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. 2022 Sep;9(9):1437-1448.
doi: 10.1002/acn3.51645. Epub 2022 Aug 11.

Glial fibrillary acidic protein in cerebrospinal fluid of patients with spinal muscular atrophy

Maren Freigang #  1 , Petra Steinacker #  2   3 , Claudia D Wurster  3 , Olivia Schreiber-Katz  4 , Alma Osmanovic  4   5 , Susanne Petri  4 , Jan C Koch  6 , Kevin Rostásy  7 , André Huss  3   8 , Hayrettin Tumani  3 , Benedikt Winter  9 , Björn Falkenburger  1   10 , Albert C Ludolph  3   8 , Markus Otto  2 , Andreas Hermann #  11   12 , René Günther #  1   10
Affiliations

Glial fibrillary acidic protein in cerebrospinal fluid of patients with spinal muscular atrophy

Maren Freigang et al. Ann Clin Transl Neurol. 2022 Sep.

Abstract

Objective: Activated astroglia is involved in the pathophysiology of neurodegenerative diseases and has also been described in animal models of spinal muscular atrophy (SMA). Given the urgent need of biomarkers for treatment monitoring of new RNA-modifying and gene replacement therapies in SMA, we examined glial fibrillary acidic protein concentrations in cerebrospinal fluid (cGFAP) as a marker of astrogliosis in SMA.

Methods: 58 adult patients and 21 children with genetically confirmed 5q-associated SMA from four German motor neuron disease specialist care centers and 30 age- and sex-matched controls were prospectively included in this study. cGFAP was measured and correlated to motor performance and disease severity. Additionally, we compared cGFAP with neurofilament light chain concentrations in cerebrospinal fluid (cNfL).

Results: cGFAP concentrations did not differ from controls but showed higher levels in more severely affected patients after adjustment for patients' age. Normalized cNfL values were associated with disease severity. Within 14 months of nusinersen treatment, cGFAP concentrations did not change, while cNfL decreased significantly.

Interpretation: cGFAP is not an outstanding biomarker in SMA, but might support the hypothesis that glial activation is involved in SMA pathology. Unlike previously suggested, cNfL may be a promising biomarker also in adult patients with SMA, which should be subject to further investigations.

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Conflict of interest statement

MF reports non‐financial support from Biogen outside the submitted work.

PS reports no disclosures. CDW has received honoraria from Biogen as an advisory board member and for lectures and as a consultant and advisory board member from Hoffmann‐La Roche. She also received travel expenses from Biogen. OSK has received honoraria as a speaker/consultant and/or funding for travel expenses from the German Neuromuscular Society “Deutsche Gesellschaft fuer Muskelkranke” (DGM e.V.), Novartis, Biogen GmbH, Biermann Verlag GmbH, MK + S ‐ Medizin, Kommunikation & Service GmbH, and the Jain Foundation, outside the submitted work; and research support from the DGM e.V., outside the submitted work. AO has received honoraria from Biogen for lectures. SP has received grants from the German Neuromuscular Society, the Federal Ministry of Education and Research, the German Israeli Foundation for Scientific Research and Development, and the EU Joint Programme for Neurodegenerative Disease Research; and other support from Cytokinetics, Desitin Pharma, Biogen, Novartis, and Teva outside of the submitted work. JCK has received payment for consultation and advisory board participation from Biogen, Hoffmann‐La Roche and AveXis. KR has no conflicts of interest to declare that are relevant to the content of this article. AHu has no conflicts of interest to declare that are relevant to the content of this article. HT funding for research projects, lectures, and travel from Alexion, Bayer, Biogen, Celgene/Bristol‐Myers‐Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi/Genzyme, Siemens and Teva, and received research support from Chemische Fabrik Karl Bucher GmbH, German Multiple Sclerosis Society (DMSG), and the German Ministry for Education and Research (BMBF). BW declares honoraria for lectures, travel support for meetings, and advisory board participation for Biogen, Novartis and Roche. BF has no conflicts of interest to declare that are relevant to the content of this article. ACL has received personal fees from AB Science, Biogen, Cytokinetics, GlaxoSmithKline, Orion Pharma, Novartis, Tau Rx Therapeutics, Teva, Mitsubishi, and Hoffmann‐La Roche outside of the submitted work. MO has no conflicts of interest to declare that are relevant to the content of this article. AH received royalties from BIOGEN and DESITIN as an advisory board member. RG has received honoraria from Biogen as an advisory board member and for lectures and as a consultant and advisory board member from Hofmann‐La Roche. He also received travel expenses and research support from Biogen.

Figures

Figure 1
Figure 1
Study profile. SMA, spinal muscular atrophy; MND, motor neuron disease; cGFAP, glial fibrillary acidic protein concentration in cerebrospinal fluid; cNfL, neurofilament light chain concentration in cerebrospinal fluid; HFMSE, Hammersmith Functional Motor Scale Expanded; RULM, Revised Upper Limb Module; ALSFRS‐R, revised ALS Functional Rating Scale; CHOP INTEND, Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders.
Figure 2
Figure 2
cGFAP concentrations before treatment initiation. (A) Baseline cGFAP concentrations comparing diseased individuals (closed circles; N = 79) to controls (open circles; N = 30). Horizontal line shows median, whiskers illustrate interquartile range (0.25–0.75), each icon represents an individual patient. (B) Correlation between age and cGFAP concentration before treatment initiation; each icon represents an individual person; shades of green distinguish SMA type, open circles display controls. Solid line shows regression line of patients with SMA, dashed line shows regression line of controls. cGFAP, glial fibrillary acidic protein concentration in cerebrospinal fluid. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
cNfL concentrations before treatment initiation. (A) Association between age and cNfL concentration before treatment initiation; each icon represents an individual person; shades of purple distinguish SMA type. Solid line indicates upper limit of normal (reported by Yilmaz et al.), dashed line shows predicted cNfL concentration (calculated using regression formula determined by Yilmaz et al.). (B) Correlation between cGFAP and cNfL concentration before treatment initiation; each icon represents an individual person; shades of gray distinguish SMA type. cNfL, neurofilament light chain concentration in cerebrospinal fluid; cGFAP, glial fibrillary acidic protein concentration in cerebrospinal fluid; N = 73. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 4
Figure 4
Dynamic of cGFAP and cNfL during nusinersen treatment. (A) Change of cGFAP and cNfL concentration during 14 months of nusinersen treatment plotted against age at start of treatment. Colored areas are created by the difference between baseline and follow‐up for cGFAP and cNfL, respectively. When more than one paired data set was available for the corresponding age, the mean was plotted. Dark green or dark purple areas illustrate a decrease in cGFAP or cNfL, respectively, from baseline to 14‐month follow‐up. (B) Fold change of cGFAP concentrations during nusinersen treatment from baseline (V1) to 14‐month follow‐up (V7). Each colored circle represents the median value of the respective subgroup at follow‐up measurement; color shading distinguishes SMA type. Each tick on the x‐axis indicates a nusinersen administration. cGFAP, glial fibrillary acidic protein concentration in cerebrospinal fluid; cNfL, neurofilament light chain concentration in cerebrospinal fluid. [Colour figure can be viewed at wileyonlinelibrary.com]
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