Screening for the Risk of Deanimation

The term “screening” is used in medicine to describe routine examinations or diagnostic procedures of a defined group of individuals to identify diseases or risk factors for same at an early stage. Screening is usually categorized as a  “preventive medical examination” or a  “checkup,” and its aim is to increase the life expectancy of those examined  by reducing the incidence or severity of life threatening disease and enhancing the quality of life. The most accurate examination methods possible should be used to identify as many diseases as possible still in their non-symptomatic phase, so that early treatment or change in life style can be initiated.

It is critically important to understand that the purpose of a “deanimation screening scan” (DSS) is not primarily to interfere with the course of disease or to extend the duration of life during this life cycle. Rather, it is to predict or to warn of impending  deanimation with increased accuracy and precision. Any contemporary medical or health benefits are thus incidental. Indeed, it is precisely when DSSing is used to determine or influence current medical interventions that it becomes dangerous. Knowing when you are likely to deanimate with greater precision, for sole purpose of improving your cryopreservation, carries little if any risk of iatrogenesis beyond that which would be present if you found out you were dying at a later time, or didn’t find out and suddenly collapsed in cardiac arrest from a heart attack, or suffered a massive stroke. It is only when the course of treatment is altered by obtaining the data, or looking at it (see “The Black Box of the Baseline,” below) that DSSing becomes either a practical or an ethical conundrum.

The first problem we confront in a screening test for deanimation risk is that we are moving in completely uncharted waters. We have no benchmarks or baselines on which to structure our screening program, save for a modest number of pilot programs that have been undertaken to evaluate full body scanning as a primary tool for the detection of cancer and atherosclerosis in the general population, or in selected subpopulations. For now, these will have to serve as the basis for our protocols, as well as the important cautionary lessons learned from other screening programs.

For reasons of safety, (see Radiation & Risk, below) Magnetic Resonance Imaging (MRI) is preferred over Computerized Tomography (CT), because no ionizing radiation is employed in making the image. MRI has some important limitations at this time, most notably only a few centers have devices that image the coronary vessels with sufficient precision  to allow risk  assessment for coronary artery disease (CAD).  Similarly, screening for Alzheimer’s Disease (AD),(beta amyloid deposits) also requires CT-PET scanning and the associated exposure to ionizing radiation.  So, for the present, CT is the only way to screen for CAD and AD. For this reason, and for those who for economic reasons may need to use CT imaging, it is worthwhile to briefly discuss the much hyped “risks” of radiation from whole body CT scans and this is done in some detail below.

Figure 25: Typical finding in an elderly woman who under prophylactic full body MRI scanning during a clinical trial in Germany to determine if full body scanning would reduce morbidity and mortality from cardiovascular disease and cancer. (Gohde, et al.)

A specimen imaging protocol is presented as Appendix 1 and is taken from the study by Gohde, et al., “Prevention without radiation – a strategy for comprehensive early detection using magnetic resonance imaging,” which was itself a pilot study in the use of MRI as a screening tool for cancer and cardiovascular disease.

The Mechanics

Currently, there is only one way to get a  DSS and that is to do it yourself.  There are several reasons, which will be discussed directly, why that is not a good idea, or certainly not the ideal way  to pursue DSSing. There are a number of reasons for this, starting with the potential for harm. Primum non nocere is the first dictum in medicine: first do no harm. Information is the most powerful force in the universe and information concerning you own health and welfare is especially important. It is also information that you cannot be objective about. It just isn’t possible. It is for this reason that no good physician treats himself or his immediate family in life or death matters as the sole or usually even the primary caregiver. In fact, speaking from experience as a person knowledgeable in medicine, I have found that wise counsel and advice I can (and do) easily give to others  is strangely absent from my own ears when I am the patient.

This lack of objectivity is more than a nuisance, it can be truly dangerous; and here I will have recourse to an actual example. The first four people to undergo DSSing have done so over the past 11 months. These were all individuals who were over 60 and who had not had consistent (or recent) “physicals.” All were counseled about the dangers of VOMIT and about the negative psychological impact of potentially finding out “something was wrong.” All four individuals had significant anomalies on their scans – two of which were life threatening and these were (or are) being medically managed.

In the other two cases, the scans revealed anomalies that might merit further medical evaluation in testing, and in both cases, the decision was wisely made not to pursue those tests. Why? That’s a complicated question, and I’ll answer it by explaining the circumstances of one of these people:

Mr. Ling is an 82 year old man who is in excellent health. He is physically active, mentally sharp and still working part time in his profession of many years.  He underwent a DSS five months ago. The findings were, overall, very good. His coronary calcium score was roughly a third lower than expected for his age, he had no signs of neoplasms, or of peripheral or central atherosclerosis, and the only abnormal cardiovascular finding was evidence of mitral valve regurgitation, which was deemed not serious and not likely to progress rapidly. However, a number of nodules were found in his right lung, along with some enlarged lymph nodes. The radiologist who reviewed the scan suggested a possible biopsy, with or without “bronchoalveolar lavage” (BAL).

While Mr. Ling is in good health, he is an 82 year old man and BAL requires sedation with propofol or a similar drug, and carries with it the risk of significant complications.  As to a CT-guided needle biopsy of the lung masses or the lymph nodes, this is this discussion that took place between Mr. Ling and the radiologist who interpreted his scan: “OK, let’s consider what this could be? I’m not sick – never felt better, so it’s not TB or something infectious? And if it’s cancer, well, what kind of treatment options would I have at my age for lung cancer with lymph node involvement?”

Those were great questions, and as it turned out, the radiologist was only playing it safe – he doesn’t want to get sued if Mr. Ling finds out he has cancer and a lawyer says to  a jury, “The doctor who imaged him said, ‘You’re in you 80s, I see this kind of thing all the time. Don’t worry about it.”  The radiologist ended by noting, “Since you are planning on following up in a year with another scan, we’ll see if anything has changed then.” And Mr. Ling is fortunate to have sufficient financial means that if he wants to pop in for a scan two months later, he can do that, too.

The problem is, most people aren’t in Mr. Ling’s position, and many will be unable to reason their way past the information that they have “masses” or “lumps” in their lungs and “enlarged lymph nodes in their chests!” That kind of worry cannot only be expensive, it can be damaging to one’s health, and corrosive to one’s quality of life. The information from DSSing should be given in the proper context, in the proper way, by the proper people, with the proper knowledge.  Absent that, it can do real harm. And if the scan does reveal a grave or untreatable medical condition, then there is all the more reason for the person to have the necessary resources at hand to help him cope and plan.

Ideally, this program would be part of a comprehensive Member Survival Program (MSP) administered by the cryonics organization (CO) and there would be a staff person whose job it would be to maintain communications with members, encourage compliance with MSP protocols (including the preferred imaging protocol) and collect and manage the resulting data stream.

