Mar 09 2017

Alzheimer’s and Stem Cells

ADA recent article in The Mercury News reports on the work of a neurosurgeon who is injecting fat-derived stem cells into the brains of Alzheimer’s patients. The reports is, unfortunately, typical. It revolves around a heart-wrenching anecdote, while giving the facts with the usual false balance.

This is the perfect storm for dubious treatments – Alzheimer’s disease (AD) is a progressive dementia that causes sufferers to slowly lose their memories and ability to think. It is a growing problem with our aging population. There are some modest symptomatic treatments for AD but nothing which alters the course of the disease, or can stop or reverse it.

There is no doubt that the need for an effective treatment is great, but that does not justify lower the standards of science in medicine. If anything it means we have to be more careful.

Added to this is the hype and allure of stem cells, which are progenitor cells that can turn into specific cell types. The general idea with stem cell therapy is that the stem cells will replace damaged or dying cells, repair organs, and reverse disease. This is tricky technology, however, and as is common the hype is running ahead of the science. That is a recipe for exploitation and quackery. Fake stem cell clinics have popped up around the world, promising cures but just robbing the desperate of their remaining health and large amounts of money.

Stem cell medicine is legitimate science but needs to be researched properly. It is not easy to get stem cells to do what we want. They may not develop into the kind of cell we need, or “take up shop” and start functioning. They may not survive long, or they may just turn into tumors. The science is progressing, but we are a long way from stem cells as a panacea.

The Mercury News article focuses on neurosurgeon, Christopher Duma. He is taking fat cells from patients, deriving stem cells from the fat, and then injecting them unaltered into the brains of Alzheimer’s patients. This is a very crude use of stem cells. They are not neuronal stem cells, destined to become brain tissue. It seems highly implausible that just dumping fat stem cells into the brain will accomplish anything useful, let alone reverse the brain-wide degeneration of AD.

If Duma thinks he is onto something, or just wants to try a hail-Mary pass for a desperate disease, then the proper thing to do would be to start with animal studies. Do some plausibility testing.  Yes, it takes time, but the time is well-invested. Yes it takes money and resources, but you get those resources by convincing someone that you have a scientifically sound idea.

Duma, according to the article, tried to get IRB approval for a study without animal testing but was denied. Another lab did rat testing for him, to test for safety, and this did earn him IRB approval for a Phase I study. These are generally feasibility and safety studies but not efficacy trials. He did not have funding for the study, however.  He apparently charged Jack Sage (the patient featured in the article) $10,000 each for eight treatments of stem cells as part of the Phase I study (not covered by insurance). It is generally considered unethical to charge a patient for an experimental treatment.

The News article spends a lot of time recounting how well Sage is doing. His memory and function are improving, which should not happen with AD. They make passing reference to the placebo effect, but that does not seem to explain the improvement they are describing.

The article makes passing mention of this:

Shankle, a renowned expert in cognitive disease – he is the author of the Memory Performance Index that is used around the world – diagnosed Sage with two problems: Alzheimer’s disease and hydrocephalus (fluid on the brain). Sage needed a shunt in his brain to drain the fluid and relieve the pressure.

So Sage received a shunt to treat the hydrocephalus in addition to the stem cells injections. You see the obvious problem here? How do we know that the alleged improvement in Sage is not entirely due to treating the hydrocephalus. Duma says that Sage was a perfect subject, but this would make him a terrible subject. Hydrocephalus can cause dementia, and a shunt can cure the hydrocephalus and reverse the dementia. The article, however, does not point this out or even ask about it, just mentions the shunt in passing.

Conclusion

From the article it seems we have a well-meaning neurosurgeon pursuing a treatment for AD that has some plausibility, but not much. It is more than a bit of wishful thinking to believe that unaltered fat-derived stem cells are going to have any significant clinical effect on AD. If only it were that easy.

But if he thinks there is some potential here I would expect him to be pristine in conducting proper research. This is an invasive procedure, and patients and their families will be desperate. He does hope to get a grant and then he can waive the fee for subjects, but he should have done that for the Phase I study.

The Mercury News article is a huge part of the problem here. The article is designed to give false hope to patients while providing just enough false balance to give plausible deniability.

