Category Archives: Neurology & Psychiatry

Another neuropharmacologic surprise.

Our genome contains 826 different genes for G Protein Coupled Receptors (GPCRs) which are targeted by at least 475 FDA approved drugs (Nature vol. 587 p. 553 ’20 ). Yet part of the fascination of reading the current literature is the surprises it brings.

Our basic understanding was that the GPCRs sit on the surface of the cell waiting for ligands outside the cell to bind to it, which produces a conformational change on the cytoplasmic side of the cell membrane, changing the way the GPCR binds to the G protein, triggering all sorts of effects inside the cell.

As far as I recall, we never thought that different GPCRs would bind to each other in the cell membrane, even though a single cell can express ‘up to’ 100 different GPCRs [ Mol. Pharm. vol. 88 pp. 181 – 187 ’15 ].  Neurons express GPCRs and some are thought to be involved in neuropathic pain

But that’s exactly what Proc. Natl. Acad. Sci. vol. 119 e2123511119  ’22  is saying.

First a few definitions, if you’re as rusty about them as I was

A cytokine is an extracellular protein or peptide  helping cells to communicate with each other.  A chemokine is an extracellular protein which attracts cells.

Our genome has over 50 chemokines.  Most are  proteins with about 70 amino acids. The are classified by where the cysteines lie in them.  We have 23 receptors for chemokines, 18 of which are GPCRs.   Binding is promiscuous — a given chemokine binds to multiple receptors, and a given receptor binds to multiple chemokines.

Clearly the chemokines and their receptors are intimately involved in inflammation which always involves cell migration.  Neurons express chemokine receptors GPCRs and some are thought to be involved in neuropathic pain.

We also know that the nervous system is involved in immune function, particularly inflammation.  One prominent neurotransmitter is norepinephrine, and a variety of receptors bind to it.  There are 3 alpha1 norepinephrine receptors (a, b and d), all of which are GPCRs.

What is so shocking is that alpha1 GPCRs bind to chemokine receptors (forming heteromers), and that this binding is required for chemokines to have any effect on cell migration.  Even more interesting is that binding of norepinephrine to the alpha1 component of the heteromer INHIBITs cell migration.

So how many of our 826 GPCRs bind to each other, and what effects do they have?

Reading the literature is like opening presents, you find new fascinating toys to play with, some of which may actually benefit humanity

 

A new way to look at ALS (thank God)

It’s always good when a new way to look at a basically untreatable disease comes along.  We’ll know soon if looking at filamin A will be useful for Alzheimer’s disease.  Here’s another:  something we’ve known about for years (polyphosphate) may be important in Amyotrophic Lateral Sclerosis (ALS).   I used riluzole for ALS, but never saw any benefit.  It may have slowed the decline, but riluzole never stopped disease progression.

It is stated that 10% of ALS is familial, but I think this is an overstatement.  Even so mutations in a variety of proteins(superoxide dismutase 1 (SOD1) TDP43, C9orf72) do cause ALS, and studying them has taught us a lot about ALS.  There is plenty of work to do.  In 2016 a mere 160 mutations in the 153 amino acids of SOD1 had been found, but we still don’t know how they cause ALS despite hundreds of papers on the subject.  The proteins have allowed us to make mouse models of ALS, by putting in one or the other of mutated SOD1, TDP43, C9orf72 in motor neurons (or in whole animals)

Some real gumshoe work led to polyphosphate [ Neuron vol. 110 pp. 1603 – 1605 ’22 ].  Obviously in ALS, the motor neurons die, but recent work has shown that motor neurons are killed by neighboring astrocytes (containing any of the 3 the mutant proteins), when they are cultured together.   Normal astrocytes don’t do this.

So a lot of hard work found that it was polyphosphate in the supernatant fluid that was the killer.

So what is polyphosphate?  It’s been known for years, and is found in ALL cells — bacterial, plant, animal.  It also produced abiotically in volcanic exudates and deep sea steam vents.  No one knows what it does, so it has been called a molecular fossil.  Again teleology should inform biologic research (but it doesn’t).  Polyphosphate must be doing something useful or it wouldn’t be present in all living cells.

Chemically, polyphosphate is a chain of HUNDREDS to THOUSANDS of phosphate residues linked by high energy phosphoanhydride bonds.

