Organ transplant patients may not get dementia
trevorklee.com
trevorklee.com
Wow, was I ever wrong. This article says it's not too uncommon for people to live 30 years after their transplant. Other articles say that even the obese are eligible for transplantation now. Very impressive.
https://wexnermedical.osu.edu/blog/how-long-do-transplanted-...
That being said, I know life extension and nootropics and all that jazz is a really popular topic with tech bros, so its worth noting the side effects of calcineurin inhibitors are really bad.
It's also neat ciclosporin was isolated from some scandanavian fungus living in the soil. Makes me sad thinking about how once we are able to significantly understand and appreciate genetics and related biotechnology later this century, half of the species on earth will already be gone, their amazing biological traits and compounds lost forever.
I would be interested in whether it's survivorship bias, or lack of in this case.
I learned yesterday that a heart has a shelf life of about 6 hours and liver is 12
https://en.wikipedia.org/wiki/Organ_donation#Opt-in_versus_o...
Another fun fact. The US government spends more on dialysis than the budget for NASA.
Which is precisely the reason such sales are outlawed worldwide.
Are Iranian kidney donors the ones getting scammed?
If we enticed poor people to sell their kidneys, some percentage of them would wind up needing kidneys again without an ability to pay for them.
This turns into a kidney marketplace where the rich win out over the poor.
FCFS with triage based on need, immunocompatibility, and health outcome is the most equitable model.
In theory. In practice rich people can jump ahead the line no matter what system. I.e. Steve Jobs and the liver that went to waste.
https://www.cnn.com/2009/HEALTH/06/24/liver.transplant.prior...
Diabetes and uncontrolled high blood pressure are the top cause of kidney failure. These two conditions are far more common in the poor, and far more likely to be poorly managed.
Also if the price of a kidney relative to median income in the U.S. was similar to Iran, then a kidney would cost $15,000. This is expensive but still far cheaper than dialysis. And there is no reason an ACA plan or Medicaid wouldn't pay for it.
Same could be said for gambling and sales tax.
Sadly, economics dictate a lot of people's health is going to be like. Living/Work conditions lifestyle, diet are all influenced by wealth.
Poor people work most of the dirty and unhealthy jobs that significantly cut short life spans. Wealth and lifespans are known to be strongly correlated.
As countries we are perfectly comfortable reserving vaccines blocking poor countries with patents, polluting a lot more or exploiting their labor in terrible conditions we wouldn't tolerate. Compared to what we are willing to accept already this doesn't seem worse.
If a commercial system could save more lives(probably more likely rich) it is not that much worse for poor than it already is.
I recently contracted a shiga toxin producing E. coli strain which was cultured from my bowels. I also cultured entericocci (ETEC) but that’s not relevant to the discussion. I am lucky Shiga toxin E. coli (remember this famous Jack In The Box Breakout, FTW https://en.m.wikipedia.org/wiki/1993_Jack_in_the_Box_E._coli... ) did not affect my kidneys.
I am a dual US|European Union (Croatian) national. Croatia has one of the highest (ethical) transplant rates in the world. Let it be known that I would get it in Croatia over the USA.
I've heard it said that "you're not dead until you're warm and dead", but 6-12 hours doesn't seem like a lot of time, to make sure you're not coming back.
e.g., I drown in an icy pond, and I'm found after 5 hours. I might be revived, I might not...but the heart only has an hour before it's toast.
The longest human is known to be revived is only in the range 10-15 minutes. Brain damage is quite likely at this point. The longest for an animal is for cat - 1 Hour.
Only clinically dead people are eligible for organ transplantation
> Reduced body temperature, or therapeutic hypothermia, during clinical death slows the rate of injury accumulation, and extends the time period during which clinical death can be survived. The decrease in the rate of injury can be approximated by the Q10 rule, which states that the rate of biochemical reactions decreases by a factor of two for every 10 °C reduction in temperature. As a result, humans can sometimes survive periods of clinical death exceeding one hour at temperatures below 20 °C.[20] The prognosis is improved if clinical death is caused by hypothermia rather than occurring prior to it; in 1999, 29-year-old Swedish woman Anna Bågenholm spent 80 minutes trapped in ice and survived with a near full recovery from a 13.7 °C core body temperature. It is said in emergency medicine that "nobody is dead until they are warm and dead."[21] In animal studies, up to three hours of clinical death can be survived at temperatures near 0 °C.[22][23]
I'd rather not be harvested too quickly, when I could have been revived without issue.
