A week ago, I wrote about an example of one of the most common topics on this blog, the infiltration of pseudoscientific medicine and outright fantasy into academic medicine, a trend I like to refer to as quackademic medicine. The institution was George Washington University, and the dubious intervention was something called the MEND™ Protocol, which is sold as a treatment for Alzheimer’s disease by Muses Labs. As I described, it’s a protocol that appears to rely on a proprietary computer algorithm of some kind that, according to Muses Labs, produces a “personalized” treatment plan for Alzheimer’s disease. As if the proprietary computer algorithm wasn’t a big enough red flag for you, the results of the algorithm, at least as far as I could tell, produced a list of “integrative medicine” interventions ranging from the unobjectionable (e.g., exercise, getting 8 hours of sleep a night, treating sleep apnea if present) to those lacking evidence (e.g., gluten-free or low glycemic diets) to the highly dubious (basically, a boatload of supplements). In support of the MEND™ Protocol, Muses Labs touted a study by Dale E. Bresden that didn’t read like a study at all. Basically, it was a case series, and it was close to impossible to figure exactly what was used in each patient.

Leave it to me to have such fantastic timing, though. The dubious study I mentioned above dates back to 2014; so it was due for updating. Guess what? On the very day I was writing that post for last week, there was a press release announcing the publication of a followup study, Pre and post testing show reversal of memory loss from Alzheimer’s disease in 10 patients: Small trial succeeds using systems approach to memory disorders. Let’s just say this press release…exaggerates. (Imagine that!) For one thing, the MEND™ Protocol can hardly be called a “systems” approach. At least, if it can, we have no way of knowing because nowhere is the approach described in anything resembling sufficient detail to allow a careful evaluation of its “systems approach.”

Just like last time, Bredesen is laying down woo babble (like Star Trek technobabble, only with woo) like this:

Effective treatment of Alzheimer’s disease has been lacking, but recently a novel programmatic approach involving metabolic enhancement was described, with promising anecdotal results [3]. This treatment is based on connectomic studies [4] and previous transgenic findings [5] as well as epidemiological studies of various monotherapeutic components of the overall program [6]. The approach is personalized, responsive to suboptimal metabolic parameters that reflect a network imbalance in synaptic establishment and maintenance vs. reorganization, and progressive in that continued optimization is sought through iterative treatment and metabolic characterization.

OK, maybe it’s not as impressive as last time, with its claim of “synaptic reconstruction” invoking mechanisms like “periodically activating autophagy, blocking prionic tau amplification, increasing beta-amyloid clearance, inhibiting beta-amyloid oligomerization, minimizing inflammation, normalizing neurotrophic factors, reducing ApoE Ɛ4- mediated signals, reducing stress, reducing tau phosphorylation, restoring cholinergic neuro- transmission, and reversing memory loss,” from which the protocol targets “specific biological mechanisms are then prioritized and prescribed to optimize key biological mechanisms.” Maybe Bredesen was told to tone it down.

As Steve Novella notes, basically, this protocol appears to look at every marker Muses Labs can find that has been implicated in Alzheimer’s disease without actually bothering to figure out if these markers are actually etiologically linked to Alzheimer’s disease (i.e., might cause it) or are just epiphenomena (i.e., are coincidental or linked to something else that’s linked to Alzheimer’s disease and not causative). I referred to the MEND™ protocol as functional medicine on steroids, because, whether the scientists at Muses Labs know it or not, that’s exactly what functional medicine does: Measure a lot of markers that basic science and/or epidemiological studies have tentatively linked to various diseases without regard to whether these markers have been shown to have a causative role in these diseases, and then try to fix their abnormal levels. In doing so, functional medicine ignores an adage I’ve been taught since I was a resident: Treat the patient, not the lab values.

In any case, given that the new publication by Bredesen et al, Reversal of cognitive decline in Alzheimer’s disease, is a followup to the 2014 case series, I wondered if it would correct some of the glaring flaws in the previous study, such as its failure to provide any details that could allow a reader to evaluate whether the protocol has any value. Heck, there still isn’t enough detail to figure out on what basis sets of interventions were chosen for individual patients. Moreover, the study is uncontrolled. There is only one group, and all of the patients studied improved, at least subjectively.

This time, the only difference is that some seemingly “objective” data on each patient are included, such as tests of cognitive function and quantitative MRI. Of course, quantitative MRI is not straightforward to carry out and prone to many pitfalls and artifacts. Without a careful description of how MRI data were obtained for each patient, along with representative imaged, it’s impossible to tell if the investigators knew the potential pitfalls and took steps to minimize them. Given Bredesen’s history, I have to wonder.

Certainly, they appear not to have known the pitfalls of using FDG-PET scanning either. PET scans measure glucose utilization, and in part Bredesen relies on these scans showing glucose hypo-metabolism (decreased glucose uptake/utilization) to conclude that they have cognitive impairment. However, this has been found in subjects without cognitive impairment, particularly APOE-epsilon carriers, and 9/10 of the patients described are APOE-epsilon(+). Consequently, the significance of Bredesen’s FDG-PET findings regarding cognitive impairment are unclear.

More frustratingly, there was no indication how these patients were selected. Case series are usually supposed to be just that, a series of cases, usually consecutive. The reason for including consecutive cases is to minimize the tendency to cherry pick only the best cases and leave out cases with less favorable results. If the case series isn’t consecutive, then it’s very critical to know how the patients were selected for inclusion. In other words, you have to predefine rigorous selection criteria by which you will select your patients for inclusion in the case series. Barring that, it’s hard not to wonder if the patients were picked for best results, in which case what you have is a best case series. As we know from the example of Nicolas Gonzalez’s best case series of 12 patients with pancreatic cancer treated with his protocol, which involved many supplements and coffee enemas, best case series can be very misleading. Gonzalez’s series appeared to show results better than historical controls, but when his protocol was finally tested in a controlled clinical trial, the patients receiving his protocol actually did worse than controls, and that’s saying a lot, given how poorly patients with pancreatic cancer do in general. I strongly suspect that Bredesen’s patients are a best case series, but I can’t prove it. On the other hand, if it’s not a cherry picked series of cases, Breseden et al give no indication of it and every indication of their series not being consecutive.