Like this —

HO – PO2 – OH  + HO -PO2 -OH –>  HO – PO2 – 0 – PO2 – OH + H20

— the – O – in the middle is the phosphoanhydride bond

The authors treated motor neurons in culture with polyphosphate and found that it killed 40% of them.  So what?  Schmidt’s law of pharmacology, says that enough of anything will do anything,  So they looked at the spinal cords of patients dying of ALS and found that polyphosphate levels were higher than in neurologically normal controls.

So it’s open season on polyphosphate. Finding out what it does in normal cells, finding out how it kills motor neurons, finding out if decreasing its levels will help ALS (it does in cultures of motor neurons but that’s a long way from a living patient).  It’s an entirely new angle on an awful disease, with no useful treatment.  There is simply an enormous amount of work to be done.

Watch this space.

 

 

The brain gets more complicated the closer you study it

When our tools were blunt, the brain looked a lot simpler than it does now.

Example #1:  Locus coeruleus (LC).  This is a tiny group of neurons deep in the brain.  It looks blue to the naked eye, if you’ve gone to medical school as I have and dissected a brain.  This is held to be due to neuromelanin produced by the neurotransmitter  it uses (norepinephrine).  Neurons using dopamine as a neurotransmitter also produce neuromelanin but it’s brown.  The two differ by just one oxygen atom.

The LC is tiny in primates, only 15,000 – 50,000 neurons depending on species and who you read..  The rat (where most experiments are done) has only 1,500 in a space 1000 microns (1 millimeter) x 200 x 500 microns.

So until now any attempt to stimulate the locus coeruleus with an electrode alerted the animal.

Why? Two reasons.

1. The LC is so small that any electrode stimulating it, stimulated every neuron.

2.  Because that tiny nucleus sends fibers all over the brain, releasing norepinephrine everywhere, and not just at synapses.  This is called volume neurotransmission. Most places on the axons of a LC neuron showing synaptic vesicles (where norepinephrine is found), don’t have a dendrite or any sort synaptic specialization next to them.  So the LC innervates the whole brain, in the same way that our brain innervates our muscles.

Stimulate the LC of a rat and the brain is flooded with norepinephrine and the animal wakes up.

Well that was the case until technology marched on and miniaturization of electrodes allowed us to record from a 10 – 20 neurons at a time in the LC when stimulation was applied.  Those responding to a given stimulus were called ensembles.  Of 285 single LC neurons studied in 15 rats, 115 participated in multiple ensembles, 149 participated only in a single ensemble and 21 didn’t participate in any.  Activity of different ensembles produced different brain states — not all were wide awake.  You can read all about this in Proc. Natl. Acad. Sci. vol. 119 e21116507119 ’22.

Volume neurotransmission is  important because the following neurotransmitters use it — dopamine, serotonin, acetyl choline and norepinephrine. Each has only a small number of cells using them as a transmitter.  The ramification of these neurons is incredible.

For instance, “human serotonergic neurons, which are estimated to extend axons for 350 meters”  [ Science vol. 366 3aaw9997 p. 4 ’19 ], so the fibers are everywhere in the brain.  I couldn’t find a statistic for axons of the locus coeruleus but those of neurons using acetyl choline as a neurotransmitter are estimated to have axons extending for 31 meters.

So now you see why massive release of any of the 4 neurotransmitters mentioned (norepinephrine, serotonin, dopamine, acetyl choline) would have profound effects on brain states.  The four are vitally involved in emotional state and psychiatric disease. The SSRIs treat depression, they prevent reuptake of released serotonin.  Cocaine has similar effects on dopamine.  The list goes on and on and on.

Maybe be we’ll be able to slice and dice these nuclei in the future to produce more subtle effects on brain function.

 

Example #2:  Dendritic diversity  — that’s for next time.  This post is long enough.

Cassava’s Cognition Maintenance Study may prove Simufilam works

The FDA will approve less than perfect therapies if there is nothing useful for a serious condition.  Consider the following from Proc. Natl. Acad. Sci. vol. 119 e2120512119 ’22

“KRAS is the most frequently mutated oncogene in human cancer, with mutations detected across many lineages, particularly in the pancreas, colon, and lungs. Among the most commonly activating KRAS mutations at codons 12, 13, and 61, G12C occurs in ∼13% of lung and 3% of colorectal carcinomas and at lower frequencies in other tumors.

