President Biden possibly has Occult Hydrocephalus (Normal Pressure Hydrocephalus)

President Biden possibly has Occult Hydrocephalus (Normal Pressure Hydrocephalus).  That’s quite a mouthful. Here are  three levels of explanation, short, medium and long depending on what you already know.

The short explanation — justification for each statement later  – “Extraordinary claims require extraordinary evidence.”  ― Carl Sagan

l. President Biden had a subarachnoid hemorrhage due to an aneurysm in his head years ago.

2. President Biden is in early dementia

3. President Biden is having changes in his walking, one of the reasons leading to his recent medical evaluation

Subarachnoid hemorrhage is one of the most common causes of Occult Hydrocephalus (Normal Pressure Hydrocephalus { NPH } )

Symptoms of NPH are progressive dementia and gait disturbance. So he fits the pattern.

A brief primer on hydrocephalus.  We all have water on the brain (e.g. cerebrospinal fluid  {CSF } ).  We make about two pints a day in the ventricular system of the brain which lies deep in the brain — https://en.wikipedia.org/wiki/Ventricular_system.  It flows out of the ventricles to the surface of the brain where it flows over the surface and is absorbed.   You can imagine what happens if there is a problem absorbing CSF.  Secretion doesn’t stop and the ventricles get bigger  (the origin of the term hydrocephalus), and pressure rises usually along with headache and serious neurologic problems.

It is thought that after subarachnoid hemorrhage, scarring occurs impeding CSF flow, just enough to enlarge the ventricles, but not enough to raise pressure in the head.  Amazingly this can occur years after the bleed and is called normal pressure hydrocephalus (NPH) or occult hydrocephalus (occult because it doesn’t present in the usual way with headache etc. etc.)

NPH was discovered in the late 60s when I just entered neurology.  It was tremendously exciting for patients and docs, because it represented a treatable cause of dementia.  The treatment is placement of a shunt (hollow pipeline) from the ventricular system to the surface of the brain (or elsewhere).

It is extraordinarily easy to diagnose hydrocephalus these days. Just do an MRI or a CT scan and see how big the ventricles actually are.  It is important to note that President Biden should never have an MRI.  High magnetic fields are used, and if the clip placed on his aneurysm by the neurosurgeon contained any magnetic material, the clip would be ripped off the artery causing a fatal hemorrhage. This has actually happened to a few unfortunate patients in the early days of MRI and Biden’s aneurysm surgery was 1988 in the early days of MRI.

The medium explanation

l. Biden’s cerebral aneurysm — I have a whole post on the subject — https://luysii.wordpress.com/2020/12/08/bidens-cerebral-aneurysm/ which is reproduced below the ***

Interestingly, I knew the neurosurgeon who operated on him (Neal Cassell), back in the day when I was a neurology resident and he was a Penn undergraduate, already very interested in neurosurgery.

The post concludes with “I think the chances of occult hydrocephalus developing 32 years after the aneurysm are remote. If it were going to happen it would have already. In the meantime, watch him start to walk.”  Well that was written 8 December ’20, and he’s having trouble walking now.

2. Biden is in early dementia — certainly the most controversial statement in the post.  It’s based on years of clinical experience trying to taking care of demented patients.  Don’t take my work for it  please look at the following post — it contains lots of clips of him speaking (C-SPAN etc. etc.)– just look at them and make up your own mind if he is functioning normally during them.  Remember the symptoms of early dementia are always intermittent.  Here’s the link Vhttps://luysii.wordpress.com/2021/08/20/biden-is-in-early-dementia-yet-more-evidence/. The entire post is reproduced below the &&&&

3. Biden is having changes in his walking — this is the easiest — https://www.whitehouse.gov/wp-content/uploads/2021/11/President-Biden-Current-Health-Summary-November-2021.pdf.  It is incredibly detailed and thorough, I’m not going to reproduce it, but here are a few quotes “The president’s gait is perceptibly stiffer and less fluid than it was a year ago.”

 

 

They put down his gait disturbance to a mild peripheral neuropathy, old foot fracture, spinal arthritis, but they didn’t consider NPH.

I think he should have a CT scan of his head (never an MRI for the reasons above).  It might reveal a treatable cause of his early dementia.