Basically, this new case series is no better than the 2014 case series. It just sounds more science-y.

As Steve Novella notes:

The data, of course, is unblinded, meaning that it is very unreliable. In my experience as a neurologist, cognitive function can be very subjective. It is affected by mood, by transient things such as sleep, and there is also a huge element of subjective perception.

Some of the subjects did better on neuropsychological testing, but there is a known practice effect to such standardized tests. Patients always do better on the second taking.

They present 10 cases, but there is no mention of how these 10 cases were selected and if they are representative.

I also note that the authors refer to patients as having “Alzheimer’s disease” when in fact they should have referred to them as “Alzheimer’s type dementia.” AD is a pathological diagnosis, and there is no mention of brain biopsy on any of the cases. They met clinical criteria for Alzheimer’s type dementia, which is not the same as confirming AD.

Exactly. While a preliminary case series of ten subjects is not unreasonable as a pilot study, without a clear description of clear inclusion criteria, how each set of interventions was chosen for each patient, clear descriptions of the exact protocol followed, and predefined criteria for success, a case series like Bredesen’s is virtually worthless even to tell us if there’s anything worth following up on with a randomized controlled trial.

There are a number of other red flags in the study as well. For instance, in Table 1, one of the patients is referred to as having “Mild Cognitive Impairment (MCI), type 2 (and possibly type 3 (toxic)).” In a previous article (published in Aging, natch!), Bredesen defines “toxic” Alzheimer’s disease thusly:

Alzheimer’s disease is one of the most significant healthcare problems today, with a dire need for effective treatment. Identifying subtypes of Alzheimer’s disease may aid in the development of therapeutics, and recently three different subtypes have been described: type 1 (inflammatory), type 2 (non-inflammatory or atrophic), and type 3 (cortical). Here I report that type 3 Alzheimer’s disease is the result of exposure to specific toxins, and is most commonly inhalational (IAD), a phenotypic manifestation of chronic inflammatory response syndrome (CIRS), due to biotoxins such as mycotoxins.

Upon what does he base this? What is CIRS? It turns out that Bredesen bases his hypothesis on the work of Dr. Ritchie Shoemaker:

Over the past two decades, elegant work from Dr. R. Shoemaker and his colleagues has demonstrated unequivocally that biotoxins such as mycotoxins are associated with a broad range of symptoms, including cognitive decline (summarized in [5]). These researchers and clinicians identified a constellation of symptoms, signs, genetic predisposition (HLA-DR/DQ haplotypes), and laboratory abnormalities characteristic of patients exposed to, and sensitive to, these biotoxins. The resulting syndrome has been designated chronic inflammatory response syndrome (CIRS).

Let’s just say that Dr. Shoemaker has been graced with his very own entries in Casewatch, including a copy of a warning letter from the FDA. Shoemaker’s website, SurvivingMold, is what I like to call a “target-rich environment” that I might have to look into in more detail one day. Basically, he’s into chronic Lyme disease (a nonexistent diagnosis) and blames many chronic conditions on mold.

There are other red flags. For instance, Bredesen didn’t disclose some relevant conflicts of interest (COIs). One such COI was that he was one of the founders of Muses Labs. He didn’t disclose this for his 2014 paper. Of course, he is no longer affiliated with Muses Labs, but that doesn’t mean he doesn’t still have a COI. For example, he is the founder of MPI Cognition, as shown in this recent press release. On the MPI Cognition website:

The Protocol provides a comprehensive personalized program designed to improve cognition and reverse the cognitive decline of SCI, MCI, and early Alzheimer’s disease. Continued research and testing by Dr. Bredesen began by evolving MEND into The Bredesen Protocol, which has identified new and previously unrecognized causes of Alzheimer’s disease.

How did he do it? Prepare for new woo babble:

Medicine is undergoing a radical transformation, from 20th-century medicine to 21st-century medicine: 20th-century medicine uses small data sets—like looking at sodium and potassium but not the genome or metabolome or epigenome—to attempt to diagnose very complex illnesses in very complicated organisms—human beings. 20th-century medicine makes a diagnosis of what—Alzheimer’s or cardiovascular disease or hypertension—without understanding why. 20th-century medicine uses a one-size-fits-all, monotherapeutic approach, and has been largely unsuccessful in treating chronic illnesses such as Alzheimer’s disease, other neurodegenerative conditions, cancer, and cerebrovascular disease.

21st-century medicine is completely different: larger data sets are used to identify network changes that characterize chronic illnesses, revealing the “why” for each person—this is the etiodiagnosis. Prevention and early symptomatic approaches are emphasized. Addressing the cause of each condition in a comprehensive and personalized, programmatic way leads to improved outcomes, and each program is repeatedly optimized over time, to ensure sustained improvement.

Actually, the curmudgeon in me can’t help but point out that it has yet to be demonstrated convincingly that “precision medicine” or “personalized medicine” actually does produce better outcomes. One can’t help but point out the example of the SHIVA Trial, where precision medicine for cancer was tested against standard of care and failed to do better. Precision medicine might some day be shown to be as great as Bredesen claims, but it hasn’t yet. More importantly, we have no way of knowing if what Bredesen is doing is really precision medicine and a lot of indications (the supplements, the exercise, the many labs) that it is not.

Finally, you too can learn the modified MEND™ Protocol/The Bredesen Protocol if you want. MPI Cognition offers 4 day training programs that “cover all aspects of The Bredesen Protocol, from the scientific data and background to the key factors for success to the critical tests and follow-up to the best methods for sustaining success.” I wonder how much CPI Cognition charges for this training course. Whatever the cost, though, it’s clear to me that Bredesen’s latest case series falls far more into the category of marketing literature than scientific literature.

Comments

  1. #1 Eric Lund
    June 24, 2016

    proprietary computer algorithm

    I missed that bit the last time around.

    Granted that medicine has a different culture from my field, as well as IP issues that don’t arise in my field (i.e., studies involving commercial products under development), but in my field, that wouldn’t fly. The major journals in my field expect you to provide source code on request, for the obvious reason that it allows anyone so inclined to reproduce your results. It helps that data in my field is normally publicly available, which is obviously impractical (or even illegal, due to HIPAA and similar laws) in many medical studies.