Also even if revied would you even want to ? While anna as an exception didn't suffer from brain damage , it is likely, and even she had long term issues with nerve function paralysis etc.
Anna and other similar cases are a extreme rarity. policy shouldn't be made basis a one in a million chance, that's why we have vaccines enforced for example.
You can always opt-out or not opt-in depending in on jurisdiction I am sure.
There are plenty of people who opt for cryogenic storage after they die in the hope technology will evolve to revive them. That's natural step to this argument in a way , what if I could be revived some day even if not today ?
Ultimately handling life and death are intensely personal choices.
Well, that's the thing. "warm and dead" is above and beyond the criteria you referenced earlier, "clinical death". I'd hope you're right, but I'm not convinced you are. It doesn't seem like it from what I've seen.
And, the cooling factor in brain damage prevention is becoming more widely known these days. Anna wasn't just a fluke.
According to that article, clinical death != warm and dead.
[0] is the Australian College of Intensive Care guidelines on organ harvesting. There are strict criteria around when a person is considered dead and for organ donation that means brain death.
I’m not sure what you’re worried about, this was easily discoverable - clinical death is not the criteria that is used for the determination of organ donation eligibility
[0] https://csds.qld.edu.au/sdc/Provectus/ELI/Module%202%20-%20O...
No, I'm asking a question and having a discussion, and you decided to jump in with your hostile skepticism that's completely unwarranted. Chill out.
No, there's a tone of 'exactly how dead is dead'. If you look at the other commenter, sometimes doctors jump the gun.
> far from ‘I’m interested in this topic and would like to have a discussion to learn more’ as a QAnon follower is from a PhD student
Congrats, you've managed to drag in completely unrelated politics.
You're assuming the worst of me. You're comparing me to a Qanon follower, apparently. You're giving (unfounded) credit to a commenter who called me a 'covid vaccine denier'. Seems like you're implying that I'm not acting in good faith.
It's like you're looking for people that fit your preconceptions, and shoehorning me into it. That's prejudice, plain and simple. Chill out.
No, they don't - you made a misunderstanding which perpetuated a line of questioning which isn't a practical concern. Brain Death + other criteria depending on jurisdiction is a pre-requisite for cadaveric organ donation
As to the rest, you have approached this from the perspective of 'prove to me that X doesn't happen' which is perilously close to that of the antivax/antiscience brigades.
I apologise for thinking the worst of you but I wasn't the only one which perhaps reflects on the approach you have taken in your line of questioning in these highly polarised times
> you have approached this from the perspective of 'prove to me that X doesn't happen'
There's absolutely nothing wrong with that. If I'm thinking of buying a power tool, then 'prove to me that <rapid unplanned disassembly> doesn't happen' is an appropriate tone, and exactly the kind of skeptical questioning that should take place: it's my problem if the problem happens.
I don't care what kind of political climate we're in; you don't get to tell me what kinds of questions I'm not supposed to ask.
Doctors occasionally jump the gun: https://www.fox6now.com/news/father-accused-in-hours-long-st...
If it did, heart transplants wouldn’t work at all.
Motorcycles are sometimes called "donorcycles" because of the high likelihood that any given crash will be fatal, and that the rider is young and healthy and thus a highly desirable source of transplant material.
Only by ghouls.
But calling names the other way won't help and I can see why the donorcycle term has stuck. There is enough of an element of truth to make it stick.
Florida motorcyclists are not generally required to wear helmets. Therefore they more efficiently get to the "donor" stage.
Riding a motorbike is amazing fun, but if you ride long enough, something terrible will happen. Every rider has a story of an accident. Although you are more manoeuvrable than a car, can get out ahead of traffic, are smaller, can see more, and are more keenly alert... a little tap you'd hardly notice in a car can kill you.