The bottom line is that a Phase I study is not news for the public. Most treatments at the Phase I level will not pan out. This is the level where treatment ideas should be discussed and debated among researchers and experts. If, for some reason, a science reporter thinks that such preliminary evidence is news-worthy, then you better do a great job putting the evidence and the treatment into context, which they did not do here.

33 responses so far

33 Responses to “Alzheimer’s and Stem Cells”

  1. Lane Simonianon 09 Mar 2017 at 11:01 am

    If it were only so simple as replacing dead neurons with stem cells. But there are many other problems in Alzheimer’s disease including the scarcity of neurotransmitters needed for the retrieval of short-term memory, sleep, mood, social recognition, and alertness, synaptic dysfunction, mitochondrial dysfunction, damage to tau proteins needed for neurotransmissions, the inadequate flow of blood in the brain and limited transport of glucose which can lead to delusions, and high levels of psychological stress which can lead to hallucinations. It is difficult to see how stem cell therapy can address all of these problems. And in any case, the olfactory bulb and the hippocampus are the two parts of the brain in which neurons can be regenerated on their own. Unfortunately, the pathway by which this process occurs (the phosphatidylinositol 3-kinase/Akt pathway) is blocked in Alzheimer’s disease. Unblock the pathway and you likely do not need stem cell therapy.

    The damage outlined above is the result of nitration, oxidation, lipid peroxidation, and DNA damage done by peroxynitrite (ONOO-).

    http://www.genome.jp/kegg/pathway/hsa/hsa05010.html

    The pathway to the formation of peroxynitrite early in Alzheimer’s disease is protein kinase C activation and NMDA receptor overactivation.

    http://www.frontiersin.org/files/Articles/131867/fncel-09-00091-HTML/image_m/fncel-09-00091-g003.jpg

    Various forms of amyloid, psychological stress, environmental toxins (various air pollutants, pesticides, industrial toxins, and mercury, for instance), chronic heavy smoking, and an unhealthy diet (a diet high in sugar, carbohydrates, salt, and high fructose corn syrup) are among several of many factors that activate protein kinase C alpha early in Alzheimer’s disease. Without protein kinase C alpha and the subsequent oxidative stress there is no Alzheimer’s disease:

    “Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.”

    As Alzheimer’s disease continues, protein kinase C activity often decreases as a result of damage to upstream receptors (receptor tyrosine kinases and g protein-coupled receptors). Then the progression of the disease depends on the following: NMDA receptor overactivation, peroxynitrite formation, perpetual NMDA receptor activation (in part because peroxynitrite prevents the transport and uptake of glutamate).

    The key to treating the disease is the following:

    Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer’s Disease: Understanding the Therapeutics Strategies

    “We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

    In conclusion, through this review, we have tried to give our perspective on the wide variety of interaction between NMDAR-mediated oxidative stresses with the etiology of Alzheimer’s disease. NMDAR-mediated oxidative stress mechanisms are likely to play an important role in the synapse dysfunction in the pathogenesis of AD. Moreover, mitochondrial-mediated oxidative stress and apoptosis are also suggested to be contributing factors in AD pathogenesis. Furthermore, oxidative stress-mediated kinase and tau phosphorylation provides a connection of synapse dysfunction in AD. As we are not getting complete remedies from antioxidant therapy or known NMDAR antagonist drug used for AD pathology, should we go for combinational therapy? Or are there so many intermediate molecules between NMDAR to neurodegeneration? Should we go for target intermediate molecules? Therefore, understanding the role of oxidative stress-associated molecule and kinases in synapse dysfunction during AD pathogenesis may also lead to the development of mechanism-based therapeutics and better constructive strategies.”

    The best peroxynitrite scavengers limit neuronal cell death by removing glutamate from NMDA receptors (excitotoxicity). This includes but is certainly not limited to cannabidiol, eugenol (in various essential oils via aromatherapy), ferulic acid in Korean red ginseng and heat processed ginseng, and in rice bran oil and Angelica archangelica (Feru-guard). This is precisely why many of these compounds have helped to partially reverse cognitive decline in small-scale clinical trials in Alzheimer’s disease (and by partially blocking beta-adrenergic 1 receptors ferulic acid has also led to improvements in neuropsychiatric problems in people with Alzheimer’s disease, dementia with Lewy Bodies, and frontotemporal lobe dementia).

