Early lipofuscin accumulation in frontal lobe epilepsy
Objective This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD). Methods Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical marke...
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| Veröffentlicht in: | Annals of neurology 2016-12, Vol.80 (6), p.882-895 |
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| creator | Liu, Joan Y.W. Reeves, Cheryl Diehl, Beate Coppola, Antonietta Al-Hajri, Aliya Hoskote, Chandrashekar Mughairy, Salim al Tachrount, Mohamed Groves, Michael Michalak, Zuzanna Mills, Kevin McEvoy, Andrew W. Miserocchi, Anna Sisodiya, Sanjay M. Thom, Maria |
| description | Objective
This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD).
Methods
Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of (mTOR) pathway activation and inhibition, cellular autophagy, and synaptic vesicle‐mediated trafficking as well as proteomics analysis. Findings were correlated with pre‐/postoperative clinical, imaging, and electrophysiological data.
Results
Excessive lipofuscin accumulation was observed in abnormal dysmorphic neurones in 6 cases, but not in seven FCD type IIB and 7 pathology‐negative cases, despite similar age and seizure histories. Abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. The mTOR pathway was activated, as in cases with dysplasia, but the immunoreactivities of nucleoporin p62, DEP‐domain containing protein 5, clathrin, and dynamin‐1 were different between groups, suggesting that enhanced autophagy flux and abnormal synaptic vesicle trafficking contribute to early lipofuscin aggregation in these cases, compared to suppression of autophagy in cases with typical dysplasia. Cases with abnormal neuronal lipofuscin showed subtle magnetic resonance imaging cortical abnormalities that localized with seizure onset zone and were more likely to have a family history.
Interpretation
We propose that excess neuronal lipofuscin accumulation in young patients with FLE represents a novel pathology underlying this epilepsy; the early accumulation of lipofuscin may be disease driven, secondary to as‐yet unidentified drivers accelerating autophagic pathways, which may underpin the neuronal dysfunction in this condition. Ann Neurol 2016;80:882–895 |
| doi_str_mv | 10.1002/ana.24803 |
| format | Article |
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This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD).
Methods
Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of (mTOR) pathway activation and inhibition, cellular autophagy, and synaptic vesicle‐mediated trafficking as well as proteomics analysis. Findings were correlated with pre‐/postoperative clinical, imaging, and electrophysiological data.
Results
Excessive lipofuscin accumulation was observed in abnormal dysmorphic neurones in 6 cases, but not in seven FCD type IIB and 7 pathology‐negative cases, despite similar age and seizure histories. Abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. The mTOR pathway was activated, as in cases with dysplasia, but the immunoreactivities of nucleoporin p62, DEP‐domain containing protein 5, clathrin, and dynamin‐1 were different between groups, suggesting that enhanced autophagy flux and abnormal synaptic vesicle trafficking contribute to early lipofuscin aggregation in these cases, compared to suppression of autophagy in cases with typical dysplasia. Cases with abnormal neuronal lipofuscin showed subtle magnetic resonance imaging cortical abnormalities that localized with seizure onset zone and were more likely to have a family history.
Interpretation
We propose that excess neuronal lipofuscin accumulation in young patients with FLE represents a novel pathology underlying this epilepsy; the early accumulation of lipofuscin may be disease driven, secondary to as‐yet unidentified drivers accelerating autophagic pathways, which may underpin the neuronal dysfunction in this condition. Ann Neurol 2016;80:882–895</description><identifier>ISSN: 0364-5134</identifier><identifier>EISSN: 1531-8249</identifier><identifier>DOI: 10.1002/ana.24803</identifier><identifier>PMID: 27766665</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>Autophagy ; Brain - metabolism ; Epilepsy ; Epilepsy, Frontal Lobe - metabolism ; Humans ; Lipofuscin - metabolism ; Magnetic Resonance Imaging ; Neuroimaging ; Neurons - metabolism ; Neurons - ultrastructure ; Pathology ; Proteomics ; TOR Serine-Threonine Kinases - metabolism</subject><ispartof>Annals of neurology, 2016-12, Vol.80 (6), p.882-895</ispartof><rights>2016 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association</rights><rights>2016 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.</rights><rights>2016 American Neurological Association</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4593-4940944632c55587c47ca5e763d5f25d880a581ff893d9fa94797352624af4393</citedby><cites>FETCH-LOGICAL-c4593-4940944632c55587c47ca5e763d5f25d880a581ff893d9fa94797352624af4393</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fana.24803$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fana.24803$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>314,777,781,1412,27905,27906,45555,45556</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27766665$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Joan Y.W.</creatorcontrib><creatorcontrib>Reeves, Cheryl</creatorcontrib><creatorcontrib>Diehl, Beate</creatorcontrib><creatorcontrib>Coppola, Antonietta</creatorcontrib><creatorcontrib>Al-Hajri, Aliya</creatorcontrib><creatorcontrib>Hoskote, Chandrashekar</creatorcontrib><creatorcontrib>Mughairy, Salim al</creatorcontrib><creatorcontrib>Tachrount, Mohamed</creatorcontrib><creatorcontrib>Groves, Michael</creatorcontrib><creatorcontrib>Michalak, Zuzanna</creatorcontrib><creatorcontrib>Mills, Kevin</creatorcontrib><creatorcontrib>McEvoy, Andrew W.</creatorcontrib><creatorcontrib>Miserocchi, Anna</creatorcontrib><creatorcontrib>Sisodiya, Sanjay M.</creatorcontrib><creatorcontrib>Thom, Maria</creatorcontrib><title>Early lipofuscin accumulation in frontal lobe epilepsy</title><title>Annals of neurology</title><addtitle>Ann Neurol</addtitle><description>Objective
This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD).
