In neurodegenerative diseases, changes in neuronal proteins in the cerebrospinal fluid and blood are viewed as potential biomarkers of the primary pathology in the central nervous system (CNS). Recent reports suggest, however, that level of neuronal proteins in fluids also alters in several types of epilepsy in various age groups, including children. With increasing evidence supporting clinical and sub-clinical seizures in Alzheimer's disease, Lewy body dementia, Parkinson's disease, and in other less common neurodegenerative conditions, these findings call into question the specificity of neuronal protein response to neurodegenerative process and urge analysis of the effects of concomitant epilepsy and other comorbidities. In this article, we revisit the evidence for alterations in neuronal proteins in the blood and cerebrospinal fluid associated with epilepsy with and without neurodegenerative diseases. We discuss shared and distinctive characteristics of changes in neuronal markers, review their neurobiological mechanisms, and consider the emerging opportunities and challenges for their future research and diagnostic use.

1st Department of Neurology St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Medical Genetics 3rd Faculty of Medicine Charles University Ruská 87 Prague 10000 Czech Republic

Faculty of Engineering and Science University of Greenwich London Chatham Maritime Kent ME4 4TB UK

Multimodal and Functional Neuroimaging Research Group CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

National Institute of Mental Health Topolova 748 Klecany 25067 Czech Republic

Zobrazit více v PubMed

Mattson MP, Magnus T. Ageing and neuronal vulnerability. Nat Rev Neurosci. 2006;7:278–294. doi: 10.1038/nrn1886. PubMed DOI PMC

Saxena S, Caroni P. Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron. 2011;71:35–48. doi: 10.1016/j.neuron.2011.06.031. PubMed DOI

Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL, Bohr VA. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol. 2019;15:565–581. doi: 10.1038/s41582-019-0244-7. PubMed DOI

G.B.D.D.F. Collaborators Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019, Lancet. Public Health. 2022;7:e105–e125. PubMed PMC

Wareham LK, Liddelow SA, Temple S, Benowitz LI, Di Polo A, Wellington C, Goldberg JL, He Z, Duan X, Bu G, Davis AA, Shekhar K, Torre A, Chan DC, Canto-Soler MV, Flanagan JG, Subramanian P, Rossi S, Brunner T, Bovenkamp DE, Calkins DJ. Solving neurodegeneration: common mechanisms and strategies for new treatments. Mol Neurodegener. 2022;17:23. doi: 10.1186/s13024-022-00524-0. PubMed DOI PMC

Young PNE, Estarellas M, Coomans E, Srikrishna M, Beaumont H, Maass A, Venkataraman AV, Lissaman R, Jimenez D, Betts MJ, McGlinchey E, Berron D, O'Connor A, Fox NC, Pereira JB, Jagust W, Carter SF, Paterson RW, Scholl M. Imaging biomarkers in neurodegeneration: current and future practices. Alzheimers Res Ther. 2020;12:49. doi: 10.1186/s13195-020-00612-7. PubMed DOI PMC

Ovsepian SV, Olefir I, Westmeyer G, Razansky D, Ntziachristos V. Pushing the boundaries of neuroimaging with optoacoustics. Neuron. 2017;96:966–988. doi: 10.1016/j.neuron.2017.10.022. PubMed DOI

Chen JJ. Functional MRI of brain physiology in aging and neurodegenerative diseases. Neuroimage. 2019;187:209–225. doi: 10.1016/j.neuroimage.2018.05.050. PubMed DOI

Hallett M, de Haan W, Deco G, Dengler R, Di Iorio R, Gallea C, Gerloff C, Grefkes C, Helmich RC, Kringelbach ML, Miraglia F, Rektor I, Strycek O, Vecchio F, Volz LJ, Wu T, Rossini PM. Human brain connectivity: clinical applications for clinical neurophysiology. Clin Neurophysiol. 2020;131:1621–1651. doi: 10.1016/j.clinph.2020.03.031. PubMed DOI

Koikkalainen J, Rhodius-Meester H, Tolonen A, Barkhof F, Tijms B, Lemstra AW, Tong T, Guerrero R, Schuh A, Ledig C, Rueckert D, Soininen H, Remes AM, Waldemar G, Hasselbalch S, Mecocci P, van der Flier W, Lotjonen J. Differential diagnosis of neurodegenerative diseases using structural MRI data. Neuroimage Clin. 2016;11:435–449. doi: 10.1016/j.nicl.2016.02.019. PubMed DOI PMC

Jack CR, Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12:207–216. doi: 10.1016/S1474-4422(12)70291-0. PubMed DOI PMC