    The pathways leading to Alzheimer’s disease are relatively clearly laid out and at least some of the compounds that intervene in those pathways are known. Find better compounds either in natural products or in synthetic drugs and one can likely do even better.

  2. Nareedon 09 Mar 2017 at 2:01 pm

    “If only it were that easy”

    Those are words to live by. Much of the problem with science reporting is that it tends to skip the difficulties inherent in research, and more important in applied science like medicine and engineering.

    Granted these tend to be technical, and don’t make for good reading necessarily, but they should be mentioned. Asimov did rather well pointing them out, without going into details, in his science popularization essays.

  3. Fair Persuasionon 09 Mar 2017 at 3:15 pm

    Jack Sage is a walking medical experiment with 12 heart stints, a shunt and extra insertion of his fat cells in the brain. The Mercury News states that this insertion of extra fat cells into the brain for surgical purposes has been a surgical standard since the 1920s. Dr. Duma states that he is doing nothing new. Can anyone expound on this surgical technique which has been around about 100 years?

  4. tb29607on 09 Mar 2017 at 3:58 pm

    FP,
    During neurosurgical procedures the covering of the brain (dura mater) is cut. Afterwards spinal fluid leaks out of the incision in his covering and the flow of fluid prevents healing. In order to prevent spinal fluid leakage and allow healing some fat tissue is placed at the incision site. This is very different from injecting cells into the ventricle of the brain which can only be accomplished by pushing a needle through brain tissue.

  5. hardnoseon 09 Mar 2017 at 6:53 pm

    “It is a growing problem with our aging population.”

    Of course. Blame it on age. Can’t be the toxic drugs or the poison food and water.

  6. chikoppion 09 Mar 2017 at 10:06 pm

    [hardnose] Of course. Blame it on age. Can’t be the toxic drugs or the poison food and water.

    The epidemiology is clear. Every 5 years over the age of 65 the risk of Alzheimer’s approximately doubles. Therefore, the statement, “It is a growing problem with our aging population,” is a true statement. Nothing in this article “blames Alzheimer’s on age” or speaks to the precipitating factors in any way.

  7. Fair Persuasionon 10 Mar 2017 at 10:39 am

    Thanks tb29607 for a clear explanation of the surgical procedure. Based on Dr. Duma’s technique, the addition of fat mass to the brain would prevent the brain’s natural shrinkage with old age. Radiology could reveal a large new brain mass after surgery with the fat implant. But for a functional brain mass, the hypothesis for stem neuron cells to be planted in the ventricles might work.

  8. Fair Persuasionon 10 Mar 2017 at 11:17 am

    Perhaps the stem neuron cells could be pushed through the ventricles to a specific location within the brain for functional effectiveness. I would not want to create a brain clog.

  9. Fair Persuasionon 10 Mar 2017 at 11:55 am

    I have not read anywhere that Duma diagnosed Jack Sage’s Alzheimer’s disease with a proper brain biopsy. Only with accurate diagnosis based on biopsy could you attempt medical treatment. His neurosurgical operation did not address any form of Alzheimer’s disease. I believe the frontal cortex would be the area of medical interest for Alzheimer’s disease.

  10. Fair Persuasionon 10 Mar 2017 at 2:07 pm

    How do we rule out the Sage heart attack in 2016 from Duma’s experimental brain injections? Jack Sage’s brain is the command center for his body.

  11. BillyJoe7on 10 Mar 2017 at 3:27 pm

    FP,

    “I have not read anywhere that Duma diagnosed Jack Sage’s Alzheimer’s disease with a proper brain biopsy. Only with accurate diagnosis based on biopsy could you attempt medical treatment”

    Alzheimers Disease is a clincal diagnosis and it is treated without a confirming brain biopsy.

