Metabolomic, proteomic, and transcriptomic changes in adults with epilepsy on modified Atkins diet

Leitner, Dominique F.; Siu, Yik; Korman, Aryeh; Lin, Ziyan; Kanshin, Evgeny; Friedman, Daniel; Devore, Sasha; Ueberheide, Beatrix; Tsirigos, Aristotelis; Jones, Drew R.; Wısnıewskı, Thomas; Devinsky, Orrin

doi:10.1111/epi.17540

Cited by 5 publications

(4 citation statements)

References 60 publications

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“…A comparison of the significant proteins common to each pairwise comparison was evaluated by a Venn diagram generated from InteractiVenn (78). Celltype annotations for each protein were evaluated in comparison to a reference choroid plexus dataset (79), as we have similarly done previously in other brain regions with enrichment evaluated by a Fisher's exact test (54,70,71,73,80,81). The signaling pathways associated with the differentially expressed proteins were assessed by Ingenuity Pathway Analysis (IPA, Qiagen).…”

Section: Discussionmentioning

confidence: 99%

Localized proteomic differences in the choroid plexus of Alzheimer's disease and epilepsy patients

et al. 2023

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IntroductionAlzheimer's disease (AD) and epilepsy are reciprocally related. Among sporadic AD patients, clinical seizures occur in 10–22% and subclinical epileptiform abnormalities occur in 22–54%. Cognitive deficits, especially short-term memory impairments, occur in most epilepsy patients. Common neurophysiological and molecular mechanisms occur in AD and epilepsy. The choroid plexus undergoes pathological changes in aging, AD, and epilepsy, including decreased CSF turnover, amyloid beta (Aβ), and tau accumulation due to impaired clearance and disrupted CSF amino acid homeostasis. This pathology may contribute to synaptic dysfunction in AD and epilepsy.MethodsWe evaluated control (n = 8), severe AD (n = 8; A3, B3, C3 neuropathology), and epilepsy autopsy cases (n = 12) using laser capture microdissection (LCM) followed by label-free quantitative mass spectrometry on the choroid plexus adjacent to the hippocampus at the lateral geniculate nucleus level.ResultsProteomics identified 2,459 proteins in the choroid plexus. At a 5% false discovery rate (FDR), 616 proteins were differentially expressed in AD vs. control, 1 protein in epilepsy vs. control, and 438 proteins in AD vs. epilepsy. There was more variability in the epilepsy group across syndromes. The top 20 signaling pathways associated with differentially expressed proteins in AD vs. control included cell metabolism pathways; activated fatty acid beta-oxidation (p = 2.00 x 10−7, z = 3.00), and inhibited glycolysis (p = 1.00 x 10−12, z = −3.46). For AD vs. epilepsy, the altered pathways included cell metabolism pathways, activated complement system (p = 5.62 x 10−5, z = 2.00), and pathogen-induced cytokine storm (p = 2.19 x 10−2, z = 3.61). Of the 617 altered proteins in AD and epilepsy vs. controls, 497 (81%) were positively correlated (p < 0.0001, R2 = 0.27).DiscussionWe found altered signaling pathways in the choroid plexus of severe AD cases and many correlated changes in the protein expression of cell metabolism pathways in AD and epilepsy cases. The shared molecular mechanisms should be investigated further to distinguish primary pathogenic changes from the secondary ones. These mechanisms could inform novel therapeutic strategies to prevent disease progression or restore normal function. A focus on dual-diagnosed AD/epilepsy cases, specific epilepsy syndromes, such as temporal lobe epilepsy, and changes across different severity levels in AD and epilepsy would add to our understanding.

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Section: Discussionmentioning

confidence: 99%

Localized proteomic differences in the choroid plexus of Alzheimer's disease and epilepsy patients

et al. 2023

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“…Dietary strategies can provide seizure control in patients who do not respond to antiseizure drugs ( Sills et al, 1986 ; Martin-McGill et al, 2020 ; Leitner et al, 2023 ). There are several types of dietary therapies, all of which are high in fat, to some extent restricted in carbohydrates, and associated with ketosis.…”

Section: Epilepsymentioning

confidence: 99%

Parkinson’s disease, epilepsy, and amyotrophic lateral sclerosis—emerging role of AMPA and kainate subtypes of ionotropic glutamate receptors

Vukolova,

Yen,

Khmyz

et al. 2023

Front. Cell Dev. Biol.

