Category Archives: Neurology & Psychiatry

An incredible way to look at the brain

http://www.pnas.org/content/115/27/6940 [ Proc. Natl. Acad. Sci. vol. 115 pp. 6940 – 6945 ’18 ] demonstrates an incredible new way to visualize brain structures.  I don’t think the paper is behind a paywall, so follow the link and look at the movies.

The technique can be used on paraffin embedded brain.  Not to be tried at home unless you have a microCT with a liquid jet anode source, and a high resolution synchrotron instrument with special Xray waveguide optic.

No staining was involved, and they used electron contrast to show purkinje cells, granule cells, and the ramified dendritic tree of the Purkinje cells in a 1 cubic millimeter punch ‘biopsy’ of paraffin embedded cerebellum.

The moves are incredible, as unlike the standard CT or MRI, you can move a plane through the images (the movies show this), stop it at leisure.  Visualization of a plane moving through the material shows what the brain looks like in 3 d.  Then there are a few 3 d reconstructions (presented as 2 dimensional projective drawings we’re used to seeing), but even these can be moved around.

Words are inadequate.  Go to the link and look at the movies.  Let me know if you have trouble reaching it.

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The Gambler’s fallacy is actually based on our experience

We don’t understand randomness very well. When asked to produce a random sequence we never produce enough repeating patterns thinking that they are less probable. This is the Gambler’s fallacy.  If heads come up 3 times in a row, the Gambler will bet on tails on the next throw   Why?  This reasoning is actually based on experience.

The following comes from a very interesting paper of a few years ago  [ Proc. Natl. Acad. Sci. vol. 112 pp. 3788 – 3792 ’15 ].  There is a surprising amount of systematic structure lurking within random sequences. For example, in the classic case of tossing a fair coin, where the probability of each outcome (heads or tails) is exactly 0.5 on every single trial, one would naturally assume that there is no possibility for some kind of interesting structure to emerge, given such a simple form of randomness.

However if you record the average amount of time for a pattern to first occur in a sequence (i.e., the waiting time statistic), it is longer for a repetition (head–head HH or tail–tail TT  (an average of six tosses is needrequired) than for an alternation (HT or TH, only four tosses is needed). This is despite the fact that on average, repetitions and alternations are equally probable (occurring once in every four tosses, i.e., the same mean time statistic).

For both of these facts to be true, it must be that repetitions are more bunched together over time—they come in bursts, with greater spacing between, compared with alternations (which is why they appear less frequent to us). Intuitively, this difference comes from the fact that repetitions can build upon each other (e.g., sequence HHH contains two instances of HH), whereas alternations cannot.

Statistically, the mean time and waiting time delineate the mean and variance in the distribution of the interarrival times of patterns (respectively). Despite the same frequency of occurrence (i.e., the same mean), alternations are more evenly distributed over time than repetitions (they have different variances) — which is exactly why they appear less frequent, hence less likely.

Then the authors go on to develop a model of the way we think about these things.

“Is this latent structure of waiting time just a strange mathematical curiosity or could it possibly have deep implications for our cognitive level perceptions of randomness? It has been speculated that the systematic bias in human randomness perception such as the gambler’s fallacy might be due to the greater variance in the interarrival times or the “delayed” waiting time for repetition patterns. Here, we show that a neural model based on a detailed biological understanding of the way the neocortex integrates information over time when processing sequences of events is naturally sensitive to both the mean time and waiting time statistics. Indeed, its behavior is explained by a simple averaging of the influences of both of these statistics, and this behavior emerges in the model over a wide range of parameters. Furthermore, this averaging dynamic directly produces the best-fitting bias-gain parameter for an existing Bayesian model of randomness judgments, which was previously an unexplained free parameter and obtained only through parameter fitting. We show that we can extend this Bayesian model to better fit the full range of human data by including a higher-order pattern statistic, and the neurally derived bias-gain parameter still provides the best fit to the human data in the augmented model. Overall, our model provides a neural grounding for the pervasive gambler’s fallacy bias in human judgments of random processes, where people systematically discount repetitions and emphasize alternations.”