In a car you tend to hurt other people including any kids, etc that may be along for the ride.
As per sibling comment, maybe the only reason they are tolerated is that the risk is statistically largely to the rider themselves.
IE the person taking the risk is largely the target of the consequences.
If motorcycles somehow magically penetrated into peoples cars in a crash I think people would rule them out pretty quick.
While fatalities per passenger-mile may be 24x cars (as below), you have to realize that the population riding motorcycles in the U.S. is not a random sampling. These people aren't trying to get around, they're acting out an image. For that behavior I don't blame them, but it is what it is.
Anecdotally, a little less than half of U.S. motorcyclists are fat, bald, drunk dudes riding Harleys or Harley look-alikes with the legal minimum protective gear (which in some states is none at all), while another little less than half are young, shirtless dudes on sportbikes. To their credit, they are wearing full-face helmets (because you can't go 200mph without one). Also, something like half of motorcycle fatalities involve alcohol[0]. Yikes.
<10% of motorcyclists are riding reasonable, well-maintained bikes with a modicum of skill and all of the proper protective gear.
So while motorcycling qua motorcycling may be more dangerous than driving a car per vehicle-mile, the difference is probably a lot smaller when controlling for differences in the behavior of people doing it. To put it in perspective, in the U.S., if motorcycling is ~30x deaths per vehicle mile compared to cars, bicycling is ~20x (though you do get exercise, which extends your life). And miles per motorcycle (or bicycle) are << miles per car per year in the U.S. People don't realize, but moving to the suburbs and driving everywhere vs. living in the city is taking the same sort of risk one might by motorcycling. </rant>
Patients living 7 years instead of dying in short order is a pretty good trick for doctors to be working. For pessimism to make sense, there needs to be some better option than that available.
A dead 40 year old, regardless of whether they had a transplant at 30 or not, is probably not going to have dementia.
I would hope that would be before any right-weight candidate had been ruled out. Otherwise it's grossly unfair.
Nonetheless, would it be unfair to give transplants to manual laborers and motorcycle riders as their chances of dying early are high?
Another side effect of cyclosporin is increased hair growth. Every where. I shaved my ears while taking it. I saw women on cyclosporin growing beards.
The person(s) who figure out why will become very rich. Imagine a rogaine (minoxidil) that actually worked.
I've shared this tidbit a few times. I've met (socially) a few people working in pharma. One was even working on hair growth.
I don't think anyone I've told ever believed me. It's so weird how silos increase as knowledge expand.
The other side effects of cyclosporin truly suck. I doubt I'd ever use it off-label, in hopes of saving some brain cells.
But I hope someone can learn from cyclosporin and maybe find alternatives.
There is a much more direct causal link as auto-immunity has been implicated in AD progression for years, e.g. [1-11]. I can't find the paper right now, but I once saw a very compelling longitudinal study where they regularly measured cognitive performance as well as several immunity markers in older subjects. Basically, every transient increase in antibody levels (IIRC, but they may have been tracking some other marker of immune system activation) was followed by a step decline in cognitive performance.
[1] Lopez (1991) Serum auto-antibodies in Alzheimer's disease
[2] Aisen (1996) Inflammation and Alzheimer disease
[3] D'Andrea (2005) Add Alzheimer’s disease to the list of autoimmune diseases
[4] Carter (2010) Alzheimer's Disease: A Pathogenetic Autoimmune Disorder Caused by Herpes Simplex in a Gene-Dependent Manner
[5] Reddi et al (2011) Autoimmunity in Alzheimer’s disease: increased levels of circulating IgGs binding Aβ and RAGE peptides
[6] Sardi et al (2011) Alzheimer's disease, autoimmunity and inflammation. The good, the bad and the ugly
[7] Marchese (2013) Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease
[8] Li et al. (2018) Dementia and Alzheimer's disease risks in patients with autoimmune disorders
[9] Arshavski (2020) Alzheimer’s Disease: From Amyloid to Autoimmune Hypothesis
[10] Itzhaki et al (2020) Do infections have a role in the pathogenesis of Alzheimer disease?