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Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission and are implicated in various neurological disorders. In this review, we discuss the role of the two fastest iGluRs subtypes, namely, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, in the pathogenesis and treatment of Parkinson’s disease, epilepsy, and amyotrophic lateral sclerosis. Although both AMPA and kainate receptors represent promising therapeutic targets for the treatment of these diseases, many of their antagonists show adverse side effects. Further studies of factors affecting the selective subunit expression and trafficking of AMPA and kainate receptors, and a reasonable approach to their regulation by the recently identified novel compounds remain promising directions for pharmacological research.

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“…[22][23][24] Similarly, the ketogenic diet, which shifts the body's energy metabolism from glucose-based to fat-based energy generation, has proven effective in treating drug-resistant childhood epilepsy and reducing the duration of SE in patients with super-refractory SE. [25][26][27] The benefits of the ketogenic diet may also stem from altered tryptophan-kynurenine metabolism and increased production of the N-methyl-d-aspartate (NMDA) receptor antagonist, kynurenic acid. 28 To date, there have been no metabolomic studies conducted in blood or CSF from adult patients with SE.…”

Section: Introductionmentioning

confidence: 99%

“…For instance, cholesterol‐lowering drugs could prevent harmful cholesterol accumulation in neurons after the onset of SE 22–24 . Similarly, the ketogenic diet, which shifts the body's energy metabolism from glucose‐based to fat‐based energy generation, has proven effective in treating drug‐resistant childhood epilepsy and reducing the duration of SE in patients with super‐refractory SE 25–27 . The benefits of the ketogenic diet may also stem from altered tryptophan–kynurenine metabolism and increased production of the N ‐methyl‐ d ‐aspartate (NMDA) receptor antagonist, kynurenic acid 28 …”

Section: Introductionmentioning

confidence: 99%

Metabolomic changes in adults with status epilepticus: A human case–control study

Hanin,

Chollet,

Demeret

et al. 2024

Epilepsia

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ObjectiveStatus epilepticus (SE) is a life‐threatening prolonged epileptic seizure that affects ~40 per 100 000 people yearly worldwide. The persistence of seizures may lead to excitotoxic processes, neuronal loss, and neuroinflammation, resulting in long‐term neurocognitive and functional disabilities. A better understanding of the pathophysiological mechanisms underlying SE consequences is crucial for improving SE management and preventing secondary neuronal injury.MethodsWe conducted a comprehensive untargeted metabolomic analysis, using liquid chromatography coupled with high‐resolution mass spectrometry (LC‐HRMS), on plasma and cerebrospinal fluid (CSF) samples from 78 adult patients with SE and 107 control patients without SE, including 29 with CSF for both groups. The metabolomic fingerprints were compared between patients with SE and controls. Metabolites with differences in relative abundances that could not be attributed to treatment or nutrition provided in the intensive care unit were isolated. Enrichment analysis was performed on these metabolites to identify the most affected pathways.ResultsWe identified 76 metabolites in the plasma and 37 in the CSF that exhibited differential expression in patients with SE compared to controls. The enrichment analysis revealed that metabolic dysregulations in patients with SE affected primarily amino acid metabolism (including glutamate, alanine, tryptophan, glycine, and serine metabolism), pyrimidine metabolism, and lipid homeostasis. Specifically, patients with SE had elevated levels of pyruvate, quinolinic acid, and keto butyric acid levels, along with lower levels of arginine, N‐acetylaspartylglutamate (NAAG), tryptophan, uracil, and uridine. The tryptophan kynurenine pathway was identified as the most significantly altered in SE, resulting in the overproduction of quinolinic acid, an N‐methyl‐d‐aspartate (NMDA) receptor agonist with pro‐inflammatory properties.SignificanceThis study has identified several pathways that may play pivotal roles in SE consequences, such as the tryptophan kynurenine pathway. These findings offer novel perspectives for the development of neuroprotective therapeutics.

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Metabolomic, proteomic, and transcriptomic changes in adults with epilepsy on modified Atkins diet

Cited by 5 publications

References 60 publications

Localized proteomic differences in the choroid plexus of Alzheimer's disease and epilepsy patients

Localized proteomic differences in the choroid plexus of Alzheimer's disease and epilepsy patients

Parkinson’s disease, epilepsy, and amyotrophic lateral sclerosis—emerging role of AMPA and kainate subtypes of ionotropic glutamate receptors

Metabolomic changes in adults with status epilepticus: A human case–control study

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