Fascinating stuff

Omar Khayyam and the embryology of the cerebral cortex

“The moving finger writes; and, having writ, moves on”.  Did Omar Khayyam realize he was talking about the embryology of the human cerebral cortex?  Although apparently far removed from chemistry, embryology most certainly is not.  The moving finger in this case is an enzyme modifying histone proteins.

In the last post (https://luysii.wordpress.com/2018/06/04/marshall-mcluhan-rides-again/) I discussed how one site in the genome modified  the expression of a protein important in cancer (myc) even though it was 53,000 positions (nucleotides) away.  When stretched out into the usual B-form DNA shown in the text books this would stretch 1.7 microns or 17% of the way across the diameter of the usual spherical nucleus.  If our 3,200,000 nucleotide genome were chopped up into pieces this size some 60,000 segments would have to be crammed in.  Clearly DNA must be bent and wrapped around something, and that something is the nucleosome which is shaped like a fat disk.  Some 160 or so nucleotides are wrapped (twice) around the circumference of the nucleosome, giving a 10fold compaction in length.

The nucleosome is made of histone proteins, and here is where the moving finger comes in.  There are all sorts of chemical modifications of histones (some 130 different chemical modifications of histones are known).  Some are well known to most protein chemists, methylation of the amino groups of lysine, and the guanido groups of arginine, phosphorylation and acetylation  of serine and threonine.  Then there are the obscure small modifications –crotonylation, succinylation and malonylations.  Then there are the protein modifications, ubiquitination, sumoylation, rastafarination etc. etc.

What’s the point?  All these modifications determine what proteins and enzymes can and can’t react with a given stretch of DNA.  It goes by the name of histone code, and has little to do with the ordering of the nucleotides in DNA (the genetic code).  The particular set of histone modifications is heritable when cells divide.

Before going on, it’s worth considering just how miraculous our cerebral cortex is.  The latest estimate is that we have 80 billion neurons connected by 150 trillion synapses between them.  That’s far too much for 3.2 nucleotides to explicitly code for.

It turns out that almost all neurons in the cerebral cortex are born in a small area lining the ventricles.  They then migrate peripherally to form the 6 layered cerebral cortex.  The stem cell of the embryonic cortex is something called a radial glial cell which divides and divides each division producing 1 radial glial cell and 1 neuron which then goes on its merry way up to the cortex.

Which brings us (at last) to the moving finger, an enzyme called PRDM16 which puts a methyl group on two particular lysines  (#4 and #9) of histone H3.  PRDM16 is highly enriched in radial glia and nearly absent in mature neurons.  Knock PRDM16a out in radial glia, and the cortex is disorganized due to deficient neuronal migration.  Knock it out in newly formed neurons and the cortex is formed normally.  The moving finger having writ (in radial glia) moves on and is no longer needed (by mature neurons). “nor all thy Piety nor Wit shall lure it back to cancel half a line.  Nor all thy tears wash out a word of it”.

You may read more about this fascinating work in Neuron vol. 98 pp. 867 – 869, 945 – 962 ’18

The other uses of amyloid (not all bad)

Neurologists and drug chemists pretty much view amyloid as a bad thing.  It is the major component of the senile plaque of Alzheimer’s disease, and when deposited in nerve causes amyloidotic polyneuropathy.  A recent paper and editorial casts amyloid in a different light [ Cell vol. 173 pp. 1068 – 1070, 1244 – 2253 ’18 ].  However if amyloid is so bad why do cytomegalovirus, herpes simplex viruses and E. Coli make proteins to prevent a type of amyloid from forming.