The long explanations 

***

Biden’s cerebral aneurysm

A friend sent me a semi-hysterical rant from a neurosurgeron about the dangers of President Biden’s cerebral aneurysm. Not to worry. This happened in 1988 and was successfully clipped although it ruptured during surgery. The only possible complication at this point is normal pressure hydrocephalus (occult hydrocephalus). That’s a medical mouthful so here’s some background to put it all into context.

If you’ve ever seen a blister on an inner tube, that’s what a cerebral aneurysm looks like. They usually look like a round ball on the side of an artery in the brain. They look nothing like an aneurysm of the aorta. To treat them, one puts a clip around the neck of the aneurysm, so to prevent the pressure in the adjacent artery from bursting it. As Dr. Tom Langfitt, the neurosurgeon who taught medical students, interns and residents at Penn Med in the 60’s said “they’ll stare you down every time”. To put a clip around the neck of the aneurysm you have to jiggle and move it, which may cause it to break. This happened during surgery on President Biden in 1988.

Remarkably, Neal Kassell, the neurosurgeon operating on President Biden was an undergraduate at Penn when I was a neurology resident there in ’67 – ’68. Even before med school (graduating Penn Med in’72) he was vitally interested in neurosurgery and hung around the hospital and would observe Langfitt in action in the OR.

What is there to worry about? Relatively little. It is possible that Biden is developing another aneurysm. One well known complication of a ruptured intracranial aneurysm is something called occult hydrocephalus (or normal pressure hydrocephalus). Blood is extremely inflammatory, and the inflammation can resolve causing scarring (fibrosis) of the linings of the brain. This can impede the flow of spinal fluid.

What are the symptoms? Cognitive decline for one, something that’s been endlessly discussed by pundits, politicians and the voters. The other symptom which even you can look for is difficulty walking, in particular beginning to walk. People with this seem to have feet glued to the floor and have problems initiating walking.

Diagnosis — in Biden’s case, a CAT scan to see if the cerebral ventricles are larger than they should be — https://en.wikipedia.org/wiki/Ventricular_system has great pictures and explanation.

Why not an MRI — because the clips used back in 1988 contain magnetizable material, and entering the strong magnetic fields of an MRI scanning would rip the clips off the aneurysm and kill Biden.

I think the chances of occult hydrocephalus developing 32 years after the aneurysm are remote. If it were going to happen it would have already. In the meantime, watch him start to walk.

Biden is in early dementia — yet more evidence

This is the third post arguing that Biden is in early dementia.  Today’s post is  based on his performances on the 18th of August and today 20 August.  The previous 2 posts can be found below the ***

Addendum: 23 August.  Don’t take my word for it.  All the material in this post  is evidence — please look at the linked videos and quotations and decide for yourself.  Your conclusions may be different from mine, but at the least you will see the evidence on which mine are based.   If you disagree, I’d love to see a comment. 

On the 18th in an interview on ABC with George Stephanopoulos a transcript contains the following exchange

“STEPHANOPOULOS: I– I think a lot of– a lot of Americans, and a l– even a lot of veterans who served in Afghanistan agree with you on the big, strategic picture. They believe we had to get out. But I wonder how you respond to an Army Special Forces officer, Javier McKay (PH). He did seven tours. He was shot twice. He agrees with you. He says, “We have to cut our losses in Afghanistan.” But he adds, “I just wish we could’ve left with honor.”

BIDEN: Look, that’s like askin’ my deceased son Beau, who spent six months in Kosovo and a year in Iraq as a Navy captain and then major– I mean, as an Army major. And, you know, I’m sure h– he had regrets comin’ out of Afganista– I mean, out of Iraq.”

Doesn’t he know which branch of the service his son was in? Did he think his son was in Afghanistan?  My wife and I know where our 4 uncles served in world war two.

Unsurprisingly, ABC did not put this exchange on the air.  It was only found by reading the transcript.  Pravda could have done no better.

Today

“President Biden: (12:15) Look, let’s put this thing in perspective here. What interest do we have in Afghanistan at this point with Al Qaeda gone? ”

They aren’t gone according to Pentagon spokesman John Kirby.  At a briefing following Biden’s remarks Kirby said that there remains an al Qaeda presence in Afghanistan.

Wasn’t Biden told this?  If he was did he forget it?  Where is the shrink from Yale who wanted remove Trump using article 25 of the Constitution back in the day.

At least the questions he’s getting are no longer of the “what’s your favorite ice cream?” variety.

Here are two such questions.

