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[Preprint]. 2024 Mar 6:2024.03.02.583073.

doi: 10.1101/2024.03.02.583073.

A WORLDWIDE ENIGMA STUDY ON EPILEPSY-RELATED GRAY AND WHITE MATTER COMPROMISE ACROSS THE ADULT LIFESPAN

Judy Chen¹, Alexander Ngo¹, Raúl Rodríguez-Cruces¹, Jessica Royer¹, Maria Eugenia Caligiuri², Antonio Gambardella^{2

3}, Luis Concha⁴, Simon S Keller^{5

6}, Fernando Cendes⁷, Clarissa L Yasuda⁷, Marina K M Alvim⁷, Leonardo Bonilha⁸, Ezequiel Gleichgerrcht⁸, Niels K Focke⁹, Barbara Kreilkamp⁹, Martin Domin¹⁰, Felix von Podewils¹¹, Soenke Langner¹², Christian Rummel¹³, Roland Wiest¹³, Pascal Martin¹⁴, Raviteja Kotikalapudi^{14

9}, Benjamin Bender¹⁵, Terence J O'Brien^{16

17}, Benjamin Sinclair^{16

17}, Lucy Vivash^{16

17}, Patrick Kwan¹⁷, Patricia M Desmond¹⁷, Elaine Lui¹⁷, Gian Marco Duma¹⁸, Paolo Bonanni¹⁸, Alice Ballerini¹⁹, Anna Elisabetta Vaudano^{20

19}, Stefano Meletti^{20

19}, Manuela Tondelli^{19

21}, Saud Alhusaini^{22

23}, Colin P Doherty^{24

25}, Gianpiero L Cavalleri^{22

25}, Norman Delanty^{22

25}, Reetta Kälviäinen^{26

27}, Graeme D Jackson²⁸, Magdalena Kowalczyk²⁸, Mario Mascalchi²⁹, Mira Semmelroch²⁸, Rhys H Thomas³⁰, Hamid Soltanian-Zadeh^{31

32}, Esmaeil Davoodi-Bojd³³, Junsong Zhang³⁴, Matteo Lenge³⁵, Renzo Guerrini^{35

36}, Emanuele Bartolini³⁷, Khalid Hamandi^{38

39}, Sonya Foley³⁸, Theodor Rüber^{40

41}, Tobias Bauer^{40

41}, Bernd Weber⁴², Benoit Caldairou⁴³, Chantal Depondt⁴⁴, Julie Absil⁴⁵, Sarah J A Carr⁴⁶, Eugenio Abela⁴⁶, Mark P Richardson⁴⁶, Orrin Devinsky⁴⁷, Heath Pardoe⁴⁷, Mariasavina Severino⁴⁸, Pasquale Striano^{48

49}, Domenico Tortora⁴⁹, Erik Kaestner⁵⁰, Sean N Hatton⁵¹, Donatello Arienzo⁵⁰, Sjoerd B Vos^{52

