Medium-chain Triglyceride Supplementation Research Articles

Ketogenic diets composed of long-chain and medium-chain fatty acids induce cardiac fibrosis in mice

PurposeHeart diseases are the leading cause of death worldwide. Metabolic interventions via ketogenic diets (KDs) have been used for decades to treat epilepsy, and more recently, also diabetes and obesity, as common comorbidities of heart diseases. However, recent reports linked KDs, based on long-chain triglycerides (LCTs), to cardiac fibrosis and a reduction of heart function in rodents. As intervention using medium-chain triglycerides (MCTs) was recently shown to be beneficial in murine cardiac reperfusion injury, the question arises as to what extent the fatty acid (FA)-composition in a KD alters molecular markers of FA-oxidation (FAO) and modulates cardiac fibrotic outcome. MethodsThe effects of LCT-KD as well as an LCT/MCT mix (8:1 ketogenic ratio) on cardiac tissue integrity and the plasma metabolome were assessed in adult male C57/BL6NRJ mice after eight weeks on the respective diet. ResultsBoth KDs resulted in increased amount of collagen fibers and cardiac tissue was immunologically indistinguishable between groups. MCT supplementation resulted in i) profound changes in plasma metabolome, ii) reduced hydroxymethylglutaryl-CoA synthase upregulation, and mitofusin 2 downregulation, iii) abrogation of LCT-induced mitochondrial enlargement, and iv) enhanced FAO profile. Contrary to literature, mitochondrial biogenesis was unaffected by KDs. We propose that the observed tissue remodeling is caused by the accumulation of 4-hydroxy-2-nonenal protein adducts, despite an inconspicuous nuclear factor (erythroid-derived 2)-like 2 pathway. ConclusionWe conclude that regardless of the generally favorable effects of MCTs, they cannot inhibit 4-hydroxy-2-nonenal adduct formation and fibrotic tissue formation in this setting. Furthermore, we support the burgeoning concern about the effect of KDs on the cardiac safety profile.

Short- and long-term cognitive and metabolic effects of medium-chain triglyceride supplementation in rats

Medium-chain triglycerides (MCT) possess neuroprotective properties. However, the long-term metabolic consequences of supplementing a regular diet with cognition-enhancing doses of MCT are largely unknown. We studied the effects of chronic (28 days) supplementation of regular diet with different doses of MCT oil (1, 3, or 6 g/kg/day) or water (control) on working memory (Y-maze), behavior in the Open Field, spatial learning (Morris water maze), and weight of internal organs in male Wistar 2.5-m.o. Rats. In a separate experiment, we evaluated acute (single gavage) and chronic (28 days) effects of MCT or lard supplementation (3 g/kg) on blood biochemical parameters. MCT-1 and MCT-3 doses improved working memory in YM. In MWM, MCT-6 treatment improved spatial memory. Chronic MCT-1 or MCT-3 treatment did not affect internal organ weight, while MCT-6 dose increased liver weight and the brown/white adipose tissue ratio. Acutely, MCT administration elevated blood β-hydroxybutyrate and malondialdehyde levels. Chronic MCT administration (3 g/kg) did not affect the blood levels of glucose, lactate, pyruvate, acetoacetate, β-hydroxybutyrate, total and HDL cholesterol, triglycerides, malondialdehyde, and aspartate transaminase and alanine transaminase activities. Therefore, daily supplementation of standard feed with MCT resulted in mild intermittent ketosis. It improved working memory at lower concentrations without significant adverse side effects. At higher concentrations, it improved long-term spatial memory but also resulted in organ weight changes and is likely unsafe. These results highlight the importance of monitoring the metabolic effects of MCT supplementation alongside cognitive assessment in future studies of MCT's neuroprotective properties.

