Long-term progression of clinician-reported and gait performance outcomes in hereditary spastic paraplegias

Diana Maria Cubillos Arcila; Gustavo Dariva Machado; Valéria Feijó Martins; Vanessa Bielefeldt Leotti; Rebecca Schüle; Leonardo Alexandre Peyré-Tartaruga; Jonas Alex Morales Saute

doi:10.3389/fnins.2023.1226479

Long-term progression of clinician-reported and gait performance outcomes in hereditary spastic paraplegias

Front Neurosci. 2023 Sep 22:17:1226479. doi: 10.3389/fnins.2023.1226479. eCollection 2023.

Authors

Affiliations

¹ Graduate Program in Medicine, Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
² Exercise Research Laboratory, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
³ Division of Medical Genetics, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
⁴ Graduate Program in Human Movement Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁵ Biostatistics Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
⁶ Department of Statistics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁷ Division of Neurodegenerative Diseases, Department of Neurology, Heidelberg University, Heidelberg, Germany.
⁸ Division of Neurology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
⁹ Neurogenetics, Clinical Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
¹⁰ Department of Internal Medicine, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Abstract

Introduction: Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative diseases in which little is known about the most appropriate clinical outcome assessments (COAs) to capture disease progression. The objective of this study was to prospectively determine disease progression after 4.5 years of follow-up with different clinician-reported (ClinRO) and gait performance outcomes (PerFOs).

Methods: Twenty-six HSP patients (15 SPG4, 5 SPG7, 4 SPG5, 2 SPG3A) participated in this single-center cohort study in which the ClinRO: Spastic Paraplegia Rating Scale; and the PerFOs: 10-meters walking test and timed-up and go (TUG), at self-selected and maximal walking speeds; Locomotor Rehabilitation Index; and 6-min walking test were performed at baseline and after 1.5 (18 patients) and 4.5 (13 patients) years.

Results: In the 3-year interval between the second and third assessments, significant progressions were only found in PerFOs, while in the overall 4.5 years of follow-up, both PerFOs and ClinROs presented significant progressions. The progression slopes of COAs modeled according to the disease duration allowed the estimation of the annual progression of the outcomes and sample size estimations for future clinical trials of interventions with different effect sizes. TUG at maximal walking speed was the only COA capable of differentiating subjects with a worse compared to a stable/better impression of change and would require the smallest sample size if chosen as the primary endpoint of a clinical trial.

Discussion: These findings indicate that both performance and clinician-reported outcomes can capture long-term progression of HSPs, with some PerFOs presenting greater sensitivity to change. The presented data are paramount for planning future disease-modifying and symptomatic therapy trials for this currently untreatable group of diseases.

Keywords: clinical outcome assessment; clinician-reported outcomes; gait analysis; hereditary spastic paraplegias; performance outcomes.

Grants and funding

This study was funded by FIPE-HCPA (GPPG-HCPA 2017–0341), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), FAPERGS/MS/CNPq 08/2020 – PPSUS (Grant No. 21/2551–0000088-0), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (Grant No. PROEX: 0730/2020). DC was supported by CAPES, and JS was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).