53

54}, Mina Ryten^{52

55}, Peter N Taylor^{52

56}, John S Duncan^{52

53}, Christopher D Whelan²², Marian Galovic⁵⁷, Gavin P Winston^{52

53

58}, Sophia I Thomopoulos⁵⁹, Paul M Thompson⁵⁹, Sanjay M Sisodiya^{52

53}, Angelo Labate⁶⁰, Carrie R McDonald⁵⁰, Lorenzo Caciagli^{52

55}, Neda Bernasconi⁴³, Andrea Bernasconi⁴³, Sara Larivière^{1

61}, Dewi Schrader⁶², Boris C Bernhardt¹

Affiliations

¹ Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
² Neuroscience Research Center, University Magna Græcia, Catanzaro, CZ, Italy.
³ Institute of Neurology, University Magna Græcia, Catanzaro, CZ, Italy.
⁴ Institute of Neurobiology, Universidad Nacional Autónoma de México, Querétaro, México.
⁵ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
⁶ Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.
⁷ Department of Neurology, University of Campinas--UNICAMP, Campinas, São Paulo, Brazil.
⁸ Department of Neurology, Emory University, Atlanta, GA, USA.
⁹ Department of Neurology, University of Medicine Göttingen, Göttingen, Germany.
¹⁰ Institute of Diagnostic Radiology and Neuroradiology, Functional Imaging Unit, University Medicine Greifswald, Greifswald, Germany.
¹¹ Department of Neurology, University Medicine Greifswald, Epilepsy Center, Greifswald, Germany.
¹² Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
¹³ Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern, Bern, Switzerland.
¹⁴ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁵ Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Germany.
¹⁶ Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.
¹⁷ Departments of Medicine and Radiology, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia.
¹⁸ Scientific Institute IRCCS E.Medea, Epilepsy Unit, Conegliano (TV), Italy.
¹⁹ Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, Modena, Italy.
²⁰ Neurology Unit, OCB Hospital, Azienda Ospedaliera-Universitaria, Modena, Italy.
²¹ Primary Care Department, Azienda Sanitaria Locale di Modena, Modena, Italy.
²² Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland.
²³ Department of Neurology, Alpert Medical School of Brown University, Providence, RI, USA.
²⁴ Department of Neurology, St James' Hospital, Dublin, Ireland.
²⁵ FutureNeuro SFI Research Centre, Dublin, Ireland.
²⁶ Epilepsy Center, Neuro Center, Kuopio University Hospital, Member of the European Reference Network for Rare and Complex Epilepsies EpiCARE, Kuopio, Finland.
²⁷ Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
²⁸ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne VIC 3010, Australia.
²⁹ Neuroradiology Research Program, Meyer Children Hospital of Florence, University of Florence, Florence, Italy.
³⁰ Transitional and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
³¹ Contol and Intelligent Processing Center of Excellence (CIPCE), School of Electrical and Computer Engineering, University of Tehran, Tehran, Iran.
³² Departments of Research Administration and Radiology, Henry Ford Health System, Detroit, MI, USA.
³³ Department of Neurology, Henry Ford Health System, Detroit, MI, USA.
³⁴ Cognitive Science Department, Xiamen University, Xiamen, China.
³⁵ Child Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy.
³⁶ Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy.
³⁷ IRCCS Stella Maris Foundation, Pisa, Italy.
³⁸ Cardiff University Brain Research Imaging Centre (CUBRIC), College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
³⁹ The Welsh Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK.
⁴⁰ Department of Neuroradiology, University Hospital Bonn, Bonn, Germany.
⁴¹ Department of Epileptology, University Hospital Bonn, Bonn, Germany.
⁴² Institute of Experimental Epileptology and Cognition Research, University Hospital Bonn, Bonn, Germany.
⁴³ Neuroimaging of Epilepsy Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁴⁴ Department of Neurology, Hôpital Erasme, Hôpital Universitaire de Bruxelles (HUB), Université Libre de Bruxelles, Brussels, Belgium.
⁴⁵ Department of Radiology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
⁴⁶ School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.
⁴⁷ Department of Neurology, NYU Grossman School of Medicine, New York, NY, United States.
⁴⁸ IRCCS Istituto Giannina Gaslini, Genova, Italy.
⁴⁹ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy.
⁵⁰ Department of Radiation Medicine and Applied Sciences; Department of Psychiatry, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, United States.
⁵¹ Department of Neurosciences, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, United States.
⁵² Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
⁵³ Chalfont Centre for Epilepsy, Bucks, UK.
⁵⁴ Centre for Medical Image Computing, University College London, London, UK.
⁵⁵ MRI Unit, Epilepsy Society, Chalfont St Peter, Bucks, UK.
⁵⁶ CNNP Lab, ICOS group, Newcastle University, Newcastle upon Tyne, United Kingdom.
⁵⁷ Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zürich, Zürich, Switzerland.
⁵⁸ Department of Medicine, Division of Neurology, Queen's University, Kingston, ON, Canada.
⁵⁹ Imaging Genetics Center, Mark & Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
⁶⁰ Neurophysiopathology and Movement Disorders Clinic, Regional Epilepsy Center, University of Messina, Italy.
⁶¹ Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard University, Boston, MA, USA.
⁶² BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

PMID: 38496668
PMCID: PMC10942350
DOI: 10.1101/2024.03.02.583073

A WORLDWIDE ENIGMA STUDY ON EPILEPSY-RELATED GRAY AND WHITE MATTER COMPROMISE ACROSS THE ADULT LIFESPAN

Judy Chen et al. bioRxiv. 2024.

[Preprint]. 2024 Mar 6:2024.03.02.583073.

doi: 10.1101/2024.03.02.583073.