“In locally advanced or metastatic non–small-cell lung cancer (NSCLC) patients with KRASG12C mutations who have received at least one prior systemic therapy”  treatment with sotorasib resulted in the following “objective response  in 37.1% of the patients, with a median duration of response was 11.1 months.”   This is hardly a cure, but nonetheless “This promising anticancer activity has resulted in accelerated approval from the US Food & Drug Administration”

Which brings me to the current CMS study from Cassava Sciences.  I’ll let them speak for themselves. https://finance.yahoo.com/news/cassava-sciences-reports-first-quarter-130000375.html

Cognition Maintenance Study (CMS) – on-going
In May 2021, we initiated a Cognition Maintenance Study (CMS). This is a double-blind, randomized, placebo-controlled study of simufilam in patients with mild-to-moderate Alzheimer’s disease. Study participants are randomized (1:1) to simufilam or placebo for six months. To enroll in the CMS, patients must have previously completed 12 months or more of open-label treatment with simufilam. The CMS is designed to evaluate simufilam’s effects on cognition and health outcomes in Alzheimer’s patients who continue with drug treatment versus patients who discontinue drug treatment. The target enrollment for the CMS is approximately 100 subjects. Over 75 subjects have been enrolled in the CMS and 35 have completed the study.”

Even though the open label study was not randomized, this one will be.

Only someone who has actually taken care of  patients would know the following.  People who are getting no benefit from a drug will soon stop taking it.  This was particularly true for my experience with Cognex for Alzheimer’s disease.

Which is exactly why the fact that 75 patients who’ve been on Simufilam have decided to continue on in the CMS study.  Presumably they feel they are getting some benefit.

There are two possible hookers to this

l. The patients are being paid to enter CMS

2. The original cohort was 200, not all of whom have finished the 1 year.  So we don’t know how many could have been in CMS but chose not to.

As I discussed in an earlier post, the most impressive thing (to me at least) was that at 9 months 5/50 had significant improvement in their cognition — here’s a link — https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/.

The CMS study should give us an idea of how they fared at 1 year and  at 18 months.

If:

l. gains in cognition were maintained on Simufilam

2. gains in cognition were lost off Simufilam

FDA approval should follow quickly.

Results on the 75 will be available this year.   Also available this year will be 1 year results on all 200 entering the open label study.

There are two other double blind studies in progress which will provide  more definitive answers, but they are far from full and will take much longer to complete.  So stay tuned.

Does getting COVID19 shrink your brain?

Does getting COVID19 shrink your brain?  A paper from last Thursday’s Nature says yes.  Not only that, but it slows you mentally. Here’s a link: https://www.nature.com/articles/s41586-022-04569-5.pdf.   and a reference: Nature vol. 604 pp. 697 – 707 ’22.

Here’s what they did.  Take 785 people over 50 from England. Have 401 get infected with the pandemic virus, after obtaining MRI scans, all sorts of data including mental function about them.   Then repeat the MRI and mental tests  4 – 5 months after the infection.  Compare the two groups and there’s your answer.

The moral among you must be wondering how they ever got this past an Institutional review board.  It didn’t.  This was an experiment of nature on participants in the UK Biobank — https://en.wikipedia.org/wiki/UK_Biobank.  Starting in 2006 and ending in 2010 some 100,000 people (ages 40 – 69 on entry) from the United Kingdom (UK) were intensively studied (they donated urine, saliva and blood, filled out questionnaires, and consented to access to their electronic health records).   Planned follow up is 30 years.  All this before we had any idea about the pandemic to hit us in 2020.

Obviously the control group without infection, must be as similar as possible to the infected group and I think the authors tried their hardest.  Even so the control group was a bit older, and the infected group had slightly lower cognitive abilities.

The average time between the two scans was 3 years.  The average time from COVID19 to the second scan was 141 days.  The scans were done before Omicron hit.  Even so only 15/401 had to be hospitalized.  This is consistent with the mildness of the pandemic presently.  On 9 April 22 Shanghai reported some 23,000 positive PCR tests (for Omicron), but only one thousand or so were symptomatic.   Excluding the 15 from analysis didn’t change the result.  I’ve heard from clinicians, that the severely ill are usually obese.  This is partly true for the 15 hospitalized (average Body Mass Index 29.3) vs. the 386 not hospitalized (BMI – 26.6).

