# Neurodegeneration Biomarkers in Epilepsy: A Critical Review of Current Findings

**Authors:** Ambra Butera, Simona D’Antoni, Antonio Gennaro Nicotera, Maria Vincenza Catania, Carla Consoli, Graziana Ceraolo, Giulia Spoto, Maria Ludovica Albertini, Gabriella Di Rosa, Maurizio Elia

PMC · DOI: 10.3390/life16020296 · 2026-02-09

## TL;DR

This review explores the connection between epilepsy and neurodegeneration, focusing on biomarkers that could help understand disease progression in children.

## Contribution

The paper provides a critical review of current findings on neurodegeneration biomarkers in epilepsy, particularly in developmental and epileptic encephalopathies.

## Key findings

- Epilepsy and neurodegeneration are linked, with increased neuronal excitability preceding seizures in some conditions.
- Neurodegeneration biomarkers are poorly defined in children despite being well-established in adults.
- DEEs are now viewed as dynamic disorders with evolving pathophysiology rather than static genetic conditions.

## Abstract

Developmental and epileptic encephalopathies (DEEs) represent the most severe group of epilepsies, characterized by drug-resistant seizures, frequent occurrence of epileptiform activity, developmental delay or cognitive impairment. Recent insights have reframed DEEs from static, genetically determined conditions to dynamic disorders with complex and evolving pathophysiology. Several recent studies suggest a link between epilepsy and neurodegeneration, with increased neuronal excitability preceding seizures in conditions characterized by abnormal protein aggregation. Neurodegeneration, defined as the selective and progressive loss of neuronal cells leading to cognitive and functional decline, underlies many progressive neuronal diseases. Although neurodegeneration biomarkers are widely recognized as markers of disease progression in adults, their role in children is still poorly defined and at times controversial. This narrative review aims to summarize current knowledge on the relationship between epilepsy and neurodegeneration, with a focus on potential biomarkers and their implications for disease mechanisms and progression.

## Linked entities

- **Diseases:** epilepsy (MONDO:0005027)