Brain energy rescue with ketones improves cognitive outcomes in MCI

AbstractBackgroundAn emerging strategy to delay the onset of Alzheimer disease (AD) is to use ketones to overcome the progressive brain energy deficit caused by deteriorating brain glucose metabolism in mild cognitive impairment (MCI). Ketones (acetoacetate and beta‐hydroxybutyrate) are the brain’s main alternative fuel to glucose; in contrast to glucose, ketone metabolism by the brain is now known to be unaffected in MCI and AD. Successful brain energy rescue with ketones in MCI was recently reported.MethodsIn the 6‐month, randomized, placebo‐controlled Benefic Trial (NCT02551419), the active arm was a ketogenic medium chain triglyceride (kMCT) supplement in a lactose‐free skim milk emulsion (15 g kMCT twice/day; n = 39 completers). The placebo arm was a non‐ketogenic iso‐energetic vegetable oil (n = 44 completers). Brain ketone and glucose metabolism were assessed by PET.ResultsPerformance on all five cognitive domains improved significantly over 6 months in the kMCT group: (i) Episodic memory (trial 1, Free and Cued Recall Test) increased by 1 word (+0.5 Δ Z‐score); (ii) Executive function (Verbal Fluency Test) correct answers increased by 2 words (+0.3 Δ Z‐score) but decreased by 1 word on placebo (‐0.1 Δ Z‐score), time taken on the Stroop Colour Naming Test decreased by 1 sec (p = 0.09), and errors on the Trail Making Test increased by 0.8 on placebo (p = 0.02); (iii) Language (Boston naming test) correct answers increased by 1.3 words. (iv) Processing speed increased directly with higher brain ketone uptake in several white matter tracts. (v) Improved attention was directly associated with increased ketone uptake and functional connectivity in the dorsal attention network.ConclusionsImproved cognition correlating positively with improved brain energy supply by ketones suggests a direct link to brain energy status. The moderate effect size of this kMCT intervention indicates a clinically meaningful benefit on certain cognitive outcomes, some of which relate directly to risk of MCI progressing to AD. Other potential ketogenic interventions that have been less well studied in MCI or AD include a ketogenic diet and ketone salts or esters. Whether brain energy rescue with ketones can delay the onset or progression of AD should now be assessed.

Medium-chain triglycerides may improve memory in non-demented older adults: a systematic review of randomized controlled trials

BackgroundKetosis has been exploited for its neuroprotective impact and treatment of neurological conditions via ketone production. Exogenous medium-chain triglyceride (MCT) supplementation may induce nutritional ketosis. The aim of this systematic review is to explore the effects of MCTs on memory function in older adults without cognitive impairment.MethodsA systematic literature search of PubMed, Cochrane Library, Scopus, and Web of Science was employed from inception until April 2022 for randomized controlled trials (RCTs) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, investigating the impact of MCT oils on components of memory. Risk of bias (RoB2) tool was utilized for quality assessment.ResultsSix trials were included for qualitative synthesis, in which two studies examined the effect of MCTs through a ketogenic meal. MCT supplementation compared to controls was associated with improved indices of memory function in 4 out of 6 studies, particularly working memory. A meta-analysis was not employed due to the low number of studies, therefore, a true effect measure of MCT supplementation was not explored.ConclusionsMCT supplementation may enhance working memory in non-demented older adults. These effects may be more prominent in individuals with lower baseline scores, from short and long-term supplementation. Further studies are warranted to confirm these findings in terms of optimal dose and MCTs composition, which may protect from memory decline during aging.

Metabolic fingerprinting of dogs with idiopathic epilepsy receiving a ketogenic medium-chain triglyceride (MCT) oil.

Consumption of medium-chain triglycerides (MCT) has been shown to improve seizure control, reduce behavioural comorbidities and improve cognitive function in epileptic dogs. However, the exact metabolic pathways affected by dietary MCT remain poorly understood. In this study, we aimed to identify changes in the metabolome and neurotransmitters levels relevant to epilepsy and behavioural comorbidities associated with the consuming of an MCT supplement (MCT-DS) in dogs with idiopathic epilepsy (IE). Metabolic alterations induced by a commercial MCT-DS in a population of 28 dogs with IE were evaluated in a 6-month multi-centre, prospective, randomised, double-blinded, controlled cross-over trial design. A metabolic energy requirement-based amount of 9% MCT or control oil was supplemented to the dogs' stable base diet for 3 months, followed by the alternative oil for another 3 months. A validated, quantitative nuclear magnetic resonance (NMR) spectroscopy platform was applied to pre- and postprandially collected serum samples to compare the metabolic profile between both DS and baseline. Furthermore, alterations in urinary neurotransmitter levels were explored. Five dogs (30%) had an overall reduction in seizure frequency of ≥50%, and were classified as MCT-responders, while 23 dogs showed a ≤50% reduction, and were defined as MCT non-responders. Amino-acid metabolism was significantly influenced by MCT consumption compared to the control oil. While the serum concentrations of total fatty acids appeared similar during both supplements, the relative concentrations of individual fatty acids differed. During MCT supplementation, the concentrations of polyunsaturated fatty acids and arachidonic acid were significantly higher than under the control oil. β-Hydroxybutyric acid levels were significantly higher under MCT supplementation. In total, four out of nine neurotransmitters were significantly altered: a significantly increased γ-aminobutyric acid (GABA) concentration was detected during the MCT-phase accompanied by a significant shift of the GABA-glutamate balance. MCT-Responders had significantly lowered urinary concentrations of histamine, glutamate, and serotonin under MCT consumption. In conclusion, these novel data highlight metabolic changes in lipid, amino-acid and ketone metabolism due to MCT supplementation. Understanding the metabolic response to MCT provides new avenues to develop better nutritional management with improved anti-seizure and neuroprotective effects for dogs with epilepsy, and other behavioural disorders.