Vemuri P, Jack CR., Jr Role of structural MRI in Alzheimer's disease. Alzheimers Res Ther. 2010;2:23. doi: 10.1186/alzrt47. PubMed DOI PMC

Jack CR, Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9:119–128. doi: 10.1016/S1474-4422(09)70299-6. PubMed DOI PMC

Whitwell JL, Jack CR, Jr, Parisi JE, Knopman DS, Boeve BF, Petersen RC, Ferman TJ, Dickson DW, Josephs KA. Rates of cerebral atrophy differ in different degenerative pathologies. Brain. 2007;130:1148–1158. doi: 10.1093/brain/awm021. PubMed DOI PMC

Mak E, Su L, Williams GB, O'Brien JT. Neuroimaging characteristics of dementia with Lewy bodies. Alzheimers Res Ther. 2014;6:18. doi: 10.1186/alzrt248. PubMed DOI PMC

Babiloni C, Blinowska K, Bonanni L, Cichocki A, De Haan W, Del Percio C, Dubois B, Escudero J, Fernandez A, Frisoni G, Guntekin B, Hajos M, Hampel H, Ifeachor E, Kilborn K, Kumar S, Johnsen K, Johannsson M, Jeong J, LeBeau F, Lizio R, Lopes da Silva F, Maestu F, McGeown WJ, McKeith I, Moretti DV, Nobili F, Olichney J, Onofrj M, Palop JJ, Rowan M, Stocchi F, Struzik ZM, Tanila H, Teipel S, Taylor JP, Weiergraber M, Yener G, Young-Pearse T, Drinkenburg WH, Randall F. What electrophysiology tells us about Alzheimer's disease: a window into the synchronization and connectivity of brain neurons. Neurobiol Aging. 2020;85:58–73. doi: 10.1016/j.neurobiolaging.2019.09.008. PubMed DOI

Jeong J. EEG dynamics in patients with Alzheimer's disease. Clin Neurophysiol. 2004;115:1490–1505. doi: 10.1016/j.clinph.2004.01.001. PubMed DOI

McMackin R, Muthuraman M, Groppa S, Babiloni C, Taylor JP, Kiernan MC, Nasseroleslami B, Hardiman O. Measuring network disruption in neurodegenerative diseases: new approaches using signal analysis. J Neurol Neurosurg Psychiatry. 2019;90:1011–1020. doi: 10.1136/jnnp-2018-319581. PubMed DOI PMC

Solje E, Benussi A, Buratti E, Remes AM, Haapasalo A, Borroni B. State-of-the-art methods and emerging fluid biomarkers in the diagnostics of dementia—a short review and diagnostic algorithm. Diagnostics (Basel). 2021;11. PubMed PMC

Zetterberg H, Blennow K. Moving fluid biomarkers for Alzheimer's disease from research tools to routine clinical diagnostics. Mol Neurodegener. 2021;16:10. doi: 10.1186/s13024-021-00430-x. PubMed DOI PMC

Simren J, Ashton NJ, Blennow K, Zetterberg H. An update on fluid biomarkers for neurodegenerative diseases: recent success and challenges ahead. Curr Opin Neurobiol. 2020;61:29–39. doi: 10.1016/j.conb.2019.11.019. PubMed DOI

Kocurova G, Ricny J, Ovsepian SV. Autoantibodies targeting neuronal proteins as biomarkers for neurodegenerative diseases. Theranostics. 2022;12:3045–3056. doi: 10.7150/thno.72126. PubMed DOI PMC

Ovsepian SV, O'Leary VB. Adult neurogenesis in the gut, homeostatic autoimmunity and neurodegenerative disease biomarkers. Neuroscience. 2022 doi: 10.1016/j.neuroscience.2022.09.019. PubMed DOI

Barro C, Zetterberg H. The blood biomarkers puzzle—a review of protein biomarkers in neurodegenerative diseases. J Neurosci Methods. 2021;361:109281. doi: 10.1016/j.jneumeth.2021.109281. PubMed DOI

Hansson O. Biomarkers for neurodegenerative diseases. Nat Med. 2021;27:954–963. doi: 10.1038/s41591-021-01382-x. PubMed DOI

Setoain X, Carreno M, Pavia J, Marti-Fuster B, Campos F, Lomena F. PET and SPECT in epilepsy. Rev Esp Med Nucl Imagen Mol. 2014;33:165–174. PubMed