Under such a scheme, upon intake (approval of cryopreservation arrangements) all members would have (at their option) completed a comprehensive health history and demographic information questionnaire, most of which would be completed as part of their membership application. The data from this questionnaire, as well as any electronic medical records the member may choose to provide, would be entered into the CO’s comprehensive member data base. The availability of this data would then allow for downstream refinement of the “one size fits all” scan protocol being proposed here, by allowing for individual risk assessment for CVD and cancer. This would flag members at elevated risk of early onset of these diseases to consider commencing scanning surveillance at an earlier age.

The Schrödinger Scan: the Black Box of The Baseline

Unless otherwise indicated, the first (baseline) scan would be done at age 45 for men and age 50 for women. In order to completely avoid any deleterious negative psychological effects, as well any potentially harmful effects from VOMIT (as discussed above), the baseline scan remains blinded and unexamined for 1 year after it is made. This done by providing written instructions to the radiologist reviewing the scan to seal the report unless there are unequivocal findings of life threatening pathology.

At the end of the year long blind period, the scan is examined and any anomalies noted. If the member chooses, a repeat scan can be done to resolve any questions or concerns raised by the baseline imaging. For example, if what appears to be a suspicious mass or nodule was found, a rescan a year later will very likely disclose if it is a neoplasm e.g., it will have grown or spread). It may seem counter intuitive to not look at data which you have paid for, experienced inconvenience to get, and which “might” save your life, but that is the necessary price that must be paid for this intervention to be used safely.

The baseline scan must be regarded as the first part of something that will not “happen,” or be completed for another year – like a bulb that has been planted to bloom in the spring, or a bond that will not mature for another 12  months. The scan itself is only a part of the process: the necessary information to safely interpret it does not appear until the required interval of time has elapsed. After all, before this protocol was proposed, no one ever got scanned and they felt just fine about it (until they dropped over in cardiac arrest).  For those of a quantum bent, consider it an extended version of Schrödinger’s famous experiment, except instead of the cat in the box, it’s a CAT scan in the box.

Scan Intervals & Exceptions

If the baseline is “negative,” showing no evidence of evolving pathological processes that merit intervention or further monitoring, then it is being proposed that the next scan take place 5 years later. Similarly, with each subsequent negative “healthy” scan, the next scan would be 5 years hence until age 81, at which point scans would be done every 2 years until cryopreservation ensues.

Figure 26: Proposed algorithm for Deanimation Screening Scan intervals and actions.

These scan intervals are arbitrary and will no doubt need to be refined over time as experience is gained. Intuitively, it seems that there should be a relationship between scan intervals and increasing age, and it is possible to configure scan intervals based on things like increasing risk of SCA or terminal illness with age. However, until some real world experience is gained, a conservative approach which minimizes costs and maximizes the opportunity for benefit, seems best. There are lots of programmers, mathematicians and similarly qualified people in cryonics and if any are interested in working with me, I am interested in generating scan interval algorithms based on the rising risk of disease and death with age (if you are interested, contact me at m2darwin@aol.com)

Going it Alone?

If a decision is made to proceed with DSSing on an individual basis, there are a number of important things to keep in mind and to do:

* Do consider carefully the possible impact this decision will have on you and on your family. In fact, give some thought to discussing this with your spouse or significant other before moving ahead.

* Do select a good imaging center with competent and caring staff who can give you good counsel about the procedure and the results. Imaging centers that offer full body scans are often used to counseling patients: make sure the one you select is a good one. Talk with the staff about your concerns before you commit to being imaged.

* Do explain to the radiologist who will interpret your images that you are having a baseline scan done and you only want to know if there is unequivocal pathology present that requires immediate or urgent medical intervention. If you can’t get that assurance from him, ask for your results only in writing on the same disk on which your scan is written.

* Don’t look at your scan or the written report that accompanies it. If you have a reliable and willing CO, send a copy to them and ask them to send you the results a year from when they receive the media with the images and the report on it. Duplicate CDs are typically made and given upon request at no charge, or for a small fee at the time you are imaged, or when you come for your results. Bring your own media to save money!

* Do provide a copy of the disk with the scan on it to your medical surrogate and to anyone who is on you ICE (in case of emergency) contact list on your mobile phone. The reason for doing so is that, should you experience SCA during the blinded waiting period, the scan may still save you from autopsy if it documents the presence of CAD, or some other pathology that could have caused your sudden and unexpected deanimation.

* Don’t  rely on the DSS to keep you out of trouble, or to reassure that everything is OK, should you develop serious health concerns. Just because a scan shows no indication of pathology does not necessarily mean that there is none. If you have signs or symptoms that would have prompted medical attention absent scanning, act on them in the same way after scanning. Let your physician decide if the scan is significant in the context of any illness or concerns.

* Don’t forget that the scan intervals are 5 years and that is more than enough time for serious disease to develop. Indeed, the 5 year window is a long one, especially where cancer is concerned. A DSS is not a health promotion or a disease prevention program. It’s primary purpose is to let you know you are terminally ill, not to assist you in avoiding that eventuality.

* Do know that if you have atherosclerosis, “vasculopathy” and you want to monitor progression of the disease, your scan intervals will have to be much shorter than 5 years – probably 6 months to 1 year, depending upon the severity, your response to medical intervention, and so on.

Economies of Scale?

Medical imaging is a highly competitive, non-monolithic industry consisting of many operators, large and small, both independent and institutionally affiliated. Such market environments inevitably encourage the drive to survive, and thus typically offer the discriminating consumer the opportunity for real bargains. I made a number of calls to imaging centers around the US and discussed the possibility of group discounts and “scan plans” wherein members of an organization or group, even just a group of like minded individuals, could get deep discounts on scans. The majority of centers I spoke with were receptive to this idea, and several discussed specific numbers which were anywhere from 20% to 60% lower than their standard walk-in fee.

Thus, it should be possible for groups of cryonicists in a given geographical area to make arrangements with a local imaging center for scans. The same was also true when I inquired about group or institutional discounts for carotid and abdominal ultrasound screenings, with the difference being that in some cases, prices went from ~ $350 per screen to ~ $60 per screen, providing the group could be scheduled for the same time and place.

The Pre-Cryopreservation Baseline CT Scan

Figure 27: A hypothetical pre- and post-cryopreservation  CT cerebral angiogram. The post-perfusion image would be obtained by administering radiocontrast agent(s) into the perfusate immediately, or shortly before discontinuing cryoprotective perfusion, prior to deep cooling to storage temperature.