Cell death isn’t what it used to be.  Back in the day, they just died when things didn’t go well.  Now we know there are a variety of ways that cells die, and all of them have rather specific mechanisms.  Apoptosis (aka programmed cell death) is a mechanism of cell death used widely during embryonic development.  It allows the cell to die very quietly without causing inflammation.  Necroptosis is entirely different, it is another type of programmed cell death, designed to cause inflammation — bringing the immune system in to attack invading pathogens.

Two proteins (Receptor Interacting Protein Kinase 1 — RIPK1, and RIPK3) bind to each other forming amyloid, that looks for all the world like typical amyloid –it binds Congo Red, shows crossBeta diffraction and has a filamentous appearance.  Fascinating chemistry aside, the amyloid formed is crucial for necroptosis to occur, which is why various bugs try to prevent it.

The paper above describes the structure of the amyloid formed — unusual in itself, because until now amyloid was thought to involve the aggregation of a single protein.

The proteins are large: RIPK1 contains 671 amino acids, and RIPK3 contains 518.  They  both contain RHIMs (Receptor interacting protein Homotypic Interaction Motifs) which are fairly large themselves (amino acids 496 – 583 of RIPK1 and 388 – 518 of RIPK3).  Yet the amyloid the two proteins form use a very small stretches (amino acids 532 – 543 from RIPK1 and 451 – 462 from RIPK3).  How the rest of these large proteins pack around the beta strands of the 11 amino acid stretches isn’t discussed in the paper.  Even within these stretches, it is two consensus tetrapeptides (IQIG from RIPK1, and VQVG from RIPK3) that do most of the binding.

Even if you assume that I (Isoleucine) Q (glutamine) G (glycine) V (valine) occur at a frequency of 5%, in our proteome of 20,000 proteins assuming a length of amino acids IQIG and VQVG should occur 10 times each.  This may explain why 300/20,000 of our proteins contain a 100 amino acid  segment called BRICHOS which acts as a chaperone preventing amyloid formation. For details see — https://luysii.wordpress.com/2018/04/01/a-research-idea-yours-for-the-taking/.

Just another reason to take up the research idea in the link and find out just what other things amyloid is doing within our cells in the course of their normal functioning.

 

Cultural appropriation, neuroscience division

If Deng Xiaoping can have Socialism with Chinese Characteristics, I can have a Chinese saying with neuroscientific characteristics — “The axon and the dendrite are long and the nucleus is far away” mimicking “The mountains are high and the Emperor is far away”. The professionally offended will react to the latest offense du jour — cultural appropriation  — of course.  But I’m entitled and I spoke to my Chinese daughter in law, and people over there found it flattering and admiring of Chinese culture that the girl in Utah wore a Chinese cheongsam dress to her prom.

Back to the quote.  “The axon and the dendrite are long and the nucleus is far away”.  Well, neuronal ends are far away from the cell body — the best example are axons from the sacral spinal cord which in an NBA player can be a yard long.  But forget that, lets talk about the ends of dendrites which are much closer to the cell body than that.

Presumably neurons have different types of dendrites so they can respond to different types of inputs. Why should dendrites respond identically if their inputs are different? They don’t.    A dendrite responding to acetyl choline will express neurotransmitter receptors distinct from another dendrite on the same neuron distinct from a dendrite responding to dopamine.  The protein cohorts of axons and dendrites are different.  How does this come about?  Because the untranslated part of mRNA on the 3′ end (3’UTR) contains a sequence called a zipcode which binds to specific proteins which then move the mRNA to a specific location in the neuron (axon or dendrite).  Presumably all dendrites initially had the same complement of mRNA.

So depending on what’s happening at a particular dendrite on a neuron, more or less of a given protein is made.   This is way too abstract.  Suppose you want to strengthen a synapse.  You’d make more of a neurotransmitter receptor or an ion channel for whatever transmitter that dendrite is getting.