Methods
Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of (mTOR) pathway activation and inhibition, cellular autophagy, and synaptic vesicle‐mediated trafficking as well as proteomics analysis. Findings were correlated with pre‐/postoperative clinical, imaging, and electrophysiological data.
Results
Excessive lipofuscin accumulation was observed in abnormal dysmorphic neurones in 6 cases, but not in seven FCD type IIB and 7 pathology‐negative cases, despite similar age and seizure histories. Abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. The mTOR pathway was activated, as in cases with dysplasia, but the immunoreactivities of nucleoporin p62, DEP‐domain containing protein 5, clathrin, and dynamin‐1 were different between groups, suggesting that enhanced autophagy flux and abnormal synaptic vesicle trafficking contribute to early lipofuscin aggregation in these cases, compared to suppression of autophagy in cases with typical dysplasia. Cases with abnormal neuronal lipofuscin showed subtle magnetic resonance imaging cortical abnormalities that localized with seizure onset zone and were more likely to have a family history.
Interpretation
We propose that excess neuronal lipofuscin accumulation in young patients with FLE represents a novel pathology underlying this epilepsy; the early accumulation of lipofuscin may be disease driven, secondary to as‐yet unidentified drivers accelerating autophagic pathways, which may underpin the neuronal dysfunction in this condition. Ann Neurol 2016;80:882–895</description><subject>Autophagy</subject><subject>Brain - metabolism</subject><subject>Epilepsy</subject><subject>Epilepsy, Frontal Lobe - metabolism</subject><subject>Humans</subject><subject>Lipofuscin - metabolism</subject><subject>Magnetic Resonance Imaging</subject><subject>Neuroimaging</subject><subject>Neurons - metabolism</subject><subject>Neurons - ultrastructure</subject><subject>Pathology</subject><subject>Proteomics</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><issn>0364-5134</issn><issn>1531-8249</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNqNkE1LIzEYgMOibKu7B_-ADHjRw2i-3nwcS1F3WVsvLu4tpGkCo-nMmHTQ_nvjVntYEDYQQuB5H5IHoSOCzwnG9MK29pxyhdkXNCbASK0o13tojJngNRDGR-gg5weMsRYEf0UjKqUoC8ZIXNoUN1Vs-i4M2TVtZZ0bVkO066Zrq3IPqWvXNlaxW_jK9030fd58Q_vBxuy_v5-H6PfV5d30R31ze_1zOrmpHQfNaq451pwLRh0AKOm4dBa8FGwJgcJSKWxBkRCUZksdrOZSSwZUUG4DZ5odotOtt0_d0-Dz2qya7HyMtvXdkA1RoHnZlPwHygCILI8p6Mk_6EM3pLZ85E2IFSMKi0KdbSmXupyTD6ZPzcqmjSHYvHU3pbv5272wx-_GYbHyyx35EboAF1vguQTcfG4yk_nkQ1lvJ5q89i-7CZsejZBMgrmfX5sZvZ_O_8DM_GKvgSSXxw</recordid><startdate>201612</startdate><enddate>201612</enddate><creator>Liu, Joan Y.W.</creator><creator>Reeves, Cheryl</creator><creator>Diehl, Beate</creator><creator>Coppola, Antonietta</creator><creator>Al-Hajri, Aliya</creator><creator>Hoskote, Chandrashekar</creator><creator>Mughairy, Salim al</creator><creator>Tachrount, Mohamed</creator><creator>Groves, Michael</creator><creator>Michalak, Zuzanna</creator><creator>Mills, Kevin</creator><creator>McEvoy, Andrew W.</creator><creator>Miserocchi, Anna</creator><creator>Sisodiya, Sanjay M.</creator><creator>Thom, Maria</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201612</creationdate><title>Early lipofuscin accumulation in frontal lobe epilepsy</title><author>Liu, Joan Y.W. ; Reeves, Cheryl ; Diehl, Beate ; Coppola, Antonietta ; Al-Hajri, Aliya ; Hoskote, Chandrashekar ; Mughairy, Salim al ; Tachrount, Mohamed ; Groves, Michael ; Michalak, Zuzanna ; Mills, Kevin ; McEvoy, Andrew W. ; Miserocchi, Anna ; Sisodiya, Sanjay M. ; Thom, Maria</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4593-4940944632c55587c47ca5e763d5f25d880a581ff893d9fa94797352624af4393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Autophagy</topic><topic>Brain - metabolism</topic><topic>Epilepsy</topic><topic>Epilepsy, Frontal Lobe - metabolism</topic><topic>Humans</topic><topic>Lipofuscin - metabolism</topic><topic>Magnetic Resonance Imaging</topic><topic>Neuroimaging</topic><topic>Neurons - metabolism</topic><topic>Neurons - ultrastructure</topic><topic>Pathology</topic><topic>Proteomics</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Joan Y.W.