  12. Lightnotheaton 10 Mar 2017 at 4:01 pm

    chikoppi-
    I think what hardnose was trying to say was that Dr. Novella was implying that the increased incidence of Alzheimer’s, rather than the disease itself, was due to an increase in the elderly population. While hardnose was suggesting that it was instead due to certain toxins in our food and water, about which he presumably thinks that Dr. Novella and others like him are in denial. I say I THINK that’s what he meant, with hardnose it’s often hard to tell. In any case, I’m wondering what the data is on that. Does the increase in Alzheimer’s roughly match the increase in the elderly population? If not, what are the prevailing scientific theories about why it is getting more (or less) prevalent?

  13. Fair Persuasionon 10 Mar 2017 at 10:02 pm

    @BillyJoe7

    Alzheimer’s Disease requires brain biopsy for a definitive diagnosis.

  14. Fair Persuasionon 10 Mar 2017 at 10:51 pm

    Shankle’s Memory Performance Index is not able to diagnose the underlying pathology leading to cognitive impairment. The reporter for the Mercury News failed his readers by reporting false information.

  15. BillyJoe7on 11 Mar 2017 at 12:10 am

    FP,

    “Alzheimer’s Disease requires brain biopsy for a definitive diagnosis”

    Yes, a DEFINITIVE diagnosis of Alzheimer’s Disease requires a brain biopsy.
    But a brain biopsy, if done at all, is performed only as part of a post-mortem examination.

    To be clear: a patient is diagnosed with – and treated for – Alzheimer’s Disease on the basis of symtoms, blood and urine tests, and various types of brain scans.
    But not by performing a brain biopsy.

    In other words, the following statement you made is false:

    “Only with accurate diagnosis based on biopsy could you attempt medical treatment”

    No big deal, just correcting a false impression you have.

  16. BillyJoe7on 11 Mar 2017 at 12:11 am

    Sorry, I forgot the link: https://www.nia.nih.gov/alzheimers/topics/diagnosis

  17. BillyJoe7on 11 Mar 2017 at 12:34 am

    FP,

    “Shankle’s Memory Performance Index is not able to diagnose the underlying pathology leading to cognitive impairment. The reporter for the Mercury News failed his readers by reporting false information”

    I think you’re reaching a bit here.
    The reporter does not claim that the MPI is able to distinguish between causes of dementia.
    He says that Shankle – the author of the Memory Performance Index that is used around the world – diagnosed Sage with Alzheimer’s disease.
    You are assuming that the reporter is implying that he did this solely on the basis of his MPI test.
    That assumption is unwarranted.
    Here is the direct quote:

    “Shankle, a renowned expert in cognitive disease – he is the author of the Memory Performance Index that is used around the world – diagnosed Sage with two problems: Alzheimer’s disease and hydrocephalus (fluid on the brain)”

    You seem to be hung up on irrelevant issues in this thread for some reason.

  18. Steven Novellaon 11 Mar 2017 at 7:04 am

    Alzheimer’s disease is indeed a pathological diagnosis, usually made at autopsy.

    The clinical diagnosis is Alzheimer’s type dementia, which means you clinically have a chronic global dementia and other causes have been ruled out. The terms are often lazily conflated.

    AD is not confined to the frontal lobes. It affects the whole brain. There is a distinct dementia type called frontotemporal dementia.

    Treating based on the clinical diagnosis is reasonable and is the standard of care. A clinical trial would not require a brain biopsy.

  19. BillyJoe7on 11 Mar 2017 at 9:36 am

    Interesting…none of the sites I looked at (including the National Institutes of Aging) distinguish between “Alzheimers’s Disease” and “Alzheimer’s type dementia”. The initial diagnosis, based on symtoms, is “Dementia” and then, as a result of blood tests and scans, it is narrowed down to subtypes like “Alzheimer’s type dementia”, “Lewy Body Disease” (or should that be “Lewy Body Type Dementia”?), “Fronto-Temporal Lobe Dementia” and “Vascular Dementia”. However, the patients with “Alzheimer’s Type Dementia” are almost invariably referred to as having “Alzheimer’s Disease”. Anyway…you learn something new every day!

  20. Lane Simonianon 11 Mar 2017 at 12:47 pm

    The two parts of the brain most affected by Alzheimer’s disease are the hippocampus and the frontal cortex. There are no certain biomarkers for the disease, but declining levels of glutathione–the brain’s master antioxidant–may turn out to be the best one. As oxidative stress increases glutathione levels decline and as glutathione levels decline oxidative stress increases.

