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://clinicaltrials.gov/ct2/show/NCT04006418?term=NCT04006418&draw=2&rank=1.

Outcome Measures and Biomarkers for Clinical Trials in Hereditary Spastic Paraplegia: A Scoping Review

“…Serum and CSF NfL levels were able to differentiate patient vs. control groups or historical control values in all studies. Serum and CSF NfL levels were shown to correlate with SPRS scores in two studies [ 29 , 42 ] but this correlation was not present in the other two studies [ 32 , 43 ] ( Supplementary Material S2 ). Plasma and CSF 25- and 27-OHC were significantly elevated in individuals with HSP- CYP7B1 (SPG5) compared to controls or reported normative values in all four studies [ 35 , 43 , 44 , 45 ].…”

“…Serum and CSF NfL levels were shown to correlate with SPRS scores in two studies [ 29 , 42 ] but this correlation was not present in the other two studies [ 32 , 43 ] ( Supplementary Material S2 ). Plasma and CSF 25- and 27-OHC were significantly elevated in individuals with HSP- CYP7B1 (SPG5) compared to controls or reported normative values in all four studies [ 35 , 43 , 44 , 45 ]. In the few longitudinal studies, there was no change over time in NfL levels [ 32 ] or 25- and 27-OHC levels [ 35 , 44 ].…”

“…Volumetric analysis showed atrophy in certain parts of the brain or spine in patients with HSP [29,31,43,80].…”

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

“…Following the publication of the original article [1] it was brought to our attention that author Dairong Cao's affiliation had inadvertently been changed to "2. Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350005, China" during the implementation of the author's corrections.…”