If it is at all possible, a final vital CT scan of the head (at least) should be done as close to the time of cryopreservation as possible. This scan should be done with contrast and with no concerns about clinical radiation dose limitations, since the member will be terminal. The objective of this scan is to document, in as much detail (highest resolution) possible, the morphology of the brain and its vasculature. The imaging technique used should be one that optimizes resolution of the cerebral angiogram. The reason for making these images is that they should allow for many important determinations about the quality of initial stabilization and cryoprotective perfusion and cryoprotectant distribution in the brain to be made, at leisure, during the period the patient is in storage.

If contrast agent(s) is injected into the perfusion circuit shortly, or immediately prior to the discontinuation of perfusion, it should be possible to obtain a post-vitrification angiogram, which in turn should allow for evaluation of cerebrovascular patency, as well as assist in determining the anatomical landmarks within the cryopreserved tissue. It should also be possible to add other kinds of tracers to the perfusate, which might allow for quantification of regional distribution of cryoprotectants, or of other molecular species of interest not only within the brain vasculature, but within the brain parenchyma, as well. Again, the presence of a baseline pre-cryopreservation scan will likely be of great importance in allowing accurate interpretation of post-cryopreservation images.

This scan must be a CT, as opposed to an MRI, since MRI scans are unobtainable in deep hypothermia, or in the solid state.

Radiation & Risk

When the mass media talk about the “risks” from radiation associated with CT scanning, the first question that should spring to mind is, “Risks to who?” Sensitivity to ionizing radiation varies based on the cell age and mitotic cycle, and what this means in practical terms is that the younger you are, the greater the risk radiation presents to you.  Children thus have a much higher relative risk when compared to adults due to their rapid cell division and cell differentiation rate.

Figure 28: The risk of developing cancer as a result of radiation exposure is strongly age dependent and decays dramatically as people age. By the time an individual is in his 60s, 70s or 80s, the risk of neoplastic disease from medical imaging becomes negligible. Adapted from ICRP Publication 60 (1990).
 

These data also demonstrate that you cannot simply use the average relative risk shown in Table 1 to estimate the increased incidence of cancer due to radiation exposure. In order to do this analysis correctly, you need take into consideration the age of all individuals in the irradiated group. For instance, a man of 80 has a life expectancy of about 8 years, versus 33 years for a man of 45. Thus the risk to individuals over the age of 70 is, for all practical purposes, essentially nil. Table 2 illustrates what the  American College of Radiology considers minimal to high radiation doses in “absolute” terms.

This is why there is an increase in the relative risk values for the “entire population”  if children are included in that evaluation. However, even a quick glance at Figure 28 (above), where the estimated lifetime risk that radiation will result in cancer (carcinogenesis) is presented relative to the person’s age, shows that children have a 10% – 15% lifetime risk from radiation exposure, while individuals over the age of 60 have minimal to no risk (due to the latency period for cancer and the person’s life expectancy).  The accepted latency period is, by the way ~ 10 years.

Table 1 shows the relative risk of developing cancer per sievert (Sv) unit of radiation exposure. Tables 3 and 4 provide some comparison benchmarks of radiation exposure both in relative terms (low, medium, high) and in terms of common, specific medical imaging procedures used in regional CT.

So, let’s put this information in the context of a cryonicist wishing to reduce his risk of unexpected deanimation. The protocol being proposed here assumes a baseline scan at age 45 for males (50 for females) which, if free of any indication of ongoing morbid processes, is to  be repeated in 5 years, at age 51. If than scan is negative, subsequent scans would be performed at intervals of 5 years (if negative) until age 81, at which time the scan interval would decrease to 2 years. If we assume a lifetime cancer risk of approximately 1 in 1000 and a total of 7 scans  until age 81, at which point any further risk from radiation exposure becomes irrelevant, we might expect to see an increase in the lifetime risk of cancer from approximate 33% to 34%.  Even if the number of scans were more than doubled to 20; one per two years during the interval between age 50 and age 80, the lifetime risk of cancer would increase at most to ~ 35%.[1] This of course, assumes that all DSSs are CT, as opposed to MRI.

These risk calculations are based on the linear no-threshold (LNT) model of radiation risk.  This model assumes that the carcinogenicity of radiation is proportional to dose, even down to the lowest levels.  No one really knows how carcinogenic low-dose radiation is, because the carcinogenicity of low doses is so small that it’s practically impossible to measure. The official position of the Health Physics Society is that quantitative estimates of risk for doses below 50 mSv per year (100 mSv lifetime) cannot be made.[2]

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As useful aside, if you are interested in the progress being made in medical imaging, I would highly recommend the blog Magnetic Resonance Imaging: To See and Be Amazed: http://limpeter-mriblog.blogspot.com/ The site contains many beautiful images and is a treasure trove of information on both the mainstream progress, and the esoterica of MRI

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End of Part 4

(ischemia) ~85% of the time!

By Mike Darwin

Removing a Central Objection to Cryonics

In case you missed it, what I just said in that slim paragraph at the end of the preceding part of this article has profound implication because it has the potential to remove what is unarguably one of  the largest and the most rational objections that there are to cryonics. That objection is that roughly two-thirds of those who have made cryonics arrangements will not be cryopreserved under good conditions, and that half of all those signed up will be cryopreserved under very adverse conditions, such as autopsy or long (greater than 12 hours) post cardiac arrest delay. The recent advances in non-invasive medical imaging I’m about to discuss here offer the opportunity to we cryonicists to make many, if not most such losses all but unnecessary.

Figure 17: False color CT 3-D reconstruction of a patient’s intracranial arterial vascular tree. The orange-red, cheery shaped anomaly behind the right eye is a large aneurysm. The brain and other intracranial soft tissues have been digitally subtracted to facilitate a complete and unobstructed view of the patient’s arterial vasculature.

The image that you see in Figure 17 is now a perfectly pedestrian medical image that can be obtained from a garden variety CT scanner available at most diagnostic imaging centers in mid-sized cities anywhere in the world. This particular image has the brain, the soft tissue and everything digitally subtracted from it but the patient’s arterial tree and skull. The cherry shaped protrusion on the right is an aneurysm which, if were to rupture, could cost the patient his life or leave him profoundly disabled.

Figure 18: Many brain aneurysms can be treated non-surgically by passing a very thin platinum wire within the aneurysm where the wire coils up to form a yarn-like ball inside the weakened, ballooned-out area of the vessel wall. A clot subsequently forms around the coil and the vessel eventually closes off the opening to what was once the aneurysm.

Fortunately, there is a procedure  called “coiling” (Figure 18) which allows most such aneurysms to be successfully treated. Sadly, very people with brain aneurysms know that they have one until it ruptures – by which time it is almost always too late treat it effectively.

Scan Your Troubles Away?