    Glutathione: a molecular whistleblower for Alzheimer’s disease

    One phenomenon that has gained a strong foothold as a lead player in Alzheimer’s pathology is ‘oxidative stress’. Oxidative metabolism – the process that yields all cells the energy required for survival – produces highly reactive oxidative byproducts, which if not curtailed wreak absolute havoc on a neuronal cell. To defuse these oxidizing products, the brain cells manufacture antioxidants, which act to police and neutralize these rabble-rousers. The predominant of these brain antioxidants – Glutathione aka GSH– has long been indirectly implicated in Alzheimer’s…

    The hippocampi – the brain centres for learning and memory – are one of the earliest regions to be sabotaged by Alzheimer’s pathology. Our data revealed that GSH levels plummet in the hippocampi of patients with Alzheimer’s as well as those with MCI. The frontal cortices – brain CEOs responsible for a variety of executive functions – are chronologically affected later in Alzheimer’s. GSH levels mimic this chronology with no changes in the cortices of MCI [mild cognitive impairment] patients, but significant reduction in those of Alzheimer’s patients. Interestingly, GSH remains unaffected in the cerebellum – a brain region unaffected by Alzheimer’s till late stages. It appears GSH decline is not ubiquitous but rather a region-specific phenomenon that appears to precisely map the progression of Alzheimer’s in our brains.

    Could it then be that GSH levels would be able to act like a detector test for MCI and Alzheimer’s? It appears that may well be the case. Using only GSH levels in the hippocampi and frontal cortices as indicators, we were able to differentiate between healthy subjects and MCI patients as well as between patients with MCI and Alzheimer’s with a remarkably high accuracy.

    The answer would again seem simple–just increase glutathione levels in the brain, but glutathione does not enter cells well and the transport of one of its key precursor molecules–cysteine–is inhibited in Alzheimer’s disease. Certain bacteria in yogurt increase glutathione levels so that is potentially an option. The other option is to increase levels of antioxidants that as closely as possible mimic the effects of glutathione.

  21. Lane Simonianon 11 Mar 2017 at 1:55 pm

    The factors that lower glutathione levels also increase the risk for Alzheimer’s disease:

    “Unfortunately, a rogue’s gallery of culprits is waiting to rob you of your supply of glutathione. Common threats to glutathione levels include environmental toxins and pollution, pharmaceutical and over-the-counter medications, poor diet, trauma, infection and stress.”

  22. BillyJoe7on 11 Mar 2017 at 5:18 pm

    I’m pretty sure no one else is actually reading Lane Simonian’s “contributions” here, but just to put you in the picture, his post at 12:47pm is, apart from his short introductory paragraph, a direct quote from here:

    https://atlasofscience.org/glutathione-a-molecular-whistleblower-for-alzheimers-disease/

    Although it is pretty obvious that his “contribution” is a direct quote, I consider it to deceitful to post direct quotes without using actual quotation marks or without attribution of the source of the quote.
    As it turns out the site from which he obtained his quote is described as follows:

    “Atlas of Science was started by scientists to promote the dissemination of scientific research. We believe that the spread of the latest scientific results, and in particular the researcher’s own interpretation of these results could be more efficient.
    Atlas of Science provides the opportunity for scientists to write and publish a short and accessible summary of their latest research. The summaries should be based on peer-reviewed articles”

    In other words, scientists promoting their own research and interpretations of their research. That they “should” be based on peer-reviewed articles, means they mat not necessarily be so. Nothing particurly wrong with this, but it should be made clear that this is not a consensus view of experts in the field but individual scientists interpretations of their own latest research.

  23. BillyJoe7on 11 Mar 2017 at 5:31 pm

    Unfortunatley his latest contribution, which IS in quotation marks, but is not attributed, is actually from here:

    http://www.naturalhealth365.com/glutathione-antioxidants-2054.html

    The “Natural News” website is a cornucopia of medical quackery.
    It has articles promoting homoeopathy, natural healing, detoxification, herbalism, vitamin C, and quack cancer cures, and demonizes GMOs and vaccines.