Stephanie Ramos: (18:42)
Yeah. Thank you, Mr. President, two questions for you. The military has secured the airport, as you mentioned, but will you sign off on sending US troops into Kabul to evacuate Americans who haven’t been able to get to the airport safely?

President Biden: (18:56)
We have no indication that they haven’t been able to get in Kabul through the airport.

Given the incompetence of our intelligence this may actually be what Biden has been told.  Reports from Kabul say exactly the opposite.  It is also possible that Biden has been told what is going on there and simply forgot or is lying.

I have friends who have told me they’d rather have a demented Biden than an undemented Trump.  It looks like they’re getting their wish.

Here’s the previous post which contains older evidence.

*****

Biden is in early dementia — more evidence

In an earlier post (reproduced below the ***) I gave my reasons based on (presumably unedited) tapes of the President for concluding that President Biden is in the early stages of dementia.  I am a retired board certified neurologist and occasional board examiner with 34 years of clinical experience.

Here is further evidence.

In a town hall meeting put on by CNN 21 July President Biden became rather incoherent and confused when answering “When will children under 12 be able to get vaccinated.”

Here is the (presumably) unedited video of the meeting — https://www.cnn.com/2021/07/21/politics/full-president-joe-biden-cnn-town-hall-july-21/index.html.

The question was asked 6 minutes and 20 seconds into the recording.  The response starts to make not much sense at 7 minutes and at 7 minutes 21 seconds, he briefly becomes incoherent.  He continues on in this vein up to about 8 minutes.

This is what early dementia looks like.

Well that’s my opinion.  Look at the tape and make your own.

****  The earlier post

Biden is in early dementia — the evidence

As a neurologist I am often asked about Biden’s mental capacity.  My first post on the subject occurred after the first debate with Trump.  I thought he was intact — you can read about it here.

https://luysii.wordpress.com/wp-admin/post.php?post=5200&action=edit&calypsoify=1

Then I was asked to comment on the possibility that his previous operation for aneurysm could be causing trouble. I didn’t think this was likely as so much time had passed.  Interestingly, I knew the neurosurgeon as a Penn undergraduate when I was a neurology resident.  You can read the post at the end — Biden’s cerebral aneurysm.

That was written last December.

I changed my opinion after his press conference. of 14 June ’21 https://www.youtube.com/watch?v=PAWRHM4i3Dg
I strongly suggest you look at the segment at 15 minutes where his response makes little sense, and then he shuts down completely for 7 seconds, apparently quite confused. That’s my reading of the video. Form your own opinion.

Then on June 23rd I was sent another clip where he was confused

— https://www.c-span.org/video/?512595-1/president-biden-attends-us-eu-summit-brussels

It is an 8 minute speech, and the clip can be found at 2 minutes, again showing an episode of confusion.

 

But first a story:

As a third year medical student on psychiatry rotation,  I interviewed a Bryn Mawr student who was on the psych ward (my wife was also an undergraduate at the time).  I well knew the intensity of the place, and how much pressure the girls (see the end of the post) put on themselves.  So I talked and talked and commiserated with her.  After a pleasant enough time the I concluded the interview and left.   The teaching psychiatrist asked me what I thought, and I told him how frigtening I found it given what I knew about Bryn Mawr. He asked me if I found out that she thought the television was talking to her.  Basically by yapping when she went off track, I kept her sane.

So I learned to shut up, and let people tell me what was wrong with them.  This is why Biden likely did well during the debates. The short time given to answer and the barrage of questions and interruptions kept him focused.

It really came home as I looked at the whole 8 minutes of the second clip trying to find the brief period of confusion.  Please look at the whole clip yourself and draw your own conclusions.  I see a pleasant,  rambling, slow thinking,  occasionally confused old man.

 

This is what early dementia looks like.

I was severely criticized by a follower after the first post.  Here it is,  “Issuing alarmist statements about his mental health is reprehensible. You are not his physician. Moreover, armchair diagnosis is frowned upon by the American Psychiatric Association.I’ve been following your blog for several years and also have been reading you comments on the “in the pipeline” blog. On the basis of that experience I had not expected to stoop that low.”

In my defense, I was defeated by the new WordPress editor which wouldn’t let me bring in the evidence shown here.  Apparently it was a (still extant) incompatibility of Safari with the editor.   I was still impressed enough by how confused Biden looked that I posted it anyway.