The question logically arises, “Why not look inside everyone’s head if we have the technology to do so? Wouldn’t that allow us to identify not only the people who have aneurysms they don’t know about, but also everyone who has a tumor, or a narrowed coronary or carotid artery, or a gallstone, or anything else wrong with them that they don’t know about? In fact, why not scan their whole bodies and see if anything is amiss? Wouldn’t that allow us to nip most slowly progressing degenerative diseases in the bud?”

The answer to that question is a qualified “Yes and no.” The first and most important qualification to consider is the very substantial difference between them and us. They are going to die and, hopefully, we are not. Once you are content to die, it doesn’t really make a great difference exactly how it happens and it certainly doesn’t make any difference what happens to you afterwards. They will pay exactly nothing to avoid laying around dead for x-hours, or to avoid being autopsied. We, on the other hand, will pay something. That is a huge divide, because, as it turns out, the first and greatest barrier to such universal screening using CT and/or MRI is its adverse cost to benefit ratio.

Figure 19:  The rapid advance of computing and the high demand for ever more sophisticated medical images has driven the cost of 3-D CT and MRI scanning down to ~ $200 for a head scan $800 for a whole body scan.  http://www.superiorbodyscan.com/?gclid=CP_d5Neyiq8CFWwGRQodsHQX-w

While there are many CT and MRI machines, they are kept adequately busy, or perhaps just a little less busy than some of their owners would like, imaging sick and the worried well or hypochondriacal people. If the entire population, or even some modest fraction of it were to suddenly present for imaging, the system would crash. CT and MRI machines are very expensive and while the cost of scans has dropped dramatically, they are still not free. On the macro-level, governments, insurance companies and economists are constantly struggling to determine which therapeutic and diagnostic interventions offer the best return for the money invested in them.

The Problems of Bite Back and VOMIT

Surprisingly, information obtained from diagnostic tests can sometimes not only fail to yield any benefit, in which the case the money spent on the test is wasted, they can also cause harm. A recent example of this, much in the news, is the Prostate Specific Antigen (PSA) test used as a screening tool for prostate cancer (Figure 20). (http://www.pbs.org/newshour/rundown/2011/10/psa-testing-controversy-reignites-over-screening-debate.html) The problem with the PSA test as a screening tool is that to be effective in that capacity it requires a fairly long baseline, a good deal of contextual information (the patient’s race, family history, medications, and so on) and it requires good clinical judgment as well as a ‘patient’ patient.

Figure 20: It was anticipated that the PSA test, used as a screening tool for prostate cancer, would significantly reduce both the morbidity and mortality from the disease. It has so far failed to do so.

A single high PSA reading, or even several, may mean nothing. Most often it is the trend, rather than the absolute number; this is particularly true for black men.  In short, it’s a test that takes a lot of time and thought to interpret and use well and as such is probably not well suited to mass screening where a “yes” or “no” answer is sought before proceeding to costly, invasive and possibly injurious further evaluation.  Yet another problem is that even when prostate cancer is found and treated, it turns out that very few lives are saved because most of those cancers are slow growing and in men who will die of something else before the cancer kills them. Thus, the cost to benefit ratio of the PSA is being questioned, not the least of which because it causes many men to suffer and even die from treatments from which they did not benefit!

This is very much where medicine is today with respect to the “medical imaging singularity.” While it is possible to “look inside” just about everybody, the cost to benefit ratio for the health care system and for the “man on the street” would not justify it. In fact, it would be a medical catastrophe.

To understand why this is so it is necessary to understand three things. The first and most important of these is something called VOMIT, which is a very serious form of bite back associated with our new found ability to see inside patients with increasing exactitude. VOMIT stands for Victim of Medical Imaging Technology and refers to patients who suffer unnecessary interventions for abnormalities observed by imaging or other investigational technology, but which were not found during surgery or subsequent invasive diagnostic interventions. (Hayward, 2003) Here, I will go further and extend the definition of VOMIT to include any diagnostic finding which result in a diagnostic or therapeutic intervention which is not cost effective or causes harm to the patient. That is a very important caveat and tall order to fill, as we shall soon see.

The second is the relatively straightforward one of the ratio of the dollar benefit of resources expended to dollar benefit returned in years of productive life saved as a result of the intervention. Even in cases where early diagnosis saves lives, such as in breast cancer screening, the economic returns are equivocal. It is also often the case that “early” diagnosis with existing imaging technology is still not early enough to cure the disease. As a result, the patient suffers a longer, more miserable course of treatment and the healthcare system is subjected to greater expense with no return.

The third is the problem of information overload and it is somewhat related to VOMIT. The truism that a picture is worth a thousand words is probably a vast understatement. A single 3-D medical image contains a vast wealth of information – information which has heretofore been unavailable to both the clinician and his patient.  This might seem like a good thing, and in the long run it will be, but for now, and for a long while to come the details of the landscapes being revealed will, to a great extent, be terra incognito.

The Danger of TMI

When advances in microelectronics allowed for 24-hour ECG monitoring in the 1970s,  it became possible for clinicians for the first time to see the beat by beat electrical activity of their patients’ hearts for up to a day at a time, or longer. Prior to that, they were limited by the enormous quantities of paper tracings that would be required and the need to confine the patient to the clinic or laboratory. Now, with the advent of the compact and mobile “Holter monitor,” it was possible to capture the patient’s ECG data continuously under ambulatory, real-world conditions (Figure 21). Physicians were awash in a veritable sea-tide of data!

Figure 21: The Model 445 Mini-Holter Recorder which was released in 1976 allowed clinicians for the first time to “see” their patients’ ECGs under real-world conditions and for prolonged periods of time.

The problem was , they assumed, quite understandably, that they knew what it all meant. After all, doctors had been looking at patients’ ECGs for decades in their offices, in hospitals, at bedsides in homes and in physiology laboratories. They knew how to read  an ECG! So, when they discovered that some of their patients had periodic bouts or “runs” of very worrisome arrhythmias, they did the prudent and rational thing – they treated them for these arrhythmias with medications. Unfortunately, the result was the opposite of that expected; a significant increase in morbidity and mortality in these patients, because it turns out that in a subpopulation of healthy people, those arrhythmias were benign and not indicative of any health problem.  Thus, misinterpretation of the “same” information they were confident in dealing with in small chunks, presented in bulk and in a different context, was one of the unforeseen and arguably unforeseeable bite back consequences of Holter monitoring technology. (Harrison, 1978)

The Last Heart Attack?