[11] Lim et al (2020) Alzheimer Disease Pathogenesis: The Role of Autoimmunity
The point the authors were trying to make is that if you have AD, any inflammation, even asymptomatic ones, will potentially worsen your cognitive performance. The most interesting feature of that graph was to me that the cognitive performance actually remained fairly constant in between infections/inflammations, and decline was not gradual but in a step-wise fashion.
[0] https://en.wikipedia.org/wiki/ISRIB
Maybe in bread heavy cultures it's not a widespread issue because the majority of people have evolved some kind of resistance?
The fact we stick around for so long is because having healthy grandparents is still beneficial to grandchildrens' survival.
Fermented foods, which are largely considered good for heath, are full of yeast.
So you could refine that last bit to
> We're taxing and confusing our immune systems by eating.
if that were truly the case.
Well this is not wrong. I'm no expert, but it seems as though not eating (or drinking) would result in less need for inmune system activity, at least in the digestive track. Of course, you'd die, but maybe that was the cost of healthy living all along
Fermented foods and mushrooms can be good at fighting cancer precisely because they ramp up the immune system. In fact yeast is used as an adjuvant inside of vaccines for this purpose.
What's insane is that it is both known and not known that yeast causes inflammation by science. Used as adjuvant, used to "boost" immunity, yet not understood to be a cause of general low-grade systemic inflammation when in our food supply.
Opportunistic Strains of Saccharomyces cerevisiae: A Potential Risk Sold in Food Products https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705302/
Though I guess it will have as much wild yeast land on it as any other food in your plate but I don't think that's what the parent comment was referencing.
Source: I've been involved in small commercial cheese making for years.
For example, Dectin-1 is one of many innate cellular receptors that launch inflammatory responses when Bread yeast (and others) is detected (and possibly 1,3 beta glucans from wheat). We are in a genetic war with saccharomyces cerevisia, inside of our DNA. And not just us, all animals need to be in this war, because otherwise we'd die.
https://en.wikipedia.org/wiki/CLEC7A
So if all this is true, does it make sense to put yeast extract in your gravy tonight?
I can easily imagine someone with a genetic trait that malforms a single protein could end up with a heritable sensitivity to one particular yeast strain, and not all yeast, everywhere.
African sleeping sickness is an infection that results in a person going into a kind of coma. The parasite constantly changes its molecular interface with the host which is supposed to confuse the hosts immune system. This places a huge burden on the immune system and results in the host becoming hungry all the time, despite already being full. These patients will stuff themselves while growing progressively more tired. And eventually they fall asleep permanently. Inflammatory signals slow metabolism or something to that effect and this change in metabolism causes the body to feel as though it’s starved of energy and so the patients feel hunger. Inflammation and metabolism are linked.
A man with schizophrenia was cured after a bone marrow transplant. The New York Times wrote about it recently. Symptoms of age including cognitive decline have been reversed in mice and humans through blood dilution/ blood transfusion probably due to reduction in the concentration of inflammatory molecules in the blood that are produced by ones own body. Inflammation/metabolism is the biggest medical revolution on the horizon. Especially since COVID has made it a grant-worthy topic now and doctors can’t deny that chronic fatigue syndrome is real anymore. It’s funny how all those people who insisted that CFS wasn’t real are now nowhere to be found to answer for their mistake.
Oh a many of them are still out there. Now pushing CBT and GET as a cure all for Long COVID.
I can understand why a neurologist would suggest CBT. All my wife's test results are normal, so the neurologist has no remedies available. People do get psychosomatic illnesses, and in those cases CBT does help. That doesn't mean that my wife has a psychosomatic illness, but there's no test for that either - can't hurt to try
(FWIW this is not the way my wife saw it - she was pretty furious and felt like the neurologist was demeaning her condition)
They all recovered after B1 in form of TTFD plus supporting therapy.
You don't know what tests were done, you don't know any of her other symptoms. I don't understand how you can be "pretty sure she is thiamine deficient".