  2. #2 Todd W.
    http://www.harpocratesspeaks.com
    June 24, 2016

    I notice that, once again, he did not get IRB review for this study, just like his 2014 paper.

  3. #3 Wzrd1
    June 24, 2016

    I see, in his writings, something not uncommonly witnessed when working with dementia patients, word salad.
    “…as well as epidemiological studies of various monotherapeutic components of the overall program.”
    OK, if it’s monotherapy, how does it have multiple components? That’d be polytherapy.
    So, under his daffynition at the outset, I’m on a half dozen simultaneous monotherapies, at the same time as well.
    Or something.

    Just one more shyster in a field that embarrass used car salesmen.

  4. #4 Eric Lund
    June 24, 2016

    I see, in his writings, something not uncommonly witnessed when working with dementia patients, word salad.

    TBF, word salad isn’t exclusively a symptom of dementia. For a fictional example, see Gabby Johnson’s “authentic frontier gibberish” in Blazing Saddles. In the real world, it crops up often in bureaucratese (where it frequently takes the form of “buzzword bingo”) and political speech (Sarah Palin being the most notorious but hardly the only US example).

    Of course, I don’t know Dr. Bredesen well enough to rule out dementia, but there are enough problems with the study as it is. We don’t need to invent speculative reasons for distrusting it.

  5. #5 Helianthus
    June 24, 2016

    @ Wzrd1

    Maybe he meant “different studies, each focusing on one or more single-component therapies”.
    Um, I’m reaching, here. I agree that’s not clearly worded.

    To my shame, packing sexy buzzwords and big scientific words into a grant request or an article introduction is something I have seen done by different colleagues (and sometimes I added my own layer).
    Occasionally, the result was word salad.

    It’s the result of overdoing it and lacking a good proofreader. It’s more likely to arise in another language, or if one doesn’t have much to say. Something about dazzling them with brilliance or dazing them with BS.

    Well, it could also be that me and my colleagues are totally bonkers. Sometimes I wonder.

  6. #6 JDK
    June 24, 2016

    “21st-century medicine is completely different: larger data sets are used to identify network changes that characterize chronic illnesses, revealing the “why” for each person—this is the etiodiagnosis.” BS on so many levels!
    He should read Stephen Jay Gould’s The Median is Not The Message. Where in that cloud of thousands of points in the data set is the individual waiting for a ‘personalized’ treatment plan? Are they in the centre of the distribution? The tails? And if the data set is based on BS relationships between variables, what then? No worries, we have a great line of unicorn saddles on special this week!

    • #7 Wzrd1
      June 24, 2016

      @JDK #6, now now, I get a personalized treatment plan from my allopathic doctor.
      A specific set of blood pressure medications, adjusted and titrated to maintain my blood pressure to a humanly survivable blood pressure level, thyroid suppression medication that is also titrated to keep my thyroid hormone levels at a humanly survivable level, etc.
      All treatment is individualized to a degree, as each patient is indeed different, with different medical conditions and their own physiological idiosyncrasies.
      What the quack is doing is playing on the notion that patient care is not individualized upon patient need, throwing buzz words in to not dazzle with the brilliance of a new treatment method, but baffle with the bullshit.

  7. #8 Militant Agnostic
    Where the large print giveth and the fine print taketh away.
    June 24, 2016

    I appears that Orac is unwilling to Step Right Up to 21st Century Medicine.

  8. #9 Phlebas
    UK
    June 24, 2016

    Proprietary, secret squirrel, un-peer reviewed technology shows ground breaking results.
    Theranos anyone?

  9. #10 Rich Bly
    Ocean Shores
    June 24, 2016

    My father died from dementia (it is not what is on death cert) 3 years ago and I can see how a scam like this would appeal to many people. Mom whished for nothing more than 2 more months so they could reach their 60th anniversary.

    We didn’t know or see the signs of dementia early, so education of people is very important. I have a younger brother that to me is showing signs of early onset dementia. He has many of the factors that may lead to dementia: obese, diabetic, inactive, out of shape, and doesn’t read or perform other intellectual actives.

  10. #11 rs
    June 24, 2016

    “Proprietary, secret squirrel, un-peer reviewed technology shows ground breaking results.”

    Heh! But meteorites and shovels have hard data to prove that they do it better.

  11. #12 Lane Simonian
    June 24, 2016

    At the core, I only have three “scientific” objections to this protocol: one is that it is quite complicated so that it would be difficult for someone with memory impairment or their caregiver to follow, two it has not been determined which elements of the protocol may be most effective (some such as hormone replacement therapy may be counterproductive for some individuals), three it may be ineffective or much less effective for someone with mild to moderate Alzheimer’s disease.

    The key pieces to Alzheimer’s disease is laid out in the following:

    “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.”

    The data indicate that… PKC activation mediates ONOO- [peroxynitrite] generation, which results in the oxidation and depletion of glutathione…

    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 [glutathione] levels plummet in the hippocampi of patients with Alzheimer’s as well as those with MCI.

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

    Reducing stress (yoga, meditation, a walk in the woods, etc.), consuming less sugar, salt, and carbohydrates, reducing exposure to environmental toxins, treating chronic infections, etc. all reduce protein kinase C activation. But it is not a matter of simply inhibiting protein kinase C (which as the disease progresses likely remains high in only those with neuropsychiatric problems). The key is as the brain’s own antioxidant–glutathione–is exhausted–external antioxdiants must be used in its place. Several antioxidants were used in this protocol but likely not the most effective ones–particularly as the disease progresses. Here are links to clinical trials in which peroxynitrite scavengers were used to treat mild to moderate Alzheimer’s disease.

    http://www.ncbi.nlm.nih.gov/pubmed/20377818

    http://www.ncbi.nlm.nih.gov/pubmed/22780999

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/

    This protocol while not perfect is a step in the right direction because much of it addresses the risk factors and likely cause of Alzheimer’s disease (oxidative stress).