It is well established that axons and dendrites store mRNAs and make proteins from them far from the nucleus (aka the emperor).  If you think about it, just how a receptor for dopamine gets to a dendrite receiving dopamine and not to a dendrite (on the same neuron) getting glutamic acid as a transmitter, is far from clear.  There are zipcodes distinguishing axons from dendrites, but I’m unaware that there are zipcodes for dopamine dendrites distinct from other types of dendrites.

If that weren’t enough consider [ Neuron vol. 98 pp. 495 – 511 ’18 ].  Even for an mRNA coding for the same protein (presumably transcribed from just one gene), there can be more than one type of 3’UTR (and this in the same cell).  Note also that 3’UTRs are longer in neurons than in other tissues.

So the authors looked at the mRNAs in dendrites — they did this by choosing a tissue (the hippocampus) where rows of cell bodies are well separated from their dendrites.  They found that for a given dendritic mRNA there was more than one 3’UTR, and that the mRNAs with longer 3’UTRs had longer halflives.  Even more exquisitly neuronal activity altered the proportion of the different 3’UTR isoforms. The phenomenon is quite general — over 50% of all genes and over 70% of genes enriched in neurons showed multiple 3′ UTRs.

So there is a whole control system built into the dendritic system, and it varies with what is happening locally.

The emperor emits directives (mRNAs) but what happens locally is anyone’s guess

A pile of spent bullets — take II

I can tell you after being in neurology for 50 years that back in the day every microscopic inclusion found in neurologic disease was thought to be causative.  This was certainly true for the senile plaque of Alzheimer’s disease and the Lewy body of Parkinsonism.  Interestingly, the protein inclusions in ALS weren’t noticed for decades.

However there are 3 possible explanations for any microscopic change seen in any disease.  The first is that they are causative (the initial assumption).  The second is that they are a pile of spent bullets, which the neuron uses to defend itself against the real killer.  The third is they are tombstones, the final emanations of a dying cell, a marker for the cause of death rather than the cause itself.

An earlier post concerned work that implied that the visible aggregates of alpha-synuclein in Parkinson’s disease were protective rather than destructive — https://luysii.wordpress.com/2018/01/07/are-the-inclusions-found-in-neurologic-disease-attempts-at-defense-rather-then-the-cause/.

Comes now Proc. Natl. Acad. Sci. vol. 115 pp. 4661 – 4665 ’18 on Superoxide Dismutase 1 (SOD1) and ALS. Familial ALS is fortunately less common than the sporadic form (under 10% in my experience).  Mutations in SOD1 are found in the familial form.  The protein contains 153 amino acids, and as 6/16 160 different mutations in SOD1 have been found.  Since each codon can contain only 3 mutations from the wild type, this implies that, at a minimum,  53/153 codons of the protein have been mutated causing the disease.  Sadly, there is no general agreement on what the mutations actually do — impair SOD1 function, produce a new SOD1 function, cause SOD1 to bind to something else modifying that function etc. etc.  A search on Google Scholar for SOD1 and ALS produced 28,000 hits.

SOD1 exists as a soluble trimer of proteins or the fibrillar aggregate.   Knowing the structure of the trimer, the authors produced mutants which stabilized the trimer (Glycine 147 –> Proline) making aggregate formation less likely and two mutations (Asparagine 53 –> Isoleucine, and Aspartic acid 101 –> Isoleucine) which destabilized the trimer making aggregate formation more likely.  Then they threw the various mutant proteins at neuroblastoma cells and looked for toxicity.

The trimer stabilizing mutant  (Glycine 147 –> Proline) was toxic and the destabilizing mutants  (Asparagine 53 –> Isoleucine, and Aspartic acid 101 –> Isoleucine)  actually improved survival of the cells.  The trimer stabilizing mutant was actually more toxic to the cells than two naturally occurring SOD1 mutants which cause ALS in people (Alanine 4 –> Valine, Glycine 93 –> Alanine).  Clearly with these two something steric is going on.

