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. 2024 Sep;11(9):2382-2391.
doi: 10.1002/acn3.52152. Epub 2024 Jul 19.

CSF biomarkers of neurotoxicity in childhood cancer survivors after cranial radiotherapy or surgery

Erik Fernström  1 , Marianne Jarfelt  1 , Malin Blomstrand  1 , Birgitta Lannering  2 , Markus Axelsson  3 , Pontus Wasling  3 , Thomas Björk-Eriksson  4   5 , Henrik Zetterberg  6   7   8   9   10   11 , Marie Kalm  12
Affiliations

CSF biomarkers of neurotoxicity in childhood cancer survivors after cranial radiotherapy or surgery

Erik Fernström et al. Ann Clin Transl Neurol. 2024 Sep.

Abstract

Objective: Treatment of pediatric brain tumors is associated with potential long-term cognitive sequelae. Patients treated with craniospinal irradiation for posterior fossa tumors are at high risk. New biomarkers that could help to differentiate treatment effects from other causes of cognitive dysfunction would be valuable in tailoring optimal survivorship care. Biomarkers that reflect biological mechanisms behind treatment-associated cognitive decline would also be important in the evaluation of future treatment regimens for pediatric brain or skull base tumors.

Methods: In this biomarker-finding study, 10 adult survivors of pediatric medulloblastoma, skull base tumors, and posterior fossa low-grade glioma underwent study specific lumbar puncture at a minimum of 17 years following treatment. We analyzed cerebrospinal fluid biomarkers reflecting neuron and astrocyte integrity, amyloid metabolism, inflammation, extracellular matrix, synaptic integrity, and blood-brain barrier function. The values were compared with biomarker levels in healthy controls of comparable age.

Results: Biomarkers reflecting neuronal injury (neurofilament light chain protein), astrocyte injury or activation (glial fibrillary acidic protein) as well as inflammation (YKL-40) were significantly elevated in cancer survivors compared to controls. Biomarkers reflecting amyloid metabolism showed a pattern of decrease in patients treated for medulloblastoma.

Interpretation: The results suggest a potential chronic low-grade neurodegeneration and astrocyte activation in patients treated for pediatric brain or skull base tumors. Protein biomarkers of CNS disease could potentially be used to increase our understanding of the contribution from different tumor treatments with regard to long-term symptoms in cancer patients.

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Conflict of interest statement

HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). MK is an employee at AstraZeneca.

Figures

Figure 1
Figure 1
Levels of biomarkers reflecting neuron or synapse degeneration. Astro, patients with low‐grade astrocytoma of the posterior fossa; SB, patients with skull base tumors; MB, patients with medulloblastoma.
Figure 2
Figure 2
Levels of biomarkers reflecting astrocyte degeneration, inflammation, and blood–brain barrier function. Astro, patients with low‐grade astrocytoma of the posterior fossa; SB, patients with skull base tumors; MB, patients with medulloblastoma.
Figure 3
Figure 3
(A–E) Levels of biomarkers reflecting amyloid metabolism and extracellular matrix integrity. (F) Correlation between sAPPα and brevican. Correlation coefficients represent Spearman's rho. Astro, patients with low‐grade astrocytoma of the posterior fossa; SB, patients with skull base tumors; MB, patients with medulloblastoma.
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References

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