{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T20:40:08Z","timestamp":1789332008400,"version":"build-2803163510"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,11,5]],"date-time":"2022-11-05T00:00:00Z","timestamp":1667606400000},"content-version":"vor","delay-in-days":3,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GeoMx Whole Transcriptome Atlas Neuroscience"},{"name":"Lerner Research Institute Center of Excellence for Epilepsy and Co-morbidities Research"},{"name":"Cleveland Clinic Epilepsy Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Memory dysfunction is prevalent in temporal lobe epilepsy, but little is known about the underlying pathophysiological etiologies. Here, we use spatial quantitation to examine differential expression of targeted proteins and transcripts in four brain regions essential for episodic memory (dentate gyrus, CA3, CA1, neocortex) between temporal lobe epilepsy patients with and without episodic memory impairment. Brain tissues were obtained from dominant temporal lobectomies in 16 adults with pharmacoresistant temporal lobe epilepsy associated with hippocampal sclerosis. Verbal memory tests from routine pre-operative clinical care were used to classify episodic memory as impaired or intact. Digital spatial profiling of a targeted protein panel and the whole transcriptome was performed using tissue sections from the temporal neocortex and hippocampus. We performed differential expression and pathway enrichment analysis between the memory groups within each temporal lobe region. Several proteins associated with neurodegenerative disease were overexpressed in the neocortex of patients with impaired memory, corroborating our prior findings using bulk transcriptomics. Spatial transcriptomics identified numerous differentially expressed transcripts in both neocortical and hippocampal subregions between memory groups, with little overlap across subregions. The strongest molecular signal was observed in the CA3 hippocampal subregion, known to play an essential role in memory encoding. Enrichment analyses revealed BDNF as a central hub in CA3-related networks regulating phenotype-relevant processes such as cognition, memory, long-term potentiation and neuritogenesis (Padj &amp;lt; 0.05). Results suggest memory impairment in temporal lobe epilepsy with hippocampal sclerosis is associated with molecular alterations within temporal lobe subregions that are independent from hippocampal cell loss, demographic variables and disease characteristics. Importantly, each temporal subregion shows a unique molecular signature associated with memory impairment. While many differentially expressed transcripts and proteins in the neocortex have been associated with neurodegenerative disorders\/processes, differentially expressed transcripts in hippocampal subregions involve genes associated with neuritogenesis and long-term potentiation, processes essential for new memory formation.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac285","type":"journal-article","created":{"date-parts":[[2022,11,5]],"date-time":"2022-11-05T15:48:05Z","timestamp":1667663285000},"source":"Crossref","is-referenced-by-count":8,"title":["Molecular and subregion mechanisms of episodic memory phenotypes in temporal lobe epilepsy"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5442-4912","authenticated-orcid":false,"given":"Robyn M","family":"Busch","sequence":"first","affiliation":[{"name":"Epilepsy Center, Neurological Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"},{"name":"Department of Neurology, Neurological Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"},{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6389-3059","authenticated-orcid":false,"given":"Lamis","family":"Yehia","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8676-0788","authenticated-orcid":false,"given":"Ingmar","family":"Bl\u00fcmcke","sequence":"additional","affiliation":[{"name":"Epilepsy Center, Neurological Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"},{"name":"Institute of Neuropathology, University Hospitals Erlangen , Schwabachanlage 6, D\u201391054 Erlangen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0606-7639","authenticated-orcid":false,"given":"Bo","family":"Hu","sequence":"additional","affiliation":[{"name":"Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Prayson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Neurological Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"},{"name":"Department of Anatomic Pathology, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0133-4427","authenticated-orcid":false,"given":"Bruce P","family":"Hermann","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Wisconsin , 1685 Highland Avenue, Madison, WI 53705 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imad M","family":"Najm","sequence":"additional","affiliation":[{"name":"Epilepsy Center, Neurological Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"},{"name":"Department of Neurology, Neurological Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3693-5145","authenticated-orcid":false,"given":"Charis","family":"Eng","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"},{"name":"Taussig