Primary And Secondary Outcomes
Primary outcomes were within and betweengroup changes in MDSUPDRS Parts 1 to 4 from the mean of the two baseline clinical visits to week 8 after commencing the diet intervention. Secondary outcomes were within and betweengroup changes in metabolic parameters, including weight, BMI, HbA1C, triglycerides, HDL, LDL, total cholesterol, urate, and CRP.
Environmental Toxins And Als
We recently spent 3 days at Shell Harbour just south of the Wollongong area and we loved it!
As beautiful as it was I couldnt help but be concerned about the toxins being released into the air from the steel production plants. Dr. Yerbury lives in the area and is conducting his research at the University of Wollongong. I know toxins play a role in many diseases and wondered about an ALS connection. I found this paper: Association of Environmental Toxins With Amyotrophic Lateral Sclerosis
I also shared that Im a total research geek and pretty passionate about the power of nutrition, lifestyle and environmental factors because this was how I was able to eliminate my own anxiety and panic attacks.
You can learn more about Dr. Yerbury and his publications here. We appreciate the work him and his research team are doing and thank him for sharing his story.
It would be wonderful if some of this information can help Dr. Yerbury and even be considered for future research by his very passionate research team. I also hope this information will be helpful for you or a loved one suffering with ALS or MND.
Study Selection And Features
We identified 63 publications in the bibliographical search that met the criteria inclusion for the present review . Scientific studies included in the systematic review were also included and described .
The aim of the 25 scientific studies was to ascertain the effectiveness of the ketogenic diet or low-carbohydrate diet in refractory epilepsy, GLUT1-DS, AD, and PD, although 6 experimental studies on new methods parallel to ketone-state induction were included the methods were triheptanoin therapy, the AAV-hSLC2A1 compound, the AC-1202 oral ketogenic compound, the oral administration of ketone monoester, diet with enantiomeric precursor of ketone bodies, and carbohydrate isocaloric diet and drink with emulsified MCT.,,,,,
Overall, 5 studies focused on refractory epilepsy, 8 focused on GLUT1-DS, 9 on AD, and 3 on PD. The studies selected included between 1 and 152 participants, which, although making it difficult to generalize the results, once again highlights that this is an emerging field of research that might perhaps provide major benefits.
The systematic reviews we used also ruled out the effectiveness of the ketogenic diet in the aforementioned diseases owing to the underlying neurophysiological processes that appear to be linked to mitochondrial function, oxidative stress, and inflammation. They also highlighted the need for more in-depth research into the subject.,,,
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Neurotransmitters And Ion Channel Regulation
- Ungerstedt U.
- Amark P.
Epilepsy Res.Neurochem. Int.Ann. Neurol.
J. Neurosci. Res.Neurochem. Int.Neurochem. Int.
Epilepsy Res.Epilepsy Res.
- Yellen G.
- Puhl III, H.L.
- Ikeda S.R.
J. Neurosci.Ann. Neurol.J. Neurochem.
J. Clin. Invest.J. Clin. Invest.
Ketogenic Diets And The Nervous System: A Scoping Review Of Neurological Outcomes From Nutritional Ketosis In Animal Studies
Published online by Cambridge University Press: 28 June 2021
- The University of Sydney, Faculty of Medicine and Health, Sydney, Australia
- Tara Field
- The New South Wales Ministry of Health , Sydney, Australia
- Fereshteh Pourkazemi
- The University of Sydney, Faculty of Medicine and Health, Sydney, Australia
- Kieron Rooney
- The University of Sydney, Faculty of Medicine and Health, Sydney, Australia
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Mitochondrial Dysfunction In The Pathogenesis Of Alzheimer’s Disease And Parkinson’s Disease
Studies on cognitively normal individuals with a maternal family history of AD, carriers of the AD-risk allele, ApoE4, and animal models suggest that one of the earliest recognizable features of AD is a decrease in cerebral glucose metabolism . Although the exact cascade of pathological events remains to be determined, and may vary among individuals, evidence suggests that a decrease in cGM may coincide with, or even precede, the preclinical deposition of amyloid . The AD-associated deficiency in cGM is attributable to impaired mitochondrial oxidative phosphorylation and is consistent with the observation that electron transport chain complex IV is less active than normal, both in diagnosed AD patients and in individuals at high risk for developing AD .
