A therapy to reverse cognitive decline

This 2018 human study presented the results of 100 patients’ personalized therapies for cognitive decline:

“The first examples of reversal of cognitive decline in Alzheimer’s disease and the pre-Alzheimer’s disease conditions MCI (Mild Cognitive Impairment) and SCI (Subjective Cognitive Impairment) have recently been published..showing sustained subjective and objective improvement in cognition, using a comprehensive, precision medicine approach that involves determining the potential contributors to the cognitive decline (e.g., activation of the innate immune system by pathogens or intestinal permeability, reduction in trophic or hormonal support, specific toxin exposure, or other contributors), using a computer-based algorithm to determine subtype and then addressing each contributor using a personalized, targeted, multi-factorial approach dubbed ReCODE for reversal of cognitive decline.

An obvious criticism of the initial studies is the small number of patients reported. Therefore, we report here 100 patients, treated by several different physicians, with documented improvement in cognition, in some cases with documentation of improvement in electrophysiology or imaging, as well.”

https://www.omicsonline.org/open-access/reversal-of-cognitive-decline-100-patients-2161-0460-1000450-105387.html “Reversal of Cognitive Decline: 100 Patients”

The lead author commented on Josh Mitteldorf’s informative post A cure for Alzheimer’s? Yes, a cure for Alzheimer’s!:

  1. “We have a paper in press, due to appear 10.22.18 (open access, JADP, I’ll send a copy as soon as available), showing 100 patients with documented improvement – some with MRI volumetrics improved, others with quantitative EEG improvements, others with evoked response improvements, and all with quantitative cognitive assessment improvement. Some are very striking – 12 point improvements in MoCA, for example – others less so, but all also have subjective improvement. Hopefully this will address some of the criticisms that we haven’t documented improvement in enough people.
  2. We were just turned down again for a randomized, controlled clinical trial, so on the one hand, we are told repeatedly that no one will believe that this approach works until we publish a randomized, controlled study, and on the other hand, we’ve been turned down (first in 2011/12, and now in 2018), with the complaint that we are trying to address more than one variable in the trial (as if AD is a single-variable disease!). Something of a catch-22. We are now resubmitting (unfortunately, the IRBs are not populated by functional medicine physicians, so they are used to seeing old-fashioned drug studies), and we’ll see what happens.
  3. I’ve been extending the studies to other neurodegenerative diseases, and it has been impressive how much of a programmatic response there seems to be in these “diseases.”
  4. I agree with you that there are many features in common with aging itself.
  5. You made a good point that APP is a dependence receptor, and in fact it functions as an integrating dependence receptor, responding to numerous inputs (Kurakin and Bredesen, 2015).
  6. In the book and the publications, we don’t claim it is a “cure” since we don’t have pathological evidence that the disease process is gone. What we claim is “reversal of cognitive decline” since that is what we document.
  7. As I mentioned in the book, AD is turning out to be a protective response to multiple insults, and this fits well with the finding that Abeta has an antimicrobial effect (Moir and Tanzi’s work). It is a network-downsizing, protective response, which is quite effective – some people live with the ongoing degenerative process for decades.
  8. We have seen several cases now in which a clinical trial of an anti-amyloid antibody made the person much worse in a time-dependent manner (each time there was an injection, the person would get much worse for 5-10 days, then begin to improve back toward where he/she was, but over time, marked decline occurred), and this makes sense for the idea that the amyloid is actually protecting against pathogens or toxins or some other insult.
  9. It is important to note that we’ve never claimed that all people get better – this is not what we’ve seen. People very late in the process, or who don’t follow the protocol, or who don’t address the various insults, do not improve. It is also turning out to be practitioner dependent – some are getting the vast majority of people to improve, others very few, so this is more like surgery than old-fashioned prescriptive medicine – you have to do a somewhat complicated therapeutic algorithm and get it right for best results.
  10. I’m very interested in what is needed to take the next step in people who have shown improvement but who started late in the course. For example, we have people now who have increased MoCA from 0 to 9 (or 0 to 3, etc.), with marked subjective improvement but plateauing at less than normal. These people had extensive synaptic and cellular loss prior to the program. So what do we need to raise the plateau? Stem cells? Intranasal trophic support? Something else?
  11. I haven’t yet seen a mono-etiologic theory of AD or a mono-therapeutic approach that has repeatedly positive results, so although I understand that there are many theories and treatments, there doesn’t seem to be one etiology to the disease, nor does there seem to be one simple treatment that works for most. It is much more like a network failure.”

At a specific level:

  • “There doesn’t seem to be one etiology to the disease,
  • nor does there seem to be one simple treatment that works for most.
  • We don’t have pathological evidence that the disease process is gone.”

For general concepts, however:

  • “AD is turning out to be a protective response to multiple insults,
  • It is a network-downsizing, protective response, which is quite effective.
  • The amyloid is actually protecting against pathogens or toxins or some other insult.”