S3465 Protein-Losing Enteropathy Associated With SHOC2 Gene Mutation in Noonan-Like Syndrome

Introduction: Protein-losing enteropathy (PLE) is the abnormal loss of protein through the gastrointestinal tract and has been associated with many diseases. The group of disorders including Noonan syndrome and Noonan-like syndromes (NS) consist of various dysmorphic features and congenital abnormalities. Multiple gene mutations paired with diverse phenotypic presentations have made identifying relationships between genotype and phenotype challenging, particularly with PLE in NS. In rare cases, PLE has been reported with NS, but few genetic associations have been made. Our case describes a possible connection between PLE and the SHOC2 gene mutation. Case Description/Methods: A 21-year-old female with a history of NS presented to our outpatient clinic with lower extremity edema and diarrhea with four watery bowel movements per day for 3 months. Labs revealed albumin of 2.4 g/dL, creatinine of 0.35 mg/dL, and potassium of 3.1 mEq/L. Acute hepatitis panel and anti-tissue transglutaminase were negative. Stool studies were positive for Clostridioides difficile and she was treated with oral vancomycin. She had an unremarkable esophagogastroduodenoscopy and colonoscopy. Computed tomography enterography suggested altered lymphatic drainage, and a lymphangiogram showed abdominal collateral lymphatics and iliac lymphangiectasia. Overall, these findings were consistent with PLE. A high protein diet and medium-chain triglyceride supplementation were initiated, and she had normalization of serum albumin levels. Genetic analysis showed a SHOC2 gene mutation. Discussion: PLE consists of loss of serum proteins through the digestive tract, which may initially present as hypoalbuminemia in the absence of liver disease. This disorder is important to recognize due to the association between low albumin and increased mortality risk. Lymphatic disease presenting with lymphedema, chylothorax, and lymphangiectasia is well known in NS and may play a role in PLE development. PLE has been tied to the mutation of protein tyrosine phosphatase non-receptor type 11, but to our knowledge, has not been reported with SHOC2 mutation. Because little is understood about PLE in NS, there is no standard treatment. However, supplementation with medium-chain triglycerides and periodic albumin infusions has proven effective. The association between PLE and NS may be more common than acknowledged. This case identifies SHOC2 mutation with PLE and encourages consideration of PLE in NS in hopes of decreasing mortality and increasing quality of life.

Chyle Leak After Axillary Node Clearance in Breast Cancer Surgery—A Rare Complication and a Proposed Management Strategy from the British and Italian Experience

Chyle leak after axillary surgery is a rare complication that lacks consensus and management guidelines. This study aimed to present the experiences of two centers in chyle leak management after axillary node clearance for breast cancer. Furthermore the authors provide a review of its pathophysiology and clinical diagnostic methods. They compare approaches for management of the axilla with those for other locations. A multicentre case series descriptive analysis of chyle leak after breast cancer axillary node clearance between 1 January 2013 and 31 May 2020 was performed. The center in the United Kingdom and the center in Italy performed 655 and 4969 axillary node clearances, respectively. Four patients experienced chyle leaks. All the leaks had left-sided surgery (3 patients had level 3 clearances with mastectomy and implant-based breast reconstructions; 1 patient had level 2 clearance with therapeutic mammoplasty). All the leaks appeared within 3 days after surgery. Leak duration was between 11 and 29 days. The maximum daily output was 600 mL. All the leaks were treated conservatively with nutritional team support together with close drainage monitoring. The management strategy included a low-fat diet, a high-protein diet, total parenteral nutrition, and medium chain triglyceride supplements, as well as other elements. No negative effects on oncoplastic and reconstructive breast surgery wound-healing and no delays in adjuvant treatment were observed. The incidence of chyle leak after breast cancer axillary node clearance was 0.07%. Early diagnosis and close monitoring together with conservative management involving nutritional team support can result in successful treatment of chyle leak without negative sequalae of breast cancer oncologic treatment.

Supplementation of Regular Diet With Medium-Chain Triglycerides for Procognitive Effects: A Narrative Review.