The PD brain is similarly characterized by a decrease in ATP levels and a corresponding decrease in electron transport chain protein function although, in PD, complex I activity is impaired . In fact, animal models of PD often rely on toxins that inhibit complex I to induce mitochondrial dysfunction and parkinsonism . Furthermore, not only are the environmental risk factors of PD associated with mitochondrial dysfunction, but all the major known risk genes for PD affect mitochondrial function, including SNCA, LRRK2, VPS35, GBA, CHCHD2, PINK1, Parkin, DJ-1, PLA2G6, ATP13A2, and FBXO7 .
Metabolic Changes Associated With The Use Of The Ketogenic Diet
In the course of the KD, the body modifies its metabolism to its fasting-related form. In the initial stage of the KD, blood glucose concentration lowers, and the insulin-to-glucagon ratio is decreased. A higher glucagon concentration leads to mobilization of glucose acquisition from its resources in the liver . Following two or three days of fasting or after a drastic reduction of carbohydrate supplementation in the diet , glycogenesis is suppressed and glucose reserves begin to be insufficient for the normal course of fat oxidation through the supply of oxaloacetate in the Krebs cycle , as well as to meet the demands of the Central Nervous System . Since CNS uses glucose as a primary energy source, after 23 days of fasting it has to identify an alternative source of energy, which is provided by the ketone bodies acetoacetate, 3-hydroxybutyrate, and acetone. The process of their production is called ketogenesis, and occurs mainly in the mitochondrial matrix of hepatic cells .
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Carbohydrate Restriction As A Protective Mechanism
A key aspect of the ketogenic diet is carbohydrate restriction. The role of decreased carbohydrates in neuroprotection has been investigated through the use of 2-deoxy-d-glucose , a glucose analog that is not metabolized by glycolysis. found that administration of 2-DG to adult rats at a nontoxic dose for 7 consecutive days produced dramatic protection against hippocampal damage and functional neurological deficits induced by the seizure-inducing excitotoxin kainate. In addition, 2-DG was protective against glutamate-induced and oxidative stress-induced neuronal death in cell culture. The authors also found that reduced glucose availability induces stress proteins, including GRP78 and HSP70, which they proposed act to suppress ROS production, stabilize intracellular calcium, and maintain mitochondrial function.
Search Strategy And Selection Criteria
The literatures analyses on the ketogenic diet in the context of neurodegenerative diseases was based on the principles of a structured literature review, a tool used in developing evidence-based knowledge in a rigorous and relevant way . Publications included in PubMed, the Cochrane Library, and Google Scholar were analyzed, including original research articles, meta-analyses, and systematic reviews. The searched terms were: ketogenic diet, neurodegenerative disease, Alzheimers disease, and Parkinsons disease, in combination with specific terms, such as metabolism, cognition, beta-hydroxybutyrate, acetoacetate, ketogenic formula, and medium chain triglyceride related to ketogenic diet complications and side effects. The review concentrated primarily on publications from the last 10 years, but also included highly regarded older publications.
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Alzheimer’s Disease And Ketogenic Diet
As in other chronic diseases, treatments for AD can be divided into two categories: symptomatic treatments and treatments that are potentially able to modify disease’s history . Despite some FDA approved drugs like acetyl cholinesterase inhibitors and memantine currently no effective treatment exists to prevent, modify, or stop AD. Most of the approved drugs for treatments only offer a moderate symptomatic effect . As for other diseases the development of effective treatments is hindered by the not complete knowledge of AD etiology even now that the amyloid cascade hypothesis has been extensively studied. This pathogenetic hypothesis is based on the neurotoxic characteristics of -amyloid and on its accumulation related initiation of a cascade of neurotoxic events, including not only the formation of well-known neurofibrillary tangles but also chronic inflammatory responses, an increase in oxidative stress, and in conclusion a mitochondrial dysfunction . The two major lesions in AD are caused by distinct proteins, tau in the case of the neurofibrillary tangles and amyloid -protein in the case of amyloid plaques.