For a framework of an AD cure to be valid, each source of each insult that evoked each “protective response” should be traced.

Longitudinal studies would be preferred inside this framework. These study designs would investigate evidence of each insult’s potential modifying effect on each “protective response” that could affect the cumulative disease trajectory of each individual.

In many cases, existing study designs would be adequate if they extended their periods to the end of the subjects’ natural lifetimes. One AD-relevant example would be extending the prenatally-restraint-stressed model used in:

The framework would also encourage extending studies to at least three generations to investigate evidence for transgenerational effects, as were found in:


Epigenetic transgenerational inheritance mechanisms that lead to prostate disease

This 2019 Washington rodent study found:

“Ancestral exposure to the toxicant vinclozolin induces an epigenetic transgenerational increase in susceptibility to prostate pathology in F3 [male great-grandchildren] generation rats. These results are in agreement with previous studies which found a transgenerational increase in rates of prostatic epithelial atrophy, cystic hyperplasia, and prostatitis in the transgenerational F3 and F4 [male great-great-grandchildren] generations after exposure of F0 [great-great-grandmother] generation pregnant rats to vinclozolin. These effects were accompanied by transgenerational changes in mRNA expression in F3 generation ventral prostate epithelial cells.

A number of previous transgenerational studies have shown no ventral prostate histopathology or disease detected. Therefore, observations suggest ancestral exposure specificity in the ability to induce the transgenerational inheritance of prostate disease.

There was also no increase in prostate histopathology in the directly exposed F1 [male children] or F2 [male grandchildren] generation vinclozolin lineage rats compared to controls.

prostate pathology

The mechanism by which epigenetic transgenerational inheritance affects prostate epithelium involves control of gene expression by DNA methylation and lncRNAs. It will be necessary to determine the exact gene targets of these epigenetic modifications to determine further mechanisms.

Future studies need to investigate if similar mechanisms are at work in human males who have adult-onset BPH or prostate cancer. Ancestral exposures to toxicants and epigenetic transgenerational inheritance may contribute to the development of prostate disease in men today.”

The study’s above bolded sentence added to the evidence that epigenetic effects may skip generations. A study by the same group, Epigenetic transgenerational inheritance of ovarian disease, found in females:

There was no increase in ovarian disease in direct fetal exposed F1 or germline exposed F2 generation vinclozolin or DDT lineage rats compared to controls.

A disturbance in the paradigm of child abuse referenced other studies that found generation-skipping effects.

Serious researchers are closer to discovering evidence for precise mechanisms of epigenetic transgenerational inheritance. It’s well past time that other researchers performing studies like Burying human transgenerational epigenetic evidence take their work seriously enough to truly investigate human evidence for epigenetic transgenerational inheritance.

What are more important funding priorities than such human studies?

https://www.nature.com/articles/s41598-019-38741-1 “Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Prostate Pathology and Stromal-Epithelial Cell Epigenome and Transcriptome Alterations: Ancestral Origins of Prostate Disease”

Disproving the cholesterol paradigm

This 2018 review presented evidence that:

“For half a century, a high level of total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) has been considered to be the major cause of atherosclerosis and cardiovascular disease (CVD), and statin treatment has been widely promoted for cardiovascular prevention. However, there is an increasing understanding that the mechanisms are more complicated and that statin treatment, in particular when used as primary prevention, is of doubtful benefit.

The authors of three large reviews recently published by statin advocates have attempted to validate the current dogma. This article delineates the serious errors in these three reviews as well as other obvious falsifications of the cholesterol hypothesis.

Our search for falsifications of the cholesterol hypothesis confirms that it is unable to satisfy any of the Bradford Hill criteria for causality and that the conclusions of the authors of the three reviews are based on:

  • Misleading statistics,
  • Exclusion of unsuccessful trials and by
  • Ignoring numerous contradictory observations.

The association between the absolute risk reduction of total mortality in 26 statin trials [squares] included in the study by Silverman et al. and in 11 ignored trials [triangles] and the year where the trial protocols were published. The vertical line indicates the year where the new trial regulations were introduced.

In 2004–2005, health authorities in Europe and the United States introduced New Clinical Trial Regulations, which specified that all trial data had to be made public. Since 2005, claims of benefit from statin trials have virtually disappeared.

This paradigm was proven wrong eighty years ago! How much longer will its harmful consequences continue?

https://www.tandfonline.com/doi/full/10.1080/17512433.2018.1519391 “LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature”

An hour of the epigenetic clock

This 2018 presentation by the founder of the epigenetic clock method described the state of the art up through July 2018. The webinar was given on the release day of The epigenetic clock now includes skin study.

Segments before the half-hour mark provide an introduction to the method and several details about the concurrently-released study. The Q&A section starts a little before the hour mark.

Stuck in the wrong paradigm

This 2019 article questioned the paradigm of determining substance carcinogenicity:

“In the absence of robust epidemiological data, the final arbiter of whether a chemical is considered to be a carcinogen or not has been based on the outcome of long-term rodent bioassays. This approach is incompatible with the current knowledge of the etiology of cancer. The current view of the etiology of cancer suggests that it is not useful to consider carcinogenicity as a single hazardous property with its own hazard category.