## Full-text entities

- **Genes:** SNCA (synuclein alpha) [NCBI Gene 6622] {aka NACP, PARK1, PARK4, PD1}, APOE (apolipoprotein E) [NCBI Gene 348] {aka AD2, APO-E, ApoE4, LDLCQ5, LPG}, DMXL2 (Dmx like 2) [NCBI Gene 23312] {aka DEE81, DFNA71, EIEE81, PEPNS, RC3}, App (amyloid beta precursor protein) [NCBI Gene 11820] {aka Abeta, Abpp, Adap, Ag, Cvap, E030013M08Rik}, SPTAN1 (spectrin alpha, non-erythrocytic 1) [NCBI Gene 6709] {aka DEE5, DEVEP, EIEE5, HMN11, HMND11, NEAS}, BACE1 (beta-secretase 1) [NCBI Gene 23621] {aka ASP2, BACE, HSPC104}, NEFL (neurofilament light chain) [NCBI Gene 4747] {aka CMT1F, CMT2E, CMTDIG, NF-L, NF68, NFL}, MAPT (microtubule associated protein tau) [NCBI Gene 4137] {aka DDPAC, FTD1, FTDP-17, MAPTL, MSTD, MTBT1}, Snca (synuclein, alpha) [NCBI Gene 20617] {aka NACP, alpha-Syn, alphaSYN}, APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Psen1 (presenilin 1) [NCBI Gene 19164] {aka Ad3h, PS-1, PS1, S182}, FOXG1 (forkhead box G1) [NCBI Gene 2290] {aka BF1, BF2, FHKL3, FKH2, FKHL1, FKHL2}, ATP6V1A (ATPase H+ transporting V1 subunit A) [NCBI Gene 523] {aka ARCL2D, ATP6A1, ATP6V1A1, DEE93, HO68, IECEE3}, IL1A (interleukin 1 alpha) [NCBI Gene 3552] {aka IL-1 alpha, IL-1A, IL1, IL1-ALPHA, IL1F1}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Iba1 (induction of brown adipocytes 1) [NCBI Gene 114737], Glul (glutamate-ammonia ligase) [NCBI Gene 14645] {aka GS, Glns}, Kcna1 (potassium voltage-gated channel, shaker-related subfamily, member 1) [NCBI Gene 16485] {aka Kca1-1, Kv1.1, MBK1, Mk-1, Shak, mceph}, Scn8a (sodium channel, voltage-gated, type VIII, alpha) [NCBI Gene 20273] {aka C630029C19Rik, NaCh6, Nav1.6, dmu, med, mnd-2}, TSC2 (TSC complex subunit 2) [NCBI Gene 7249] {aka LAM, PPP1R160, TSC4}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, Kcnj10 (potassium inwardly-rectifying channel, subfamily J, member 10) [NCBI Gene 16513] {aka BIR10, BIRK-1, Kir1.2, Kir4.1}, SCN1A (sodium voltage-gated channel alpha subunit 1) [NCBI Gene 6323] {aka DEE6, DEE6A, DEE6B, DRVT, EIEE6, FEB3}, Nefm (neurofilament, medium polypeptide) [NCBI Gene 18040] {aka NF-M, NF160, NF165, Nef3, Nfm}, UCHL1 (ubiquitin C-terminal hydrolase L1) [NCBI Gene 7345] {aka HEL-117, HEL-S-53, NDGOA, PARK5, PGP 9.5, PGP9.5}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, Nefl (neurofilament, light polypeptide) [NCBI Gene 18039] {aka CMT2E, NF-L, NF68, Nfl}, TSC1 (TSC complex subunit 1) [NCBI Gene 7248] {aka LAM, TSC}, P2rx7 (purinergic receptor P2X, ligand-gated ion channel, 7) [NCBI Gene 18439] {aka P2X(7), P2X7R}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, Ppara (peroxisome proliferator activated receptor alpha) [NCBI Gene 19013] {aka 4933429D07Rik, Nr1c1, PPAR-alpha, PPARalpha, Ppar}, KCNA1 (potassium voltage-gated channel subfamily A member 1) [NCBI Gene 3736] {aka AEMK, EA1, HBK1, HUK1, KV1.1, MBK1}, DNM1 (dynamin 1) [NCBI Gene 1759] {aka DEE31, DEE31A, DEE31B, DNM, EIEE31}, Gabrg1 (gamma-aminobutyric acid type A receptor subunit gamma 1) [NCBI Gene 14405] {aka GabaA, GabaA/BZ}, CDKL5 (cyclin dependent kinase like 5) [NCBI Gene 6792] {aka CFAP247, DEE2, EIEE2, ISSX, STK9}, STXBP1 (syntaxin binding protein 1) [NCBI Gene 6812] {aka DEE4, MUNC18-1, N-Sec1, NSEC1, P67, RBSEC1}, PTPA (protein phosphatase 2 phosphatase activator) [NCBI Gene 5524] {aka PARK25, PP2A, PPP2R4, PR53}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, SCN8A (sodium voltage-gated channel alpha subunit 8) [NCBI Gene 6334] {aka BFIS5, CERIII, CIAT, DEE13, EIEE13, MED}, GRIN2A (glutamate ionotropic receptor NMDA type subunit 2A) [NCBI Gene 2903] {aka EPND, FESD, GluN2A, LKS, NMDAR2A, NR2A}, Uchl1 (ubiquitin carboxy-terminal hydrolase L1) [NCBI Gene 22223] {aka PGP 9.5, PGP9.5, UCH-L1, UCHL-1, gad}, Nefh (neurofilament, heavy polypeptide) [NCBI Gene 380684] {aka NF-H, NF200, Nfh, mKIAA0845}, GFAP (glial fibrillary acidic protein) [NCBI Gene 2670] {aka ALXDRD}, ALB (albumin) [NCBI Gene 213] {aka FDAHT, HSA, PRO0883, PRO0903, PRO1341}, Gfap (glial fibrillary acidic protein) [NCBI Gene 14580]
- **Diseases:** stroke (MESH:D020521), multisystem atrophy (MESH:D019578), Non refractory epilepsy (MESH:D000069279), Neurological diseases (MESH:D020271), hypoxic (MESH:D002534), AIE (MESH:D001327), neuronal diseases (MESH:D016472), SSD (MESH:C563928), CTX (MESH:D019294), focal epilepsy (MESH:D004828), NFT (MESH:D055956), post-traumatic encephalopathies (MESH:D000070627), epileptic disorders (MESH:D009358), Post-Traumatic Epilepsy (MESH:D004834), DEEs (MESH:C562695), Epilepticus (MESH:D013226), damage (MESH:D020263), Seizures (MESH:D012640), Neurological disorders (MESH:D009461), neurodevelopmental disturbances (MESH:D014832), mitochondrial dysfunction (MESH:D028361), alcoholism (MESH:D000437), Parkinson's disease (MESH:D010300), cerebral palsy (MESH:D002547), inflammation (MESH:D007249), headache (MESH:D006261), injury to (MESH:D014947), Neurodegeneration (MESH:D019636), cortical atrophy (MESH:D001284), neuroinflammation (MESH:D000090862), meningitis (MESH:D008580), dementia with Lewy bodies (MESH:D020961), synucleinopathies (MESH:D000080874), febrile seizures (MESH:D003294), autism (MESH:D001321), BBB disruption (MESH:C536830), IGE (MESH:C562694), TBI (MESH:D000070642), cardiac arrest (MESH:D006323), tumor (MESH:D009369), TLE (MESH:D004833), neurotoxic (MESH:D020258), inflammatory CNS disorders (MESH:D018746), AD (MESH:D000544), cortical lesions (MESH:D054220), PNES (MESH:D000091323), Lewy (MESH:D018827), dementia (MESH:D003704), amyloid (MESH:C000718787), drug (MESH:D000081015), epileptiform activity (MESH:D014277), neuronal damage (MESH:D009410), infectious disorders (MESH:D003141), brain tumors (MESH:D001932), generalized epilepsy (MESH:D004829), astrocytic dysfunction (MESH:D001254), axonal injury (MESH:D001480), cognitive and functional decline (MESH:D003072), TSC (MESH:D014402), developmental delay (MESH:D002658)
- **Chemicals:** iron (MESH:D007501), Diazepam (MESH:D003975), lithium (MESH:D008094), nitric oxide (MESH:D009569), glutamate (MESH:D018698), GABA (MESH:D005680), lipid (MESH:D008055), Bicinchoninic acid (MESH:C047117), carbon 11 (MESH:C000615233), ATP (MESH:D000255), reactive oxygen species (MESH:D017382), PiB (MESH:C475519), pilocarpine (MESH:D010862), K+ (MESH:D011188), 18F-flutemetamol (MESH:C581552), PTZ (MESH:D010433), Abetax- (-), kainic acid (MESH:D007608)
- **Species:** Canis lupus familiaris (dog, subspecies) [taxon 9615], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116]

## Figures

1 figure with captions in the complete paper: https://tomesphere.com/paper/PMC12942254/full.md

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Source: https://tomesphere.com/paper/PMC12942254