Ok that makes sense. I understand more now. You are saying with only the methyb12 and other basics you ended up with some definite improvements in some ways but drove yourself into folate insufficiency that was made worse by folic acid and plant folates and only improved when you brought in sufficient levels of the deadlock quartet. Got it. I think you are mixing two things up here to reach your conclusion. You are assuming that fatty acids are used directly in brain energy metabolism because you and others feel better and think better on LCF. The two are not necessarily linked. Your brain / CNS and body are interconnected. If your body has more energy and vitality, your autonomic nervous system will be happier. And vice versa. There is often a false division when looking at clinical symptoms sometimes. The BBB prevents most fatty acids from getting across. The lipid regulation in the brain is very tight. Has to be. There are transport channels for choline and acetyl COA but not to be used for energy metabolism. More for myelin, membranes and acetylcholine formation, etc.. So yes fatty acids can help the CNS but is it NOT for energy. That is glucose and to a lesser extent ketones. I agree adb12 is important. But adb12 has importance to the health of the mitochondria and peroxynitite removal. I don't dispute the elevated MMAs in Parkinson's, et al. But that does not say anything about the primary metabolic aspects of neurons. Not even close. Also why do you never bring up the high levels of microglial activation and inflammation now know to be signatures of most of the CNS diseases you listed. You focus exclusively it seems on the MMA levels. Why not the inflammation? Can't that tie back into adb12 / BH4 and peroxynitite removal and the low MMAs are a correlative finding? As far as carnitine goes with the brain you cannot even ABSORB carnitine in the CNS unless either (a) it is acetyl-carnitne or (b) you have a very leaky BBB. However, if someone has a very leaky BBB, I have no idea how they will react to l-carnitine (note the fumarate will be long gone by the time anything gets past the leaky BBB). Will it be used as a primary pathway for energy metabolism? Dunno. Again inflammation and microglial activation is elevated also. And I am sorry again to have to re-iterate this but ... without a leaky BBB (which admittedly may be a big component of all of this) you cannot absorb LCF in the brain. It does not cross a healthy BBB. It just doesn't. Now why the LCF has such a dramatic effect on the limbic system as you have observed, I do not know. If it is not an indirect effect through the periphery (which is not impossible given how there is a big chunk of the ANS living in your abdomen) or it is not due to a leaky BBB ... then I don't know why. Btw I am not sure why you think I am dismissing anything. I am simply trying to understand things. Clinical trial and error is not enough for me being a physicist and bioinformatics professional. Sorry that is just the way I am built. Nor did I intend my simple response about the Krebs cycle and brain metabolism to in any way be considered adversarial. In fact my intent was to SUPPORT your idea that mitochondria in the brain are relevant. Let me repeat that: I was supporting you. I have no idea why Rich Vank would ever think mitochondria in the brain are not important for neuronal health. Of course they are. Is adb12 important? Sure. But your conjecture that adb12 is important BECAUSE of the MMA pathways alone is by no means a given. It simply is not going to be the primary adjunct to the Krebs cycle. It could be a block if too low but it will never be the main fuel ... that is all I was trying to say by those comments. Just like burning fatty acids is not the main fuel in the brain. If your only conclusion based on your clinical experiences and people's reaction to carnitine is that burning fatty acids in the brain will bolster the Krebs cycle or the MMA pathway being stimulated will power the TCA on its own ... well then let's just choose to disagree. What is so wrong with theory? Theory and experiment go hand in hand. Again I don't doubt your observations. I also NEVER in this or any other posts challenged your deadlock quartet idea. I find it quite attractive. I am just trying to understand why things happen. Is that so bad? Engineering is great but civilization would not have gotten very far if there wasn't theory as well to work with it. Anyways I already stated my points about adb12 and LCF with respect to the brain. L-carnitine is not absorbable through BBB unless the BBB is damaged ... which may very well be the case for many with CFS and is KNOWN to be the case with MS, ALS and is now being suspected with Parkinson's. The Omega 3s are important for sure. Ironically the DHA is a major component in BBB integrity. So ... maybe a leaky BBB is highly relevant to this discussion. Maybe people with a leaky BBB hyper-react to LCF at the limbic system level. Which if so means I am probably in for a rough ride since my Stiff Person Syndrome only occurs because of a leaky BBB, but that is a separate issue. No argument. I already posted how biotin affects the Krebs cycle since there seemed to be some confusion on the forums about it. Biotin plays a critical role in the brain. How else do you think the pyruvate from glycolysis gets into the Krebs cycle in the brain? I also agree that biotin can really speed things up and so there is an important balance with other factors. No doubt. Definitely is a good avenue for further research. As would any of the critical cofactors for entry into the Krebs cycle. Biotin though may be of more importance due to its pivotal role in the brain. Btw biotin is also now believed to be a critical cofactor for glutamine synthetase. That could be huge for the brain function as well. I am not sure why this even came up here. I have no clue why MCV is showing up here. I have no disagreement about your views of cycbl or hb12. Nor does what I am saying about the Krebs cycle and brain metabolism have anything whatsoever to do with cycbl or hb12 or their malignant use by the medical community. I am simply talking biochemistry. Ironically a new outsider reading your post would presume that I must disagree with everything that you propose. Huh? Far from that. So why all of this? No one said you have to prove anything. Thought this was an open forum with dialog. Understanding is important to many of us. Again my comments were to SUPPORT your side of the argument you had with Rich Vank in that brain mitochondria are directly relevant to neuronal health. Peace.