If you are right and she can fix a year of misery by taking an over-the-counter supplement then I will be over the moon, but in order to convince her to try yet another remedy-suggested-by-someone-on-the-internet I'd like to hear more about your diagnosis
Indicating that this is a neurological problem.
>you don't know any of her other symptoms
I can only imagine as you did not communicate them. But let me guess: fatigue, brain fog, possibly panic attacks, tingling/burning sensations in feet or hands, limbs numbing especially at night, the sensation of suffocation or dissatisfaction with breathing, the sense of a blocked nose while there is no stuff in there, headaches, spatial disorientation, loss of short-term memory, impacted ability to speak and learn new things, GI and cardiovascular issues. All that while having a normal (>= 96%) O2 saturation in the blood.
>I don't understand how you can be "pretty sure she is thiamine deficient".
She may have an acquired mitochondrial dysfunction caused by the oxidative stress induced by the active phase of illness. Which is unfortunately pretty typical for Covid [1] and 30% of survivors will have metabolic and neurological complications as the result, regardless of the severity of the original illness.
This is the first thing to check given the symptoms, but most of neurologists are unaware of it yet. You can do a formal test that checks for that condition: transketolase.
I am also including some materials that might help: [2], [3]
[1] https://journals.physiology.org/doi/full/10.1152/ajpcell.004...
I can also totally understand why a neurologist would suggest CBT, because as you say, they find nothing, and thus have nothing else to offer.
But it's clearly not just psychosomatic, so think-yourself-better like CBT can hurt and will hurt, because it won't work.
Current thinking - among numerous researchers (and fwiw, her specialist) - is that endothelial damage is causing long covid symptoms. There is some progress towards identifying the cause, if not the treatment, yet.
Hope that helps some.
https://www.timesofisrael.com/covid-pieces-that-trigger-stro...
https://academic.oup.com/eurheartj/article/41/32/3038/590115...
https://pubmed.ncbi.nlm.nih.gov/34375505/ https://www.degruyter.com/document/doi/10.1515/labmed-2021-0...
Or is CFS now an acceptable term for things like 'long COVID' ?
A few years ago, I had a fun experience - all of a sudden, I was absurdly exhausted (not just "tired", but "physically could not reliably get out of bed sometimes") from the time I woke up to the time I went to sleep, independent of how much I was sleeping (or the quality of the sleep), or what I ate, or [...]. I didn't have headaches, or fever, or anything else, I was just perpetually exhausted.
As it turns out, I came back with a suddenly positive mono test where I had never had one before, and once a few weeks passed, it did too. But it gave me some reference for how it feels to be perpetually not just mentally but physically exhausted, with the potential of it never ending (since mono can have permanent repercussions, as someone I know discovered).
I think "post-viral syndrome" is the term getting traction now for "long COVID" and post-mono consequences and the like, but AIUI the criteria are the same save CFS not requiring an infection as a trigger event.
There is no probably here. The experiment is real and its results too, but the underlying mechanism is being hotly debated with no clear favorite. One of the competing explanations is dilution of badly folded albumine.
"Blocking complement function by deleting C3 rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in TauP301S mice, improving neurophysiological and behavioral measurements. In addition, C3 protein is elevated in AD patient brains, including at synapses, and levels and processing of C3 are increased in AD patient CSF and correlate with tau."
An earlier cohort study[1] of nearly 100k humans said "Low baseline levels of complement C3 were associated with high risk of AD"
1: https://pubmed.ncbi.nlm.nih.gov/30243924/ 2: https://www.cell.com/cell-reports/pdf/S2211-1247(19)30964-7....
The immune system is a crazy thing about which the medical community knows far less than one would think. There's some fascinating potential in there if it can be well-understood (not just 'hacked').
This is just an album that was inspired by what James Leyland Kirby (The Caretaker) read on dementia. It does not have anything to do with actually experiencing dementia.
We have works of art that allude to or generate all sorts of human feelings. While perhaps "the real deal" would be a piece of music written by someone who was actually going through the ordeal themselves it absolutely reminds me of collections of paintings or books created by artists with progressing dementia.
