From the <a href="http://www.i-sis.org.uk/isisnews/i-sisnews9-25.php">Institute of Science in Society</a> journal, No 9/10 July 2001.

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Dietary Interventions for Alzheimer?s & Parkinson?s

While the hunt goes on for genes for Alzheimer?s and Parkinson?s, and ?cure? in the form of foetal cell transplant turned into nightmare, senior NIH scientist Richard Veech is developing a promising approach that will involve dietary intervention. Dr. Mae-Wan Ho puts us in the picture.

A team, headed by Richard Veech, senior scientist in the United States National Institutes of Health (NIH), has made discoveries that may lead to a simple, effective treatment for Alzheimer?s and Parkinson?s diseases. A metabolic shunt that feeds into the core metabolic cycle, can protect cultured neurons from the kinds of damages involved in those neurodegenerative diseases [1]. Veech was in exuberant, confident mood when I met him recently at a special workshop on the biophysics of aging, convened by gerontologist Dr. Walter Bortz in Berkeley.

Alzheimer?s disease affects 5 million and Parkinson?s disease about 500 000 in the United States. The incidence of Alzheimer?s is expected to increase as the population ages, as its prevalence rises from 2.5% of those at 65 years of age to 47% of those over 85 years of age. Patients lose recent memory; the neurotransmitter acetylcholine decreases in the brain, and neurons die in the part of the brain known as the hippocampus, where the protein fragment, Ab1-42, accumulate in characteristic plaques (patches). .Alzheimer?s disease is generally regarded as multi-factorial. Approximately 20% of cases appear related to abnormalities of Ab1-42 metabolism associated with genetic defects mapped to chromosome 1, 14, 19 or 21. That leaves at least 80% associated with other factors, which include brain trauma, ischemia (decreased blood flow) insulin resistance, or impairment of brain energy metabolism.

Parkinson?s disease symptoms include muscle rigidity and tremor of the hands, and is diagnosed by aggregates of the proteins a?synuclein and ubiquitin in neurons, and death of neurons that use the neurotransmitter dopamine in the part of the brain known as substantia nigra. The disease can be associated with genetic abnormalities, environmental toxins or infections, and can be treated, at least temporarily, by the drug L-dopa. Experimentally, a syndrome indistinguishable from Parkinson?s disease can be induced by the heroin analogue, 1-methyl-4-phenylpyridinium (MPP+), which is taken up by the dopamine transporter protein into the neurons. In the neurons, MPP+ inhibits the activity of NADH dehydrogenase, the first enzyme of the ?electron transport chain? in the mitochondria, which oxidises the metabolic products of glucose in a core cycle of reactions ? the tricarboxylic acid (TCA) cycle - that extract energy to power all living activities.

The brain uses a dis-proportionately large amount of energy for its weight, and it needs to extract it directly from glucose. The brain is unable to use fatty acids (breakdown products of fats) or amino acids (breakdown products of proteins), which can enter the TCA cycle through branch points in other tissues. <b>A metabolite the brain can use is ketones, which can feed directly into the TCA cycle.</b>

Richard Veech?s team found that <b>ketones protect neurons from both MPP+, which induces Parkinson?s disease, and the protein fragment A1-42, which accumulates in the brain of Alzheimer?s patients. Not only that, addition of ketones alone actually increased the number of surviving neurons from the hippocampus, suggesting that ketones may even act as growth factors for neurons in culture. </b>

The team?s work goes back to the 1990s, when they started using ?metabolic control analysis? (see Box) to study glucose metabolism in working rat hearts perfused with glucose, to which ketones or insulin or both have been added [2]. Insulin is a hormone that reduces glucose concentration in the blood, and deficiency of insulin is associated with type I diabetes.

Radioactive glucose was used to keep track of the rate at which glucose disappears and becomes transformed into different metabolites including glycogen (a storage product which is a large polymer of glucose). The results show that no single enzyme controls glucose metabolism. Instead, different enzymes are in control, depending on the prevailing conditions. For example, the heart works better in the presence of either ketones or insulin, but the combination of both ketones and insulin is no better than either alone. In the presence of glucose only, glycogen is broken down. With the addition of ketones, insulin or both, glycogen is synthesised. The concentrations of practically all the metabolites downstream of glucose are changed, many significantly, by the addition of ketones or insulin or both; as are the concentrations of the major energy intermediates, ATP and creatine phosphate.