It is now widely accepted that ketosis (a physiological state characterized by elevated plasma ketone body levels) possesses a wide range of neuroprotective effects. There is a growing interest in the use of ketogenic supplements, including medium-chain triglycerides (MCT), to achieve intermittent ketosis without adhering to a strict ketogenic diet. MCT supplementation is an inexpensive and simple ketogenic intervention, proven to benefit both individuals with normal cognition and those suffering from mild cognitive impairment, Alzheimer's disease, and other cognitive disorders. The commonly accepted paradigm underlying MCT supplementation trials is that the benefits stem from ketogenesis and that MCT supplementation is safe. However, medium-chain fatty acids (MCFAs) may also exert effects in the brain directly. Moreover, MCFAs, long-chain fatty acids, and glucose participate in mutually intertwined metabolic pathways. Therefore, the metabolic effects must be considered if the desired procognitive effects require administering MCT in doses larger than 1 g/kg. This review summarizes currently available research on the procognitive effects of using MCTs as a supplement to regular feed/diet without concomitant reduction of carbohydrate intake and focuses on the revealed mechanisms linked to particular MCT metabolites (ketone bodies, MCFAs), highlighting open questions and potential considerations.

Cross Sectional Survey of Canine Idiopathic Epilepsy Management in Primary Care in the United Kingdom.

The aims of this study are to gain insight on how primary care veterinarians in the UK diagnose and treat canine idiopathic epilepsy (IE) and what they perceive as challenges in the management of canine IE. Two hundred and thirty-five primary care veterinarians took part in this survey. The questionnaire asked about the type of practice the respondent worked in, any relevant post-graduate qualifications, how many years' experience they had in practice and the participant's canine IE caseload. Participants were asked how they diagnose canine IE, how they select antiseizure drugs (ASDs) and how they assess outcome. The questionnaire also explored which information sources they have access to for deciding on canine IE treatment, challenges that may be faced when managing these cases and areas in which more support can be provided. 94.5% of participants (n = 222/235) managed <10 canine IE cases in a year and 87.8% (n = 206/235) used phenobarbital as their first line ASD. The reported mean initial phenobarbital dose was 2.1 mg/kg (standard deviation = 0.71) every 12 h. When considering how closely participants aligned with IVETF guidelines on the topics of diagnosis, ASD initiation and outcome assessment, on average participants would score around half of the available points. 53.2% (n = 125/235) of respondents recommended neutering in canine IE and 46.8% (n = 110/235) did not. 53.2% (n = 125/235) did not recommend any additional treatments for canine IE beyond use of ASDs. 23.4% recommended Purina Neurocare diet (n = 55/235), 12.8% recommended environmental modification (n = 30/235), and 6.8% (n = 16/235) recommend medium chain triglyceride supplements. In this study participants found managing client expectations to be most challenging alongside canine IE emergency management. The main limitation of this study is the relatively low response rate and therefore the results may not reflect the entire small animal veterinary profession in the UK. However, the results of this study represent a starting point to inform educational resources and support strategies to improve quality care of canine IE in primary care.

Minimal Effects of Medium-Chain Triglyceride Supplementation on the Intestinal Microbiome Composition of Premature Infants: A Single-Center Pilot Study.

Compared to term infants, the microbiota of preterm infants is less diverse and often enriched for potential pathogens (e.g., members of the family Enterobacteriaceae). Additionally, antibiotics are frequently given to preterm infants, further destabilizing the microbiota and increasing the risk of fungal infections. In a previous communication, our group showed that supplementation of the premature infant diet with medium-chain triglyceride (MCT) oil reduced the fungal burden of Candida spp. in the gastrointestinal tract. The objective of this study was to determine whether MCT supplementation impacts the bacterial component of the microbiome. Pre-term infants (n = 17) receiving enteral feedings of either infant formula (n = 12) or human milk (n = 5) were randomized to MCT supplementation (n = 9) or no supplementation (n = 8). Fecal samples were taken at randomization and prior to MCT supplementation (Week 0), on days 5–7 (Week 1) and day 21 (Week 3). After DNA extraction from samples, the QIIME2 pipeline was utilized to measure community diversity and composition (genera and phyla). Our findings show that MCT supplementation did not significantly alter microbiota diversity or composition in the gastrointestinal tract. Importantly, there were no significant changes in the family Enterobacteriaceae, suggesting that MCT supplementation did not enrich for potential pathogens. MCT holds promise as a therapeutic intervention for reducing fungal colonization without significant impact on the bacterial composition of the host gastrointestinal tract.

Impact of medium-chain triglycerides on gait performance and brain metabolic network in healthy older adults: a double-blind, randomized controlled study.