If you assemble and then read over the Alcor case summaries of the last 40 years it is impossible not to be shocked by the seemingly high incidence of sudden and unexpected cardiac arrests. Because my data set is incomplete for Alcor, I can’t be definitive, but the number seems to be somewhat higher than for the same subpopulation of people from the general population (white, middle class, etc). Until, that is, you consider that most cryonicists are male. So, as you read accounts of cryonicists in their 40s and 50s arresting while scuba diving, while taking a nap or watching television, in part what you are seeing is selection bias at work. The point is, no one ever died of “sudden heart disease” a “sudden aneurysm” or, for that matter “a sudden cancer.” These are degenerative disease that takes years to decades to develop. While still difficult to detect in their nascent stages, their terminal lesions are usually very visible many months and sometimes for even for many years before they end lives.

Figure 22: Coronary artery calcium scoring using computed tomography and carotid intima media thickness and plaque using B-mode ultrasonography offer the prospect of detecting almost all coronary artery disease before it reaches the stage where it can cause a heart attack or sudden cardiac arrest.

There has been a great deal of media attention lately to an initiative called SHAPE; The Society for Heart Attack Prevention and Eradication,  which aims to all but eliminate heart attacks by combining CT of the heart to obtain a “myocardial calcium score” (a powerful risk predictor of heart attack)(Figure 22) and carotid intima media thickness and plaque using B-mode ultrasonography as part of a three step program to eliminate heart disease. The next two steps in SHAPE’s plan are a “polypill” combination of blood pressure and anti-atherosclerosis drugs and finally, perhaps, a vaccine. A similar “Last Heart Attack in America” initiative focused on coronary scanning along with dietary interventions to reverse atherosclerosis has been the focus of a feature length documentary on CNN in which former US President Bill Clinton is prominently  featured as a spokesman and advocate. The common ground of these two initiatives is that almost no one dies of a heart attack without there being  glaring evidence present in their hearts years before the infarct occurs. It is only necessary to look for it!

There can be no question that as imaging technology evolves, and as medical acumen catches up with what is available, that such imaging will become a routine part of any checkup  for patients whose age and risk profile merit it (and eventually, if they live long enough, that means most patients). As it stands right now, if you are a middle aged man or woman with a significant risk profile for heart disease, and you have a heart attack, it’s my personal opinion you have ample grounds to sue your physician for negligence.  Right now, that’s just my opinion, so it doesn’t count for anything, but the point is that sooner or later this, or a better coronary imaging modality is going to become the standard of care and heart attacks will become a rare event – a thing of the past – a relic from a time when doctors couldn’t see inside of you.

Ultrasound Investigations

There are cheaper, simpler and completely risk free ways (in terms of radiation) to  find out whether you have atherosclerosis or not.  The most predictive of these for money is the carotid ultrasound (CUS) test.

Figure 23: The carotid ultrasound scan is  a simple, non-invasive diagnostic investigation that employs sound waves to create an image of the two large blood vessels in the neck that supply most of the blood to the brain. If there is a buildup of plaque or a thickening of the limning of these two arteries the person is at increased risk of stroke and there is a high probability that there is also systemic atherosclerosis present. If there is evidence of severe narrowing of one or both of the vessels, then it becomes urgent that medication and possibly surgery be used to correct the condition in order to avoid the likelihood of a crippling or lethal stroke.

This simple, non-invasive test takes just a few minutes and uses ultrasound waves to image the carotid arteries and the blood flowing through them (Figure 23). If there is thickening of the arterial wall, or plaque present, then it is a virtual certainty that the person has systemic atherosclerosis and warrants a more extensive workup. This test is often also “packaged”  with a quick “look-see” at the abdominal aorta also using ultrasound, to rule out the possibility of an abdominal aortic aneurysm – something that is more common in smokers once they reach middle age, and beyond.

If you shop around diligently, the cost a CUS can be as little as your transportation costs to the health fare or community center where it is being offered, often as a “loss leader” by health care providers or medical imaging companies seeking more remunerative business opportunities (if they find something amiss during the CUS).  The cost of such an evaluation can range from as little as $60, to as much as $380.

A CUS is ideal for people on a budget and for those under age 45 with no history of heart disease, cancer or other pathology or risk factors that might put them at increased risk of sudden cardiac arrest.

Why Full Body Scans?

Figure 24: The full body CT or MRI scan is often offered as “add-on” to the complete or the “executive’s” physical. Many imaging centers offer these scans without the need of the patient’s person physician prescribing the scan using their in-house radiologists to write the order for the test. http://www.prevenium.com/contact.asp

 Put simply, there is no substitute for seeing, or to put a new twist on an old adage: a picture is worth a thousand medical tests. While the origins of all of the degenerative diseases that kill us are at the molecular level, mostly we die as a consequence of the macro-level changes they inflict on our bodies, even if the coup de gras is rooted in the action of things like adhesion molecules and inflammatory pathways; as is the case with most heart attacks. It is the large, easily “seen” bulges of aneurysms, masses of plaque or tumor that kill, and these almost always take years to develop. What this means practically is that, with a few exceptions, aside from suicide, homicide and accident, virtually no one has to die – or to deanimate without plenty of advance warming. The implications for cryonics are as obvious as they are profound.

End of Part 3

(ischemia) better than ~85% of the time!

By Mike Darwin

Ischemia: The Problem of “Long Down Time”

 Almost every cryonicist I’ve ever spoken with envisions his cryopreservation will occur under ideal circumstances. He will be diagnosed with  some vague and ill defined terminal illness, bravely decide to end futile treatment and then enter hospice with a team of skilled and caring cryonics personnel at his bedside. He will nap, read, watch TV, and then, near the end, nod off surrounded by loved ones as the cryonics personnel hover nearby. This may not be the most attractive picture in any absolute sense, but it is certainly as reassuring a one as it is possible to find in contemporary cryonics. And while many, or even most cryonicists may find this scenario credible, much of the rest world doesn’t.

 Figure 10:  Approximate U.S. distribution of predictable deaths by cause based on 2004 data. Note that ~57% of all deaths occur sufficiently suddenly, or under circumstances such as accidents, which preclude standby or other cryonics stabilization measures. Chart derived from data: [National Vital Statistics Report, Volume 53, Number 5 (October 2004)]. This data may be compared to the data in Figure 10 to see how closely the US national incidence of sudden and unpredictable death map that of Alcor’s experience (Figure 11).

One likely reason for the scarcity of biomedical people involved in cryonics is that their actual, day-to-day experience is at sharp odds with the scenario I’ve just laid out above.  In countless hours of both focused and casual conversations with such individuals, what emerges is a sense of incredulity about the reversibility of the damage these professional and technical people witness as a part of their duties caring for the very old, and the critically ill dying; not to mention that large fraction of people who die suddenly and without warning, end up as DOAs in the emergency department or coroner’s cases. Regardless of whether their opinions prove the valid ones, we are clearly failing to communicate to them and to the community at large, an experience of cryonics which is not so biomedically adverse.