Galovic M, van Dooren VQH, Postma TS, Vos SB, Caciagli L, Borzi G, Cueva Rosillo J, Vuong KA, de Tisi J, Nachev P, Duncan JS, Koepp MJ. Progressive cortical thinning in patients with focal epilepsy. JAMA Neurol. 2019;76:1230–1239. doi: 10.1001/jamaneurol.2019.1708. PubMed DOI PMC

Jardim AP, Duarte JTC, Lancellotti CLP, Carrete H Jr, Centeno RS, Scorza CA, Cavalheiro EA, Guaranha MSB, Yacubian EMT. Granule cell dispersion is associated with hippocampal neuronal cell loss, initial precipitating injury, and other clinical features in mesial temporal lobe epilepsy and hippocampal sclerosis. Seizure. 2021 Aug;90:60-66. 10.1016/j.seizure.2021.05.024. Epub 2021 May 31. PMID: 34162493. PubMed

Thom M, Koepp M. Tau protein in drug-resistant epilepsy and cognitive decline. In: Janigro D, Nehlig A, Marchi A (Eds.) Inflammation and Epilepsy: New Vistas. Progress in Inflammation Research, Springer; 2021.

Obrocki P, Khatun A, Ness D, Senkevich K, Hanrieder J, Capraro F, Mattsson N, Andreasson U, Portelius E, Ashton NJ, Blennow K, Scholl M, Paterson RW, Schott JM, Zetterberg H. Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course—a joint PhD student course at University College London and University of Gothenburg. Alzheimers Res Ther. 2020;12:20. doi: 10.1186/s13195-020-00586-6. PubMed DOI PMC

Pitkanen A, Ndode-Ekane XE, Lapinlampi N, Puhakka N. Epilepsy biomarkers—toward etiology and pathology specificity. Neurobiol Dis. 2019;123:42–58. doi: 10.1016/j.nbd.2018.05.007. PubMed DOI PMC

Rana A, Musto AE. The role of inflammation in the development of epilepsy. J Neuroinflammation. 2018;15:144. doi: 10.1186/s12974-018-1192-7. PubMed DOI PMC

Hanin A, Lambrecq V, Denis JA, Imbert-Bismut F, Rucheton B, Lamari F, Bonnefont-Rousselot D, Demeret S, Navarro V. Cerebrospinal fluid and blood biomarkers of status epilepticus. Epilepsia. 2020;61:6–18. doi: 10.1111/epi.16405. PubMed DOI

Li Z, Cao W, Sun H, Wang X, Li S, Ran X, Zhang H. Potential clinical and biochemical markers for the prediction of drug-resistant epilepsy: a literature review. Neurobiol Dis. 2022;174:105872. doi: 10.1016/j.nbd.2022.105872. PubMed DOI

Zaitsev AV, Smolensky IV, Jorratt P, Ovsepian SV. Neurobiology, functions, and relevance of excitatory amino acid transporters (EAATs) to treatment of refractory epilepsy. CNS Drugs. 2020;34:1089–1103. doi: 10.1007/s40263-020-00764-y. PubMed DOI

Molinuevo JL, Ayton S, Batrla R, Bednar MM, Bittner T, Cummings J, Fagan AM, Hampel H, Mielke MM, Mikulskis A, O'Bryant S, Scheltens P, Sevigny J, Shaw LM, Soares HD, Tong G, Trojanowski JQ, Zetterberg H, Blennow K. Current state of Alzheimer's fluid biomarkers. Acta Neuropathol. 2018;136:821–853. doi: 10.1007/s00401-018-1932-x. PubMed DOI PMC

Zou K, Abdullah M, Michikawa M. Current biomarkers for Alzheimer's disease: from CSF to blood. J Pers Med. 2020;10. PubMed PMC

Janelidze S, Stomrud E, Palmqvist S, Zetterberg H, van Westen D, Jeromin A, Song L, Hanlon D, Tan Hehir CA, Baker D, Blennow K, Hansson O. Plasma beta-amyloid in Alzheimer's disease and vascular disease. Sci Rep. 2016;6:26801. doi: 10.1038/srep26801. PubMed DOI PMC

Schraen-Maschke S, Sergeant N, Dhaenens CM, Bombois S, Deramecourt V, Caillet-Boudin ML, Pasquier F, Maurage CA, Sablonniere B, Vanmechelen E, Buee L. Tau as a biomarker of neurodegenerative diseases. Biomark Med. 2008;2:363–384. doi: 10.2217/17520363.2.4.363. PubMed DOI PMC

Sergeant N, Delacourte A, Buee L. Tau protein as a differential biomarker of tauopathies. Biochim Biophys Acta. 2005;1739:179–197. doi: 10.1016/j.bbadis.2004.06.020. PubMed DOI