There is no bright line between carcinogens and non-carcinogens but rather there is a continuum with some chemicals having high potential, some having no potential, and others having potential at a point along the continuum. This continuum exists alongside other adverse effects. One problem is being stuck in the old practice of wishing to reproduce the binary “carcinogen/non-carcinogen” results of the long-term bioassay rather than move to a new paradigm in assessing the chemical’s position on the spectrum of carcinogenic potential.

The two-year bioassay has such high variability (because of the variability of the carcinogenic process it is trying to measure and the interplay between dose limiting toxicity and cell proliferation inducing toxicity) that the outcome of the assay for compounds with low to intermediate carcinogenic potential is little more than a lottery. After half a century, it has only been used to evaluate less than 5% of chemicals that are in use. It is not reproducible because of the probabalistic nature of the process it is evaluating combined with dose limiting toxicity, dose selection, and study design.”

Unscientific research paradigms will eventually collapse because they can’t withstand the scrutiny of the scientific method. Too bad the coauthors didn’t kill off this one while they were still in positions at the U.S. Environmental Protection Agency, World Health Organization, etc.

https://www.sciencedirect.com/science/article/pii/S0273230019300248 “Chemical carcinogenicity revisited 2: Current knowledge of carcinogenesis shows that categorization as a carcinogen or non-carcinogen is not scientifically credible” (not freely available)

Random events

This floated into my backyard overnight:

Later, from Turn of a Friendly Card:

Time flowing like a river
Time beckoning me
Who knows when we shall meet again
If ever
But time keeps flowing like a river
To the sea

Goodbye my love
Maybe for forever
Goodbye my love
The tide waits for me
Who knows when we shall meet again
If ever

But time keeps flowing like a river
On and on to the sea
To the sea
Til it’s gone forever
Gone forever
Gone forevermore

Goodbye my friend
Maybe for forever
Goodbye my friend
The stars wait for me
Who knows where we shall meet again
If ever

But time keeps flowing like a river
On and on to the sea
To the sea
Til it’s gone forever
Gone forever
Gone forevermore

Epigenetic causes of sexual orientation and handedness?

This 2018 Austrian human study subject was various associations of prenatal testosterone levels to fetal development:

“The available evidence suggests, albeit not conclusively, that prenatal testosterone levels may be one cause for the association of sexual orientation with handedness. Associations among women were consistent with predictions of the Geschwind–Galaburda theory (GGT), whereas those among men were consistent with predictions of the callosal hypothesis. However, research on the associations between sexual orientation and handedness appears to be compromised by various methodological and interpretational problems which need to be overcome to arrive at a clearer picture.

The GGT posits that high prenatal testosterone levels cause a delay in the fetal development of the left cerebral hemisphere which results in a right-hemisphere dominance and hence in a tendency for left-handedness. According to the GGT, high prenatal testosterone levels entail not only a masculinization of the female fetus, but also a feminization of the male fetus (contrary to neurohormonal theory). Overall, the male fetus is subjected to higher levels of intrauterine testosterone than the female fetus. The GGT is thus consistent with the higher prevalence of left-handedness among men than among women.

The callosal hypothesis applies to men only and assumes, in line with neurohormonal theory, that low prenatal testosterone levels are associated with later homosexuality. According to the CH, high prenatal testosterone enhances processes of cerebral lateralization through mechanisms of axonal pruning, thereby resulting in stronger left-hemisphere dominance and a smaller corpus callosum. Consistent with this, women have a larger corpus callosum than men.”

The study’s Limitations section included the following:

  1. “Limitations of the current study pertain to the self-report nature of our data. Behavioral data may provide differing results from those obtained here.
  2. Assessment of sexual orientation relied on a single-item measure. Utilization of rating scales (e.g., the Kinsey Sexual Orientation Scale) or of multi-item scales, and assessing different components of sexual orientation, would have allowed for a more fine-grained analysis and for a cross-validation of sexual orientation ratings with sexual attraction.
  3. Albeit both our samples were large, the proportions of bisexual and homosexual individuals were, expectedly, only small, as were effects of lateral preferences. Thus, in analysis we could not differentiate bisexual from homosexual individuals. Bisexual and homosexual individuals may differ with regard to the distribution of lateral preferences.
  4. Some effect tests in this study have been underpowered. Independent replications with even larger samples are still needed.”

The largest unstated limitation was no fetal measurements. When a fetus’ epigenetic responses and adaptations aren’t considered, not only can the two competing hypotheses not be adequately compared, but causes for the studied phenotypic programming and other later-life effects will also be missed.

https://link.springer.com/article/10.1007/s10508-018-1346-9 “Associations of Bisexuality and Homosexuality with Handedness and Footedness: A Latent Variable Analysis Approach”