  24. jsterritton 11 Mar 2017 at 7:02 pm

    BillyJoe7…

    I, too, have been reading Lane Simonian’s increasingly Messianic drive-by comments with horror. The cherry-picking is troubling enough (Lane lifts whole conclusion sections from dubious studies to shoehorn into his ever-growing “nitro-oxidative” stress model of AD causation/cure). Now he is making pronouncements like “the key to treating the disease is the following…” and “the pathways leading to Alzheimer’s disease are relatively clearly laid out and at least some of the compounds that intervene in those pathways are known.”

    Sheesh!

    As a sad counterbalance to Lane’s know-it-all-ism, the state of the science on AD treatment continues to be one of clinical failure. Science has been chronicling the particularly despondent results of drug research. Researchers have found any number of intriguing causal frameworks to investigate, but none respond to treatment and hypotheses must become increasingly elaborate to account for clinical failure. Anyone who claims to know the cause and cure of AD should step up and receive their Nobel. Lane is beginning to sound like a seller of false hope — can’t figure out his angle, though. I wish he’d go to science school and put his energies into something productive instead of resorting to Galileo gambits to prop up his pet theories.

  25. Lane Simonianon 11 Mar 2017 at 8:07 pm

    I forgot to double space at the end to make it a block quote, but that was a minor mistake.

    People have been trying to figure out my angle for years, and it frustrates them because I have no angle. I had two relatives who died from Alzheimer’s disease and my mother had the disease for eight years before dying of unrelated causes. Curiosity and personal experience have driven my interest in trying to understand the disease.

    Some sources are easier to criticize than others, but no one is picking this out of thin air.

    Let’s try a few:

    “Glutathione protects astrocytes from peroxynitrite-mediated mitochondrial damage: implications for neuronal/astrocytic trafficking and neurodegeneration.”

    “Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease”

    “Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.”

    “…peroxynitrite formation in cerebral blood vessels is needed for the cerebrovascular effects of Abeta…These effects of Abeta were abolished by ROS scavengers (tempol, MnTBAP), NADPH oxidase inhibition (gp91ds-tat), NOS inhibition (L-NNA) and by the peroxynitrite decomposition catalyst FeTPPS or PARP inhibition. Thus, Abeta leads to endothelial DNA damage and PARP activation via oxidative–nitrosative stress.”

    “Furthermore, conditioned media derived from CT105-treated astrocytes [c terminal fragment of amyloid precursor protein] enhanced neurotoxicity and pretreatment with NO and peroxynitrite.
    scavengers attenuated its toxicity…”

    “A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).”

    “Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng.”

    “Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer’s disease.”

    It is not cherry picking when every factor that causes nitro-oxidative stress increases the risk for Alzheimer’s disease, when oxidants can be directly and indirectly linked to every feature of Alzheimer’s disease, and where specific peroxynitrite scavengers have partially reversed Alzheimer’s disease in small-scale human clinical trial. It is up to the people who use ad hominem attacks, use words like cherry-picking and pseudoscience, attack sources rather than findings, and provide no scientific evidence to the contrary to offer a constructive alternative hypothesis.

  26. jsterritton 11 Mar 2017 at 10:38 pm

    @Lane Simonian

    “It is up to the people who use ad hominem attacks, use words like cherry-picking and pseudoscience, attack sources rather than findings, and provide no scientific evidence to the contrary to offer a constructive alternative hypothesis.”

    This is precisely why you need to go to “science school.” The lack of “a constructive alternative hypothesis” does not make yours valid. That’s science 101. The burden of proof lies with you to support your claims, not with others to disprove them. AD research is flummoxed by the complexities of the disease and drug research is essentially at a standstill. Making grand claims like you do — e.g., “the key to treating the disease is…” and “the pathways leading to Alzheimer’s disease are relatively clearly laid out” — is irresponsible and, frankly, weird (you are not a researcher, let alone an expert).

  27. Lane Simonianon 11 Mar 2017 at 11:01 pm

    No. I have met my part of the burden. I have provided multiple lines of evidence in support of the nitro-oxidative hypothesis for Alzheimer’s disease based on thirteen years of research. All that you have provided in response is to claim that it is cherry-picking. Show me where I am wrong and I will listen. Otherwise you are just blowing smoke.