Stomrud E, Hansson O, Zetterberg H, Blennow K, Minthon L, Londos E. Correlation of longitudinal cerebrospinal fluid biomarkers with cognitive decline in healthy older adults. Arch Neurol. 2010;67:217–223. doi: 10.1001/archneurol.2009.316. PubMed DOI

Clark CM, Xie S, Chittams J, Ewbank D, Peskind E, Galasko D, Morris JC, McKeel DW, Jr, Farlow M, Weitlauf SL, Quinn J, Kaye J, Knopman D, Arai H, Doody RS, DeCarli C, Leight S, Lee VM, Trojanowski JQ. Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol. 2003;60:1696–1702. doi: 10.1001/archneur.60.12.1696. PubMed DOI

Karikari TK, Pascoal TA, Ashton NJ, Janelidze S, Benedet AL, Rodriguez JL, Chamoun M, Savard M, Kang MS, Therriault J, Scholl M, Massarweh G, Soucy JP, Hoglund K, Brinkmalm G, Mattsson N, Palmqvist S, Gauthier S, Stomrud E, Zetterberg H, Hansson O, Rosa-Neto P, Blennow K. Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020;19:422–433. doi: 10.1016/S1474-4422(20)30071-5. PubMed DOI

Magalhaes P, Lashuel HA. Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson's disease and other synucleinopathies. NPJ Parkinsons Dis. 2022;8:93. doi: 10.1038/s41531-022-00357-0. PubMed DOI PMC

Chang CW, Yang SY, Yang CC, Chang CW, Wu YR. Plasma and serum alpha-synuclein as a biomarker of diagnosis in patients with Parkinson's disease. Front Neurol. 2019;10:1388. doi: 10.3389/fneur.2019.01388. PubMed DOI PMC

Menke RA, Gray E, Lu CH, Kuhle J, Talbot K, Malaspina A, Turner MR. CSF neurofilament light chain reflects corticospinal tract degeneration in ALS. Ann Clin Transl Neurol. 2015;2:748–755. doi: 10.1002/acn3.212. PubMed DOI PMC

Yuan A, Nixon RA. Neurofilament proteins as biomarkers to monitor neurological diseases and the efficacy of therapies. Front Neurosci. 2021;15:689938. doi: 10.3389/fnins.2021.689938. PubMed DOI PMC

Gaetani L, Blennow K, Calabresi P, Di Filippo M, Parnetti L, Zetterberg H. Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry. 2019;90:870–881. doi: 10.1136/jnnp-2018-320106. PubMed DOI

Lista S, Hampel H. Synaptic degeneration and neurogranin in the pathophysiology of Alzheimer's disease. Expert Rev Neurother. 2017;17:47–57. doi: 10.1080/14737175.2016.1204234. PubMed DOI

Lista S, Toschi N, Baldacci F, Zetterberg H, Blennow K, Kilimann I, Teipel SJ, Cavedo E, Dos Santos AM, Epelbaum S, Lamari F, Dubois B, Nistico R, Floris R, Garaci F, Hampel H, Alzheimer Precision Medicine Initiative Cerebrospinal fluid neurogranin as a biomarker of neurodegenerative diseases: a cross-sectional study. J Alzheimers Dis. 2017;59:1327–1334. doi: 10.3233/JAD-170368. PubMed DOI

Larner AJ. Epileptic seizures in AD patients. Neuromolecular Med. 2010;12:71–77. doi: 10.1007/s12017-009-8076-z. PubMed DOI

Neri S, Mastroianni G, Gardella E, Aguglia U, Rubboli G. Epilepsy in neurodegenerative diseases. Epileptic Disord. 2022;24:249–273. doi: 10.1684/epd.2021.1406. PubMed DOI

Xu Y, Lavrencic L, Radford K, Booth A, Yoshimura S, Anstey KJ, Anderson CS, Peters R. Systematic review of coexistent epileptic seizures and Alzheimer's disease: Incidence and prevalence. J Am Geriatr Soc. 2021;69:2011–2020. doi: 10.1111/jgs.17101. PubMed DOI

Voglein J, Kostova I, Arzberger T, Noachtar S, Dieterich M, Herms J, Schmitz P, Ruf V, Windl O, Roeber S, Simons M, Hoglinger GU, Danek A, Giese A, Levin J. Seizure prevalence in neurodegenerative diseases-a study of autopsy proven cases. Eur J Neurol. 2022;29:12–18. doi: 10.1111/ene.15089. PubMed DOI