At the same time, the effciency of the working heart increases by 25% in the presence of either insulin or ketones, and by 36% in the presence of both. The increase in efficiency is accompanied by dramatic changes in key metabolites in energy metabolism (those reactions leading directly to generating ATP in the mitochondria). The most interesting finding is that ketones appear to change the profile of energy metabolism in ways similar to insulin, which the researchers conclude, may have important clinical consequences. It has been shown previously that increase in blood ketones to levels observed after a 48h fast almost completely reversed the mitochondrial abnormalities associated with insulin deficiency. Moderate increases in circulating ketones, the authors suggest, "should be viewed as a beneficial compensation for insulin deficiency and perhaps also for geriatric patients or others with peroxidative damage to the processes of mitochondrial energy transduction" [4].<b> Could it be that ketones may also help type I diabetes?</b>

The next obvious step is phase I clinical trial in Alzheimer?s and Parkinson?s patients. The problem is that ketones can?t be taken directly because they are too acidic. A trimer (a molecule that consists of three ketones joined end to end) is neutral, and would be suitable as a food supplement. The bad news for Veech is: no drug company will make the stuff for him, while the institution Veech works for, the NIH, does not even consider his research worth funding in the mad dash for genetic causes of diseases and gene-based drug and interventions.

The good news is that the Navy will be funding the project, so the clinical trial will go ahead after all. Watch this space.

(For further details contact Dr. Veech, rveech~dicbr.niaaa.nih.gov).

1. Y, Takeshima T, Mori N, Nakashima K, Clarke K and Veech RL. D--Hydroxybutyrate protects neurons in models of Alzheimer?s and Parkinson?s disease. PNAS 2000: 97: 5440-4.
2. Kashiwaya Y, Sato K, Tsuchiya N, Thomas S, Fell DA, Veech RL and Passonneau JV. Control of glucose utilization in working perfused rat heart. Journal of Biological Chemistry 1994: 269: 25502-14.
3. See Kacser H. On parts and wholes in metabolism. In The Organization of Cell Metabolism (G.R. Welch and J.S. Clegg, eds), Plenum Publishing Corporation, 1987. For a more accessible account of metabolic control analysis, see Ho MW. Choreographer and dancer in Bioenergetics, S327 Living Processes, Bk 2 (M W. Ho ed.), Open University Press, Milton Keynes, 1995.
4. Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda GK, Chance B, Clarke K and Veech RL. Insulin, ketone bodies, and mmitochondrial energy trans-duction. The Faseb Journal 1995: 9: 651-8.

Thanks Kristine for posting that article. Richard Veech is the scientist that Gary Taubes spoke of in his New York Times article as saying that ketones are the heart and brain's preferred fuel.

I had read before that the heart preferred ketones, but this is the first evidence I've seen on the beneficial effects on the brain. It is very comforting as I had read in a college textbook and by low-carb dissenters that the brain does not function well without glucose.

Thanks again.

Here is the abstract by Dr. Veech:

IUBMB Life 2001 Apr;51(4):241-7

Ketone bodies, potential therapeutic uses.

Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr.

Unit on Metabolic Control, LMMB/NIAAA, Rockville, Maryland, USA.

Ketosis, meaning elevation of D-beta-hydroxybutyrate (R-3hydroxybutyrate) and acetoacetate, has been central to starving man's survival by providing nonglucose substrate to his evolutionarily hypertrophied brain, sparing muscle from destruction for glucose synthesis. Surprisingly, D-beta-hydroxybutyrate (abbreviated "betaOHB") may also provide a more efficient source of energy for brain per unit oxygen, supported by the same phenomenon noted in the isolated working perfused rat heart and in sperm. It has also been shown to decrease cell death in two human neuronal cultures, one a model of Alzheimer's and the other of Parkinson's disease. These observations raise the possibility that a number of neurologic disorders, genetic and acquired, might benefit by ketosis. Other beneficial effects from betaOHB include an increased energy of ATP hydrolysis (deltaG') and its linked ionic gradients. This may be significant in drug-resistant epilepsy and in injury and anoxic states. The ability of betaOHB to oxidize co-enzyme Q and reduce NADP+ may also be important in decreasing free radical damage. Clinical maneuvers for increasing blood levels of betaOHB to 2-5 mmol may require synthetic esters or polymers of betaOHB taken orally, probably 100 to 150 g or more daily. This necessitates advances in food-science technology to provide at least enough orally acceptable synthetic material for animal and possibly subsequent clinical testing. The other major need is to bring the technology for the analysis of multiple metabolic "phenotypes" up to the level of sophistication of the instrumentation used, for example, in gene science or in structural biology. This technical strategy will be critical to the characterization of polygenic disorders by enhancing the knowledge gained from gene analysis and from the subsequent steps and modifications of the protein products themselves

Y'know how I found this? I came across a livejournal thread where a gal mentioned that she's starting Atkins. Most of the comments she received were positive , but of course, some people "warned" her of the "dangers." One person wrote, "Keep this in mind: your brain requires glycogen to function properly. If your carbohydrate intake is low enough to induce ketosis, you are literally starving you brain for energy..." Gimme a break. So I did a google search trying to find the source of the idea that ketones are the preferred fuel. Voila.

Actually it has been used for years to control seizures in people (mainly kids) that are not able to control them with medication. That was my first knowledge of a ketogenic diet, because my daughter has seizures. I was surprised to learn that that was what the Atkins diet was! There's even a movie about it - "First Do No Harm", starring Meryl Streep.

It makes perfect sense that they would also help with other neurological disorders.