To do that, it is first necessary to move beyond  anyone’s scenarios or suppositions and evaluate the reality of what is actually happening to the patients we cryopreserve. That turns out to be a hard thing to determine with any degree of precision, because none of the cryonics organizations maintain any kind of statistical database on their members’ cryopreservations. How many cryopatients have dementia? How many were autopsied? What is the mean ischemic time from cardiac arrest to the start of cardiopulmonary support (CPS)? How many patients have ischemic times of 2-5 minutes, 5-10 minutes, 15-30 minutes, 12 hours, 14 hours, 5 days? What is the mean age at cryopreservation? [Absence of data on this last question I find particularly amusing in a group of people supposedly preoccupied with longevity and "life extension": how long are they living, on average?]  There is currently no way to tell.

There is not even any way to determine the age, gender, or any of dozens of other potentially critically important demographic details that are, or could be vital in assuring quality cryopreservations, reducing ischemic times, or reducing known iatrogenenic events. A concern of mine for onto three decades now is that we have no way to spot adverse epidemiological events that might be associated with our unique dietary supplement or other lifestyle practices. Perhaps most incredibly, there are no written criteria, however arbitrary, to assign any degree of quality, or lack thereof, to the cryopreservation a given patient has received (let alone that a given Cryonics Organization (CO) provides, on average). This had lead to what has become known as “the last one is always the best one” to date rating system, wherein each case that is not either an existential or an iatrogenic disaster, is pronounced by the staff who carried it out as, “the best case we’ve done so far!”

We cryonicists may be in some kind of willful, data free fog about what our situation is, however, it’s a safe bet to assume that most of the rest of the world, based on their own professional and personal experiences, are not so ignorant. The first step towards a solution is to understand the scope and severity of the problem by getting reliable numbers. While that is not easy to do, the Alcor Life Extension Foundation does maintain a crude, if incomplete accounting of all the patients they have placed into cryopreservation: http://www.alcor.org/cases.html. A cursory analysis of this yields the following breakdown. Even basic data such as cause and mode of death are missing from ~20 of the cases listed there – these have necessarily been excluded from the analysis below.

Figure 11: A major hurdle to evaluating quality in cryonics operations is the lack of any outcomes (e.g., reanimation followed by evaluation) or of any surrogate markers or scoring systems to serve as evaluation tools to determine not only the quality of cryopreservation care being given, but also the objective neurocognitive status of the patients when they enter cryopreservation. For the purposes of this analysis very crude criteria were used to assess the quality of the patient as a finished product at the end of cryopreservation. These were normothermic ischemic time between cardiac arrest and the start of CPS, catastrophic peri-arrest brain injury such as an intracranial bleed followed by prolonged cerebral no-flow before pronouncement of medico-legal death, very long warm ischemic times (> or = to 12 hours) and autopsy.

Using the criterion of “minimal ischemia” (≤15 minutes)[1], 48% of Alcor’s patients are cryopreserved under these conditions (Figure 10).  Thirty-nine percent of their patients suffer long ischemic periods of 6-12 hours or more (mostly as a result of SCA and UDA); and 13% suffer very long periods of ischemia (> or = to 24 hours) which are not currently preventable, or which conclude in autopsy prior to cryopreservation.  Put more cogently, you have less than a 50% chance of being cryopreserved (with Alcor) under conditions of minimal ischemia. While this number is discouraging, it is spectacular when compared to the Cryonics Institute, where it is somewhere in the low single digits.

Figure 12: The graph above is the same as in Figure 11, with the difference being that the losses have been expanded to include those that would be expected if the population wide incidence of end-stage, GDS-7 dementias were imposed on all the groups. The result is that percentage of patients who might reasonably be expected to have both minimal ischemia and no pre-cryopreservation GDS-7 dementias drops to just 26%.

But once again, these numbers are misleading if the criterion is cryopreservation under minimal ischemia conditions, because they do not take into account the number of patients who enter cryopreservation with dementia, or severe brain injury due to stroke, other neurovascular disease, or massive head trauma. If only dementia, at the current incidence for the general population is factored into the analysis, then the picture becomes considerably more bleak, as can be seen in Figure 10, with only 26% of  Alcor cryonics patients being preserved with relatively intact brains under reasonably good conditions.[2]

Impact of the BDDs on the Likely Survival of Personhood

Figure 13: The effect of advanced Alzheimer’s Disease on the macroscopic appearance of the brain is evident when coronally sectioned brains from an AD (R) patient and a healthy person in their mid-20s (L) are compared side by side.

Deaths from AD are typically deaths from end-stage AD, which usually implies severe global destruction of both cerebral hemispheres (Figures 13 & 14) on both a macro and microscopic level. Death due to AD is a prolonged process (~8 years from diagnosis to death), and the neurological deterioration that occurs as the disease progresses is often scored using the global deterioration scale (GDS) of primary degenerative dementias, which ranges from 1 (least) to 7 (worst) in severity. GDS scores in excess of 5 are associated with major loss of macro- and micro-scale brain structure and will be assumed here to represent serious compromises to, or the destruction of personhood.

Figure 14: The histological appearance of the brain in AD is shown in panels b and c above. In many areas of the brain there is virtually complete loss of the neuropil; the synaptic weave that interconnects neurons which can be seen in its normal state in c, the panel at the far left. The majority of the neurons and many of their supporting glial cells have died and been scavenged by macrophages and histiocyytes.  There are abundant deposits of proteinaceous plaque containing the  neurotoxin protein beta amyloid neurofibrillary tangles which are the remnants of neuronal long processes such as axons and dendrites. The extent and uniformity of the changes seen above varies from patient to patient during the course of the disease, but becomes increasingly uniform throughout both hemispheres of the cortex the longer the patient survives with a GDS score of 7 (end stage dementia).

A Deanimation Warning Device?

Figure 15: The medical imager as a deanimation prediction device?

 In his 1939 science fiction story Life-Line,” Robert Heinlein envisions a device that can predict, with considerable precision, when a person is going to die. While none of us cryonicists wants to die, most of us could certainly profit from knowing when we are going to deanimate. Better still would be also finding out how to postpone our cold dip in liquid nitrogen for a while, if it was possible to do so.

Many cryonicists will be familiar with this graph of Ray Kurzweil’s showing the impending arrival of the singularity (Figure 16).

Figure 16: Ray Kurzweil’s graph showing the exponential increase in neuro-image reconstruction which has occurred largely as a function of the exponential growth in computing capacity since 1970.

Well, if you are a cryonicist, I’m here to tell you that insofar as non/minimally-invasive medical imaging is concerned, the singularity is here.

