Ketogenic Dietary Therapy Controversies for Its Second Century

Kossoff, Eric H.; Cervenka, Mackenzie C.

doi:10.1177/1535759719890337

Cited by 13 publications

(12 citation statements)

References 36 publications

(44 reference statements)

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“…The potential of using ketogenic supplements as a complemental strategy to carbohydrate restriction is discussed as ketogenic diet therapies are increasingly investigated in conditions beyond epilepsy (Kossoff and Cervenka, 2020 ), which include MCI/AD (Krikorian et al, 2012 ; Taylor et al, 2018 ; Brandt et al, 2019 ; Nagpal et al, 2019 ; Neth et al, 2020 ; Phillips et al, 2021 ). In a previous publication from the current clinical trial (Norgren et al, 2020b ), we demonstrated that supplementation with kMCT and time-restricted feeding regarding carbohydrates provide two—optionally additive—strategies to induce transient ketosis in older adults following their normal diet.…”

Section: Discussionmentioning

confidence: 99%

“…Ketogenic diets—which are based on strict carbohydrate restriction—have been used as a treatment for epilepsy since the 1920's (Kossoff and Cervenka, 2020 ), and are increasingly investigated in other neurological conditions, including Alzheimer's Disease (AD) (Stafstrom and Rho, 2012 ; Taylor et al, 2019 ). Induction of the metabolic state ketosis, characterized by increased circulating levels of the ketone body β-hydroxybutyrate (BHB), is a hallmark of ketogenic diets (Volek et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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Serum proBDNF Is Associated With Changes in the Ketone Body β-Hydroxybutyrate and Shows Superior Repeatability Over Mature BDNF: Secondary Outcomes From a Cross-Over Trial in Healthy Older Adults

Norgren

Daniilidou

Kåreholt

et al. 2021

Front. Aging Neurosci.

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Background: β-hydroxybutyrate (BHB) can upregulate brain-derived neurotrophic factor (BDNF) in mice, but little is known about the associations between BHB and BDNF in humans. The primary aim here was to investigate whether ketosis (i.e., raised BHB levels), induced by a ketogenic supplement, influences serum levels of mature BDNF (mBDNF) and its precursor proBDNF in healthy older adults. A secondary aim was to determine the intra-individual stability (repeatability) of those biomarkers, measured as intra-class correlation coefficients (ICC).Method: Three of the arms in a 6-arm randomized cross-over trial were used for the current sub-study. Fifteen healthy volunteers, 65–75 y, 53% women, were tested once a week. Test oils, mixed in coffee and cream, were ingested after a 12-h fast. Labeled by their level of ketosis, the arms provided: sunflower oil (lowK); coconut oil (midK); caprylic acid + coconut oil (highK). Repeated blood samples were collected for 4 h after ingestion. Serum BDNF levels were analyzed for changes from baseline to 1, 2 and 4 h to compare the arms. Individual associations between BHB and BDNF were analyzed cross-sectionally and for a delayed response (changes in BHB 0–2 h to changes in BDNF at 0–4 h). ICC estimates were calculated from baseline levels from the three study days.Results: proBDNF increased more in highK vs. lowK between 0 and 4 h (z-score: β = 0.25, 95% CI 0.07–0.44; p = 0.007). Individual change in BHB 0–2 h, predicted change in proBDNF 0–4 h, (β = 0.40, CI 0.12–0.67; p = 0.006). Change in mBDNF was lower in highK vs. lowK at 0–2 h (β = −0.88, CI −1.37 to −0.40; p < 0.001) and cumulatively 0–4 h (β = −1.01, CI −1.75 to −0.27; p = 0.01), but this could not be predicted by BHB levels. ICC was 0.96 (95% CI 0.92–0.99) for proBDNF, and 0.72 (CI 0.47–0.89) for mBDNF.Conclusions: The findings support a link between changes in peripheral BHB and proBDNF in healthy older adults. For mBDNF, changes differed between arms but independent to BHB levels. Replication is warranted due to the small sample. Excellent repeatability encourages future investigations on proBDNF as a predictor of brain health.Clinical Trial Registration:ClinicalTrials.gov, NCT03904433.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serum proBDNF Is Associated With Changes in the Ketone Body β-Hydroxybutyrate and Shows Superior Repeatability Over Mature BDNF: Secondary Outcomes From a Cross-Over Trial in Healthy Older Adults

Norgren

Daniilidou

Kåreholt

et al. 2021

Front. Aging Neurosci.