As someone who lost a family member to it, I couldn't stand to listen to much of the album because it is just too on the dot.
The music's coherence and form very gradually breaks down in an unsettling way as an abstract metaphor for the neurological dilapidation. It's of course nothing at all like the experience itself, but it's just an attempt to artistically portray it very abstractly and indirectly.
(Side note: I was actually never a fan of this album or its concept after seeing it saturate music forums over the past several years, and all its associated "this album broke me" memes made me consider it pretentious and melodramatic, but the process of writing this post somehow changed my opinion.
I think maybe because I suddenly found myself in the frame of feeling compelled to defend it from what I felt was an overly unfair and dismissive critique and became aware of my own cognitive dissonance. I suppose that's one way HN's stereotypical pessimism and negativity also has some benefit. I could see myself in the mirror of your post and I didn't like what I saw.)
[1] https://www.bbc.com/news/uk-england-beds-bucks-herts-3554369... [2] https://www.wbay.com/2021/06/29/green-bay-man-nations-longes...
> Calcineurin inhibitors and azathioprine have been linked with post-transplant malignancies and skin cancers in organ transplant recipients. Non-melanoma skin cancer (NMSC) after kidney transplantation is common and can result in significant morbidity and mortality. The results of several studies suggest that calcineurin inhibitors have oncogenic properties mainly linked to the production of cytokines that promote tumor growth, metastasis and angiogenesis.
Bummer
And each type of organ has different priority criteria. Kidneys for example you have a wait time and compatibility score. Liver is by MELD score and how healthy the person it (sick enough to need it but not too sick!)
Also a lot of transplant patients fall under Medicare and are not rich at all.
My experience. Had out of control undiagnosed autoimmune condition.
Started developing major dementia.
Eventually (20 years) got autoimmune diagnosed and under control. Also started blood thinners. Dementia resolved quickly.
Here's some pseudoscience, you may also find the parent comment interesting.
What are the chances of a random control group of 14 over 85 year olds also not getting dementia?
If it's very common, and you would usually expect 7 of them to develop dementia, then 0 cases in the test group is potentially impressive. If it's quite rare and you would usually expect only one of the control group to get dementia, then it's not that impressive that the test group had 0, and easily down to chance
so we could expect about 5 people with dementia in that control group, and the test group got 0, so not bad
First, transplants are about as close to a life-changing miracle as you can imagine. By which I mean night and day change for a reasonable subset of patients. The fact that we now have anything like access to interchangeable parts that can let people live extremely normal lives is absolutely remarkable. Before transplant there were times when I was too weak to walk. One month after transplant I could walk a mile, three months after five miles.
There is zero question I'd be dead by now without my transplant. I might have lived a year or so more with my old one, but it would have been an unpredictable high-wire act between GI bleeds, encephalopathy, coma, and fear that any simple action might trigger an emergency trip to the emergency room. Internal bleeding and encephalopathy put my in a coma for three days and, when I came out, this PhD computer scientist couldn't remember my own kids' names. Now I'm writing this. I am simply so fortunate to be able to have this second chance in life.
As for the misleading parts, "Organ transplant patients are, by their nature, sick patients." Yes, but that's why they get transplants. Many get better. Look at livers. Viral hepatitis (in my case, Hep C) is one of the most common reasons for liver transplant. But we can cure Hep C. I was one of the first people cured before transplant with Gilead's Hep C antivirals. The new liver fixed my cirrhosis. Now I get sick less often than my kids, and my life is extremely normal except for a couple pills a day (tacrolimus) and lab tests every three months. I was a mild hemophiliac, and that was cured by the new liver as well.
If you looked at my lab tests, besides a low platelet count, I would look perfectly normal. And especially for livers, which deal with processing a lot of foreign substances in the body, so it probably more tolerant than other organs, the lifespan on them may be quite long. Older liver transplant patients can sometimes even drop their immunosuppressants completely.
So, for people who have curable diseases, the health of a transplant patient can be quite good, potentially better than their peers. There's no specific reason they as a single less healthy class (as opposed to a set of classes, which also includes people who abuse alcohol or have diseases we can't cure).
