of progression [2]. We have shown that the PSP phenotype is determined by variation at the TRIM11/17 locus [3].…”

Section: Introductionmentioning

confidence: 99%

Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy

Jabbari

Tan

Reynolds

et al. 2020

Preprint

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The genetic basis of variation in the rate of disease progression of primary tauopathies has not been determined. In two independent progressive supranuclear palsy cohorts, we show that common variation at the LRRK2 locus determines survival from motor symptom onset to death, possibly through regulation of gene expression. This links together genetic risk in alpha-synuclein and tau disorders, and suggests that modulation of proteostasis and neuro-inflammation by LRRK2 inhibitors may have a therapeutic role across disorders.

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Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

Cited by 113 publications

References 48 publications

Open‐Label Phase 1 Futility Studies of Salsalate and Young Plasma in Progressive Supranuclear Palsy

Open‐Label Phase 1 Futility Studies of Salsalate and Young Plasma in Progressive Supranuclear Palsy

Towards accurate and unbiased imaging-based differentiation of Parkinson’s disease, progressive supranuclear palsy and corticobasal syndrome

Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy

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