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“…In addition, recent studies have alerted of potential side effects (Cai et al, 2017), including an increase in serum lipidemia with concomitant increased risk of cardiovascular alterations (Zamani et al, 2016), higher risk of bone mass reduction (Simm et al, 2017), long-term alterations in the immune system (Goldberg et al, 2020), or increased probabilities for cardiac fibrosis (Xu et al, 2021). Because of these potential adverse effects, and the difficulty to adhere to the diet, different dietary formulations are being proposed to achieve a therapeutic effect with a more tolerable nutritional intervention (Dallérac et al, 2017;Kossoff and Cervenka, 2020). Furthermore, the anti-seizure efficacy in patients treated with ketogenic diets is not always replicated in experimental rodent models, which hampers research on the underlying molecular mechanisms (Holmes, 2008), This is probably due to biological differences in metabolic rates and in cellular responses to KBs between humans and rodents, as well as to the fact that ketosis is tightly controlled in humans to avoid dangerous situations, whereas mice and rats fed a ketogenic diet are allowed to eat ad libitum.…”

Section: Discussionmentioning

confidence: 99%

Ketone Bodies in the Brain Beyond Fuel Metabolism: From Excitability to Gene Expression and Cell Signaling

García-Rodríguez

Giménez-Cassina

2021

Front. Mol. Neurosci.

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Ketone bodies are metabolites that replace glucose as the main fuel of the brain in situations of glucose scarcity, including prolonged fasting, extenuating exercise, or pathological conditions such as diabetes. Beyond their role as an alternative fuel for the brain, the impact of ketone bodies on neuronal physiology has been highlighted by the use of the so-called “ketogenic diets,” which were proposed about a century ago to treat infantile seizures. These diets mimic fasting by reducing drastically the intake of carbohydrates and proteins and replacing them with fat, thus promoting ketogenesis. The fact that ketogenic diets have such a profound effect on epileptic seizures points to complex biological effects of ketone bodies in addition to their role as a source of ATP. In this review, we specifically focus on the ability of ketone bodies to regulate neuronal excitability and their effects on gene expression to respond to oxidative stress. Finally, we also discuss their capacity as signaling molecules in brain cells.

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“…When conducted properly, a ketogenic diet is tolerated [ 27 ] and it can induce an increased number of patients achieving seizure freedom over time [ 14 , 28 ]. Then, a correct management of the ketogenic diet is also important to avoid side effects [ 16 , 17 , 19 ], controversies [ 29 ], and, in some cases, a phenomenon known as the rebound effect [ 30 ], which is characterised by a paradoxical seizure worsening [ 31 ]. Thus, the initiation and maintenance of the dietary treatment are the result of concomitant efforts of paediatric neurologists/epileptologists, dieticians, families and other patients’ caregivers [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of E-Health Applications for Paediatric Patients with Refractory Epilepsy and Maintained on Ketogenic Diet

et al. 2021

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E-health technologies improve healthcare quality and disease management. The aim of this study was to develop a ketogenic diet management app as well as a website about this dietary treatment and to evaluate the benefits of giving caregivers access to various web materials designed for paediatric patients with refractory epilepsy. Forty families participated in the questionnaire survey, from January 2016 to March 2016. All caregivers were exposed to paper-based materials about the ketogenic diet, whereas only 22 received the app, called KetApp, and videos produced by dieticians. Caregivers with free access to web materials were more satisfied than the others with the informative material provided by the centre (p ≤ 0.001, Mann–Whitney test). Indeed, they showed a better attitude towards treatment, and they became more aware of dietary management in comparison to the control group (p ≤ 0.001). Moreover, caregivers provided with web materials were stimulated to pursue the treatment (p = 0.002) and to introduce it to their children and other people (p = 0.001). Additionally, caregivers supplied with web materials were more willing to help other families in choosing the ketogenic diet (p = 0.004). Overall, these findings indicate that web materials are beneficial for caregivers of paediatric patients with refractory epilepsy in our centres. Thus, the use of e-health applications could be a promising tool in the daily aspects of ketogenic diet management, and it is especially of value in the attempt to start or maintain the diet during the ongoing COVID-19 pandemic crisis.

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Ketogenic Dietary Therapy Controversies for Its Second Century

Cited by 13 publications

References 36 publications

Serum proBDNF Is Associated With Changes in the Ketone Body β-Hydroxybutyrate and Shows Superior Repeatability Over Mature BDNF: Secondary Outcomes From a Cross-Over Trial in Healthy Older Adults

Serum proBDNF Is Associated With Changes in the Ketone Body β-Hydroxybutyrate and Shows Superior Repeatability Over Mature BDNF: Secondary Outcomes From a Cross-Over Trial in Healthy Older Adults

Ketone Bodies in the Brain Beyond Fuel Metabolism: From Excitability to Gene Expression and Cell Signaling

Evaluation of E-Health Applications for Paediatric Patients with Refractory Epilepsy and Maintained on Ketogenic Diet

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