Finally, even though there are no direct or strong evidence of the usefulness of KD in humans, this nutritional approach appears promising and so deserves further clinical extensive trials.
Effects On Programmed Cell Death
The ketogenic diet may also protect against various forms of cell death. For example, the diet was protective against apoptotic cell death in mice induced by the glutamate receptor agonist and excitotoxin kainate, as evidenced by reductions of markers of apoptosis, including terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling and caspase-3 staining, in neurons in the CA1 and CA3 regions of the hippocampus . Activation of caspase-3, a member of a larger family of cysteine proteases, has been implicated in neuronal cell death produced by different brain insults including seizures and ischemia . Apoptosis in seizure models can proceed via a number of molecular pathways . One molecule that may play a role is calbindin, which is increased in mice on the ketogenic diet . Calbindin is believed to have neuroprotective activity through its capacity to buffer intracellular calcium, which is a mediator of cell death . Further, protection by the ketogenic diet may be mediated by the prevention of kainic acid-induced accumulation of the protein clusterin , which can act as a prodeath signal .
How Is Parkinsons Treated
Parkinsons cannot be cured but the hope is that some symptoms can be alleviated. Currently, a number of medications are used to help curb progression and alleviate symptoms by manipulating dopamine.
- Entacapone . Tolcapone . Opicapone . Nitecapone
- Bromocriptine. Pergolide. Pramipexole. Ropinirole
- Safinamide. Selegiline. Rasagiline
Ketogenic Diet For Als
Here is some of the information I sent to Dr. Yerbury, explaining my work as a nutritionist working with women with anxiety using nutritional psychiatry approaches. Many of these nutritional psychiatry approaches such as the SMILES study have been spear-headed in Australia by Professor Felice Jacka.
Ive recently being looking at the growing research base on the ketogenic diet and mental health and when I saw his story on ABC my first thought was I wonder if there is research on ketogenic diets and ALS/MND? After a very quick search I found these papers:
Metabolism-based therapy has been used successfully in the treatment of seizures but study of its use in other neurodegenerative disorders is growing.
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Adverse Effects Of The Ketogenic Diet
A major problem in long-term use of the KD is the adherence of patients to dietary recommendations. High volumes of fat-rich components in the diet may lead to poor tolerance. Side effects may thus include nausea, vomiting, constipation, and lower appetite. In addition, dehydration, hepatitis, pancreatitis, hypoglycemia, hypertriglyceridemia, hyperuricemia, hypertransaminemia, hypercholestorolemia, hypomagnesemia, and hyponatremia are among the adverse effects of the KD. Late effects may include reduced mineral bone density, nephrolithiasis, cardiomyopathy, deficits of vitamins and mineral components, impaired hepatic functions, neuropathy of the optic nerve, anemia, and constipation or enhanced atherosclerosis .
In order to maintain proper blood glucose concentration levels in the course of KD application, the process of gluconeogenesis is enhanced, among others, by an increased secretion of glucocorticoids, glucagon, and the growth hormone. All this results in the increased catabolism of proteins and the use of glucogenic amino acids as glucose precursors. In consequence, there is an increased secretion of metabolism nitrogen products, so diuresis in enhanced to maintain a constant dilution of these metabolites in urine , while in persons with normal kidney function, it need not exert any negative effects on the body . However, it may be a problem for persons with renal impairment to excrete larger volumes of nitrogen metabolism waste products.
Ketogenic Diet In Neuromuscular And Neurodegenerative Diseases 2014 201: 474296br
An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson’s disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism to decrease the oxidative damage associated with various kinds of metabolic stress to increase the mitochondrial biogenesis pathways and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review.
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Enhancing Healthcare Team Outcomes
To counter the obesity epidemic, some healthcare workers do recommend the ketogenic diet. However, the primary care provider, nurse practitioner, dietitian, and internist need to be aware of a few facts.
