Potential biomarker for treatment response
Here are two related SPG4 studies by researchers at the University of Tübingen in Germany. The first describes the subtle clinical signs that develop before gait is affected. The second identifies a potential biomarker most suited to assessing treatment response where symptom onset is about to occur.
A clinical test called ‘Babinski’s sign’ differentiated reliably between 30 people with a mutation for SPG4 and 26 people who did not – with all 56 being first-degree relatives of people with SPG4. Increased reflexes, ankle clonus, and hip abduction weakness were more frequent in pre-symptom onset mutation carriers but were also observed in non-mutation carriers.
An increase was also found in neurofilament levels in cerebrospinal fluid when approaching the time point of predicted disease manifestation in those with invitations for SPG4.
This cohort study aims to characterize the prodromal phase of hereditary spastic paraplegia type 4 (SPG4) by biomarkers and clinical signs and symptoms that develop before manifest gait abnormalities.
56 first-degree relatives at risk to develop SPG4 underwent blinded genotyping and standardized phenotyping, including the Spastic Paraplegia Rating Scale (SPRS), complicating symptoms, non-motor affection, Three-Minute-Walk, and neurophysiological assessment. Automated MR image analysis was used to compare volumetric properties. CSF of 33 probands was analyzed for neurofilament light chain, tau, and amyloid-ß.
30 participants turned out to be SPAST mutation carriers, whereas 26 did not inherit a SPAST mutation. Increased reflexes, ankle clonus, and hip abduction weakness were more frequent in prodromal mutation carriers but were also observed in non-mutation carriers. Only Babinski’s sign differentiated reliably between the two groups. Timed walk and non-motor symptoms did not differ between groups. Whereas most mutation carriers had total SPRS scores of two points or more, only two non-mutation carriers reached more than one point. Motor evoked potentials revealed no differences between mutation and non-mutation carriers. We found NfL but not tau or amyloid-ß to rise in CSF of mutation carriers when approaching the time point of predicted disease manifestation. Serum NfL did not differ between groups. Volumetric MRI analyses did not reveal group differences apart from a smaller cingulate gyrus in mutation carriers.
This study depicts subtle clinical signs which develop before gait abnormalities in SPG4. Long-term follow-up is needed to study the evolution of SPG4 in the prodromal stage and conversion into manifest disease. NfL in CSF is a promising fluid biomarker that may indicate disease activity in prodromal SPG4 but needs further evaluation in longitudinal studies.
SOURCE: Brain. 2022 Apr 26;awac155. doi: 10.1093/brain/awac155. Online ahead of print. PMID: 35472722 © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
The prodromal phase of hereditary spastic paraplegia type 4: the preSPG4 cohort study
Tim W Rattay 1 2 3 , Maximilian Völker 1 , Maren Rautenberg 3 4 , Christoph Kessler 1 2 3 , Isabel Wurster 1 2 , Natalie Winter 1 , Tobias B Haack 3 4 , Tobias Lindig 5 6 , Holger Hengel 1 2 3 , Matthis Synofzik 1 2 3 , Rebecca Schüle 1 2 3 , Peter Martus 7 , Ludger Schöls 1 2 3
1. Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
2. German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
3. Center for rare diseases (ZSE) University of Tübingen, Tübingen, Germany.
4. Institute of Medical Genetics and Applied Genomics, University of All Tübingen, Tübingen, Germany.
5. Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Tübingen, Germany.
6. AIRAmed GmbH, Konrad-Adenauer-Str. 13, 72072 Tübingen, Germany.
7. Institute of Clinical Epidemiology and Applied Biostatistics, University of Tübingen, Tübingen, Germany.
Potential biomarker for SPG4 discovered
Suited to assessing therapeutic response in younger people
Levels of a compound called neurofilament light chain in the serum (sNfl) change dynamically around the onset of symptoms in SPG4, making it a potential biomarker to assess response to therapeutic treatment in younger people with SPG4.
Objective: While the anticipated rise of disease-modifying therapies calls for reliable trial outcome parameters, fluid biomarkers are lacking in spastic paraplegia type 4 (SPG4), the most prevalent form of hereditary spastic paraplegia. We therefore investigated serum neurofilament light chain (sNfL) as a potential therapy response, diagnostic, monitoring, and prognostic biomarker in SPG4. The compound was found unsuitable for measurement of disease progression.
Methods: We assessed sNfL levels in 93 patients with SPG4 and 60 healthy controls. The longitudinal study of sNfL levels in SPG4 patients covered a baseline, 1-year follow-up and 2-year follow-up visit.
Results: Levels of sNfL were significantly increased in patients with genetically confirmed SPG4 compared to healthy controls matched in age and sex (p = 0.013, r = 0.2). Our cross-sectional analysis revealed a greater difference in sNfL levels between patients and controls in younger ages with decreasing fold change of patient sNfL elevation at older ages. Over our observational period of 2 years, sNfL levels remained stable in SPG4 patients. Disease severity and progression did not correlate with sNfL levels.
Interpretation: Our longitudinal data indicate a stable turnover of sNfL in manifest SPG4; therefore, sNfL levels are not suitable to monitor disease progression in SPG4. However, sNfL may be valuable as a therapy response biomarker, since its turnover could be modified by interventions. As the course of sNfL levels appears to be most dynamic around the onset of SPG4, the ability to detect a therapy response appears to be especially promising in younger patients, matching the need to initiate treatment in early disease stages.
SOURCE: Ann Clin Transl Neurol. 2022 Mar;9(3):326-338. doi: 10.1002/acn3.51518. Epub 2022 Feb 16. PMID: 35171517 © 2022 The Authors.
Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4
Christoph Kessler 1 2 , Lina Maria Serna-Higuita 3 , Carlo Wilke 1 2 , Tim W Rattay 1 2 , Holger Hengel 1 2 , Jennifer Reichbauer 1 2 , Elke Stransky 4 , Alejandra Leyva-Gutiérrez 1 2 , David Mengel 1 2 , Matthis Synofzik 1 2 , Ludger Schöls 1 2 , Peter Martus 3 , Rebecca Schüle 1 2
1. Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
2. German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
3. Department of Clinical Epidemiology and Applied Biostatistics, University of Tübingen, Tübingen, Germany.
4. Center of Neurology, University of Tübingen, Tübingen, Germany.