Neurofilament Levels in CSF and Serum in an Adult SMA Cohort Treated with Nusinersen

Rich, Kelly; Fox, Ashley; Yalvaç, Mehmet Emir; Heintzman, Sarah; Tellez, Marco; Bartlett, Amy; Severyn, Steven; Linsenmayer, Mathew; Kelly, Kristina; Reynolds, Jerry; Sterling, Gary; Weaver, Tristan; Rajneesh, Kiran; Pino, Megan G; Arnold, W. David; Elsheikh, Bakri; Kolb, Stephen J.

doi:10.3233/jnd-210735

Cited by 22 publications

(24 citation statements)

References 55 publications

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“…Analysis of neurofilaments in CSF of SMA patients undergoing nusinersen treatment likewise showed a decline in a smaller cohort of young type 1 patients [41] but no significant correlation with motor response in older patients [42][43][44]. Findings of neurofilament analyses are in line with published data [41][42][43]45,46] and validated the quality and validity of our cohort. We observed a consistent and significant decline of pNF-L not only in infants <4 years old as demonstrated earlier [41], but also in older patients with an age range from 6 to 15 years at start of treatment.…”

Section: Con Clus Ionssupporting

confidence: 88%

Cathepsin D as biomarker in cerebrospinal fluid of nusinersen‐treated patients with spinal muscular atrophy

Schorling

Kölbel

Hentschel

et al. 2022

Euro J of Neurology

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Background and purpose The therapeutic landscape of spinal muscular atrophy (SMA) has changed dramatically during the past 4 years, but treatment responses differ remarkably between individuals, and therapeutic decision‐making remains challenging, underlining the persistent need for validated biomarkers. Methods We applied untargeted proteomic analyses to determine biomarkers in cerebrospinal fluid (CSF) samples of SMA patients under treatment with nusinersen. Identified candidate proteins were validated in CSF samples of SMA patients by Western blot and enzyme‐linked immunosorbent assay. Furthermore, levels of peripheral neurofilament heavy and light chain were determined. Results Untargeted proteomic analysis of CSF samples of three SMA type 1 patients revealed the lysosomal protease cathepsin D as a candidate biomarker. Subsequent validation analysis in a larger cohort of 31 pediatric SMA patients (type 1, n = 12; type 2, n = 9; type 3, n = 6; presymptomatically treated, n = 4; age = 0–16 years) revealed a significant decline of cathepsin D levels in SMA patients aged ≥2 months at the start of treatment. Although evident in all older age categories, this decline was only significant in the group of patients who showed a positive motor response. Moreover, downregulation of cathepsin D was evident in muscle biopsies of SMA patients. Conclusions We identified a decline of cathepsin D levels in CSF samples of SMA patients under nusinersen treatment that was more pronounced in the group of "treatment responders" than in "nonresponders." We believe that our results indicate a suitability of cathepsin D levels as a possible biomarker in SMA also in older patients, in combination with analysis of peripheral neurofilament light chain in adolescents or alone in adult patients.

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Section: Con Clus Ionssupporting

confidence: 88%

Cathepsin D as biomarker in cerebrospinal fluid of nusinersen‐treated patients with spinal muscular atrophy

Schorling

Kölbel

Hentschel

et al. 2022

Euro J of Neurology

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“…18 In contrast, a few studies measuring neurofilaments in adults with SMA type 2 and 3 have shown contradictory results over a short period of follow-up (6-14 months), making it difficult to interpret the relevance of these biomarkers. [19][20][21][22] In this study, we evaluated both neuroinflammatory and neurodegenerative biomarkers in CSF and serum to assess if they could be used to measure disease progression or even predict therapeutic response as a prognostic marker, as well as how they correlate with each other and to clinical outcome measures in adults with SMA. Additionally, we investigated the effect of nusinersen treatment on a wide range of clinical outcome measures in adults with SMA type 3-4 over a follow-up period of 22 months.…”

Section: Introductionmentioning

confidence: 99%

“…A recent study in infants with SMA type 1 showed that pNfH was elevated in plasma and CSF, correlated with multiple indicators of disease severity, and rapidly declined after treatment initiation with nusinersen 18 . In contrast, a few studies measuring neurofilaments in adults with SMA type 2 and 3 have shown contradictory results over a short period of follow‐up (6–14 months), making it difficult to interpret the relevance of these biomarkers 19–22 …”

Section: Introductionmentioning

confidence: 99%

Biochemical and clinical biomarkers in adult SMA 3–4 patients treated with nusinersen for 22 months

Wel

Schaepdryver

Poesen

et al. 2022

Ann Clin Transl Neurol

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Objective To investigate biomarkers of disease progression in cerebrospinal fluid (CSF) and serum in adult patients with spinal muscular atrophy (SMA). Furthermore, we assess the clinical response to nusinersen treatment in adults with SMA over a longer follow‐up period than the previously reported 6–14 months. Methods We included 16 adults with SMA type 3–4 for nusinersen treatment over 22 months in this prospective study. We evaluated chitotriosidase‐1 (CHIT1) and chitinase‐3‐like protein 1 (YKL‐40) as neuroinflammatory biomarkers in CSF, and neurofilament light chain (NfL) and heavy chain (pNfH) as neurodegenerative markers in CSF and serum at baseline, month 6, 14 and 22, together with a wide range of clinical outcome measures. Results Levels of CHIT1 increased significantly (p = 0.048) throughout the 22‐month treatment period and pNfH decreased significantly (p = 0.022) in CSF, but both did not correlate with clinical outcome measures. YKL‐40 correlated strongly with neurofilaments in CSF (rho = 0.76) and decreased significantly (p = 0.037) in patients with improvements in the revised upper limb module (RULM). Finally, patients showed significant improvements in hand grip strength, hand motor function, medical research council (MRC) sum score, and peak expiratory flow (PEF) after 22 months of treatment. Interpretation YKL‐40 in CSF correlated with clinical improvements during nusinersen treatment. In contrast, CHIT1 and pNfH in CSF changed significantly during treatment but did not correlate with clinical outcomes. Finally, we demonstrated a sustained clinical effect of nusinersen treatment in adults after 22 months.

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“… 22 cNfL has been found to reflect disease severity and treatment response in pediatric SMA, 23 but still provides limited information in adult SMA because it overlaps with healthy controls and often shows no association with motor improvement. 24 , 25 , 26 , 27 …”

Section: Introductionmentioning

confidence: 99%

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

Freigang

Steinacker

Wurster

et al. 2022

Ann Clin Transl Neurol

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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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Neurofilament Levels in CSF and Serum in an Adult SMA Cohort Treated with Nusinersen

Cited by 22 publications

References 55 publications

Cathepsin D as biomarker in cerebrospinal fluid of nusinersen‐treated patients with spinal muscular atrophy

Cathepsin D as biomarker in cerebrospinal fluid of nusinersen‐treated patients with spinal muscular atrophy

Biochemical and clinical biomarkers in adult SMA 3–4 patients treated with nusinersen for 22 months

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

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