Cancer Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, OH 44195 , USA"},{"name":"Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine , 10900 Euclid Avenue, Cleveland, OH 44106 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,5]]},"reference":[{"issue":"4","key":"2022112207145775000_fcac285-B1","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.yebeh.2010.09.001","article-title":"Comparing patients\u2019 and practitioners\u2019 views on epilepsy concerns: A call to address memory concerns","volume":"19","author":"McAuley","year":"2010","journal-title":"Epilepsy Behav"},{"key":"2022112207145775000_fcac285-B2","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S0079-6123(02)35041-6","article-title":"Effects of chronic epilepsy on declarative memory systems","volume":"135","author":"Helmstaedter","year":"2002","journal-title":"Prog Brain Res"},{"issue":"9","key":"2022112207145775000_fcac285-B3","doi-asserted-by":"crossref","first-page":"e131","DOI":"10.1111\/epi.12319","article-title":"Neuropsychological outcomes in epilepsy surgery patients with unilateral hippocampal sclerosis and good preoperative memory function","volume":"54","author":"Baxendale","year":"2013","journal-title":"Epilepsia"},{"key":"2022112207145775000_fcac285-B4","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.yebeh.2014.05.026","article-title":"Genetics of cognition in epilepsy","volume":"41","author":"Busch","year":"2014","journal-title":"Epilepsy Behav"},{"issue":"2","key":"2022112207145775000_fcac285-B5","doi-asserted-by":"crossref","DOI":"10.1093\/braincomms\/fcab025","article-title":"Computational support, not primacy, distinguishes compensatory memory reorganization in epilepsy","volume":"3","author":"Tracy","year":"2021","journal-title":"Brain Commun"},{"issue":"3","key":"2022112207145775000_fcac285-B6","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.neuroimage.2011.03.028","article-title":"Evidence for functional specialization of hippocampal subfields detected by MR subfield volumetry on high resolution images at 4T","volume":"56","author":"Mueller","year":"2011","journal-title":"NeuroImage"},{"issue":"13","key":"2022112207145775000_fcac285-B7","doi-asserted-by":"crossref","first-page":"3280","DOI":"10.1523\/JNEUROSCI.3420-04.2005","article-title":"A dissociation of encoding and retrieval processes in the human hippocampus","volume":"25","author":"Eldridge","year":"2005","journal-title":"J Neurosci"},{"issue":"7","key":"2022112207145775000_fcac285-B8","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1111\/epi.12220","article-title":"International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: A task force report from the ILAE commission on diagnostic methods","volume":"54","author":"Bl\u00fcmcke","year":"2013","journal-title":"Epilepsia"},{"issue":"10","key":"2022112207145775000_fcac285-B9","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1111\/epi.16673","article-title":"Verbal memory dysfunction is associated with alterations in brain transcriptome in dominant temporal lobe epilepsy","volume":"61","author":"Busch","year":"2020","journal-title":"Epilepsia"},{"key":"2022112207145775000_fcac285-B10","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.trci.2019.07.003","article-title":"Sex-specific composite scales for longitudinal studies of incipient Alzheimer\u2019s disease","volume":"5","author":"Banks","year":"2019","journal-title":"Alzheimers Dement"},{"key":"2022112207145775000_fcac285-B11","first-page":"74","article-title":"Measuring longitudinal cognition: Individual tests versus composites","volume":"11","author":"Jonaitis","year":"2019","journal-title":"Alzheimers Dement"},{"key":"2022112207145775000_fcac285-B12","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/s41587-020-0472-9","article-title":"Multiplex digital spatial profiling of proteins and RNA in fixed tissue","volume":"38","author":"Merritt","year":"2020","journal-title":"Nat Biotechnol"},{"issue":"8","key":"2022112207145775000_fcac285-B13","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1212\/01.wnl.0000239828.36651.73","article-title":"Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss","volume":"67","author":"Pauli","year":"2006","journal-title":"Neurology"},{"issue":"7","key":"2022112207145775000_fcac285-B14","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1001\/archneurol.2009.125","article-title":"Neurobiological changes in the hippocampus during normative aging","volume":"66","author":"Lister","year":"2009","journal-title":"Arch Neurol"},{"issue":"5","key":"2022112207145775000_fcac285-B15","doi-asserted-by":"crossref","first-page":"6965","DOI":"10.1096\/fj.201902122RR","article-title":"Microtubule-associated protein 2 mediates induction of long-term potentiation in hippocampal neurons","volume":"34","author":"Kim","year":"2020","journal-title":"FASEB J"},{"issue":"8","key":"2022112207145775000_fcac285-B16","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1038\/mp.2015.45","article-title":"Neurofilament subunits are integral components of synapses and modulate neurotransmission and behavior in