As the late Carl Sagan said “extraordinary claims require extraordinary evidence”. So here is the evidence (finally).  Apologies for the delay.

As children, our least favorite explanation was ‘because I say so’.

Essentially that’s part of what I’m offering here.  I was involved in clinical neurology from ’67 to ’00, and at a minimum saw at least 1 demented patient a week during that time.  That’s an underestimate, as I’d make rounds on other neurologists patients when covering weekends.  I doubt that anyone reading this has similar extensive experience.

So Biden just looks like all the early dementia patients I saw during that time.  Given my experience, I think that should carry some weight.

The fact that Biden appears sharp at times is typical of early stage dementia.  I’ve certainly seen it in family and friends, with such things being excused as ‘it must have been the heat’ or ‘they must not have been feeling well’.

Why is this important?  Khrushchev’s estimate of President Kennedy’s weakness lead to the Cuban Missile Crisis of 1962. Khrushchev’s son confirmed this when he spoke at the Kennedy Center at Harvard.   Kennedy was receiving narcotics for his back.  The side effects of what little medicines we had back then weren’t appreciated.  Example: thyroid and amphetamines were used to help people lose weight.

Biden does not appear mentally strong to Putin or Xi (or me).

Non-patent trolling

A conversation with a son who is in high tech brought up what a blister on the body politic patent trolling is https://en.wikipedia.org/wiki/Patent_troll.  I told him that I’m having trouble simply trying to give an idea away.  The idea is basically that some cases of chronic fatigue syndrome are due to senescent cells.  There is a simple way to look for this — measure a master transcription factor for cellular senescence (p16INK^4a) in blood cells.  If correct, a rational therapy for CFS (senolytics) is immediately at hand.  I’ve shopped this around, and someone at Stanford involved with CFS claims that he will test it.  I’ve heard nothing so far.  The idea is free for the taking.  Therapy for CFS essentially  helps patients live their symptoms rather than diminishing them or attacking the underlying problem.

Since I”m going to Venice for 2 weeks to celebrate my wife’s birthday, there won’t be any new posts for a while — so here is the idea as presented in two posts from my blog — take it and run with it.  The patients are waiting.

Not a great way to end 2017

Not a great way to end 2017

2017 ended with a rejection of the following letter to PNAS.

As a clinical neurologist with a long standing interest in muscular dystrophy(1), I was referred many patients who turned out to have chronic fatigue syndrome (CFS) . Medicine, then and now, has no effective treatment for CFS.

A paper (2) cited In an excellent review of cellular senescence (3) was able to correlate an intracellular marker of senescence (p16^INK4a) with the degree of fatigue experienced by patients undergoing chemotherapy for breast cancer. Chemotherapy induces cellular senescence, and the fatigue was thought to come from the various cytokines secreted by senescent cells (Senescence Associated Secretory Phenotype—SASP) It seems logical to me to test CFS patients for p16^INK4a (4).
I suggested this to the senior author; however, he was nominated as head of the National Cancer Institute just 9 days later. There the matter rested until the paper of Montoya et al. (5) appeared in July. I looked up the 74 individual elements of the SASP and found that 9 were among the 17 cytokines whose levels correlated with the degree of fatigue in CFS. However, this is not statistically significant as Montoya looked at 51 cytokines altogether.

In October, an article(6) on the possibility of killing senescent cells to prevent aging contained a statement that Judith Campisi’s group (which has done much of the work on SASP) had identified “hundreds of proteins involved in SASPs”. (These results have not yet been published.) It is certainly possible that many more of Montoya’s 17 cytokines are among them.

If this is the case, a rational therapy for CFS is immediately apparent; namely, the senolytics, a class of drugs which kills senescent cells. A few senolytics are currently available clinically and many more are under development as a way to attack the aging process (6).

If Montoya still has cells from the patients in the study, measuring p16^INK4a could prove or disprove the idea. However, any oncology service could do the test. If the idea proves correct, then there would be a way to treat the debilitating fatigue of both chemotherapy and CFS—not to mention the many more medical conditions in which severe fatigue is found.
Chemotherapy is a systemic process, producing senescent cells everywhere, which is why DeMaria (2) was able to use circulating blood cells to measure p16^INK4a. It is possible that the senescent cells producing SASP in CFS are confined to one tissue; in which case testing blood for p16^INK4a would fail. (That would be similar to pheochromocytoma cells, in which a few localized cells produce major systemic effects.)