Nutritional supplementation with medium-chain triglycerides (MCTs) has the potential to increase memory function in elderly patients with frailty and dementia. Our aim was to investigate the effects of MCT on cognitive and gait functions and their relationships with focal brain metabolism and functional connectivity even in healthy older adults. Participants were blindly randomized and allocated to two groups: 18g/day of MCT oil and matching placebo formula (control) administered as a jelly stick (6g/pack, ingested three times a day). Gait analysis during the 6-m walk test, cognition, brain focal glucose metabolism quantified by 18F-fluorodeocyglucose positron emission tomography, and magnetic resonance imaging-based functional connectivity were assessed before and after a 3-month intervention. Sixty-three healthy, normal adults (females and males) were included. Compared with the control group, the MCT group showed better balance ability, as represented by the lower Lissajous index (23.1 ± 14.4 vs. 31.3 ± 18.9; P < 0.01), although no time × group interaction was observed in cognitive and other gait parameters. Moreover, MCT led to suppressed glucose metabolism in the right sensorimotor cortex compared with the control (P < 0.001), which was related to improved balance (r = 0.37; P = 0.04) along with increased functional connectivity from the ipsilateral cerebellar hemisphere. In conclusion, a 3-month MCT supplementation improves walking balance by suppressing glucose metabolism, which suggests the involvement of the cerebro-cerebellar network. This may reflect, at least in part, the inverse reaction of the ketogenic switch as a beneficial effect of long-term MCT dietary treatment.

Acute and Chronic Effects of Intermittent Ketosis Established by Medium-Chain Triglyceride Supplementation on Cognitive and Metabolic Parameters in Rats

Acute and Chronic Effects of Intermittent Ketosis Established by Medium-Chain Triglyceride Supplementation on Cognitive and Metabolic Parameters in Rats

Primary Intestinal Lymphangiectasia in a Middle-Aged Female.

Primary intestinal lymphangiectasia (PIL) is a rare disorder caused by impaired intestinal lymphatic drainage due to congenital lymphatic hypoplasia. It was first described by Waldman et al. in 1961,[1] about 205 cases have been reported.[2] The disease usually manifests before 3 years of age, and only occasionally diagnosed in adulthood. Here, we report a case of a middle-aged female who presented with chronic diarrhea and was finally diagnosed as a case of PIL. A 49-year-old female presented to the Outpatient Department of our hospital with complaints of diarrhea for 2 years. The patient reported an occurrence of diarrhea four to five times daily, which was semisolid to watery in consistency with absence of blood, mucus, or oil. The diarrhea was also not associated with tenesmus, urgency, or pain in the abdomen. On examination, her body mass index was 18 kg/m2 and there was presence of bilateral pitting edema in the lower limbs. Routine laboratory investigation revealed hemoglobin of 9 gm/dl, total leukocyte count of 4100/mm3 with 14% of lymphocytes, platelet count of 1.6 lakh/mm3 and hypoproteinemia (serum protein, 3.90 gm/dl; serum albumin, 2.10 gm/dl; serum globulin, 1.8 gm/dl). She was non-reactive for HIV and hepatitis B. Stool routine and microscopic examination was negative on three occasions and culture was negative. Upper gastrointestinal endoscopy revealed multiple scattered whitish spots in the second part of the duodenum [Figure 1]. Multiple biopsies from it revealed dilated lymphatic channels in lamina propria, muscularis mucosae and submucosa [Figure 2]. Therefore, a diagnosis of intestinal lymphangiectasia (IL) was made and further work up was done to rule out secondary causes. Her colonoscopy with terminal ileoscopy, contrast-enhanced computed tomography of chest and abdomen, echocardiography, autoimmune profile, immunoglobulin levels and hormonal profile were all normal except for reduced immunoglobulin levels. Accordingly, a final diagnosis of PIL was made and the patient was started on a low-fat, high-protein diet with medium-chain triglyceride (MCT) supplementation. Subsequently, her condition improved, and the diarrhea stopped after 1 month. The upper gastrointestinal endoscopy was repeated after 6 months, and the findings were normal with no whitish spots in the duodenum [Figure 3].Figure 1: Upper gastrointestinal endoscopy showing whitish spots in the second part of duodenumFigure 2: Duodenal biopsy showing dilated lacteals in mucosa and submucosaFigure 3: Normal upper gastrointestinal endoscopy after 6 months of dietary modificationPIL is a congenital malformation that presents with chronic diarrhea and malabsorption and is diagnosed after ruling out secondary causes. Its late onset can be explained by the patchy involvement of the small bowel. Secondary intestinal lymphangiectasia can occur due to various causes such as constrictive pericarditis, intestinal lymphoma, intestinal tuberculosis, sarcoidosis, scleroderma, Whipple's disease, Crohn's disease, autoimmune polyglandular syndrome and radiation or chemotherapy induced retroperitoneal fibrosis.[3] Intestinal lymphangiectasia in adults has few or no features of malabsorption, as in our case. Its diagnosis is done by specific endoscopic features and corresponding histopathological findings. Endoscopic features of intestinal lymphangiectasia are scattered white punctate snowflake lesions in small intestine due to dilated lacteals that cannot be washed away. Upper gastrointestinal endoscopy can diagnose 86% of intestinal lymphangiectasia cases.[4] Histopathology of small bowel will show characteristic dilated lacteals in the mucosa and submucosa. The cornerstone of its treatment is diet modification. Diet should be low in fat with substitution of long chain fatty acid with MCT, as it directly enters the portal venous system bypassing the intestinal lacteal system, thereby preventing lacteal engorgement and rupture.[5] Most of the patient respond with this treatment in few weeks with reversal of clinical and biochemical signs. In conclusion, PIL is a rare cause of chronic diarrhea, especially in adulthood, that requires meticulous examination of duodenum, as early diagnosis and treatment can reduce the morbidity and mortality. Declaration of patient consent The authors certify that they have obtained all appropriate consent forms from the patient. The patient has given her consent for images and other clinical information to be reported in the Journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal the identity. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