vivo","volume":"20","author":"Yuan","year":"2015","journal-title":"Mol Psychiatry"},{"issue":"5","key":"2022112207145775000_fcac285-B17","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1177\/1073858407302725","article-title":"Brain plasticity mechanisms and memory: A party of four","volume":"13","author":"Bruel-Jungerman","year":"2007","journal-title":"Neuroscientist"},{"issue":"7","key":"2022112207145775000_fcac285-B18","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a021758","article-title":"Structural components of synaptic plasticity and memory consolidation","volume":"7","author":"Bailey","year":"2015","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2022112207145775000_fcac285-B19","doi-asserted-by":"crossref","first-page":"46","DOI":"10.12703\/r\/10-46","article-title":"Neurofilament light: A narrative review on biomarker utility","volume":"10","author":"Narayanan","year":"2021","journal-title":"Fac Rev"},{"key":"2022112207145775000_fcac285-B20","doi-asserted-by":"crossref","first-page":"117229","DOI":"10.1016\/j.jns.2020.117229","article-title":"The relationship between neurofilament light chain and cognition in neurological disorders: A scoping review","volume":"420","author":"Ramani","year":"2021","journal-title":"J Neurol Sci"},{"issue":"8","key":"2022112207145775000_fcac285-B21","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1177\/002215540104900818","article-title":"Distribution of map2 in hippocampus and cerebellum of young and old rats by quantitative immunohistochemistry","volume":"49","author":"Di Stefano","year":"2001","journal-title":"J Histochem Cytochem"},{"key":"2022112207145775000_fcac285-B22","doi-asserted-by":"crossref","first-page":"158","DOI":"10.3389\/fnmol.2016.00158","article-title":"The role of the carboxyl-terminal sequence of tau and MAP2 in the pathogenesis of dementia","volume":"9","author":"Xie","year":"2016","journal-title":"Front Mol Neurosci"},{"issue":"2","key":"2022112207145775000_fcac285-B23","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/0959-4388(93)90214-J","article-title":"Emerging principles of intrinsic hippocampal organization","volume":"3","author":"Amaral","year":"1993","journal-title":"Curr Opin Neurobiol"},{"issue":"3","key":"2022112207145775000_fcac285-B24","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/0306-4522(89)90424-7","article-title":"The three-dimensional organization of the hippocampal formation: A review of anatomical data","volume":"31","author":"Amaral","year":"1989","journal-title":"Neuroscience"},{"issue":"9","key":"2022112207145775000_fcac285-B25","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1002\/hipo.20455","article-title":"Evaluating the differential roles of the dorsal dentate gyrus, dorsal CA3, and dorsal CA1 during a temporal ordering for spatial locations task","volume":"18","author":"Hunsaker","year":"2008","journal-title":"Hippocampus"},{"key":"2022112207145775000_fcac285-B26","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3389\/fncel.2019.00363","article-title":"Brain-derived neurotrophic factor: A key molecule for memory in the healthy and the pathological brain","volume":"13","author":"Miranda","year":"2019","journal-title":"Front Cell Neurosci"},{"issue":"7","key":"2022112207145775000_fcac285-B27","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1073\/pnas.0711863105","article-title":"BDNF Is essential to promote persistence of long-term memory storage","volume":"105","author":"Bekinschtein","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"2022112207145775000_fcac285-B28","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/nrn.2017.10","article-title":"Operation and plasticity of hippocampal CA3 circuits: Implications for memory encoding","volume":"18","author":"Rebola","year":"2017","journal-title":"Nat Rev Neurosci"},{"key":"2022112207145775000_fcac285-B29","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.neures.2018.11.003","article-title":"Function of local circuits in the hippocampal dentate gyrus-CA3 system","volume":"140","author":"Senzai","year":"2019","journal-title":"Neurosci Res"},{"issue":"1","key":"2022112207145775000_fcac285-B30","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/nan.12458","article-title":"Review: Neurodegenerative processes in temporal lobe epilepsy with hippocampal sclerosis: Clinical, pathological and neuroimaging evidence","volume":"44","author":"Tai","year":"2018","journal-title":"Neuropathol Appl Neurobiol"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcac285\/46833565\/fcac285.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/4\/6\/fcac285\/47175506\/fcac285.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/4\/6\/fcac285\/47175506\/fcac285.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T07:15:48Z","timestamp":1669101348000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcac285\/6806084"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,2]]},"references-count":30,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,11,2]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcac285","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,1]]},"published":{"date-parts":[[2022,11,2]]},"article-number":"fcac285"}}