    I am afraid that much of the skeptical community is so caught up in its certainty about the superiority of its belief and so upset with various “heretics” that this community is unable to rationally evaluate the actual science. Here, is how an anonymous reviewer presented the evidence for how to treat Alzheimer’s disease:

    [Clinical trials with over-the-counter supplements have concentrated either on items which suppress inflammation, or on antioxidants which scavenge oxygen derived free radicals. Most of these items have proved to be worthless in the treatment of Alzheimer’s disease. Similarly most drugs used to treat Alzheimer’s disease do little to slow the deterioration, but instead offer a mild temporary
    symptom relief. However, evidence has been accumulating that the primary driver of Alzheimer’s disease is a nitrogen derived free radical called peroxynitrite, which may mediate both amyloid and tau accumulation as well as their toxicity.
    Excellent results have been obtained with peroxynitrite scavengers, with reversals of Alzheimer’s disease in human clinical trials being repeatedly demonstrated. IMHO, the only thing which may be preventing the abolition of
    Alzheimer’s disease is the mental inertia of scientists, as well as the bureaucrats who fund them. Unfortunately, most bureaucrats keep throwing money into repeatedly testing discredited interventions, while ignoring successful
    ones. Common sense is anything but…]

  12. #13 See Noevo
    June 24, 2016

    Orac,
    With the illustration at top, are you saying losing to Alzheimer’s is as inevitable and natural as deciduous trees losing their leaves in the fall?

  13. #14 Mark Thorson
    June 24, 2016

    Lane, don’t forget to mention you pet therapy for AD is aromatherapy with rosemary oil. That should boost your credibility around here!

  14. #15 Mark Thorson
    June 24, 2016

    Note that the paper reports finding dramatic hippocampal enlargement in patient 1 following treatment as evaluated by quantitative MRI, but shows no photo of the brain scan. Your best result and you don’t show it? That seems rather odd.

  15. #16 Bobby Brooke
    United States
    June 24, 2016

    Thanks for the add’l post.

    First, we’re of course talking about Alzheimer’s here, not autism, so you can make that correction in the third sentence. I guess your cheerleaders don’t read that closely. 😉

    I largely agree with what the neurologist Steve Novella from SBM wrote, who you cite, which is that “While the current case series is certainly provocative, I do not think it is reasonable to use this level of evidence to make clinical claims… What we need now is a randomized double-blind placebo controlled trial.” To me, it seems the researchers understand this, although maybe not some of the people at companies seeking to promote/commercialize it (especially unaffiliated ones).

    You write that in the original research paper he’s laying down “woo babble”, but I just don’t see it as that egregious. For instance, you mention soon after the citing of “connectomic” studies, where he cites a reference: “http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546454/pdf/oncotarget-06-14092.pdf” The reference is a 25+ page peer-reviewed paper (Oncotarget, Impact Factor 6.359, ~top 5% of all journals) he co-authored with a UCLA scientist that described a new theory for Alz, and including potential pharmaceutical and other interventions that resulted from this work. Seems pretty reasonable, even interesting, no?

    Your point and/or Steve Novella’s point about patient selection is definitely valid. One reason I doubt it is highly cherry-picked though is b/c I tend to think he doesn’t operate a really high-volume clinical practice. Thanks for bringing up the pancreatic cancer example, which of course is another devastating condition (two colleagues/mentors of mine have passed away from it in the last 3 years). I think the case series analogy you describe here is relevant, but the devil is in the details, and the depth and breadth of research supporting the recommendations here appear in most cases to be far more substantial.

    You write off the characterization of Alz subtypes, due to one element of it having a loose connection to the charlatan you describe, but the theory was described more clearly in a different paper: http://www.ncbi.nlm.nih.gov/pubmed/26343025, which it seems you haven’t seen. I’m not going to champion this paper, b/c it looks like preliminary evidence based on the same case series (which he appears to be getting a lot of use out of… :), rather than a really exhaustive analysis from thousands of patients. He cites a couple relevant papers (refs 2 and 3 in particular), including the FINGER study, a RCT involving 1,260 enrolled patients, but in digging into this it doesn’t seem to provide clear evidence for any clear subtypes. So I tend to agree this is more of a theory at this point. It appears another thing he wants/needs to study through a larger RCT.

    The snarky “natch!” comment related to the journal doesn’t seem appropriate. As you’ve already described in your last article the impact factor is >6, (6.432), so it’s a decent journal. Also, take some time and look at the editors and other articles. These are quality researchers and papers in the aging field, and many have spent decades trying to distance themselves from the joke and embarrassment of all the “anti-aging” garbage that is out there.

    Also, I found it interesting that the FINGER study (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60461-5/abstract) cited within that paper appears to be a RCT again in 1,260 patients that has already demonstrated benefit of a lot of the non-controversial stuff included in this regimen, like diet/nutrition, exercise, cognitive training, and also somewhat active management of metabolic and vascular risk factors. For example, the intervention group had check-ups at 3, 9, and 18 months, compared to the controls just getting advice at the beginning of the trial. So I think it’s reasonable to conclude that the FINGER study is somewhat analogous, and more like a program (buzzword translation:”programmatic”), and that it got decent results, although not breathtaking ones, in a RCT.
    One thing you mention struck me is that you’re criticizing someone for measuring anything that hasn’t “been shown to have a causative role in these diseases”. It seems like a very high standard, especially for Alz. Would you or anyone else point me to all the markers that are causative for Alz? Are there any that are causative, and also modifiable?
    Yes, “Treat the patient, not the lab values.” That’s one of the reasons I liked this preliminary study… demonstrable improvement in functional outcomes, albeit in a small group of patients and requiring follow-up. If you think a case series and approach like this is bad, let’s not forget how many thousands of papers on Pubmed of cell line development, artificial mouse models, GWAS, etc… most of it good, solid, honest work, but let’s face it… unfortunately most of it is also a million miles from an Alz cure. We should thank our lucky stars (!) for physician researchers who have the time and wherewithal to think and also do innovative research on their own (which I consider distinct from finding the time to run an industry-sponsored trial).

    The “curmudgeon” in you can’t help but point that precision/personalized medicine doesn’t produce better outcomes. I agree with this. I imagine even Craig Venter and Lee Hood would agree with you to a significant degree, too, though they both are affiliated with companies that offer (expensive) personalized wellness programs (HLI’s Health Nucleus and Arivale Health, respectively). I’m not sure how it is pitched to people, but it should be pitched for what is, some recommendations grounded in clear evidence, but many parts still very much a science project.