Vossel KA, Tartaglia MC, Nygaard HB, Zeman AZ, Miller BL. Epileptic activity in Alzheimer's disease: causes and clinical relevance. Lancet Neurol. 2017;16:311–322. doi: 10.1016/S1474-4422(17)30044-3. PubMed DOI PMC

Ovsepian SV, O'Leary VB. Neuronal activity and amyloid plaque pathology: an update. J Alzheimers Dis. 2016;49:13–19. doi: 10.3233/JAD-150544. PubMed DOI

Yan XX, Cai Y, Shelton J, Deng SH, Luo XG, Oddo S, Laferla FM, Cai H, Rose GM, Patrylo PR. Chronic temporal lobe epilepsy is associated with enhanced Alzheimer-like neuropathology in 3xTg-AD mice. PLoS ONE. 2012;7:e48782. doi: 10.1371/journal.pone.0048782. PubMed DOI PMC

Tombini M, Assenza G, Ricci L, Lanzone J, Boscarino M, Vico C, Magliozzi A, Di Lazzaro V. Temporal lobe epilepsy and Alzheimer's disease: from preclinical to clinical evidence of a strong association. J Alzheimers Dis Rep. 2021;5:243–261. doi: 10.3233/ADR-200286. PubMed DOI PMC

Buda O, Arsene D, Ceausu M, Dermengiu D, Curca GC. Georges Marinesco and the early research in neuropathology. Neurology. 2009;72:88–91. doi: 10.1212/01.wnl.0000338626.93425.74. PubMed DOI

Mackenzie IR, Miller LA. Senile plaques in temporal lobe epilepsy. Acta Neuropathol. 1994;87:504–510. doi: 10.1007/BF00294177. PubMed DOI

Mackenzie IR, McLachlan RS, Kubu CS, Miller LA. Prospective neuropsychological assessment of nondemented patients with biopsy proven senile plaques. Neurology. 1996;46:425–429. doi: 10.1212/WNL.46.2.425. PubMed DOI

Shahim P, Rejdak R, Ksiazek P, Blennow K, Zetterberg H, Mattsson N, Rejdak K. Cerebrospinal fluid biomarkers of beta-amyloid metabolism and neuronal damage in epileptic seizures. Eur J Neurol. 2014;21:486–491. doi: 10.1111/ene.12336. PubMed DOI

Banote RK, Håkansson S, Zetterberg H, Zelano J. CSF biomarkers in patients with epilepsy in Alzheimer’s disease: a nation-wide study. Brain Commun. 2022;4(4). PubMed PMC

Cretin B, Bousiges O, Hautecloque G, Philippi N, Blanc F, Dibitonto L, Martin-Hunyadi C, Sellal F. CSF in epileptic prodromal Alzheimer's Disease: no diagnostic contribution but a pathophysiological one. Front Neurol. 2021;12:623777. doi: 10.3389/fneur.2021.623777. PubMed DOI PMC

Palmio J, Suhonen J, Keranen T, Hulkkonen J, Peltola J, Pirttila T. Cerebrospinal fluid tau as a marker of neuronal damage after epileptic seizure. Seizure. 2009;18:474–477. doi: 10.1016/j.seizure.2009.04.006. PubMed DOI

Nass RD, Akgun K, Elger C, Reichmann H, Wagner M, Surges R, Ziemssen T. Serum biomarkers of cerebral cellular stress after self-limiting tonic clonic seizures: an exploratory study. Seizure. 2021;85:1–5. doi: 10.1016/j.seizure.2020.12.009. PubMed DOI

Costa C, Romoli M, Liguori C, Farotti L, Eusebi P, Bedetti C, Siliquini S, Cesarini EN, Romigi A, Mercuri NB, Parnetti L, Calabresi P. Alzheimer's disease and late-onset epilepsy of unknown origin: two faces of beta amyloid pathology. Neurobiol Aging. 2019;73:61–67. doi: 10.1016/j.neurobiolaging.2018.09.006. PubMed DOI

Monti G, Tondelli M, Giovannini G, Bedin R, Nichelli PF, Trenti T, Meletti S, Chiari A. Cerebrospinal fluid tau proteins in status epilepticus. Epilepsy Behav. 2015;49:150–154. doi: 10.1016/j.yebeh.2015.04.030. PubMed DOI

Tabuas-Pereira M, Duraes J, Lopes J, Sales F, Bento C, Duro D, Santiago B, Almeida MR, Leitao MJ, Baldeiras I, Santana I. Increased CSF tau is associated with a higher risk of seizures in patients with Alzheimer's disease. Epilepsy Behav. 2019;98:207–209. doi: 10.1016/j.yebeh.2019.06.033. PubMed DOI

