Potential markers for sample size estimations in hereditary spastic paraplegia type 5

Abstract

Background: Aim to identify potential biomarkers to assess therapeutic efficacy for hereditary spastic paraplegias type 5 (SPG5) by investigating the clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) features.

Methods: We performed a cross-sectional study to compare SPG5 patients with age- and sex-matched healthy controls who underwent conventional and quantitative MRI techniques of spinal cord (C1-T9) and brain. SPG5 patients also underwent assessment for clinical status and CSF biomarkers (27-hydroxycholesterol, neurofilament light). We identified a set of markers with standardized effect sizes (|t|> 0.5) to estimate sample sizes for disease progression (disease duration > 14 years vs. ≤ 14 years).

Results: Seventeen genetically confirmed SPG5 patients (11 men, 6 women; age range, 13-49 years; median disease duration, 14 years) were enrolled. Compared to healthy controls, the total spinal cord area (SCA) of SPG5 patients was reduced particularly at the thoracic levels (cervical levels: 12-27%; thoracic levels 41-60%). Patients did not show significant alterations of brain signal abnormalities or atrophy relative to controls. A total of 10 surrogate markers were selected and a minimum sample size was achieved with the measurement of SCA on T9 (n = 22) much less that what would be required if using clinical disability assessment (n = 124).

Conclusions: SPG5 patients showed distinct MRI features of spinal cord atrophy without significant brain alterations. Our finding supports the measurements of spinal cord on T9 level as potential endpoint for SPG5 clinical trials. Trial registration ClinicalTrials.gov, NCT04006418. Registered 05 July 2019, https://ichgcp.net/clinical-trials-registry/NCT04006418?term=NCT04006418&draw=2&rank=1 .

Keywords: Biomarkers; Hereditary; Magnetic resonance imaging; Sample size; Spastic paraplegia.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1

Quantitative MRI to assess spinal cord area. A Processing included 3 steps: (1) composing the cervical and thoracic spinal cord with 3D-T2W-SPACE; (2) segmentation and labeling the spinal cord; (3) measurement of spinal cord cross-sectional area (SCA) and sectional diameter (RL and AP). B Area of spinal cords (C2-T9) in SPG5 patients and matched healthy controls, comparisons performed using Mann–Whitney test, **P < 0.01, ***P < 0.001. C, D Representative MRIs of SPG5 and healthy control. In SPG5 patients, a significant thinning in the spinal cord was observed (blue arrow) in the 3D T1-weighted and 3D T2-weighted sequence, respectively

Fig. 2

Conventional brain MRI evaluation. A Abnormal signals were assessed on T2, FLAIR, SWI and T1 routine sequence (above panel, from left to right). B–D Neuroradiological signs, previously reported in other subtypes of hereditary spastic paraplegias, were also assessed; B thin corpus callosum (left T1, right T2 FLAIR, green edge arrow); C T2 hyperintensity of the dentate nucleus (above T1, below T2; black edge arrow); D “Ears- of -the- Lynx” MRI sign (above T1, below T2 FLAIR, red edge arrow)

Fig. 3

Quantitative MRI to assess the structural changes of brain. A Visual rating scales to assess cerebral atrophy, OF = orbitofrontal cortex, AC = anterior cingulate, AT = anterior temporal, FI = fronto-insula, MT = medial temporal lobe, PA = posterior cortex; Visual rating was performed by two neurologists, the intraclass correlation coefficient value ranged from 0.829 to 1.000. Comparisons to each visual rating score and total visual rating scores between the SPG5 patients and the matched healthy controls (HC) were performed using the Mann–Whitney test. B Voxel-based morphometry (VBM) was performed to assess brain volume analysis alteration between healthy controls (HC) and SPG5 patients; statistical tests were evaluated at a significance level of P < 0.05 corrected for multiple comparisons with the false discovery rate (FDR). C Comparisons of the grey matter fraction (GMF) between SPG5 patients and healthy controls were performed using the Mann–Whitney test (right). D Voxel-based morphometry (VBM) was performed to assess gray matter analysis alteration between healthy controls (HC) and patients; statistical tests were evaluated at a significance level of P < 0.05 corrected for multiple comparisons with FDR. E, F Comparisons of the cerebellum volume fraction and corpus collosum volume fraction between SPG5 patients and healthy controls were performed using the Mann–Whitney test