Although senolytics might provide symptomatic treatment (something worthwhile having since medicine presently has nothing for the CFS patient), we’d still be in the dark about what initially caused the cells to become senescent. But this would be research well worth pursuing.

Anyone intrigued by the idea should feel free to go ahead and test it. I am a retired neurologist with no academic affiliation, lacking the means to test it.
References

1 Robinson, L (1979) Split genes and musclar dystrophy. Muscle Nerve 2: 458 – 464

2. He S, Sharpless N (2017) Senescence in Health and Disease. Cell 170: 1000 – 1011

3. Demaria M, et al. (2014) Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7: 165 – 176

4. https://luysii.wordpress.com/2017/09/04/is-the-era-of-precision-medicine-for-chronic-fatigue-syndrome-at-hand/

5. Montoya JG, et al., (2017) Cytokine signature associated with disease severity in chronic fatigue syndrome patients, Proc Natl Acad Sci USA 114: E7150-E7158

6. Scudellari M, (2017) To stay young, kill zombie cells Nature 551: 448 – 450

Is a rational treatment for chronic fatigue syndrome at hand?

If an idea of mine is correct, it is possible that some patients with chronic fatigue syndrome (CFS) can be treated with specific medications based on the results of a few blood tests. This is precision medicine at its finest.  The data to test this idea has already been acquired, and nothing further needs to be done except to analyze it.

Athough the initial impetus for the idea happened only 3 months ago, there have been enough twists and turns that the best way explanation is by a timeline.

First some background:

As a neurologist I saw a lot of people who were chronically tired and fatigued, because neurologists deal with muscle weakness and diseases like myasthenia gravis which are associated with fatigue.  Once I ruled out neuromuscular disease as a cause, I had nothing to offer then (nor did medicine).  Some of these patients were undoubtedly neurotic, but there was little question in my mind that many others had something wrong that medicine just hadn’t figured out yet — not that it hasn’t been trying.

Infections of almost any sort are associated with fatigue, most probably caused by components of the inflammatory response.  Anyone who’s gone through mononucleosis knows this.    The long search for an infectious cause of chronic fatigue syndrome (CFS) has had its ups and downs — particularly downs — see https://luysii.wordpress.com/2011/03/25/evil-scientists-create-virus-causing-chronic-fatigue-syndrome-in-lab/

At worst many people with these symptoms are written off as crazy; at best, diagnosed as depressed  and given antidepressants.  The fact that many of those given antidepressants feel better is far from conclusive, since most patients with chronic illnesses are somewhat depressed.

The 1 June 2017 Cell had a long and interesting review of cellular senescence by Norman Sharpless [ vol. 169 pp. 1000 – 1011 ].  Here is some background about the entity.  If you are familiar with senescent cell biology skip to the paragraph marked **** below

Cells die in a variety of ways.  Some are killed (by infections, heat, toxins).  This is called necrosis. Others voluntarily commit suicide (this is called apoptosis).   Sometimes a cell under stress undergoes cellular senescence, a state in which it doesn’t die, but doesn’t reproduce either.  Such cells have a variety of biochemical characteristics — they are resistant to apoptosis, they express molecules which prevent them from proliferating and — most importantly — they secrete a variety of proinflammatory molecules collectively called the Senescence Associated Secretory Phenotype — SASP).

At first the very existence of the senescent state was questioned, but exist it does.  What is it good for?  Theories abound, one being that mutation is one cause of stress, and stopping mutated cells from proliferating prevents cancer. However, senescent cells are found during fetal life; and they are almost certainly important in wound healing.  They are known to accumulate the older you get and some think they cause aging.

Many stresses induce cellular senescence of which mutation is but one.  The one of interest to us is chemotherapy for cancer, something obviously good as a cancer cell turned senescent has stopped proliferating.   If you know anyone who has undergone chemotherapy, you know that fatigue is almost invariable.

****

One biochemical characteristic of the senescent cell is increased levels of a protein called p16^INK4a, which helps stop cellular proliferation.  While p16^INK4a can easily be measured in tissue biopsies, tissue biopsies are inherently invasive. Fortunately, p16^INK4a can also be measured in circulating blood cells.