From the earliest days of medicine physicians have desired one thing almost above all others and that is to possess the power to peer into their patients bodies and observe the goings on there. Since the discovery of x-rays by Wilhelm Conrad Röntgen in 1895 (Crane, 1964) there has been steady progress towards the satisfaction of that desire. The development of contrast media, endoscopy, computerized axial tomography (CAT or CT) scanning and magnetic resonance imaging (MRI) scanning have allowed increasingly exact and impressive images of the interior of the living body to be made.

However, a number of serious limitations have, and to a great extent still do prevent the full realization of the physician’s idealized desire to see inside his patients at will. Those barriers are field, dimensionality and point of view, as well as resolution, color, contrast and the dollar cost of the imaging.

In the case of CT and MRI those barriers have been breached to such a degree that it is now possible for cryonicists to be able to determine with a very high degree of accuracy and precision both of what and when they are going to experience medico-legal death. A corollary of this is that in many cases it will be possible for them to avoid what would have otherwise been an unavoidable very long period of ischemia and quite likely a medico-legal autopsy  as well.

End of Part 2

How to avoid autopsy and long ‘down-time’

(ischemia) better than ~85% of the time!

By Mike Darwin

It’s easy to concentrate on the biggest and most obvious reason that cryonics hasn’t attracted wider acceptance, principally the fact that it doesn’t work “yet” and it will be a long time before we know if does. But there’s a clue to another capital reason for its slow adoption which is to be found in the failure of cryonics to attract much enthusiasm or activism within its own ranks. Why is this?

I believe a central reason for this failure is that cryonics, even as it is currently configured and accepted by those who embrace it, performs dismally. Everyone seriously involved with cryonics is painfully aware, either consciously or subconsciously, that cryonics is at least a two tier lottery. Sure, everyone knows that we’re taking a “chance” on being recovered in the future by being cryopreserved in the first place. But to even get to that round of the lottery, you have to get cryopreserved, and it would seem material whether or not you are cryopreserved well.

For some, perhaps cryonics is a ritual exercise. As long as there are remains, a freezer, someone to take the money and hang picture on the wall, then you have a chance; and all chances are created equal. Their position seems to be same as that of the millions of lottery ticket holders before the winning number is announced: we all have the same chance at the prize. If that’s your attitude, you can stop reading this right now, there’s nothing more here to interest you – not even in terms of idle entertainment value, because this discussion, from here on out is deadly serious, and brass tacks practical.

 Figure 1: The autopsy rate has declined by half in the United State between 1972 and 2007, although it has shown a slight increase since these data were collected. Source: http://www.cdc.gov/nchs/data/databriefs/db67.pdf

As Figure 1 shows, the autopsy rate, which can serve as the ultimate, population wide indicator of a very bad cryopreservation,  constituted 8.5% of all deaths in 2007. That percentage has risen slightly since then and is now at ~ 9%. The situation isn’t quite as grim as it might first appear if you break down the reasons for autopsy and note that 55.4% of autopsies were conducted as a result of deaths due to “external causes,” which means suicide, accident or homicide. If you think you are in a “lower risk” category for these, you may  be right, in which your case your risk may be fractionally smaller. And of course, not all of these autopsies were state mandated: some were requested by the next of kin, or even the decedents themselves. Still, 9% seems a reasonable, overall unavoidable loss number currently confronting cryonicists given the culture we inhabit.

Figure 2: Since the first man was cryopreserved in 1967, the demographics of autopsy have shifted increasingly from the aged to those in younger population cohorts. Source: http://www.cdc.gov/nchs/data/databriefs/db67.pdf

If the age distribution of autopsies in the US is examined, the picture gets even more uplifting if you are, or you expect to live in into old age (which is, incidentally, medically defined as 65 years of age, or older). In this age group, the incidence of autopsy has declined dramatically from 37% of all postmortems since 1972,  near the time cryonics began, to only 17% as of 2007.

However autopsy is only one of a number of factors that can and do interfere with  cryonicists achieving “good,” or even “acceptable,”  (forget  ideal), cryopreservations. The other three factors which loom large are sudden cardiac arrest (SCA), unexpected death (UD, which is different than SCA) and brain destroying diseases ( BDDs, or dementias). While Alzheimer’s Disease is the most common of the BDDs, there are others such as Pick’s, Lewy Body, Parkinson’s and the vascular dementias, which together account for 20-30% of all age-associated BDDs.

Brain Destroying Diseases (Dementias)

Autopsy is only one of a number of factors that can and do interfere with  cryonicists achieving “good,” or even “acceptable,”  (forget  ideal), cryopreservations. The other three factors which loom large are sudden cardiac arrest (SCA), unexpected death (UD, which is different than SCA) and brain destroying diseases (BDDs).

 Figure 3: Incidence of dementias as a percentage of all cause mortality in males, females and the United States population as a whole. Prepared from data in the National Vital Statistics Report Volume 59, Number 10 December 7, 2011Deaths: Final Data for 2008: 2008http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_10.pdf

 Currently, the BDDs in aggregate (including catastrophic stroke) account for ~3.2% of all deaths in the US (Figure 3). However, insofar as cryonicists are concerned, this number is likely to be misleadingly low, because most cryonicists enter cryopreservation at or after age 65, the point at which the incidence of BDDs begin to climb exponentially. (Evans DA, 1990) This number is expected to, and in fact is exploding as a consequence of both the demographic shift due to an aging population in the West and increasingly longer life spans (Figure 4).

 Figure 4: The large increase in Alzheimer’s Disease as a cause of death in the United States is largely a function of the increasing average age of the population and the survival of many additional individuals into advanced old age. Source: http://www.alz.org/downloads/Facts_Figures_2012.pdf

 Figure 5: A breakdown of dementias by type shows that Alzheimer’s Disease accounts for 47% of the total as the sole cause of the dementia and is a major contributing factor in another 28% making it by far the most common pathological mechanism in play as the cause of dementia in the elderly.  [S. Seshadri, S, Wolf, PA, Beiser, A,  Au, RU, McNulty, K, White,R, et al. Lifetime risk of dementia and Alzheimer's disease: The impact of mortality on risk estimates in the Framingham Study. Neurology, 49:1498-1504,1997.]

 Figure 6: Incidence of Alzheimer’s Disease by age cohort in the US population as of 1988.[ Evans D, et. al. Prevalence of Alzheimer' s Disease in a community population of older persons. JAMA, 262:18;2551-6, 1989.]

In the 74-84 age cohort, 19% of that population has AD (exclusive of other dementias) and in those individuals over the age of 85, the diagnosed incidence is 47%. These numbers are almost certainly low, because many of the elderly are who are institutionalized for falls, or other issues not ostensibly related to primary brain disease, go on to develop brain disease in an institutional setting and ultimately have listed as their causes of death, pneumonia, urosespsis, sepsis  secondary to decubitus ulcers, or other causes that escape epidemiological surveillance for AD. Currently, AD is responsible for 2.8% of deaths in white males men aged 65  or older and 4.7% of white males who are 85 years of age, or older. These numbers are expected to triple by the year 2050.

