Human adult neurogenesis loss corresponds with cognitive decline during epilepsy progression

Aswathy Ammothumkandy; Luis Corona; Kristine Ravina; Victoria Wolseley; Jeremy Nelson; Nadiya Atai; Aidin Abedi; Nora Jimenez; Michelle Armacost; Lina M D'Orazio; Virginia Zuverza-Chavarria; Alisha Cayce; Carol McCleary; George Nune; Laura Kalayjian; Darrin J Lee; Brian Lee; Robert H Chow; Christianne Heck; Jonathan J Russin; Charles Y Liu; Jason A D Smith; Michael A Bonaguidi

doi:10.1016/j.stem.2024.11.002

Human adult neurogenesis loss corresponds with cognitive decline during epilepsy progression

Cell Stem Cell. 2024 Dec 3:S1934-5909(24)00401-6. doi: 10.1016/j.stem.2024.11.002. Online ahead of print.

Authors

Aswathy Ammothumkandy¹, Luis Corona¹, Kristine Ravina², Victoria Wolseley³, Jeremy Nelson¹, Nadiya Atai², Aidin Abedi², Nora Jimenez⁴, Michelle Armacost⁵, Lina M D'Orazio⁶, Virginia Zuverza-Chavarria⁷, Alisha Cayce¹, Carol McCleary⁶, George Nune⁸, Laura Kalayjian⁶, Darrin J Lee⁹, Brian Lee⁹, Robert H Chow¹⁰, Christianne Heck⁸, Jonathan J Russin¹¹, Charles Y Liu¹², Jason A D Smith¹³, Michael A Bonaguidi¹⁴

Affiliations

¹ Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
² Neurorestoration Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
³ Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Physiology & Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁴ Los Angeles General Medical Center, Los Angeles, CA 90033, USA.
⁵ Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Neurology, Rancho Los Amigos National Rehabilitation Center, Downey, CA 90242, USA.
⁶ Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁷ Department of Psychology, Rancho Los Amigos National Rehabilitation Center, Downey, CA 90242, USA.
⁸ Neurorestoration Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁹ Neurorestoration Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
¹⁰ Department of Physiology & Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
¹¹ Neurorestoration Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA.
¹² Neurorestoration Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: [email protected].
¹³ Neurorestoration Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Neurology, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: [email protected].
¹⁴ Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Neurorestoration Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Gerontology, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: [email protected].

PMID: 39642885
DOI: 10.1016/j.stem.2024.11.002

Abstract

Mesial temporal lobe epilepsy (MTLE) is a syndromic disorder presenting with seizures and cognitive comorbidities. Although seizure etiology is increasingly understood, the pathophysiological mechanisms contributing to cognitive decline and epilepsy progression remain less recognized. We have previously shown that adult hippocampal neurogenesis dramatically declines in MTLE patients with increased disease duration. Here, we investigate when multiple cognitive domains become affected during epilepsy progression and how human neurogenesis levels contribute to it. We find that intelligence, verbal learning, and memory decline at a critical period of 20 years disease duration. In contrast to rodents, the number of human immature neurons positively associates with auditory verbal, rather than visuospatial, learning and memory. Moreover, this association does not apply to mature granule neurons. Our study provides cellular evidence of how adult neurogenesis corresponds with human cognition and signifies an opportunity to advance regenerative medicine for patients with MTLE and other cognitive disorders.

Keywords: co-morbidity; cognition; critical period; dementia; epilepsy; human adult neurogenesis; immature neuron; learning; memory; neural stem cell; progressive disorder.