  28. BillyJoe7on 12 Mar 2017 at 1:31 am

    Lane,

    A double space doesn’t produce a blockquote!
    If you don’t know how to make a blockquote, then use quotation marks.
    And provide a link.

    What does your 13 years of research constitute?
    We have a poster here who researched physics for 10 years and wrote a book based on his research which is a load of incomprehensible bullshit, and to which not a single physicist has paid the slightest attention.
    How do you know that you’ve done any better?

    So far, the evidence is that you read a lot of personal interpretations by scientists about their own work. Your posts here are basically direct quotes from these scientists. But what criteria do you use to decide who is correct. What is your background scientific knowledge that enables you to adjudicate the literature?

    And, of course, there’s your un-attributed quote from an obviously pseudo/anti scientific website.
    That does not inspire confidence.

  29. Lane Simonianon 12 Mar 2017 at 11:01 am

    For longer quotes, I try to separate the introductory information from the concluding information by providing considerable space between them and the quote (while that is not technically a block quote it serves the same purpose). The title indicated that it was not my words, but I did not provide enough spacing at the end of the passage. And, yes, providing links is a good idea.

    The source of the second quote does not negate the finding: everything cited there does lead to the depletion of glutathione, although the author was being very general–not identifying which environmental toxins, which drugs, and which infections contribute to the depletion of glutathione.

    My area of expertise is Latin American environmental history. I suppose that comes in handy when evaluating the possible role of particulate matter in contributing to Alzheimer’s disease in Mexico City or how high levels of mercury exposure may lead to the earlier onset of Alzheimer’s disease in family members with a presenilin 1 gene mutation in Antioquia, Colombia than it does in family members with the exact same gene in Japan (most likely brought to both regions by the Spanish in the sixteenth century). Beyond that, though, I have a background in biology–mostly ecology, conservation, and evolution–but to a more limited degree in biochemistry. I can understand the effects of nitration and oxidation on receptors, transport systems, and enzymes, I can understand how DNA damage leads to inflammation and the depletion of energy in cells, and I can understand how caspase 3 leads to the death of neurons. I understand the connection between peroxynitrite and all of the above. And though it took me years, I can trace the pathways that lead to peroxynitrite formation and how they have been implicated in Alzheimer’s disease. I don’t have to understand the whole universe of biochemistry to understand the specifics of the etiology of Alzheimer’s disease. I had to have some general background in biochemistry and the ability to put it together one piece at a time.

  30. daedalus2uon 12 Mar 2017 at 1:35 pm

    There is a great deal of misunderstanding of the role of peroxynitrite in physiology. Peroxynitrite is what is formed when nitric oxide and superoxide react. They react at near diffusion limited kinetics.

    Superoxide is an anion, and so is confined by lipid membranes. NO is an uncharged gas, so it diffuses right through lipid membranes, lipids have ~10x higher solubility for NO than does water, but that 10x is for “bulk” lipid, which lipid membranes are not. The solubility then depends on “details” of how the lipid is arranged, stress levels on it, what proteins are in it (maybe half the surface or a cell membrane is clogged with proteins (which are doing important things)), the degree of saturation of the lipids, electric field in the lipid, cholesterol, and orientation of the lipid tails of molecules (lots of cell membranes are liquid crystals with a chiral nature).

    Peroxynitrite is only observed when there are near equimolar levels of NO and superoxide. When one is in excess, then peroxynitrite and the oxidative effects of peroxynitrite (including nitration of tyrosine) are not observed.

    My conceptualization of peroxynitrite is that it is a “normal” signaling molecule that physiology uses to facilitate switching between states of oxidative stress (dominated by superoxide) and non-oxidative stress (dominated by NO). The transition from the NO dominated state to the superoxide dominated state is very rapid because there are many sources of superoxide. That state has hysteresis. Switching back to the high NO state is more difficult because the typical source of NO in physiology are the various nitric oxide synthase enzymes, eNOS, iNOS and nNOS. These are usually configured to generate signaling levels of NO, and not the bulk, macroscopic levels of NO needed to switch physiology from a state of oxidative stress to the state at rest.