Eriksson H, Lowhagen Henden P, Rentzos A, Pujol-Calderon F, Karlsson JE, Hoglund K, Blennow K, Zetterberg H, Rosengren L, Zelano J. Acute symptomatic seizures and epilepsy after mechanical thrombectomy. Epilepsy Behav. 2020;104:106520. doi: 10.1016/j.yebeh.2019.106520. PubMed DOI

Nass RD, Akgun K, Dague KO, Elger CE, Reichmann H, Ziemssen T, Surges R. CSF and serum biomarkers of cerebral damage in autoimmune epilepsy. Front Neurol. 2021;12:647428. doi: 10.3389/fneur.2021.647428. PubMed DOI PMC

Shahim P, Darin N, Andreasson U, Blennow K, Jennions E, Lundgren J, Mansson JE, Naess K, Tornhage CJ, Zetterberg H, Mattsson N. Cerebrospinal fluid brain injury biomarkers in children: a multicenter study. Pediatr Neurol. 2013;49:31–39. doi: 10.1016/j.pediatrneurol.2013.02.015. PubMed DOI

Mo L, Ding X, Tan C, Liu X, Wei X, Wang H, Zhou W, Chen L. Association of cerebrospinal fluid zinc-alpha2-glycoprotein and tau protein with temporal lobe epilepsy and related white matter impairment. NeuroReport. 2019;30:586–591. doi: 10.1097/WNR.0000000000001252. PubMed DOI

Eriksson H, Banote RK, Larsson D, Blennow K, Zetterberg H, Zelano J. Brain injury markers in new-onset seizures in adults: A pilot study. Seizure. 2021;92:62–67. doi: 10.1016/j.seizure.2021.08.012. PubMed DOI

Giovannini G, Bedin R, Ferraro D, Vaudano AE, Mandrioli J, Meletti S. Serum neurofilament light as biomarker of seizure-related neuronal injury in status epilepticus. Epilepsia. 2022;63:e23–e29. doi: 10.1111/epi.17132. PubMed DOI PMC

Ouedraogo O, Rebillard RM, Jamann H, Mamane VH, Clenet ML, Daigneault A, Lahav B, Uphaus T, Steffen F, Bittner S, Zipp F, Berube A, Lapalme-Remis S, Cossette P, Nguyen DK, Arbour N, Keezer MR, Larochelle C. Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy. Epilepsia. 2021;62:176–189. doi: 10.1111/epi.16742. PubMed DOI

Lardeux P, Fourier A, Peter E, Dorey A, Muniz-Castrillo S, Vogrig A, Picard G, Rogemond V, Verdurand M, Formaglio M, Joubert B, Froment Tilikete C, Honnorat J, Quadrio I, Desestret V. Core cerebrospinal fluid biomarker profile in anti-LGI1 encephalitis. J Neurol. 2022;269:377–388. doi: 10.1007/s00415-021-10642-2. PubMed DOI

Evers KS, Hugli M, Fouzas S, Kasser S, Pohl C, Stoecklin B, Bernasconi L, Kuhle J, Wellmann S. Serum Neurofilament Levels in Children With Febrile Seizures and in Controls. Front Neurosci. 2020;14:579958. doi: 10.3389/fnins.2020.579958. PubMed DOI PMC

Matsushige T, Inoue H, Fukunaga S, Hasegawa S, Okuda M, Ichiyama T. Serum neurofilament concentrations in children with prolonged febrile seizures. J Neurol Sci. 2012;321:39–42. doi: 10.1016/j.jns.2012.07.043. PubMed DOI

Petersen A, Gerges NZ. Neurogranin regulates CaM dynamics at dendritic spines. Sci Rep. 2015;5:11135. doi: 10.1038/srep11135. PubMed DOI PMC

Pak JH, Huang FL, Li J, Balschun D, Reymann KG, Chiang C, Westphal H, Huang KP. Involvement of neurogranin in the modulation of calcium/calmodulin-dependent protein kinase II, synaptic plasticity, and spatial learning: a study with knockout mice. Proc Natl Acad Sci U S A. 2000;97:11232–11237. doi: 10.1073/pnas.210184697. PubMed DOI PMC

Kalkan A, Demirel A, Atis SE, Karaaslan EB, Ferhatlar ME, Senturk M. A new biomarker in the differential diagnosis of epileptic seizure: Neurogranin. Am J Emerg Med. 2022;54:147–150. doi: 10.1016/j.ajem.2022.02.010. PubMed DOI