The possibility of use of the ketogenic diet and medium chain triglycerides supplementation in the support therapy of Alzheimer disease.

Diet-induced ketosis has a fasting-like effect and brings the body to increase the production of ketone bodies (KB). Works over the last decades have provided evidence of the therapeutic potential of the ketogenic diet (KD). This review focus on mainly clinical research on the effectiveness of the KD and medium-chain triglycerides (MCT) supplementation in ameliorating the severity of symptoms in Alzheimer disease (AD). A limited number of clinical studies (short-time and with a small number of participants) evaluated the role of the KD and MCT supplementation in AD as a potential dietary intervention in the therapy of this disease. These studies report that the application of KD or/and MCT supplements to older people reduces symptoms of AD. MCT supplements allow achieving an increased level of KBs in the blood even with a greater supply of carbohydrates in the diet and without any drastic changes in the habitual diet of patients. The recent literature highlights the potential benefit of using diet-induced ketosis as an additional element of therapy in AD. Since persons with AD are at risk of malnutrition, the use of KD raises certain concerns due to side effects, especially for long periods of time. MCT supplements to obtain similar clinical results without the need for drastic changes in the diet of patients.

New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.

Carnitine acyl-carnitine translocase deficiency (CACTD) is a rare autosomal recessive disorder of mitochondrial long-chain fatty-acid transport. Most patients present in the first 2 days of life, with hypoketotic hypoglycaemia, hyperammonaemia, cardiomyopathy or arrhythmia, hepatomegaly and elevated liver enzymes. Multi-centre international retrospective chart review of clinical presentation, biochemistry, treatment modalities including diet, subsequent complications, and mode of death of all patients. Twenty-three patients from nine tertiary metabolic units were identified. Seven attenuated patients of Pakistani heritage, six of these homozygous c.82G>T, had later onset manifestations and long-term survival without chronic hyperammonemia. Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15). Where recorded, ammonia levels were elevated in all but one severe case (13/14 measured) and 14/16 had hypoglycaemia. Nine classical patients survived longer-term-most with feeding difficulties and cognitive delay. Hyperammonaemia appears refractory to ammonia scavenger treatment and carglumic acid, but responds well to high glucose delivery during acute metabolic crises. High-energy intake seems necessary to prevent decompensation. Anaplerosis utilising therapeutic d,l-3-hydroxybutyrate, Triheptanoin and increased protein intake, appeared to improve chronic hyperammonemia and metabolic stability where trialled in individual cases. CACTD is a rare disorder of fatty acid oxidation with a preponderance to severe cardiac dysfunction. Long-term survival is possible in classical early-onset cases with long-chain fat restriction, judicious use of glucose infusions, and medium chain triglyceride supplementation. Adjunctive therapies supporting anaplerosis may improve longer-term outcomes.

Effects of Timing of Medium-Chain Triglycerides (8:0 and 10:0) Supplementation during the Day on Muscle Mass, Function and Cognition in Frail Elderly Adults.