    My major gripe remains that I think these articles don’t do a good job separating the pretty intriguing but early-stage research from the more questionable ways (mostly unaffiliated) people are marketing it.

    He’s not the first researcher to invent and use some buzzwords, or to use somewhat grandiose language talking about their work. If he didn’t, all the researchers doing something useless like making new iPS cell lines of hippocampal neurons using CRISPR would get all the funding.

  16. #17 John
    June 24, 2016

    One thing I don’t understand that you think Alzheimer is inevitable.
    What does the top tree figure means?

  17. #18 Bobby Brooke
    United States
    June 24, 2016

    @Wzrd1 #3

    “…as well as epidemiological studies of various monotherapeutic components of the overall program.”

    You’re misunderstanding. He obviously means he based certain individual components of the program on epidemiological studies. In other words, he selected certain components due to studies that showed a correlation of some factor, or some marker that a component influences, with a good prognosis/outcome in Alz.

    It’s not as good as having a RCT with positive results to support (but if this was the threshold for Alz, it obviously would be very slim pickins’).

    I looked at the reference he cited (http://www.ncbi.nlm.nih.gov/pubmed/23703924). It’s a paper he co-authored paper, titled “Next gen therapies for Alzheimer’s disease” (EMBO Molecular Medicine, Impact Factor 8.245). It’s a decent read though I don’t see any clear examples of this there. But I think even the non-controversial diet and lifestyle stuff would fall in this category, i.e. supported by epidemiological work primarily (although the FINGER study I mentioned does provide some evidence in a large RCT).

    • #19 Wzrd1
      June 25, 2016

      @Bobby Brooke, #17, so, he went through the data and for each prospective issue found in Alz, found a prospective treatment and combined them.
      Unless those specific issues are proved causative for the condition, it isn’t treatment, it’s throwing spaghetti against the wall to see what might stick and claiming success.
      This isn’t Pasteur and Roux, it’s Chef Boyardee, with an odd report that doesn’t include its star evidence, such as the brain imagery. To say that I’m dubious is to put it mildly.
      As one who lost my cousin’s husband and soon, a cousin to the disease, a man I immensely respected, this is disheartening.

      • #20 Bobby Brooke
        United States
        June 25, 2016

        @ Wzrd1 #18

        Yes, this was listed as one of the ways he found prospective treatments/components.

        “Unless those specific issues are proved causative for the condition, it isn’t treatment”… Would you let me know the “issues” that you know of that are causative for Alzheimer’s? Are there ones you know of that are also modifiable? I’m curious if there are any, so it seems like a very high standard for Alz.

        In the U.S. at least, doctors decide what is treatment, and they have plenty of discretion, including to use drugs off-label, and also to use things where they feel there is sound judgment behind, they’re reasonably safe, etc.

        But I agree with your sentiment somewhat here… especially with regards to those people/groups who might be “selling” the treatment, while still proven, and especially if it’s not disclosed as more investigational. It should be noted also that the MPI Cognition company actually appears to be trying to educate/train doctors on this (which Orac left out, only highlighting the direct-to-consumer/patient marketing).

        In case it hasn’t become obvious by now, I like Chef Boyardee… (the approach, albeit yes it is a shotgun approach, and yes it is obviously quite different from monkeying around with molecular mechanisms).

        Sidenote: the researcher behind this works looks at molecular mechanisms, too, in case you haven’t seen this interesting paper on APOE: https://www.sciencedaily.com/releases/2016/01/160128155753.htm

        I’m sorry to hear about your family members.

  18. #21 Lane Simonian
    June 25, 2016

    If nitro-oxidative stress is the cause of Alzheimer’s disease, then most of this protocol should have an impact on Alzheimer’s disease at least at its earliest stages.

    First the case itself:

    “The reaction product of nitric oxide and superoxide, peroxynitrite, is a potent biological oxidant. The most important oxidative protein modifications described for peroxynitrite are cysteine-thiol oxidation and tyrosine nitration.”

    Cysteine oxidation and/or tyrosine nitration causes the following damage in Alzheimer’s disease: disabling of receptors involved in short-term memory, sleep, smell, mood, alertness, and social recognition, inhibition of the transport of choline and the conversion of choline into acetylcholine (acetycholine is required for the retrieval of short-term memory), reduction in the flow of blood and the transport of glucose in the brain which can lead to delusions, prevention of the regeneration of neurons in the hippocampus, and the death of neurons.

    Cysteine oxidation can be partially reversed by compounds that donate hydrogen atoms and peroxynitrite can be scavenged by these same compounds. When peroxynitrite is scavenged it produces water and water is a putative de-nitrating agent. Thus some (but perhaps not all) of the damage described above can be reversed.

    There is a long list of factors that can contribute to nitro-oxidative stress and thus the onset of Alzheimer’s disease: the ones relevant to this study include sleep apnea, stress, chronic infections in the brain (including potentially oral infections), and a high carbohydrate diet. Addressing these risk factors for Alzheimer’s disease may potentially slow down the disease at least at the earliest stages. Antioxidants such as the ones used in this protocol can be used at any stage to at least slow down the progression of the disease. The most effective ones are called methoxyphenols such as curcumin (whose value is reduced by its poor bioavailablity), eugenol in various essential oils via aromatherapy, and syringic acid and ferulic acid in panax ginseng.

    For those who like chemistry:

    “The structural features of curcumin that can contribute to the antioxidant activity are the phenolic and the methoxy group on the phenyl ring and the 1,3-diketone system. Moreover, the antioxidant activity of curcumin increases when the phenolic group with a methoxy group is at the ortho position [16, 17]. The orthomethoxy group can form an intramolecular hydrogen bond with the phenolic hydrogen, making the H-atom abstraction from the orthomethoxyphenols surprisingly easy [18]. The H abstraction from these groups is responsible for the remarkable antioxidant activity of curcumin.”

    I understand very personally the devastation that Alzheimer’s disease causes, but I also sense how potentially close effective treatments for the disease are.

  19. #22 Bobby Brooke
    United States
    June 25, 2016

    @ Lane Simonian #20

    For the record, the 2014 paper w/ the regimen lists one component related to antioxidants, and that was based on this work from UC Irvine, describing how a medical food cocktail showed beneficial effects in a mouse model: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2984445/

    That said, from a quick look at the description of which people adhered to what, it doesn’t seem clear that any of them took any at all.