Overweight individuals with metabolic syndrome, insulin resistance, and type 2 diabetes are likely to see improvements in the clinical markers of disease risk with a well-formulated very-low-carbohydrate diet. Glucose control improves due to less glucose introduction and improved insulin sensitivity. In addition to reducing weight, especially truncal obesity and insulin resistance, low-carb diets also may help improve blood pressure, blood glucose regulation, triglycerides, and HDL cholesterol levels. However, LDL cholesterol may increase on this diet.
Also, in various studies, the ketogenic diet has shown promising results in a variety of neurological disorders, like epilepsy, dementia, ALS, traumatic brain injury, acne, cancers, and metabolic disorders.
Due to the complexity of the mechanism and lack of long-term studies, a general recommendation of the ketogenic diet for prevention of type 2 diabetes mellitus or cardiovascular disease may seem premature but is, however, not farfetched for primary weight loss.
Weight Loss Benefits Of The Keto Diet
Even though the keto diet is a popular way to lose weight, research into how well it works is lacking. A 2004 critical review of previous studies found some evidence that following a high-protein diet may be more effective for weight loss than a low-fat diet.
But this doesnt mean that the high-fat keto diet is an effective way to lose weight, especially in the long term.
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Inside The Ketogenic Diet
After a few days of fasting or a drastic reduction in carbohydrate from the diet , glucose reserves become insufficient both for normal fat oxidation through the supply of oxaloacetate in the Krebs cycle and for the supply of glucose to the CNS .
Glucose is necessary not only to supply energy for the central nervous system but also to produce pyruvate that can be transformed into oxaloacetate. Oxaloacetate must be maintained at a level sufficient to allow citric acid cycle function . Oxaloacetate is unstable and must be refurnished . The main way to produce oxaloacetate is from pyruvate that derives from glucose. In mammals pyruvate cannot be produced from acetyl-CoA as shown in the figure.
Regarding point oxaloacetate is relatively unstable at body temperature and cannot be accumulated in the mitochondrial matrix thus, in this glucose deprivation condition, it is necessary to supply oxaloacetate for an efficient functioning of the tricarboxylic acid cycle. Oxaloacetate is supplied via the anaplerotic cycle that synthesizes it from glucose through ATP dependent carboxylation of pyruvic acid by pyruvate carboxylase .
Intermittent Fasting Metabolic Switching Brain Network Stability And Disease Prevention
It would be inappropriate to extrapolate from current clinical data that particular ketogenic interventions, while helping improve symptomology and disease markers in individuals already afflicted with neurodegenerative disease, would also help to prevent disease onset in individuals at risk for AD and PD. Given the growing popularity of ketogenic diets for brain health, even among individuals as young as their twenties, it is worth noting that no long-term trials on ketogenic interventions for complete neurocognitive disease prevention have yet been performed and, therefore, worth considering that promoting metabolic flexibility may be ideal for disease prevention. For example, intermittent fasting strategies that induce ketosis but also permit the body to switch on glucose metabolism in a cyclic manner can both activate ketosis-associated cellular repair and defense pathways, while also optimally promoting healthy anabolic processes, such as the growth of synapses, during periods of carbohydrate feeding . In the literature, this is commonly referred to as activating the metabolic switch. While there is no data yet comparing the safety or efficacy of chronic ketosis vs metabolic switching for neurodegenerative disease progression, it is logical to assume that the latter may come with certain to-be-discovered advantages for the simple reason that our species evolved to intermittent fast, rather than to chronically eat ketogenic diets or consume ketone supplements .
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Health Benefits Of The Keto Diet
What has been more closely studied is the idea that the keto diet can help people with epilepsy that doesnt respond to medication.
Findings from an 11-study review, published in the Cochrane Database of Systematic Reviews in 2003, suggest that the diet may reduce seizures and other symptoms of epilepsy. However, as these studies were fairly small in size , the results cant be taken as conclusive proof that the keto diet improves epilepsy symptoms.