</creatorcontrib><creatorcontrib>Reeves, Cheryl</creatorcontrib><creatorcontrib>Diehl, Beate</creatorcontrib><creatorcontrib>Coppola, Antonietta</creatorcontrib><creatorcontrib>Al-Hajri, Aliya</creatorcontrib><creatorcontrib>Hoskote, Chandrashekar</creatorcontrib><creatorcontrib>Mughairy, Salim al</creatorcontrib><creatorcontrib>Tachrount, Mohamed</creatorcontrib><creatorcontrib>Groves, Michael</creatorcontrib><creatorcontrib>Michalak, Zuzanna</creatorcontrib><creatorcontrib>Mills, Kevin</creatorcontrib><creatorcontrib>McEvoy, Andrew W.</creatorcontrib><creatorcontrib>Miserocchi, Anna</creatorcontrib><creatorcontrib>Sisodiya, Sanjay M.</creatorcontrib><creatorcontrib>Thom, Maria</creatorcontrib><collection>Istex</collection><collection>Wiley Online Library Open Access</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Annals of neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Joan Y.W.</au><au>Reeves, Cheryl</au><au>Diehl, Beate</au><au>Coppola, Antonietta</au><au>Al-Hajri, Aliya</au><au>Hoskote, Chandrashekar</au><au>Mughairy, Salim al</au><au>Tachrount, Mohamed</au><au>Groves, Michael</au><au>Michalak, Zuzanna</au><au>Mills, Kevin</au><au>McEvoy, Andrew W.</au><au>Miserocchi, Anna</au><au>Sisodiya, Sanjay M.</au><au>Thom, Maria</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Early lipofuscin accumulation in frontal lobe epilepsy</atitle><jtitle>Annals of neurology</jtitle><addtitle>Ann Neurol</addtitle><date>2016-12</date><risdate>2016</risdate><volume>80</volume><issue>6</issue><spage>882</spage><epage>895</epage><pages>882-895</pages><issn>0364-5134</issn><eissn>1531-8249</eissn><abstract>Objective
This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD).
Methods
Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of (mTOR) pathway activation and inhibition, cellular autophagy, and synaptic vesicle‐mediated trafficking as well as proteomics analysis. Findings were correlated with pre‐/postoperative clinical, imaging, and electrophysiological data.
Results
Excessive lipofuscin accumulation was observed in abnormal dysmorphic neurones in 6 cases, but not in seven FCD type IIB and 7 pathology‐negative cases, despite similar age and seizure histories. Abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. The mTOR pathway was activated, as in cases with dysplasia, but the immunoreactivities of nucleoporin p62, DEP‐domain containing protein 5, clathrin, and dynamin‐1 were different between groups, suggesting that enhanced autophagy flux and abnormal synaptic vesicle trafficking contribute to early lipofuscin aggregation in these cases, compared to suppression of autophagy in cases with typical dysplasia. Cases with abnormal neuronal lipofuscin showed subtle magnetic resonance imaging cortical abnormalities that localized with seizure onset zone and were more likely to have a family history.
Interpretation
We propose that excess neuronal lipofuscin accumulation in young patients with FLE represents a novel pathology underlying this epilepsy; the early accumulation of lipofuscin may be disease driven, secondary to as‐yet unidentified drivers accelerating autophagic pathways, which may underpin the neuronal dysfunction in this condition. Ann Neurol 2016;80:882–895</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>27766665</pmid><doi>10.1002/ana.24803</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Annals of neurology, 2016-12, Vol.80 (6), p.882-895 |
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| language | eng |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Autophagy Brain - metabolism Epilepsy Epilepsy, Frontal Lobe - metabolism Humans Lipofuscin - metabolism Magnetic Resonance Imaging Neuroimaging Neurons - metabolism Neurons - ultrastructure Pathology Proteomics TOR Serine-Threonine Kinases - metabolism |
| title | Early lipofuscin accumulation in frontal lobe epilepsy |
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