    • #23 Wzrd1
      June 25, 2016

      The difficulties inherent in animal models are quite well displayed in the abortive TGN1412 trial.
      Looked great on paper, worked great in animal models, harmed every test subject who received the drug – badly.
      Models can help narrow down pathophysiology, but are far from highly effective in predicting pharmaceutical effects outside of their species.

  20. #24 Lane Simonian
    June 25, 2016

    @ Bobby Brooke #21. Several of the participants took antioxidants, including curcumin, melatonin, vitamin D3, bacopa monniera, Aswagandha, coconut oil, resveratrol, coenzyme Q10, and methylcobalamin.

    http://www.impactaging.com/papers/v6/n9/full/100690.html

    • #25 Wzrd1
      June 25, 2016

      @Lane, #23, interesting that curcumin is mentioned.
      Some bill it as a panacea, of which I am dubious.
      However, I’ll admit to watching tumeric used orally for an asceptic skin condition that confounded our physicians, to excellent effect. We tried pretty much everything in the book and doctor’s experience in both cases, to no avail. The local “witch doctor”, for a lack of a better term used tumeric and black pepper. He related how tumeric worked by itself, but slower.
      Further research on regional practices revealed the same treatment for this ailment, blocked, “tunneling” pores, which then behave like a sterile boil.
      Apparently, it was a local affliction, even the locals suggested it was familial and hence, genetic.
      Doctors and my senior guys theorized that the piperazine may induce inflammation, facilitating the therapeutic agent from the tumeric. Studies are ongoing, begun around 2008, so replication is conducted as a matter of course in DoD circles, release after.
      One of a handful of interesting finds over the decades, some later became known pharmaceuticals, with known dosage and purity, rather than a toss of the dice with variable sourced plants.
      See my foxglove argument above, vs digoxin. I’ll go with prescribed digoxin every time that I can get it, if I need it.
      Just as, if my guys suffered a nerve agent poisoning event, I’d not have them chew tomato plant leaves and smoke jimson weed, I’d give them enough atropine to counter initial symptoms, then 2Pam chloride to clear bound agent from the receptors. Controllable, replicable dosage defeats random sourced, variable dosage plants.
      An autoinjector or even a vial beats a truckload of plant matter and worrying about dosage for each and every patient.
      Mass casualty events suck badly enough to begin with, adding random pharmaceutical events just lowers the survival rate.
      IED’s did enough of that to begin with, as my tinnitus can attest to. -45 db worth of it in hearing loss.

  21. #26 herr doktor bimler
    June 25, 2016

    Small trial succeeds using systems approach to memory disorders

    I am at a loss to see how surrounding a small trial with wibble and calling it “systems approach” makes it anything more than a small trial, i.e 10 anecdotes with no controls or skepticism of any kind.

    “Impact Journals” are in Beall’s list as a predatory publisher, no meaningful peer review. This should make a difference for Science Daily if they want to be anything more than a pukefunnel for pimping press releases.

  22. #27 Daniel Corcos
    June 25, 2016

    @ HDB
    The editorial board is not really consistent with a predatory publisher:
    http://www.impactaging.com/editors.html
    Have you any explanation?

  23. #28 Orac
    June 25, 2016

    Your point and/or Steve Novella’s point about patient selection is definitely valid. One reason I doubt it is highly cherry-picked though is b/c I tend to think he doesn’t operate a really high-volume clinical practice. Thanks for bringing up the pancreatic cancer example, which of course is another devastating condition (two colleagues/mentors of mine have passed away from it in the last 3 years). I think the case series analogy you describe here is relevant, but the devil is in the details, and the depth and breadth of research supporting the recommendations here appear in most cases to be far more substantial.

    If the manuscript doesn’t include a detailed description of the selection criteria and exclusion criteria, I am not inclined to give the authors the benefit of the doubt. That is such utterly basic information that is absolutely necessary to evaluate the series that its omission to me is an enormous red flag. As for Aging, whether it’s predatory or not, clearly there is a problem with its peer review system if it allows articles like this to be published without such basic information. Ditto the lack of detail about the actual protocol and algorithm that was used to determine each patient’s treatment. Here’s where I disagree with Steve Novella. I don’t think the data in this paper warrant an RCT. Bredesen needs to go back to the drawing board and either publish an update to this case series with sufficient detail to allow it to be evaluated or do a proper case series.

  24. #29 Daniel Corcos
    June 25, 2016

    @ Orac
    I don’t doubt that there was a serious problem in the peer review of this article. But I can find many similar cases in journals from “non predatory” publishers. Hence the question, where does this information about predatory publishing comes from, or, alternatively, how could a predatory publisher get a prestigious editorial board?

  25. #30 Lane Simonian
    June 25, 2016

    @Wizrd1 #23 Thank you for all the interesting information and valid points. Some spices can cause inflammation, but the most common argument for using black pepper with curcumin is to increase the absorption of the curcumin. Several researchers are trying to find other ways to increase the absorption of curcumin for the treatment of Alzheimer’s disease, but I have not seen any updates for awhile.

    I take curcumin for a Celiac-like disease that may have been caused by pesticides. The nice doctor originally diagnosed it as ulcerative colitis and wanted to prescribe prednisone, but I had seen the efffects of prednisone on my father so I declined. As it seems, the same compound–peroxynitrite– that causes leaky gut also appears to cause a leaky brain. My own experience, though, has been that the curcumin has helped better with a “leaky gut” than with a “leaky brain”.

    There are a number of natural products that have been synthesized into drugs. In most cases (perhaps all cases), if I had to I would take the medicine rather than the natural product. The problem with Alzheimer’s disease is that none of the drugs are effective (although they may provide symptomatic relief for awhile).

    I have seen claims that a more effective form of eugenol has been synthesized, but as far as I know it has never been tested for Alzheimer’s disease.

    When I read that rosmarinic acid improved memory in mice, I began to use aromatherapy for my mother (it turns out the eugenol is the more effective antioxidant compound). With aromatherapy, she recognized her home again, stopped having delusions, could recognize objects (like a rose and sugar), could remember and spell her name, and became much more alert and aware. Her short-term memory improved slightly and she became a little more lucid. She was probably late stage 6 Alzheimer’s disease when we began aromatherapy. She lived five more years, steadily improving, before dying of other causes.

