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 . This treatment is based on connectomic studies  and previous transgenic findings  as well as epidemiological studies of various monotherapeutic components of the overall program . 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 ). 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.