Supplementation with 6 g/day of medium-chain triglycerides (MCTs) at dinnertime increases muscle function and cognition in frail elderly adults relative to supplementation with long-chain triglycerides. However, suitable timing of MCT supplementation during the day is unknown. We enrolled 40 elderly nursing home residents (85.9 ± 7.7 years) in a 1.5-month randomized intervention trial. Participants were randomly allocated to two groups: one received 6 g/day of MCTs at breakfast (breakfast group) as a test group and the other at dinnertime (dinner group) as a positive control group. Muscle mass, strength, function, and cognition were monitored at baseline and 1.5 months after initiation of intervention. Thirty-seven participants completed the study and were included in the analysis. MCT supplementation in breakfast and dinner groups respectively increased right arm muscle area from baseline by 1.1 ± 0.8 cm2 (P<0.001) and 1.6 ± 2.5 cm2 (P<0.001), left arm muscle area by 1.1 ± 0.7 cm2 (P<0.001) and 0.9 ± 1.0 cm2 (P<0.01), right knee extension time by 39 ± 42 s (P<0.01) and 20 ± 32 s (P<0.05), leg open and close test time by 1.74 ± 2.00 n/10 s (P<0.01) and 1.67 ± 2.01 n/10 s (P<0.01), and Mini-Mental State Examination score by 1.5 ± 3.0 points (P=0.06) and 1.0 ± 2.1 points (P=0.06). These increases between two groups did not differ statistically significantly. Supplementation with 6 g MCTs/day for 1.5 months, irrespective of ingestion at breakfast or dinnertime, could increase muscle mass and function, and cognition in frail elderly adults.

The effect of a 6-month ketogenic medium-chain triglyceride supplement on plasma cardiometabolic and inflammatory markers in mild cognitive impairment.

IntroductionMild cognitive impairment (MCI) is often accompanied by metabolic abnormalities and inflammation that might play a role in the development of cognitive impairment. The use of ketogenic medium-chain triglycerides (kMCT) to improve cognition in this population has shown promising results but remains controversial because of the potentially detrimental effect of elevated intake of saturated fatty acids on cardiovascular (CV) health and perhaps inflammatory processes. The primary aim of this secondary data analysis report is to describe changes in cardiometabolic markers and peripheral inflammation during a 6-month kMCT intervention in MCI. MethodsThirty-nine participants with MCI completed the intervention of 30 g/day of either a kMCT drink or calorie-matched placebo (high-oleic acid) for 6 months. Plasma concentrations of cardiometabolic and inflammatory markers were collected before (fasting state) and after the intervention (2 h following the last drink). ResultsA mixed model ANOVA analysis revealed a time by group interaction for ketones (P < 0.001), plasma 8:0 and 10:0 acids (both P < 0.001) and IL-8 (P = 0.002) with follow up comparison revealing a significant increase in the kMCT group (+48%, P = 0.005), (+3,800 and +4,900%, both P < 0.001) and (+147%, P < 0.001) respectively. A main effect of time was observed for insulin (P = 0.004), triglycerides (P = 0.011) and non-esterified fatty acids (P = 0.036). ConclusionUnder these study conditions, 30 g/d of kMCT taken for six months and up to 2-hour before post-intervention testing had minimal effect on an extensive profile of circulating cardiometabolic and inflammatory markers as compared to a placebo calorie-matched drink. Our results support the safety kMCT supplementation in individuals with MCI. The clinical significance of the observed increase in circulating IL-8 levels is presently unknown and awaits future studies.

Improved brain energetics and cognition after a 6‐month ketogenic intervention in mild cognitive impairment: Final results of the Benefic Trial

AbstractBackgroundKetones can partially substitute for glucose as a brain fuel and may be beneficial for cognition in older people. The objective of the randomized, placebo‐controlled Benefic Trial (NCT02551419) was to assess whether counteracting the brain energy (glucose) deficit with a ketogenic medium chain triglyceride (kMCT) supplement could improve cognitive performance in mild cognitive impairment (MCI).MethodsA cognitive battery was used to screen for MCI and cognitive outcomes after the intervention. Cognitive outcomes pre‐ and post‐intervention were obtained for the active arm (15 g kMCT twice/day in a lactose‐free skim milk emulsion; n=39 completers) and placebo arm (non‐ketogenic vegetable oil of equivalent energy value and formulation as for the kMCT; n=44 completers). Brain ketone and glucose PET were done before and at the end of the 6‐month intervention on a sub‐group of both arms (n=19/group).ResultsSeveral cognitive domains improved post‐intervention in the kMCT group (p≤0.01; ANCOVA; age and education as covariates). Specifically, Trial 1 of the Free and Cued Recall Test showed a +1 word improvement on kMCT (+0.5 Δ Z‐score), correct answers on the Verbal Fluency Test increased by 2 words on kMCT (+0.3 Δ Z‐score) but decreased by 1 word on placebo (‐0.1 Δ Z‐score), correct answers on the Boston Naming Test increased by 1.1 on kMCT only, time taken on the Stroop Colour Naming Test decreased by 1 sec on the kMCT (p=0.09), and errors on the Trail Making Test decreased by 0.9 on kMCT but increased by 0.8 on placebo (p=0.02). Brain ketone uptake increased in the kMCT arm only and directly as the increase in plasma ketones (r = 0.87, p&lt;0.01). Average drop‐out rate on both arms was 31% and, in completers, protocol adherence was 89% over six months.ConclusionsIn MCI, a kMCT supplement had a clinically meaningful effect on some cognitive outcomes directly related to risk of progression toward Alzheimer’s disease, and significantly improved brain energy supply. It is feasible for an MCI population to consume a kMCT supplement daily for six months. Acknowledgements: Financial support was provided by the Alzheimer Association USA, FRQS, Université de Sherbrooke and Nestlé Health Science.