    My grandfather was a naturopath and he treated almost everything that way. My mother almost never went to the doctor. Ironically, the one prescription drug she did take– Fosamax–may have contributed to her Alzheimer’s and to the severe esophagitis and heart problems that would eventually take her life. I am not a naturopath nor am I opposed to modern medicine; I look into both camps to try to find what will work.

    • #31 Wzrd1
      United States
      June 25, 2016

      @Lane, only one thing. If one had a leaky gut, one would have fecal coliforms in one’s blood. That would be septicemia and quite life threatening.
      The other potential leak would be into the peritoneal cavity and again, it’d result in a life threatening infection and all of the symptoms of peritonitis would be present.
      There is some weak evidence that one’s intestinal flora and fauna may contribute to some disease processes, but the evidence is extremely weak.

      As for the use of prednisone, I know quite well the effects of short term and chronic administration of the drug. Indeed, I carried injectable prednisone in my military treatment bag. My wife takes it chronically for her Lupus. Better with it than without it!

  26. #32 herr doktor bimler
    June 25, 2016

    where does this information about predatory publishing comes from, or, alternatively, how could a predatory publisher get a prestigious editorial board?

    I can only say that Jeffrey Beall has compared the publisher against his criteria and seen enough evidence of predatory or vanity practices to include it in his list:
    https://scholarlyoa.com/publishers/

    …but it hasn’t been a sufficiently egregious or entertaining case for him to devote a separate blog-post to it.

    The key question about a star-studded editorial board is whether those prestigious researchers ever get to do any editing (academics are known to accept flattering invitations without looking too closely at the source). If indeed they are reading submissions, and rejecting them or farming them out to peer reviewers, so the journal has become genuine whatever the original intentions of the publisher might have been, then Beall is amenable to reclassifying it.

    But I can find many similar cases in journals from “non predatory” publishers.

    All too true.

  27. #33 Helianthus
    June 25, 2016

    With aromatherapy, she recognized her home again […]

    Could it be that stimulating the olfactory senses of your mom triggered back memories?
    We tend to focus on visual and auditive memories, but the human sense of smell is also quite good at building souvenirs.

  28. #34 Mark Thorson
    June 25, 2016

    More likely it’s cognitive bias. He’s evaluating the results of his own putative therapy.

  29. #35 Lane Simonian
    June 25, 2016

    @Wzrd1, #31 (I think that I did it right this time).

    I suppose leaky gut is a term that I and others use too loosely. Tissue damage and intestinal inflammation might be better terms. I found an interesting parallel however between the protocol for my condition and the MEND protocol.

    http://sanjosefuncmed.com/intestinal-permeability-clinical-unwinding-leaky-gut/

    I have the luxury of avoiding the use of prednisone. I understand that not everyone has this luxury. I wish you and your wife the best.

  30. #36 Lane Simonian
    June 25, 2016

    In regards to aromatherapy, there is a strong connection between smell and memories, but in my mother’s case the main effects were in place recognition and time recognition. After a month of aromatherapy, she asked why have you been giving this to me everyday for a month. She also noticed that I had moved an object on her shelf. My sister and I took turns taking care of her. She once told me this house (my sister’s house) had an upstairs and a downstairs. I asked with surprise how did you know that. She said, “I have been living here for awhile.”

    Acetylcholine in the the hippocampus plays a critical role in spatial recognition object recognition, and sense of time. The compounds in essential oils are almost directly inhaled into the hippocampus via the nose. They begin to reverse the oxidation/nitration of choline transporters, choline acetyltransferases, and the muscarinic acetylcholine receptors. A person thus has more acetylcholine and certain aspects of their memory improve.

    Episodic memory and the ability to sort out information in part at least includes parts of the brain other than the hippocampus. My mother’s ability in these areas did not improve substantially.

    I neither invented the oxidative stress hypothesis for Alzheimer’s disease nor aromatherapy for the treatment of Alzheimer’s disease (although I began the treatment based on the possibility that rosmarinic acid could improve memory; most of the studies on aromatherapy for Alzheimer’s disease came out later). I will take a bit of the credit for putting a vast amount of research into a little different light and grin and bear the scorn, but in the end I am only slightly adding to the work of some very good scientists.

  31. #37 Narad
    June 25, 2016

    The compounds in essential oils are almost directly inhaled into the hippocampus via the nose.

    You don’t say.

  32. #38 Mark Thorson
    June 25, 2016

    Lane, you are a crank.

  33. #39 Narad
    June 26, 2016

    Oh, dear L-rd:

    [T]he plaque is likely neuroprotective because it inhibits the formation of hydrogen peroxide which may be at the heart of prion diseases.

    I spy with my little eye something that begins with the letter ‘c’.

    Anyway, Lane, I just reexamined your comment 12 expecting to find some sort of rodent payload, but I was distracted by trying to figure out where the different parts of the cut-and-paste job started and ended, as compared with your own prose, and didn’t even bother to around the corner to get PMID 17420060.

    If you can’t actually put together something coherent in your own words, at least get the quotation marks consistent and put the citations immediately after the quotes.

  34. #40 Narad
    June 26, 2016

    ^ “to go around the corner”

    (campus hotspot)

  35. #41 Lane Simonian
    June 26, 2016

    Here is one article suggesting that amyloid plaques are neuroprotective by cutting off the production of hydrogen peroxide:

    http://www.jbc.org/content/280/43/35789.abstract

    I will try to put it together as coherently as possible. Amyloid beta (either the amyloid precursor protein or amyloid oligomers) do not damage neurons unless protein kinase C is activated. When protein kinase C is activated it leads to the formation of peroxynitrite and caspase 3 (an enzyme linked to the death of neurons) and it leads to the depletion of glutathione–a critical antioxidant in the brain. Perhaps most importantly, glutathione scavenges peroxynitrite; without glutathione there is little to no protection of either neurons or maintenance of acetycholine for short-term memory.

    http://www.ncbi.nlm.nih.gov/pubmed/8940610

    The only compounds that have partially reversed memory loss in Alzheimer’s disease are specific peroxynitrite scavengers (i.e. specific antioxidants. The chart in the link below helps put a picture to the words (ONOO- is peroxynitrite and GSH is glutathione).

