The ability to advance our understanding of sudden unexpected death in epilepsy (SUDEP) is critically dependent on the comparison of postmortem brains from SUDEP cases to control brains from patients with epilepsy who died from other causes and patients without epilepsy who died suddenly. We seek to better define the evidence to support or refute leading theories about the causes of SUDEP: the role of brainstem dysfunction and the role of serotonin and adenosine. Specifically, we hypothesize that alterations of interneurons, purinergic and serotonergic systems in vital autonomic brainstem structures are increased in SUDEP compared to controls. We will use advanced 9.4T MRI imaging complemented by quantitative stereological and immunohistochemical techniques to study the neuronal, interneuronal and astrocytic densities in the central autonomic network structures such as the insula, anterior cingulate cortex, and amygdala, with a focus on critical brainstem regions (e.g., cardiorespiratory and median raphe nuclei) and the neurotransmitters serotonin and adenosine. We will leverage the world's largest collection of formalin fixed SUDEP brains, prospective collection of frozen and formalin fixed brains, and tissue from epilepsy surgery cases to study our hypotheses. Our systematic brainstem/autonomic neuropathological analysis will provide the most complete comparative map of the histopathological and biochemical autonomic system abnormalities that are altered in SUDEP. The combined study of human brain tissue and detailed phenotypic data will provide the strongest and most direct link between potential biomarkers and neuropathological studies in living patients with neuropathological findings from SUDEP cases. Our living patients can link ictal and other phenotypic markers (e.g., MRI) to activity in serotonergic (5-HT1A and 5-HT1C receptors, 5-HT transporter) and the enzyme of serotonin synthesis tryptophan hydroxylases) and purinergic (adenosine kinase activity and adenosine receptor binding) systems in their brain tissue. Our SUDEP postmortem studies will link 9.4T images of the entire brain, as well as serotonergic and purinergic activity in cortical, subcortical and brainstem regions. Together, these studies will, for the first time, bridge detailed phenotypic data, cortical and brainstem studies of serotonergic and purinergic activity. Our study will also work with SUTRA 5: Genetics and Epigenetics of SUDEP to study the potential role of nonsynonymous substitutions in serotonergic and purinergic genes, and how these relate to our quantitative stereological and immunohistochemical findings and phenotypic markers.
The proposed studies will leverage the world's largest collection of SUDEP brains to explore the role of specific histopathological and biomolecular abnormalities in the brain, focusing on critical brainstem regions and the neurotransmitters serotonin and adenosine. Comparing SUDEP and control brains, and examining tissue obtained from epilepsy surgery cases whose seizures have been extensively studied, we will assess the leading hypotheses of SUDEP causation to better understand the role of specific nerve cell types and populations, and neurotransmitter abnormalities in SUDEP. Understanding the mechanisms that underlie SUDEP can help inform strategies to prevent SUDEP, the leading cause of death in young adults with epilepsy.
|Thom, M; Boldrini, M; Bundock, E et al. (2018) Review: The past, present and future challenges in epilepsy-related and sudden deaths and biobanking. Neuropathol Appl Neurobiol 44:32-55|
|Atkin, Talia A; Maher, Chani M; Gerlach, Aaron C et al. (2018) A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy. Epilepsia 59:802-813|
|Murugesan, Arun; Rani, M R Sandhya; Hampson, Johnson et al. (2018) Serum serotonin levels in patients with epileptic seizures. Epilepsia 59:e91-e97|
|Lacuey, Nuria; Zonjy, Bilal; Hampson, Johnson P et al. (2018) The incidence and significance of periictal apnea in epileptic seizures. Epilepsia 59:573-582|
|Boldrini, Maura; Fulmore, Camille A; Tartt, Alexandria N et al. (2018) Human Hippocampal Neurogenesis Persists throughout Aging. Cell Stem Cell 22:589-599.e5|
|Patodia, Smriti; Somani, Alyma; O'Hare, Megan et al. (2018) The ventrolateral medulla and medullary raphe in sudden unexpected death in epilepsy. Brain 141:1719-1733|
|Rosenberg, Evan C; Louik, Jay; Conway, Erin et al. (2017) Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Epilepsia 58:e96-e100|
|Berg, Anne T; Altalib, Hamada H; Devinsky, Orrin (2017) Psychiatric and behavioral comorbidities in epilepsy: A critical reappraisal. Epilepsia 58:1123-1130|
|Michalak, Zuzanna; Obari, Dima; Ellis, Matthew et al. (2017) Neuropathology of SUDEP: Role of inflammation, blood-brain barrier impairment, and hypoxia. Neurology 88:551-561|
|Lhatoo, Samden D; Nei, Maromi; Raghavan, Manoj et al. (2016) Nonseizure SUDEP: Sudden unexpected death in epilepsy without preceding epileptic seizures. Epilepsia 57:1161-8|
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