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Distinct peripheral pro‐inflammatory profile associated with tuberous sclerosis complex and epilepsy

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Title: Distinct peripheral pro‐inflammatory profile associated with tuberous sclerosis complex and epilepsy
Authors: Renaud Balthazard, Rose‐Marie Drouin‐Engler, Samuel Bertrand, Faycal Zine‐Eddine, Jimmy Li, Olivier Tastet, Audrey Daigneault, Victoria H. Mamane, Gloria Gabrielle Ortega‐Delgado, Alina Maria Sreng Flores, Daniel E. Kaufmann, Philippe Major, Andrew A. House, Laurent Létourneau‐Guillon, Nathalie Arbour, Mark R. Keezer, Catherine Larochelle
Source: Epilepsia
Epilepsia, vol. 66, no. 4, pp. 1288-1303
Publisher Information: Wiley, 2025.
Publication Year: 2025
Subject Terms: Male, Adult, Inflammation, Epilepsy, Adolescent, Humans, Tuberous Sclerosis/blood, Tuberous Sclerosis/complications, Female, Epilepsy/blood, Epilepsy/complications, Cross-Sectional Studies, Young Adult, Biomarkers/blood, Cytokines/blood, Middle Aged, Glial Fibrillary Acidic Protein/blood, Inflammation/blood, GFAP, Neuroinflammation, Tuberous sclerosis complex, Tuberous Sclerosis, Glial Fibrillary Acidic Protein, Cytokines, Biomarkers, Research Article
Description: ObjectiveTuberous sclerosis complex (TSC) is a monogenetic disorder associated with sustained mechanistic target of rapamycin (mTOR) activation, leading to heterogeneous clinical manifestations. Epilepsy and renal angiomyolipoma are the most important causes of morbidity in adult people with TSC (pwTSC). mTOR is a key player in inflammation, which in turn could influence TSC‐related clinical manifestations. Reliable biomarkers are lacking to monitor and predict evolution and response to treatment for epilepsy in pwTSC. Inflammation has been implicated in epileptogenesis in non–TSC‐related epilepsy. We aimed to characterize the relation between markers of neuroglial activation/injury, markers of peripheral inflammation, and active epilepsy in pwTSC to identify accessible biomarkers and potential new therapeutic targets.MethodsWe performed a cross‐sectional study to investigate markers of central nervous system (CNS) (neurofilament light [NfL] and glial fibrillary acidic protein [GFAP]) and peripheral (45 cytokines) inflammation in the peripheral blood of pwTSC (n = 46) vs age‐ and sex‐matched healthy controls (HCs) (n = 26). In pwTSC, markers associated with active epilepsy (n = 23/46) were compared to non‐TSC epilepsy controls (n = 18). Observations on markers of neuroglial activation/injury (GFAP, NfL) were confirmed in an independent TSC cohort (n = 45; 69% with active epilepsy).ResultsWe report that TSC is characterized by elevated serum levels of marker of astrogliosis (GFAP), pro‐inflammatory molecules (interleukin 1β [IL‐1β], CXCL8) and trophic factor (epidermal growth factor [EGF]) compared to HCs and to non–TSC‐related epilepsy controls. Among pwTSC, renal angiomyolipoma presence and size was associated with IL‐15. It is notable that active epilepsy in pwTSC was associated with higher levels of GFAP compared to pwTSC without epilepsy, which was confirmed in an external validation cohort, and with elevated levels of pro‐inflammatory cytokines (IL‐17A, IL‐17C, tumor necrosis factor α [TNF‐α]), not significantly related to seizure activity or treatment with mTOR inhibitor. These associations remained significant after adjusting for age and sex.SignificanceThese results suggest that key inflammatory mediators could contribute to epileptogenesis and represent novel biomarkers and therapeutic targets in TSC.
Document Type: Article
Other literature type
File Description: application/pdf
Language: English
ISSN: 1528-1167
0013-9580
DOI: 10.1111/epi.18261
Access URL: https://pubmed.ncbi.nlm.nih.gov/39817839
https://serval.unil.ch/notice/serval:BIB_5947DACFDA6E
http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_5947DACFDA6E3
https://serval.unil.ch/resource/serval:BIB_5947DACFDA6E.P001/REF.pdf
Rights: CC BY NC
Accession Number: edsair.doi.dedup.....2b1024a1f6140d38dad8d75fd2f5901a
Database: OpenAIRE
Description
Abstract:ObjectiveTuberous sclerosis complex (TSC) is a monogenetic disorder associated with sustained mechanistic target of rapamycin (mTOR) activation, leading to heterogeneous clinical manifestations. Epilepsy and renal angiomyolipoma are the most important causes of morbidity in adult people with TSC (pwTSC). mTOR is a key player in inflammation, which in turn could influence TSC‐related clinical manifestations. Reliable biomarkers are lacking to monitor and predict evolution and response to treatment for epilepsy in pwTSC. Inflammation has been implicated in epileptogenesis in non–TSC‐related epilepsy. We aimed to characterize the relation between markers of neuroglial activation/injury, markers of peripheral inflammation, and active epilepsy in pwTSC to identify accessible biomarkers and potential new therapeutic targets.MethodsWe performed a cross‐sectional study to investigate markers of central nervous system (CNS) (neurofilament light [NfL] and glial fibrillary acidic protein [GFAP]) and peripheral (45 cytokines) inflammation in the peripheral blood of pwTSC (n = 46) vs age‐ and sex‐matched healthy controls (HCs) (n = 26). In pwTSC, markers associated with active epilepsy (n = 23/46) were compared to non‐TSC epilepsy controls (n = 18). Observations on markers of neuroglial activation/injury (GFAP, NfL) were confirmed in an independent TSC cohort (n = 45; 69% with active epilepsy).ResultsWe report that TSC is characterized by elevated serum levels of marker of astrogliosis (GFAP), pro‐inflammatory molecules (interleukin 1β [IL‐1β], CXCL8) and trophic factor (epidermal growth factor [EGF]) compared to HCs and to non–TSC‐related epilepsy controls. Among pwTSC, renal angiomyolipoma presence and size was associated with IL‐15. It is notable that active epilepsy in pwTSC was associated with higher levels of GFAP compared to pwTSC without epilepsy, which was confirmed in an external validation cohort, and with elevated levels of pro‐inflammatory cytokines (IL‐17A, IL‐17C, tumor necrosis factor α [TNF‐α]), not significantly related to seizure activity or treatment with mTOR inhibitor. These associations remained significant after adjusting for age and sex.SignificanceThese results suggest that key inflammatory mediators could contribute to epileptogenesis and represent novel biomarkers and therapeutic targets in TSC.
ISSN:15281167
00139580
DOI:10.1111/epi.18261