Authors

Affiliations

¹ Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
² Neuroscience Research Center, University Magna Græcia, Catanzaro, CZ, Italy.
³ Institute of Neurology, University Magna Græcia, Catanzaro, CZ, Italy.
⁴ Institute of Neurobiology, Universidad Nacional Autónoma de México, Querétaro, México.
⁵ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
⁶ Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.
⁷ Department of Neurology, University of Campinas--UNICAMP, Campinas, São Paulo, Brazil.
⁸ Department of Neurology, Emory University, Atlanta, GA, USA.
⁹ Department of Neurology, University of Medicine Göttingen, Göttingen, Germany.
¹⁰ Institute of Diagnostic Radiology and Neuroradiology, Functional Imaging Unit, University Medicine Greifswald, Greifswald, Germany.
¹¹ Department of Neurology, University Medicine Greifswald, Epilepsy Center, Greifswald, Germany.
¹² Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
¹³ Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern, Bern, Switzerland.
¹⁴ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁵ Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Germany.
¹⁶ Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.
¹⁷ Departments of Medicine and Radiology, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia.
¹⁸ Scientific Institute IRCCS E.Medea, Epilepsy Unit, Conegliano (TV), Italy.
¹⁹ Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, Modena, Italy.
²⁰ Neurology Unit, OCB Hospital, Azienda Ospedaliera-Universitaria, Modena, Italy.
²¹ Primary Care Department, Azienda Sanitaria Locale di Modena, Modena, Italy.
²² Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland.
²³ Department of Neurology, Alpert Medical School of Brown University, Providence, RI, USA.
²⁴ Department of Neurology, St James' Hospital, Dublin, Ireland.
²⁵ FutureNeuro SFI Research Centre, Dublin, Ireland.
²⁶ Epilepsy Center, Neuro Center, Kuopio University Hospital, Member of the European Reference Network for Rare and Complex Epilepsies EpiCARE, Kuopio, Finland.
²⁷ Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
²⁸ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne VIC 3010, Australia.
²⁹ Neuroradiology Research Program, Meyer Children Hospital of Florence, University of Florence, Florence, Italy.
³⁰ Transitional and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
³¹ Contol and Intelligent Processing Center of Excellence (CIPCE), School of Electrical and Computer Engineering, University of Tehran, Tehran, Iran.
³² Departments of Research Administration and Radiology, Henry Ford Health System, Detroit, MI, USA.
³³ Department of Neurology, Henry Ford Health System, Detroit, MI, USA.
³⁴ Cognitive Science Department, Xiamen University, Xiamen, China.
³⁵ Child Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy.
³⁶ Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy.
³⁷ IRCCS Stella Maris Foundation, Pisa, Italy.
³⁸ Cardiff University Brain Research Imaging Centre (CUBRIC), College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
³⁹ The Welsh Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK.
⁴⁰ Department of Neuroradiology, University Hospital Bonn, Bonn, Germany.
⁴¹ Department of Epileptology, University Hospital Bonn, Bonn, Germany.
⁴² Institute of Experimental Epileptology and Cognition Research, University Hospital Bonn, Bonn, Germany.
⁴³ Neuroimaging of Epilepsy Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁴⁴ Department of Neurology, Hôpital Erasme, Hôpital Universitaire de Bruxelles (HUB), Université Libre de Bruxelles, Brussels, Belgium.
⁴⁵ Department of Radiology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
⁴⁶ School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.
⁴⁷ Department of Neurology, NYU Grossman School of Medicine, New York, NY, United States.
⁴⁸ IRCCS Istituto Giannina Gaslini, Genova, Italy.
⁴⁹ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy.
⁵⁰ Department of Radiation Medicine and Applied Sciences; Department of Psychiatry, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, United States.
⁵¹ Department of Neurosciences, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, United States.
⁵² Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
⁵³ Chalfont Centre for Epilepsy, Bucks, UK.
⁵⁴ Centre for Medical Image Computing, University College London, London, UK.
⁵⁵ MRI Unit, Epilepsy Society, Chalfont St Peter, Bucks, UK.
⁵⁶ CNNP Lab, ICOS group, Newcastle University, Newcastle upon Tyne, United Kingdom.
⁵⁷ Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zürich, Zürich, Switzerland.
⁵⁸ Department of Medicine, Division of Neurology, Queen's University, Kingston, ON, Canada.
⁵⁹ Imaging Genetics Center, Mark & Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
⁶⁰ Neurophysiopathology and Movement Disorders Clinic, Regional Epilepsy Center, University of Messina, Italy.
⁶¹ Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard University, Boston, MA, USA.
⁶² BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

PMID: 38496668
PMCID: PMC10942350
DOI: 10.1101/2024.03.02.583073

Abstract

Objectives: Temporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of grey and white matter structures. Evidence supports a progressive condition although the temporal evolution of TLE is poorly defined. This ENIGMA-Epilepsy study utilized multimodal magnetic resonance imaging (MRI) data to investigate structural alterations in TLE patients across the adult lifespan. We charted both grey and white matter changes and explored the covariance of age-related alterations in both compartments.

Methods: We studied 769 TLE patients and 885 healthy controls across an age range of 17-73 years, from multiple international sites. To assess potentially non-linear lifespan changes in TLE, we harmonized data and combined median split assessments with cross-sectional sliding window analyses of grey and white matter age-related changes. Covariance analyses examined the coupling of grey and white matter lifespan curves.