So the clickbait is that being infected with the virus shrinks your brain. But does it? It is stated that there was a decrease in thickness of the cerebral cortex (the gray matter on the surface of the brain) concerned with smell and taste.

The decreases were minimal.  Have a look at figure 1a p. 701.  The changes between scans are plotted vs. age, and separately for cases and controls. As we get older the brain shrinks.  This was true for both patients and the controls, but the patients showed more shrinkage (measured by the change between successive MRIs).

What sort of shrinkage in the thickness of he cerebral cortex are we talking about here?  At most 3% and usually under 2%.  But 3% of what?  Most estimates of the thickness of the human cerebral cortex place it around 2 – 3 millimeters (range 1 to 5 millimeters).  So I got out a clear plastic ruler and found that 1 milliMeter is about the thickness of a penny?  Are they really saying that the MRI can measure thickness differences of 2 – 3% of something only 2 – 3 millimeters.

It gets worse.  Most of us have seen MRI pictures by now.  If you look closely, you’ll see that they are slices made of pixels.  These are computed slices of 3 dimensional cubes (voxels).  And what dear reader is the size of an MRI voxel — around 1 x 1 x 1 milliMeters.  So they are measuring cortical thickness with a rather blunt instrument which is 30 – 50% the size of cortical thickness.  Do you think, even with averaging of hundreds of people, that they can pick up a change in cortical thickness of several percent in something so small.

I don’t, and am amazed that the reviewers let them get away with this.

The cognitive changes are on much better ground.  But that’s for the next post.  This post is long enough.

A totally unsuspected information processing mechanism in the brain

This is pretty hard core stuff for the neurophysiology, neuropharmacology and  neuroscience cognoscenti.  You can skip it if you’re satisfied with our understanding of how the brain works, and our current treatments for neurological and psychiatric disease.  You aren’t?  Join the club and read on.

We thought we pretty much understood axons.  They were wires conducting nerve impulses (action potentials) from the cell body to their far away ends, where the nerve impulses released neurotransmitters which then affected other neurons they were connected to by synapses.

We knew that there were two places on the axon where receptors for neurotransmitters were found, allowing other neurons to control what the axon did.  The first was the place where axon leaves the cell body, called the axon initial segment (AIS).  Some of them are controlled by the ends of chandelier cells — interneurons with elaborate specialized synapses called cartridges.   The second was on the axon terminals at the synapse — the presynapse.  Receptors for the transmitter to be released were found (autoreceptors) and for other neurotransmitters (such as the endocannabinoids (( our indigenous marihuana)) released by the presynaptic cell.

Enter a blockbuster paper from Science (volume 375 pp. 1378 – 1385 ’22) science.abn0532-2.pdf.  It shows (in one particular case) that the axons themselves have receptors for a particular transmitter (acetyl choline) which partly can control their behavior.  I sure people will start looking for this elsewhere. The case studied is of particular interest to the neurologist, because the axons are from dopamine releasing neurons in the striatum.  Death of these neurons causes parkinsonism.

The work used all sort of high technology including G Protein Coupled Receptors (GPCRs) highly modified so that when dopamine hit them a fluorescent compound attached to them lit up, permitting the local concentration of dopamine to be measured in the living brain.  Another such GPCR was used to measure local acetyl choline concentration.

The dopamine axons contain a nicotinic type receptor for acetyl choline.  Stimulation of the interneurons releasing acetyl choline caused a much larger release of dopamine (in an area estimated to contain 3 to 15 million dopamine axon terminals.  The area covered by dopamine release was 3 times larger than the area covered by acetyl choline release, implying that the acetyl choline was causing the axons to fire.

The cell body of the dopamine neuron had nothing to do with it, as the phenomenon was seen in brain slices of the striatum (which have no input from the dopamine cell bodies.

They could actually study all this in living animals, and unsurprisingly, there were effects on movement with increased striatal dopamine and acetyl choline being associated with movement of the animal to the opposite side.

So this is an entirely novel mechanism for the control of neural activity.  How widespread such a mechanism is awaits further study, as is whether it is affected in various diseases, and whether manipulation of it will do any good (or harm).

Exciting times.

 

 

Sad to watch

Watch a confused old man ramble on semi-coherently and tell our troops they would be in the Ukraine.