A phase 1B multiple ascending dose study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of a medium chain triglyceride supplement in Alzheimer’s disease

AbstractBackgroundImpaired brain glucose metabolism is a prominent and early feature across neurodegenerative disorders, including Alzheimer’s disease (AD). Elevating brain ketones to bypass this metabolic failure is an emerging therapeutic strategy, with promising results in AD and Mild Cognitive Impairment (MCI). The Medium Chain Triglyceride Intervention in AD (MINT‐AD) is a randomized, placebo‐controlled Phase 1b trial investigating the pharmacokinetics and pharmacodynamics of a ketogenic supplement in Alzheimer’s disease (AD). It also explores outcome measures to support the development of larger ketogenic trials for this disorder.MethodPatients (n=32) with a clinical diagnosis of with mild‐moderate AD (MMSE 16‐26) were randomized at 4:1 to twice daily medium chain triglyceride drink (MCT – 60% C8, 40% C10) prepared as a 12% emulsion in lactose‐free milk, or placebo. A total of four dose groups were recruited, with doses ranging from 5 grams twice daily up to 25 grams twice daily, for a total of 18 days (including 8‐day drug titration). Primary outcome measures were safety, tolerability and pharmacodynamics effects of MCT supplementation on plasma ketones, and the pharmacokinetics of the MCT supplement. Exploratory outcome measures included N‐acetyl aspartate and glutamine/glutamate MR spectroscopy, functional resting brain connectivity, brain blood flow (arterial spin labeling), continuous actigraphy, ambulatory sleep EEG, and cognitive measures.ResultA total of 30 participants (94%) completed the study, with 2 subjects discontinuing early. MCT supplement up to 25 grams twice daily was safe and well tolerated in patients with mild‐moderate AD. Peak plasma ketones was seen around 4 hours post MCT ingestion. Exploratory cognitive and imaging measures are currently being analyzed and will be presented.ConclusionKetogenic MCT supplementation is safe and well tolerated in AD, with reasonably predictable pharmacokinetic and ketogenic properties. These data exploring a larger dose range should inform dose selection in future trials with MCT supplementation.

Medium-chain triglycerides dietary supplement improves cognitive abilities in canine epilepsy

ObjectiveCognitive impairments (CI) have recently been identified in canine epilepsy patients. A medium-chain triglyceride (MCT) enriched diet has been demonstrated to improve cognition in aged dogs and seizure control in canine epilepsy. This study evaluates the short-term effects of MCT-oil consumption on cognitive abilities in dogs with epilepsy, a naturally occurring animal model. MethodsA 6-month multicenter, prospective, randomized, double-blinded, controlled cross-over diet trial was conducted comparing dietary supplementation (DS) of MCT oil to a control oil. Allocation to dietary oil supplements, consisting of 9% total caloric intake, was block-randomized and supplemented into each dogs’ diet for 3 months followed by a respective switch of DS-oil for a further 3 months. Noninvasive cognitive tests and a validated psychometric tool were utilized to evaluate cognitive function and perturbations associated with dietary intervention. ResultsTwenty-nine dogs completed the trial, of which 18 completed noninvasive cognitive testing. Spatial-working memory (P = 0.008), problem-solving ability (P = 0.048), and owner-reported trainability (P = 0.041) were significantly improved during MCT-oil supplementation compared to control-DS. SignificanceMCT-oil DS improves cognition in dogs with epilepsy when compared to a control-DS. MCT supplementation may represent a promising option to address CI associated with epilepsy.