RESUMO
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.
RESUMO
Background: Little is known about the cognitive profile of Hereditary Spastic Paraplegias (HSP), where most scientific attention has been given to motor features related to corticospinal tract degeneration. Objectives: We aimed to perform a broad characterization of the cognitive functions of patients with pure and complicated HSP as well as to determine the frequency of abnormal cognitive performances in the studied subtypes. Methods: A two-center cross-sectional case-control study was performed. All individuals underwent cognitive assessment through screening tests (Mini Mental State Examination-MEEM and Montreal Cognitive Assessment-MOCA) and tests to assess specific cognitive functions (Verbal fluency with phonological restriction-FAS; Verbal categorical fluency-FAS-cat and Rey's Verbal Auditory Learning Test -RAVLT). Results: Fifty four patients with genetically confirmed HSP diagnosis, 36 with spastic paraplegia type 4 (SPG4), 5 SPG11, 4 SPG5, 4 cerebrotendinous xanthomatosis (CTX), 3 SPG7 and 2 SPG3A, and 10 healthy, unrelated control subjects, with similar age, sex, and education participated in the study. SPG4 patients had worse performances in MOCA, FAS, FAS-cat, and RAVLT when compared to controls. Most SPG4 patients presented cognitive changes not compatible with dementia, performing poorly in memory, attention and executive functions. SPG5 patients scored lower in executive functions and memory, and SPG7 patients performed poorly on memory tasks. All evaluated cognitive functions were markedly altered in CTX and SPG11 patients. Conclusions: Cognitive abnormalities are frequent in HSP, being more severe in complicated forms. However, cognitive impairments of pure HSPs might impact patients' lives, decreasing families' socioeconomic status and contributing to the overall disease burden.