    My conceptualization is that the observed nitrosative damage (nitrated proteins) observed in neurodegenertive disorders (like Alzheimer’s, Parkinson’s, Huntingtons, Lewy body neuropathies, taupathies, prion disorders, and the like, are all due to the brain staying in the oxidative stress state for too long, and “lingering” in the transition from the state dominated by superoxide while “trying” to get to a state dominated by nitric oxide.

    During the state at rest, and a state of oxidative stress, the damage rate is low (because either NO or superoxide are in excess, so no peroxynitrite is produced). During the state at rest, healing is turned on, during the state of oxidative stress, healing is turned off. During the lingering state, the damage rate is high (because both NO and superoxide are being produced), and healing is turned off.

    IMO, the idea of using stem cells to “fix” Alzheimer’s is silly. There are not enough metabolic resources in the brain to keep cells from degenerating and dying. Why wouldn’t stem cells degenerate and die when put in a place where there are insufficient resources to keep other cells from dying?

    Stem cells have the capacity to differentiate into other types of cells. Differentiating into tumor cells would be really bad (you would end up injecting tumor precursors into your brain). One of the known “causes” of tumors is unrestrained inflammation; sort of like what is going on in the brains of everyone with neurodegenerative disorders. Why would injecting stem cells into an inflamed site be a good idea?

  31. Fair Persuasionon 12 Mar 2017 at 8:39 pm

    As you point out creating more inflammation would not be a good idea. Brain tumors when removed can always grow back, varying in percentage up to 100% regrowth. This proposed experimental trial of stem cells requires more understanding of the process. Any payment of $10,000 to add love handles in the brain is not ethical.

  32. BillyJoe7on 12 Mar 2017 at 10:37 pm

    Lane,

    I think you may be missing peer review.

    This is the only way to test your views – pass them through the lens of the experts.
    The experts in this field are those who live and breathe this sub-specialty of science throughout their professional lives.
    If you do that, and listen to what they have to say, and adjust your view accordingly, you may become an expert yourself.
    And, in the process of becoming an expert…your might find yourself agreeing with the other experts!

    I alluded to Marcus Morgan before, but he is an actual crank in the true sense of the word.

    You seem to be basing your views on existing science but maybe not putting it together right – because of your lack of expertise. Not seeing the wood for the trees.
    Of course, I could be wrong, because I’m not an expert myself, but I’m basing it on your disagreement with these experts and the totally reasonable assumption that a non-expert is unlikely to be able to instruct experts in their own field.

  33. jsterritton 13 Mar 2017 at 1:00 am

    “I have provided multiple lines of evidence in support of the nitro-oxidative hypothesis for Alzheimer’s disease based on thirteen years of research.”

    And yet your “lines of evidence” lead nowhere. Aside from tiny (and sometimes absurd) studies that diverge from the consensus of AD research, your hypotheses have no substantive merit. Yet you are asking that they be accepted in and of themselves, merely because they parse for reason. Your ideas are not without reason. But you would divorce them from the clinical research that has failed to show ANY benefit from antioxidant therapies.

    I am not objecting to your hypotheses, but to the confidence you have in them, despite a dismal track record of actual research. Your ad hoc hypotheses need to be vindicated, not merely suggested and ballyhooed. Your pet theory needs a win. Until then, you should stop making grandiose claims about A) your knowledge and B) the current knowledge about the cause(s) and treatment(s) for AD.

    Simply put: you claim to posses special knowledge about a subject that baffles experts in an active field of inquiry. You cannot support those claims as a non-researcher cum University of Google hobbyist. Get your sh!t together and help in a collaborative way or stop trying to lead from behind with the arrogance of ignorance. I hope you’re right and that one day you receive that Nobel, but that day won’t come if you’re unwilling to engage in actual research and instead spend your time patting yourself on the back for the unaccomplished and arguing with idiots on the internet (like me).

    Try doing this: seek out an expert in the field (not a quack) and submit your ideas to her/him for review. Try publishing your suspicions about AD somewhere. Join a research team. Study at a university. Do something, anything in the manner in which science is done. Because right now, you just dive-bomb comment sections across the internet as if you’re looking to be “discovered,” like some brilliant AD ingenue.

    And that’s not a good look for you.

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