What caught my eye in the Cell paper was a reference to a paper about cancer [ Cancer Discov. vol. 7 pp. 165 – 176 ’17 ] by M. Demaria, in which the levels of p16^INK4a correlated with the degree of fatigue after chemotherapy.  The more p16^INK4a in the blood cells the greater the fatigue.

I may have been the only reader of both papers with clinical experience wth chronic fatigue syndrome.  It is extremely difficult to objectively measure a subjective complaint such as fatigue.

As an example of the difficulty in correlating subjective complaints with objective findings, consider the nearly uniform complaint of difficulty thinking in depression, with how such patients actually perform on cognitive tests — e. g. there is  little if any correlation between complaints and actual performance — here’s a current reference — Scientific Reports 7, Article number: 3901(2017) —  doi:10.1038/s41598-017-04353.

If the results of the Cancer paper could be replicated, p16^INK4 would be the first objective measure of a patient’s individual sense of fatigue.

So I wrote both authors, suggesting that the p16^INK4a test be run on a collection of chronic fatigue syndrome (CFS) patients. Both authors replied quickly, but thought the problem would be acquiring patients.  Demaria said that Sharpless had a lab all set up to do the test.

Then fate (in the form of Donald Trump) supervened.  A mere 9 days after the Cell issue appeared, Sharpless was nominated to be the head of the National Cancer Institute by President Trump.  This meant Dr. Sharpless had far bigger fish to fry, and he would have to sever all connection with his lab because of conflict of interest considerations.

I also contacted a patient organization for chronic fatigue syndrome without much success.  Their science advisor never responded.

There matters stood until 22 August when a paper and an editorial about it came out [ Proc. Natl. Acad. Sci. vol. 114 pp. 8914 – 8916, E7150 – E7158 ’17 ].  The paper represented a tremendous amount of data (and work).  The blood levels of 51 cytokines (measures of inflammation) and adipokines (hormones released by fat) were measured in both 192 patients with CFS (which can only be defined by symptoms) and 293 healthy controls matched for age and gender.

In this paper, levels of 17 of the 51 cytokines correlated with severity of CFS. This is a striking similarity with the way the p16^INK4 levels correlated with the degree of fatigue after chemotherapy).  So I looked up the individual elements of the SASP (which can be found in Annu Rev Pathol. 21010; 5: 99–118.)  There are 74 of them. I wondered how many of the 51 cytokines measured in the PNAS paper were in the SASP.  This is trickier than it sounds as many cytokines have far more than one name.  The bottom line is that 20 SASPs are in the 51 cytokines measured in the paper.

If the fatigue of CFS is due to senescent cells and the SASPs  they release, then they should be over-represented in the 17 of the 51 cytokines correlating with symptom severity.  Well they are; 9 out of the 17 are SASP.  However although suggestive, this increase is not statistically significant (according to my consultants on Math Stack Exchange).

After wrote I him about the new work, Dr. Sharpless noted that CFS is almost certainly a heterogeneous condition. As a clinician with decades of experience, I’ve certainly did see some of the more larcenous members of our society who used any subjective diagnosis to be compensated, as well as a variety of individuals who just wanted to withdraw from society, for whatever reason. They are undoubtedly contaminating the sample in the paper. Dr. Sharpless thought the idea, while interesting, would be very difficult to test.

But it wouldn’t at all.  Not with the immense amount of data in the PNAS paper.

Here’s how. Take each of the 9 SASPs and see how their levels correlate with the other 16 (in each of the 192 CSF patients). If they correlate better with SASPs than with nonSASPs, than this would be evidence for senescent cells being the cause some cases of CFS. In particular, patients with a high level of any of the 9 SASPs should be studied for such correlations.  Doing so should weed out some of the heterogeneity of the 192 patients in the sample.

This is why the idea is testable and, even better, falsifiable, making it a scientific hypothesis (a la Karl Popper).  The data to refute it is in the possession of the authors of the paper.

Suppose the idea turns out to be correct and that some patients with CFS are in fact that way because, for whatever reason, they have a lot of senescent cells releasing SASPs.

This would mean that it would be time to start trials of senolyic drugs which destroy senescent cells on the group with elevated SASPs. Fortunately, a few senolytics are currently inc linical use.  This would be precision medicine at its finest.

Being able to alleviate the symptoms of CFS would be worthwhile in itself, but SASP levels could also be run on all sorts of conditions associated with fatigue, most notably infection. This might lead to symptomatic treatment at least.  Having gone through mono in med school, I would have loved to have been able to take something to keep me from falling asleep all the time.