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

    The Kegg pathway for Alzheimer’s disease is also instructive (especially the lower half).

    http://www.genome.jp/kegg-bin/show_pathway?hsa05010

  36. #42 Lane Simonian
    June 26, 2016

    I will add the first step of Alzheimer’s disease to the mix. People with high levels of myo-inositol are more likely to develop Alzheimer’s disease.

    http://www.docguide.com/myo-inositol-n-acetylaspartate-are-sensitive-biomarkers-conversion-mci-alzheimers-disease?tsid=5

    The factors that contribute to high myo-inositol levels are high glucose levels (due to a high carbohydrate and high sugar diet, for instance), a high salt diet, and Down syndrome (individuals with Down syndrome have an extra chromosome containing the sodium/myo-inositol co-transporter). By age forty people with Down syndrome have the supposed biomarkers for Alzheimer’s disease: amyloid plaques and hyperphosphorylated tau, but not all go on to develop Alzheimer’s disease. Individuals with Down syndrome have high levels of hydrogen sulfide–which itself may contribute to mental impairment–but which protects against Alzheimer’s disease because hydrogen sulfide is a peroxynitrite scavenger. One can have both plaques and tau tangles in their brains, but as long as peroxynitrite is being sufficiently scavenged, a person will not develop Alzheimer’s disease. On the other hand, if intracellular calcium release is inhibited or blocked, a person can have Alzheimer’s disease with little to no plaques and relatively few tangles.

    Last chart this time showing the place of myo-inositol in the chain that leads to Alzheimer’s disease:

    http://tmedweb.tulane.edu/pharmwiki/lib/exe/fetch.php/lithium.png

    The types of receptors that act upon the myo-inositol “product” phosphatidylinositol 4,5 biphosphate (PIP2) and lead to the activation of protein kinase C are receptor tyrosine kinase, g protein coupled receptors, ionotropic receptors (such as nicotinic acetycholine receptors), and metabotropic receptors (such as certain glutamate receptors). These are the receptors that balance growth and death in the body. Overactivation of these receptors can lead either to excessive cell growth (cancer, for instance) or excessive cell death (Alzheimer’s disease, for example).

    The number of factors that can activate these receptors are numerous: they include chronic bacterial, fungal, and viral infections, high fructose corn syrup, certain drugs (such as Fosamax and chronic use of acetaminophen), pesticides such as DDT, Agent Orange (due to dioxin) and Roundup (due to the polyethoxylated tallow amine adjunct), various air pollutants (including diesel fumes, particulate matter, and carbon monoxide), aluminum fluoride, sodium fluoride, industrial solvents such as toulene and benzene, moderate to heavy smoking, psychological stress, and various genes (APOE4, presenilin gene mutations, amyloid precursor protein mutations, for instance). Alzheimer’s disease is not simply a matter of aging, it is a matter of how many factors can contribute to the onset of the disease. The MEND protocol addresses some of these issues.

    Some scientists don’t consider me a researcher. But you don’t only have to invest the time in the lab, you have to invest the time reviewing the literature. By doing the second, you come up with a better understanding of the causes and potential treatments for Alzheimer’s disease.

  37. #43 Jay Onit
    June 26, 2016

    Hi Lane, “various air pollutants (including diesel fumes, particulate matter, and carbon monoxide), ”

    Could you describe the process by which particulate matter and carbon dioxide, get into the brain?

  38. #44 Lane Simonian
    June 26, 2016

    The author of this article clearly and precisely discusses the routes by which nanoparticle air pollutants enter the brain, particularly via the nose and lungs.

    https://student.societyforscience.org/article/nano-air-pollutants-strike-blow-brain

    The section of the health effects of air pollutants on children in Mexico City is of particular interest to me as I am a Latin American environmental historian. Children exposed to high levels of air pollution in Mexico City have diffuse plaques and tau tangles in their brain and exhibit subtle signs of cognitive impairment. But when given cocoa–a peroxynitrite scavenger–their cognitive function slightly improved.

    http://www.ncbi.nlm.nih.gov/pubmed/23986703

    Oxidants (particularly various air pollutants and industrial solvents) working via inhalation are one of the routes to Alzheimer’s disease. Antioxidants –such as eugenol and linalool in various essential oils via inhalation aromatherapy–are likely one of the routes partially out of Alzheimer’s disease.

  39. #46 Murray Duffin
    Sarasota
    August 27, 2016

    The 2016 paper referenced can be found here http://www.aging-us.com/article/9R5JsRe8k4Jq7uTXj/text . The publication linked to in questioning Bredesen’s history (http://retractionwatch.com/2013/10/31/he-said-she-said-journal-of-neuroscience-expresses-concern-but-doesnt-pursue-investigation/ ) is very weak material with which to suggest a questionable history, and seems like a shameful condemnation.
    The main complaint about the 2014 study is largely overcome in 2016 by the provision of actual cognitive test results and/or analytic brain size or chemistry measurements. However the possibility of a sample selected for successful cases only remains valid.
    The concern about a more holistic approach to tests and diagnoses, followed by tailored treatment is misplaced. For 6 of the 10 patients several diagnostic blood test results are given, and there is no common pattern, which clearly supports the idea that there can be many different combinations of systemic chemistry problems that can lead to AD, meaning no monotreatment is likely to be effective in any case and for sure not in most cases. Treatment must be tailored to the specific issues. Patient #9 is especially interesting – none of the items measured are out of the normal range and she is APOE 3/3, so why does she display any cognitive impairment? It seems likely that the problem that triggered the impairment has now “healed”, and she might have been getting better even without the MEND treatment.
    I think ORAC needs to develop a more open mind and recognize the Bredesen is probably onto something very important, but still in very early days.

  40. #47 Jay Wood
    September 29, 2016

    This may shed some light on Breseden’s selection criteria, if indeed there are any, for various approaches. It is a horrifically defective paper that should never have passed peer review:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586104/

    It’s also quite interesting to see that Breseden is now hawking a book in the company of other known quacks such as “Yale’s” own David Katz, with whom SBM has tangled before.

    event.awakeningfromalzheimers.com/trailer-2c/

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