Later, he called for regime change in Russia in a speech in Poland  according to an article in the Atlantic –hardly a right wing organ. https://www.theatlantic.com/ideas/archive/2022/03/biden-putin-regime-change-russia/629397/

Addendum 27 March — a third Biden response this week which had to be walked back by the ‘ White House’  — we would respond ‘in kind’ if Russia used chemical weapons — https://www.bbc.com/news/world-europe-60870771

As a neurology resident I was taught that a quick way to find out if a patient was confused, was to just shut up and let them talk.  This is exactly what is happening with Biden abroad, out of unscripted press conferences with preselected questions from friendly reporters.

I’ve written on Biden’s probable early dementia before.  This is just more evidence. Have a look, and draw your own conclusions.

Here’s an earlier post with much more evidence (including unadulterated clips of Biden speaking).

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

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).

 

COVID19 is bad for your brain even if you aren’t hospitalized

We now know that even COVID19 that doesn’t put you in the hospital is bad for your brain.  How do we know this?  Think of how you would design an experiment to find this out using real people.

Only a monster would do something like this.  Take 800 people, study the hell out of them.  MRI their brain, do cognitive tests, know just about everything about the medical and social history.  Then expose them to the pandemic virus.  Some get infected (as judged by their health records and antibody to the virus tests).  I’ll call the infected COVID19 to save time. Wait a few months then test them all over again, MRIs, cognitive tests, medical history etc. etc.

Such an experiment was done and what follows is a description of a paper given in a link a friend sent —  doi: 10.1038/s41586-022-04569-5. Online ahead of print. PMID: 35255491.  To be noted, is that the paper is still being edited by Nature, so some things may change but I’m pretty sure the conclusions will stand.

The work was done by the UK Biobank which which recruited 500,000 volunteers   aged 40 to 60 from 2006 to 2010 and is following them for 30 years.  All donated urine, saliva and blood in addition to filling out questionnaires with consent for access to their electronic health records.  Last year the Biobank released the (anonymized hopefully) complete genome sequences of 200,000 people.

This was long before the pandemic hit.   The paper reports results on 785 participants ages 51 – 81 who had MRIs twice (once before the pandemic hit, and once afterward).  There were 401 who had been infected.  The 384 uninfected controls were selected to be matched for age, sex, ethnicity and time between the two MRIs (which were an average of 38 months apart).   The average time between becoming infected and the second MRI and testing was 20 weeks.

How many of the 785 were hospitalized?  Just 15/401 infected (3.7%) showing that most pandemic infections were pretty benign.  The 15 hospitalized were excluded from further analysis

The paper was submitted to Nature in August of 2021, long before omicron appeared on the scene.

So these are huge numbers of subjects, all of whom had been intensively studied before the pandemic hit, which makes it so valuable.

There is a huge amount of data, but here are a few of the high points. All of what follows compares the infected to uninfected controls.

l. The infected had a greater reduction in gray matter between the MRIs, particularly in that part of the brain close to the nose.2. The infected had greater reductions in brain size (but not that much, the average atrophy was 2%).

3. We all cognitively decline as we get older, but the decline was greater in the infected.

With this many people in the study, they could group people into two year bins.  So there was no atrophy in one area (relative to controls) in people between 55 and 60, but at 76 the same area showed 20% atrophy in patients but only 5% in controls.

It is obvious on looking at the graphs plotting results for the infected vs age and results for the uninfected in the same panel, that the differences between the infected and the controls increased with age.

The cognitive testing reported was rather simple — but it could be quantitated.  It was time to complete the trail A and trail B tests.  In these trials subjects are to connect a set of 25 dots as quickly as possible.  The observer notes mistakes and allows people to correct them until they get everything right.

Part A has the dots numbered and they are to be connected in order.  This is thought to test cognitive processing speed.

Part B has the first 13 integers and letters from A to L.  They are to be connected as follows 1 – A – 2 – B – 3 -C —   This is thought to test executive function.

There are, tons more data of interest to a neurologist — which particular parts of the brain are hardest hit etc. etc. but I’ll leave it to you to follow the link

 

A new metabolite modifying proteins

I stopped counting when I got up to 28 mutations capable of causing clinical Parkinson’s disease (each in a different protein).  Many of them point to the mitochondrion with production of reactive oxygen species, but figuring out how they produce disease has kept armies of researchers busy.