Is sleep deprivation like Alzheimer’s and why we need sleep in the first place

Ask a cardiologist why the heart needs to pump and you’ll get a strange look. Ask any neuroscientist why the brain needs to sleep, and they’ll scratch their head — until now perhaps. A paper in Science a few days ago may have the answer [ Science vol. 342 pp. 316 – 317, 373 – 377 ’13 ] Essentially the brain gets washed out during sleep.

First — a bit of history. The tissue of the brain is so tightly packed that it is impossible to see the cells that make it up with the usual stains used by light microscopists. People saw nuclei all right but they thought the brain was a mass of tissue with nuclei embedded in it (like a slime mold). Muscle is like that — long fibers with hundreds of nuclei here and there. It wasn’t until that late 1800′s that Camillo Golgi developed a stain which would now and then outline a neuron with all its processes. Another anatomist (Ramon Santiago y Cajal) used Golgi’s technique and argued with Golgi that yes the brain was made of cells. Fascinating that Golgi, the man responsible for showing nerve cells, didn’t buy it. This was a very hot issue at the time, and the two received a joint Nobel prize in 1906 (only 5 years after the prizes began).

How tightly packed are the cells in the brain? The shortest wavelength of visible light is 4000 Angstroms. Cells in the brain are packed far more tightly. To see the space between the brain cell external membranes you need an electron microscope (EM). Just preparing a sample for EM really fries the tissue. Neurons are packed together with less than 1000 Angstroms between them. So how much of this is artifact of preparation for electron microscopy has never been clear to me. One study injected a series of quantum dots of known diameter into the cerebral spinal fluid (CSF) to see the smallest sized dot that could insinuate itself between neurons [ Proc. Natl. Acad. Sci. vol. 103 pp. 5567 – 5572 ’06 ]. The upper limit was around 350 Angstroms. No wonder the issue was contentious when all they had was light microscopy.

Surprisingly, the PNAS paper comes up with an estimate that brain extracellular space comprises 20% of brain volume. I find this hard to accept given the above. So how does the brain get rid of waste products? It turns out that there is a circulation of cerebrospinal fluid (CSF) of sorts. Inject a tracer that you can follow into the CSF. After a period of time the tracer enters the brain along arteries (not veins) and after still more time it leaves the brain along the veins (not the arteries). How the tracer gets to veins isn’t discussed in the Science papers. This has been called by the horrible name of the glymphatic system (don’t ask).

Using a great deal of ingenuity, experimental finesse and some very cooperative mice, the flow of CSF into, through and out of the brain was studied. Several findings are striking — the extracellular space (aka interstitial volume) dearly doubles (from 14% to 23%) during sleep. More importantly, the flow into the brain decreases by 95% when you wake the mouse up. Presumably flow out of the brain decreases by the same amount during wake. CSF flow into the brain was present only in the surface exposed to bulk CSF when the animals were awake.

So what? The Abeta peptide is held by many to be the culprit in Alzheimer’s disease. When injected into the mouse cerebral cortex (hardly a physiologic procedure) Abeta peptide is cleared twice as fast from the brain during sleep. We all know that you don’t think as well when sleep deprived, and this may be why. The current thinking on Alzheimer’s is that it isn’t the visible plaques that you can see under the microscope (made largely of Abeta peptide aggregates), but the soluble form of Abeta which you can’t see which causes the trouble. This always struck me as a cop out similar to the way docs would say that labyrinthitis was due to a virus (not that anyone every isolated one). You might as well say both are due to angels (or devils).

So the difficulty thinking with sleep deprivation may be similar to Alzheimer’s disease, if similar goings on occur in our brain. Distinguish this from the sleepiness due to sleep deprivation –Alzheimer patients often have disturbed sleep patterns, but they aren’t particularly sleepy when they’re awake.

The sleepiness may be due to the build up of something else. Bulk flow of fluid is incredibly nonspecific, and will carry anything soluble along with it. Adenosine has been mentioned as one metabolite building up which makes us sleepy. Probably looking for a single compound washed out by CSF as ‘the’ cause of sleepiness or cognitive problems, is like looking for ‘the’ single compound in kidney failure causing similar symptoms. It’s everything the kidney/brain filters and gets rid of.

So, at very long last, we may have found out why we spend 1/3 of our lives asleep.