Rong H, Jin L, Wei W, Wang X, Xi Z. Alpha-synuclein is a potential biomarker in the serum and CSF of patients with intractable epilepsy. Seizure. 2015;27:6–9. doi: 10.1016/j.seizure.2015.02.007. PubMed DOI

Choi J, Kim SY, Kim H, Lim BC, Hwang H, Chae JH, Kim KJ, Oh S, Kim EY, Shin JS. Serum alpha-synuclein and IL-1beta are increased and correlated with measures of disease severity in children with epilepsy: potential prognostic biomarkers? BMC Neurol. 2020;20:85. doi: 10.1186/s12883-020-01662-y. PubMed DOI PMC

Hussein AM, Eldosoky M, El-Shafey M, El-Mesery M, Ali AN, Abbas KM, Abulseoud OA. Effects of metformin on apoptosis and alpha-synuclein in a rat model of pentylenetetrazole-induced epilepsy. Can J Physiol Pharmacol. 2019;97:37–46. doi: 10.1139/cjpp-2018-0266. PubMed DOI

Gafson AR, Barthelemy NR, Bomont P, Carare RO, Durham HD, Julien JP, Kuhle J, Leppert D, Nixon RA, Weller RO, Zetterberg H, Matthews PM. Neurofilaments: neurobiological foundations for biomarker applications. Brain. 2020;143:1975–1998. doi: 10.1093/brain/awaa098. PubMed DOI PMC

Eid T. Progressive neuronal loss in epilepsy—a long-standing conundrum finally resolved? Epilepsy Curr. 2021;21:366–368. doi: 10.1177/15357597211030385. PubMed DOI PMC

Rossini L, Garbelli R, Gnatkovsky V, Didato G, Villani F, Spreafico R, Deleo F, Lo Russo G, Tringali G, Gozzo F, Tassi L, de Curtis M. Seizure activity per se does not induce tissue damage markers in human neocortical focal epilepsy. Ann Neurol. 2017;82:331–341. doi: 10.1002/ana.25005. PubMed DOI

Thom M, Zhou J, Martinian L, Sisodiya S. Quantitative post-mortem study of the hippocampus in chronic epilepsy: seizures do not inevitably cause neuronal loss. Brain. 2005;128:1344–1357. doi: 10.1093/brain/awh475. PubMed DOI

Gorter JA, Goncalves Pereira PM, van Vliet EA, Aronica E, Lopes da Silva FH, Lucassen PJ. Neuronal cell death in a rat model for mesial temporal lobe epilepsy is induced by the initial status epilepticus and not by later repeated spontaneous seizures. Epilepsia. 2003;44:647–658. doi: 10.1046/j.1528-1157.2003.53902.x. PubMed DOI

Bertram EH, 3rd, Lothman EW. Morphometric effects of intermittent kindled seizures and limbic status epilepticus in the dentate gyrus of the rat. Brain Res. 1993;603:25–31. doi: 10.1016/0006-8993(93)91295-4. PubMed DOI

Mathern GW, Bertram EH., III Recurrent limbic seizures do not cause hippocampal neuronal loss: A prolonged laboratory study. Neurobiol Dis. 2021;148:105183. doi: 10.1016/j.nbd.2020.105183. PubMed DOI PMC

Ovsepian SV, Dolly JO. Dendritic SNAREs add a new twist to the old neuron theory. Proc Natl Acad Sci U S A. 2011;108:19113–19120. doi: 10.1073/pnas.1017235108. PubMed DOI PMC

Meng J, Ovsepian SV, Wang J, Pickering M, Sasse A, Aoki KR, Lawrence GW, Dolly JO. Activation of TRPV1 mediates calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by a retargeted botulinum toxin with anti-nociceptive potential. J Neurosci. 2009;29:4981–4992. doi: 10.1523/JNEUROSCI.5490-08.2009. PubMed DOI PMC

van den Pol AN. Neuropeptide transmission in brain circuits. Neuron. 2012;76:98–115. doi: 10.1016/j.neuron.2012.09.014. PubMed DOI PMC

Kleijmeer M, Ramm G, Schuurhuis D, Griffith J, Rescigno M, Ricciardi-Castagnoli P, Rudensky AY, Ossendorp F, Melief CJ, Stoorvogel W, Geuze HJ. Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells. J Cell Biol. 2001;155:53–63. doi: 10.1083/jcb.200103071. PubMed DOI PMC

Von Bartheld CS, Altick AL. Multivesicular bodies in neurons: distribution, protein content, and trafficking functions. Prog Neurobiol. 2011;93:313–340. doi: 10.1016/j.pneurobio.2011.01.003. PubMed DOI PMC

Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19:983–997. doi: 10.1038/nm.3232. PubMed DOI

Fassio A, Falace A, Esposito A, Aprile D, Guerrini R, Benfenati F. Emerging role of the autophagy/lysosomal degradative pathway in neurodevelopmental disorders with epilepsy. Front Cell Neurosci. 2020;14:39. doi: 10.3389/fncel.2020.00039. PubMed DOI PMC

Sproviero D, La Salvia S, Giannini M, Crippa V, Gagliardi S, Bernuzzi S, Diamanti L, Ceroni M, Pansarasa O, Poletti A, Cereda C. Pathological proteins are transported by extracellular vesicles of sporadic amyotrophic lateral sclerosis patients. Front Neurosci. 2018;12:487. doi: 10.3389/fnins.2018.00487. PubMed DOI PMC

Tricarico C, Clancy J, D'Souza-Schorey C. Biology and biogenesis of shed microvesicles. Small GTPases. 2017;8:220–232. doi: 10.1080/21541248.2016.1215283. PubMed DOI PMC

Upadhya D, Shetty AK. Promise of extracellular vesicles for diagnosis and treatment of epilepsy. Epilepsy Behav. 2021;121:106499. doi: 10.1016/j.yebeh.2019.106499. PubMed DOI PMC

Ludwig M, Leng G. Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci. 2006;7:126–136. doi: 10.1038/nrn1845. PubMed DOI

Giorgi FS, Biagioni F, Lenzi P, Frati A, Fornai F. The role of autophagy in epileptogenesis and in epilepsy-induced neuronal alterations. J Neural Transm (Vienna) 2015;122:849–862. doi: 10.1007/s00702-014-1312-1. PubMed DOI

Bakker EN, Bacskai BJ, Arbel-Ornath M, Aldea R, Bedussi B, Morris AW, Weller RO, Carare RO. Lymphatic clearance of the brain: perivascular, paravascular and significance for neurodegenerative diseases. Cell Mol Neurobiol. 2016;36:181–194. doi: 10.1007/s10571-015-0273-8. PubMed DOI PMC

Szentistvanyi I, Patlak CS, Ellis RA, Cserr HF. Drainage of interstitial fluid from different regions of rat brain. Am J Physiol. 1984;246:F835–844. PubMed

Ueno M, Chiba Y, Murakami R, Matsumoto K, Kawauchi M, Fujihara R. Blood-brain barrier and blood-cerebrospinal fluid barrier in normal and pathological conditions. Brain Tumor Pathol. 2016;33:89–96. doi: 10.1007/s10014-016-0255-7. PubMed DOI

Albargothy NJ, Johnston DA, MacGregor-Sharp M, Weller RO, Verma A, Hawkes CA, Carare RO. Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta Neuropathol. 2018;136:139–152. doi: 10.1007/s00401-018-1862-7. PubMed DOI PMC

Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, Weller RO. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008;34:131–144. doi: 10.1111/j.1365-2990.2007.00926.x. PubMed DOI

Hawkes CA, Hartig W, Kacza J, Schliebs R, Weller RO, Nicoll JA, Carare RO. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 2011;121:431–443. doi: 10.1007/s00401-011-0801-7. PubMed DOI

Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4:147ra111. doi: 10.1126/scitranslmed.3003748. PubMed DOI PMC

Ovsepian SV, Horacek J, O'Leary VB, Hoschl C. The ups and downs of BACE1: walking a fine line between neurocognitive and other psychiatric symptoms of Alzheimer's disease. Neuroscientist. 2021;27:222–234. doi: 10.1177/1073858420940943. PubMed DOI

Ovsepian SV, O'Leary VB, Zaborszky L. Cholinergic mechanisms in the cerebral cortex: beyond synaptic transmission. Neuroscientist. 2016;22:238–251. doi: 10.1177/1073858415588264. PubMed DOI PMC

Ovsepian SV, O'Leary VB, Zaborszky L, Ntziachristos V, Dolly JO. Amyloid plaques of Alzheimer's disease as hotspots of glutamatergic activity. Neuroscientist. 2019;25:288–297. doi: 10.1177/1073858418791128. PubMed DOI PMC

Ovsepian SV, Blazquez-Llorca L, Freitag SV, Rodrigues EF, Herms J. Ambient glutamate promotes paroxysmal hyperactivity in cortical pyramidal neurons at amyloid plaques via presynaptic mGluR1 receptors. Cereb Cortex. 2017;27:4733–4749. PubMed