Particularly fascinating is DJ-1, (aka PARK7) discovered in 2003 in two Dutch families when mutations  produced early onset Parkinsonism.  In December 2019 I noted that I’d taken 15 K of notes about PARK7, but that we still didn’t know how mutations cause Parkinsonism.  The mutation deletes some 14,082 nucleotides and the first 5 exons of the gene essentially destroying it.

Well, we still don’t but a new paper [ Proc. Natl. Acad. Sci. vol. 119 e2111338119 ’22 ] showed that it destroys a metabolite that no one had ever heard of.

The metabolite arises from a glycolytic intermediate (1, 3 diphospho glyceric acid).   The oxygen of the 3 phosphate attacks the carbonyl group of carbon 1 displacing the other phosphate forming a 6 membered ring containing all 3 carbons and PO2.

Here’s a link — https://www.pnas.org/doi/10.1073/pnas.2111338119

The structure is given in figure 7 D.

But there’s more, much more.  The intermediate reacts with the amino groups in proteins forming a glyceric acid modification.  PARK7 destroys the intermediate.  The protein modification was found on 80 different proteins in the brains of mice deficient in PARK7.  So now we have 80 new leads to follow, and we’ve found a completely new protein modification.

As far as we know, PARK7 is the only protein destroying the intermediate.  This explains why PARK7 is so abundant, and why its concentration is kept the same across different cell types and organisms.

Who knows how many more metabolic intermediates are out there waiting to be discovered.  Molecular biology (and drug development)  is hard because we don’t know all the players.  Here is yet another.

You can’t go wrong quoting Shakespeare

There are more things in heaven and earth, Horatio, Than are dreamt of in your philosophy.” – Hamlet (1.5.167-8),

Reprogramming glia to neurons

I must admit that I have pretty much avoided reading about reprogramming anything (fetal cells, fibroblasts, glia) to neurons to cure neurologic disease.  It seems light years away, and transplantation work to cure Parkinsonism never really worked.

However a gigantic amount of work (all experimental) has been done on reprogramming glia to neurons while my reading was elsewhere.  You can read all about it in a similarly gigantic review [ Neuron vol. 110 pp. 366 – 393 ’22 ].

But the review potentially is about much more than that, because it talks about what keeps a differentiated cell in its differentiated state.  To reprogram glia (or any cell) that must be broken, and the review contains a good deal of molecular biology on this point.

There is applicability to cancer (although this isn’t mentioned in the review).  The focus of nearly all cancer research is on stopping proliferation.  We were all taught that cancer also involves dedifferentiation.  Wouldn’t it be good if we could REdifferentiate the cancer back to its cell of origin.   The reprogramming literature and this review extensively deals with these issues (but only in the context of glia –> neurons).

Close study of one example (introduction of NeuroD1 to mouse microglia by a lentivirus) converts them to neurons (in vivo and in vitro).   Initially NeuroD1 occupies closed chromatin regions associated with bivalent epigenetic marks.

Bivalency just means two marks, one of which is associated with gene activation, the other associated with gene repression (respectively trimethylation of histone H3 on lysine 4 { H3K4Me3 } and H3K27Ac associated with repression).  Bivalent genes are thought to be in a primed state for activation although still repressed.  So this leads to the idea that cell fate may be stabilized by stringently shutting down transcription factors specifying alternative states.  Perhaps we could do something like this with neoplastic cells.

At lter stages of thei reprogramming model, bivalent regions are ‘resolved’ to a monoalent H3K4Me1 histone mark to establish neuronal identity. NeuroD1 also induces the expression of Brn2 which supports acquisition of neuronal gene expression.

The review delves further in to REST, which represses neuronal genes in nonNeuronal cells.  It binds and represses the microRNAs miR-124 and miR-9/9* which reduce the expression of SCP1 a phosphatase, which is recruited by REST on neuronal genes.  The review is full of detailed mechanistic stuff at this level.

Be prepared for a long slog through the review, there is a ton of dense information, densely presented.  It took me a week or so to get through it.

The amount of work already done is impressive.  Table 1 is a list of 32 in vivo studies (with controls) which show direct reprogramming of glia to neurons.

The techniques of introducing the reprogramming factors are discusssed:  retroviruses, lentiviruses and AdenoAssociated Viruses (AAVs).

It’s a long way from the clinic but a lot of work is ongoing.  Fascinating stuff