 Figure 7: The incidence of Alzheimer’s Disease rises roughly exponentially with age such that over 1,100 people out of 100,000 aged 86 or older have the disease.

When cryonics was launched in the mid-1960s the problem of BDDs as a threat to the workability of cryonics was not even considered.  In 1967, the year the first man was cryopreserved, the average life expectancy in the US was ~70 years and the problem of dementias was a fraction of what it currently is.  Additionally, comparatively little was known about the pathophysiology of the BDDs at that time, and there was little or no awareness within the cryonics community of their potential to degrade or altogether destroy personal identity, perhaps even years in advance of the pronouncement of medico-legal death. The problem of BDDs and of age-associated destruction of the brain is arguably the foremost biomedical obstacle confronting cryonics in the long term, and it is for this reason that I will return to this topic again later in this article in the context of discussing its early detection, with a brief discussion of treatment, and ultimately, definitive interventions to halt and reverse it.

Figure 8: The Siemens Biograph mCT PET is a positron emission tomography/computed tomography (PET•CT) scanner that enables precise measurement of metabolic processes and data quantification, including the assessment of neurological disease and malignant tissues (resolution and molecular characterization of neoplasms as small 3 mm in diameter). The device can provide quantitative measurements of brain beta amyloid protein burden.

For now, I will note that because AD is by far the most common of the BDDs and because it has a unique pathophysiological feature, a remarkable advance in early diagnosis via noninvasive  computerized tomography (CT) and positron emission tomography (PET) imaging has recently become clinical available. Beta amyloid is the protein found in the plaques characteristic of AD, and there has been intensive research over the past decade to identify radiolabeled tracer compounds that will safely cross the blood brain barrier (BBB) and bind to both beta amyloid and tau proteins. (Barrio 2008), (Black, 2004)  In February of this year, the US FDA approved the Siemens Biograph mCT, a positron emission tomography-computed tomography (PET-CT) scanner capable of not only detecting, but of quantifying  amyloid in the brain. The Biograph mCT has been very well received, and within the space of a few months the machines have appeared in most major cities in the US. The Biograph mCT in conjunction with the recently developed FDDNP, (2-(1-6-[(2-[F-18] fluoroethyl)(methyl)amino]-2-naphthylethylidene) malonitrile) tracer allows for calculation of total brain amyloid burden (Wang, 2004) and visualization of discrete amyloid containing lesions as small as ~ 3 mm in diameter (tracers for tau protein, the other primary pathological protein in AD are currently in the pipeline for FDA approval).

 Figure 9: Top: PET scan of beta amyloid deposits in the brain of a patient with early moderate Alzheimer’s disease appear in red in the image above. The beta amyloid deposits are concentrated, as expected, in the frontal and prefrontal cortices as well as in the hippocampus. Bottom: Beta amyloid distribution in the brain of a patient with early moderate AD (L) versus normal control (R). One important consequence of this imaging is the growing realization of the global range of AD’s impact on the brain. As recently as a decade ago it was believed that the destruction of brain tissues was confined largely to the hippocampus and the prefrontal cortex, especially early in the disease. It is now understood that the histological destruction of AD is widespread and that during the end-stage of the disease few if any areas can be expected to be spared.

Very early detection of AD may turn out to be critical to achieving effective treatment, or even slowing progression of the disease, since significant beta amyloid and tau deposition seem to promote ongoing inflammation and interfere with putative therapeutic drugs. A good example of this is the recent fate (Vellas, 2010) of the investigational drug  tarenflurbil ((R)-flurbiprofen ) which inhibits gamma-secretase, the enzyme that produces beta amyloid AB-42, the species of beta-amyloid that forms fibrillary plaques. (Black, 2008) Unfortunately, the drug does nothing to remove existing existing AB42 deposits, which presumably continue to exert their neuron killing and pro-inflammatory actions.

(R)-flurbiprofen is highly effective in animal models of very early AD and the drug showed significant promise in Phase I & II clinical trials. However, development of (R)-flurbiprofen was dropped when it became apparent in Phase III trials that the drug would likely only be effective in a clinical setting if it its administration was begun before clinical signs of AD developed; in other words, when beta amyloid levels were very low and would be detectable only by testing cerebrospinal fluid or, now with sensitive CT molecular imaging techniques involving the screening of subpopulations of healthy individuals at risk.

This kind of effort and application of technology and pharmacotherapy may not profitable for pharmaceutical companies, but that does not mean that it would be be worthwhile for us cryonicists. (R)-flurbiprofen  is a close chemical relative of the OTC NSAID ibuprofen and it is a metabolite of the prescription NSAID flubiprofen.  (R)-flurbiprofen  is an enantiomer of flurbiprofen (~ 5%  of (L) flubiprofen is metabolized into (R) flubiprofen by the liver after ingestion) which is completely inactive as  a COX inhibitor, and is thereby free of the anti-COX side effects associated with NSAIDS.  Despite it’s lack of both COX-I and COX-II activity, the drug does have strong anti-inflammatory activity by acting through inhibition of NF-κB and AP-1 activation pathways, and this may provide added benefit in controlling the inflammatory processes associated with AD. (Tegeder, 2001)  As an interesting aside,  (R)-Flurbiprofen has also been shown to suppress prostate tumor cells by inducing p75NTR protein expression. (Quann, 2007)

(R)-Flurbiprofen is an example of a drug with considerable therapeutic potential that will almost certainly not see clinical application due to the high cost associated with regulatory burden and the logistical hurdle of needing to start therapy years before symptoms of AD manifest themselves. (R)-Flurbiprofen might also conceivably be useful as combination therapy with  the already FDA approved skin cancer drug bexarotene (Targretin), an antineoplastic, which has been shown to reverse beta amyloid deposition in a rodent model of AD as well as to improve cognitive function. Targretin rapidly cleared beta amyloid from the brains of animals in a variety of models of AD (<2 months) and while it is not a cytotoxic chemotherapeutic agent, the drug has sufficient adverse effects that it would be problematic to administer over a period of years or decades. A combination of short term therapy with Targretin to remove beta amyloid, followed by long term administration of (R)-Flurbiprofen is a possible treatment strategy that would seem attractive to explore. The ability to dynamically monitor beta amyloid levels in the brains of patients undergoing such novel therapeutic regimens, especially outside the confines of the medical-industrial establishment, is yet another advantage of this evolving singularity in medical imaging.

End of Part 1