To answer some other questions in the discussion, the transplant process tries hard to keep someone from being able to literally buy their way onto the transplant list. For livers, priority of transplant goes by a lab test called MELD which estimates 90 day mortality. You have to be sicker than other people but healthy enough not to waste an organ. It's a fairly macabre competition.
There are, however, advantages to those with means. In the US, organ transplant is administered nationally but organs are still basically allocated regionally. If you can travel to another region in the country with a surplus of organs, you can get a transplant sooner. I did it. It saved my life.
You also need to go through a battery of tests to make sure you are, basically, a good host for the rare organ. In general you have to stop substance abuse. You need to lose weight. You need to take a physical which can disqualify you. You need to have a social support mechanism to help take care of you after surgery (in the hospital, after discharge, and long term).
Finally, you need to have insurance that will cover the potentially million dollar surgery and and complications that might follow. And that means there's another hidden process that happens in the insurance company to assess whether you're a good risk or not.
Most of those conditions strictly require wealth. All of them benefit from it, especially access to health care. On the other hand, it isn't clear that access to health care is strongly correlated with an absence of dementia, is it?
This is the exact reason dementia / Alzheimer’s research is littered with dozens of high-profile failed clinical trials; after billions and decades poured into this area and nothing to show.
I would be interested to see non-murine, primate-based(?) clinical findings before I get my hopes up again. We have seen this pattern too many times; a compelling agent, pathway, or signaling mechanism is found, targeted, and shows great promise in mice, even sometimes in primates. And once we get to human trials it fails because we cannot replicate dementia accurately in these test vehicles.
If I was born 15 years later I'd probably have gone into that field of study as it probably makes the most fiscal sense - from a national medicine standpoint - to combat these disorders and diseases at the actual source.
I wonder if there's been a metastudy on the median lifespan going up and incidence of these cognitive or neurological disorders. That is, now that humans on average are living longer, perhaps our diets are more important; and with his knowledge we can get some enhancements on regulations from the FDA or something.
Next study, designed for comparing transplantation correlation to dementia, should use a dementia scale before and after the trasplant.
The article is not a scientific paper. I hope scientific papers were so honest about conflict of interest and autocritic as this author is in this article.
This basically reads as "I got a masters in molecular bio, have never worked in the field, and want you to give me money for my next crackpot idea". That doesn't mean the idea is wrong, but this guy isn't the one who's gonna make it happen.
yes because we don't care if our software breaks every five minutes and if its clobbered together by people who have no idea what they're doing because 99% of the time it's just consumer gadgets anyway. If you deal with technologies that affect people's health that's not really how things work, or in any other serious engineering discipline.
If the semiconductor or aeronautics industry would work like the software industry your computer wouldn't boot up and the planes would double their fuel consumption every year
Yeah, you're not really gonna get away with an "oopsie woopsie!! we made a widdle fucky wucky! our elves are working vewy hard to fix this!" after you kill a few people due to negligence.
It would be hard to overstate how complicated the nervous and immune systems are. On top of the biology, the provision of medical care is also absurdly complex: there are all sorts of biases in how patients are treated, some of which turn into feedback loops. An early heart transplant might stave off vascular dementia, while a patient with severe dementia might not be eligible for transplants at all.
It is certainly possible for a new person to notice something that people already working in the field have missed. At the same time, domain knowledge is worth a lot, especially when trying to figure out if a relationship seen in messy, observational data is real. I'd be skeptical either way, but collaborating with a more established team would help a little bit.
I don't think that software, in general, has quite so many foot-guns laying around. However, people do give similar advice for cryptography and (sometimes) machine learning because those fields do offer a number of subtle ways to really foul things up.
From what I can tell, this is a humble, curious, and well-meaning guy that funds his menagerie of research interests with a successful tutoring business (a noble career in and of itself). I see absolutely no need to frame him as an unworthy crank.
> So, first of all, the confession: I’m not a neutral observer here. In talking about this paper, I’m talking my own book. My company, Highway Pharmaceuticals, is currently raising funds to get a safer, easier to use, extended-release version of cyclosporine, the most common calcineurin inhibitor, into first-in-human trials. If this paper is correct, investors should probably consider throwing money at me.