Results: In TLE, age was associated with a robust grey matter thickness/volume decline across a broad cortico-subcortical territory, extending beyond the mesiotemporal disease epicentre. White matter changes were also widespread across multiple tracts with peak effects in temporo-limbic fibers. While changes spanned the adult time window, changes accelerated in cortical thickness, subcortical volume, and fractional anisotropy (all decreased), and mean diffusivity (increased) after age 55 years. Covariance analyses revealed strong limbic associations between white matter tracts and subcortical structures with cortical regions.

Conclusions: This study highlights the profound impact of TLE on lifespan changes in grey and white matter structures, with an acceleration of aging-related processes in later decades of life. Our findings motivate future longitudinal studies across the lifespan and emphasize the importance of prompt diagnosis as well as intervention in patients.

Keywords: Epilepsy; aging; atrophy; lifespan; multimodal; temporal lobe epilepsy.

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Figures

**Figure 1.. Grey matter morphometry via median-split analysis and sliding-age window trajectories in temporal lobe epilepsy (TLE).**
**(A)** Median age of 35 was chosen as the division into young and old cohorts. All right-sided temporal lobe epilepsy (TLE) patients were flipped, with results demonstrating significant left hippocampal reductions in both young and old age cohorts, and increasing occipital grey matter atrophy with age as seen in the old cohort. There are strong group by age interaction with significant subcortical regions and some cortical involvement in the parieto-occipital regions. **(B)** After z-scoring cortical thickness and subcortical volume measures, windows of ±2 years of the age of interest were chosen, and the mean values for cortical (68 total brain regions) and subcortical regions (12 subcortical grey matter regions and bilateral ventricles and hippocampi) following the Desikan-Killiany atlas were multiplied by normally distributed weights to yield a weighted average. Global weighted-average z-scores were then plotted across age to illustrate lifespan trajectory. **(C)** In temporal lobe epilepsy (TLE) patients, older age especially past age 55 seems to be correlated with an accelerated and pronounced decline in cortical thickness. The hippocampi and other subcortical regions also show a marked decreased volume with aging.

**Figure 2.. White matter alterations via median-split analysis and sliding-age window trajectories in temporal lobe epilepsy (TLE).**
**(A)** Median age of 35 was chosen as the division into young and old cohorts. All right-sided temporal lobe epilepsy (TLE) patients were flipped, with results demonstrating almost all white matter tracts significantly decreased for fractional anisotropy (FA) measures and increased for mean diffusivity (MD) measures for both young and old TLE cohorts against their age-matched controls. **(B)** Average age trajectories were calculated for ipsilateral and contralateral white matter tracts associated with the corpus callosum, limbic, cortical-subcortical, and cortical regions. All tracts demonstrate an accelerated and pronounced decline in FA measures past age 50 and a similarly pronounced increase in MD measures past age 60.

**Figure 3.. Sliding age-window structural covariance correlations in temporal lobe epilepsy (TLE).**
Correlograms (center) showing the correlational of each region-associated age trajectory across the lifespan for CT, SVC, FA, and MD were calculated. The top 10% (*red*) and bottom 10% (*blue*) of connections were preserved to identify regions more closely associated with each grey or white matter measures. Scatter plots demonstrate the age-dependent (*grey*) distribution of z-score values against controls.

See this image and copyright information in PMC

References

1. Feigin VL, Nichols E, Alam T, et al. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459–480. - PMC - PubMed
1. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5):311–318. - PubMed
1. Tavakol S, Royer J, Lowe AJ, et al. Neuroimaging and connectomics of drug-resistant epilepsy at multiple scales: From focal lesions to macroscale networks. Epilepsia. 2019;60(4):593–604. - PMC - PubMed
1. Bernhardt BC, Bonilha L, Gross DW. Network analysis for a network disorder: The emerging role of graph theory in the study of epilepsy. Epilepsy Behav. 2015;50:162–170. - PubMed
1. Sisodiya SM, Whelan CD, Hatton SN, et al. The ENIGMA-Epilepsy working group: Mapping disease from large data sets. Hum Brain Mapp. 2020;43(1):113–128. - PMC - PubMed

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This is a preprint.

A WORLDWIDE ENIGMA STUDY ON EPILEPSY-RELATED GRAY AND WHITE MATTER COMPROMISE ACROSS THE ADULT LIFESPAN

Affiliations

A WORLDWIDE ENIGMA STUDY ON EPILEPSY-RELATED GRAY AND WHITE MATTER COMPROMISE ACROSS THE ADULT LIFESPAN

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