I don't think anyone needs credentials to have an interesting idea, but it's laughable that someone with no lab or research or business experience is an actual player in this space. I guess people can invest in him if they want. The idea that he's fundraising for human trials is laughable.
I'm afraid it appears so.
The article says they contacted the authors of both publications but haven't got a response back yet. Relevant bit:
"For my own part, I’ve contacted authors of both papers, but haven’t received substantive responses from either. I’ll update this post when/if I do."
Congrats, your kidney's been replaced and you'll have to be on immunosuppressants for the rest of your life, but at least you won't get dementia.
Curious why that isn't mentioned in the article as a contributing factor.
Rapamycin also does not have any evidence of efficacy on neurodegeneration, while there's evidence for CNI on other forms of neurodegeneration.
*Mild tremor is common with both cyclosporine and tacrolimus use, occurring in 35 to 55 percent of patients [ 79,80 ].
*Rarely, patients develop severe headache, visual abnormalities, and seizures. This syndrome is associated with acute hypertension and resembles hypertensive encephalopathy [ 77 ].
*Posterior leukoencephalopathy is usually seen on brain imaging [ 82 ].
*Cyclosporine may contribute to bone loss after organ transplantation [ 88 ]; this effect may be due to the induction of high bone turnover.
*Cyclosporine can cause hyperkalemia and hypomagnesemia, via effects on renal tubular function. Hyperuricemia and exacerbation of gout are well-described with cyclosporine.
[78]. Eidelman BH, Abu-Elmagd K, Wilson J, et al. Neurologic complications of FK 506. Transplant Proc 1991; 23:3175.
[79]. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet 1994; 344:423.
[80]. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. The U.S. Multicenter FK506 Liver Study Group. N Engl J Med 1994; 331:1110.
[81]. Wijdicks EF, Wiesner RH, Krom RA. Neurotoxicity in liver transplant recipients with cyclosporine immunosuppression. Neurology 1995; 45:1962.
Or theoretically getting dementia a decade later could protect against organ failure a decade earlier.
But I really don't think that's it. If this data is right there is probably an effect. I agree with the author that the mostly likely reason this isn't true is because of bad data.
- How are the patients selected for transplants? Scarce organs are probably not given to patients who have other serious impairments as well.
- How were the (non)-dementia patients assessed? No formal diagnosis of dementia != no dementia.
Even though being healthy helps move you up the list of organ transplant recipients. It would still be really strange if people who got organ transplants were healthier than the general population, who mostly do not need organ transplants.
>- How were the (non)-dementia patients assessed? No formal diagnosis of dementia != no dementia.
But it would be weird if organ transplant recipients were 10x less likely to get a diagnosis of dementia (assuming the same base rates). I would think because of their heavy interaction with the healthcare system they'd have a high rate of diagnosis.
Take Celiac disease as an example. It only affects ~1% of the population, but ~30% of the population has the two genes (HLA-DQ2 and DQ8) that are most strongly associated with it and those genes are also associated with other autoimmune diseases.
There are similar thoughts with respect to the hygiene hypothesis and autoimmune/immune-related disease.
https://en.wikipedia.org/wiki/Hygiene_hypothesis#Overview
Other diseases, like Parkinson's, are also associated with autoimmune diseases. I suspect that there's some trade-off with respect to the effectiveness of the immune system/how well it deals with infections/cancer and the incidence of certain diseases/pathologies, but it's not something that's as straightforward as we would like it to be.
Secondly, even if the corrolation is caused by another effect, whatever it is it's a REALLY strong corrolation, so we should find out what it is!
> This is entirely possible. Calcineurin inhibitors are dangerous and difficult to administer correctly,
I know nothing about this drug... but probably not a good idea..
> There is sufficient evidence in humans for the carcinogenicity of ciclosporin. Ciclosporin causes cancer of the skin (squamous cell carcinoma), cancer at multiple other sites, and non-Hodgkin lymphoma.