So, in this experimental system at least, the aggregate is protective and what you can’t see (microscopically) is what kills cells.

A research idea yours for the taking

Why would the gene for a protein contain a part which could form amyloid (the major component of the senile plaque of Alzheimer’s disease) and another part to prevent its formation. Therein lies a research idea, requiring no grant money, and free for you to pursue since I’ll be 80 this month and have no academic affiliation.

Bri2 (aka Integral TransMembrane protein 2B — ITM2B) is such a protein.  It is described in [ Proc. Natl. Acad. Sci. vol. 115 pp. E2752 – E2761 ’18 ] http://www.pnas.org/content/pnas/115/12/E2752.full.pdf.

As a former neurologist I was interested in the paper because two different mutations in the stop codon for Bri2 cause 2 familial forms of Alzheimer’s disease  Familial British Dementia (FBD) and Familial Danish Dementia (FDD).   So the mutated protein is longer at the carboxy terminal end.  And it is the extra amino acids which form the amyloid.

Lots of our proteins form amyloid when mutated, mutations in transthyretin cause familial amyloidotic polyneuropathy.  Amylin (Islet Amyloid Polypeptide — IAPP) is one of the most proficient amyloid formers.  Yet amylin is a protein found in the beta cell of the pancreas which releases insulin (actually in the same secretory granule containing insulin).

This is where Bri2 is thought to come in. It is also found in the pancreas.   Bri2 contains a 100 amino acid motif called BRICHOS  in its 266 amino acids which acts as a chaperone to prevent IAPP from forming amyloid (as it does in the pancreas of 90% of type II diabetics).

Even more interesting is the fact that the BRICHOS domain is found in 300 human genes, grouped into 12 distinct protein families.

Do these proteins also have segments which can form amyloid?  Are they like the amyloid in Bri2, in segments of the gene which can only be expressed if a stop codon is read through.  Nothing in the cell is perfect and how often readthrough occurs at stop codons isn’t known completely, but work is being done — Nucleic Acids Res. 2014 Aug 18; 42(14): 8928–8938.

I find it remarkable that the cause and the cure of a disease is found in the same protein.

Here’s the research proposal for you.  Look at the other 300 human genes containing the BRICHOS motif (itself just a beta sheet with alpha helices on either side) and see how many have sequences which can form amyloid.  There should be programs which predict the likelihood of an amino acid sequence forming amyloid.

It’s very hard to avoid teleology when thinking about cellular biochemistry and physiology.  It’s back to Aristotle where everything has a purpose and a design.  Clearly BRICHOS is being used for something or evolution/nature/natural selection/the creator would have long ago gotten rid of it.  Things that aren’t used tend to disappear in evolutionary time — witness the blind fish living in caves in Mexico that have essentially lost their eyes. The BRICHOS domain clearly hasn’t disappeared being present in over 1% of our proteins.

Suppose that many of the BRICHOS containing proteins have potential amyloid segments.  That would imply (to me at least) that the amyloid isn’t just junk that causes disease, but something with a cellular function. Finding out just what the function is would occupy several research groups for a long time.   This is also where you come in.  It may not pan out, but pathbreaking research is always a gamble when it isn’t stamp collecting.

 

Amyloid again, again . . .

Big pharma has spent (and lost) several fortunes trying to attack the amyloid deposits of Alzheimer’s.  But like my late med school classmate’s book — “Why God Won’t Go Away” ==https://www.amazon.com/Why-God-Wont-Go-Away/dp/034544034X, amyloid won’t go away either.   It’s a bit oblique but some 300 of our proteins contain a 100 amino acid stretch called BRICHOS.  Why? Because it acts as a chaperone protein preventing proteins with a tendency to form amyloid from aggregating into fibrils.   The amino acids form a beta sheet surrounded front and back by a single alpha helix.

[ Proc. Natl. Acad. Sci. vol. 115 pp. E2752 – E2761 ’18 ] Discusses Bri2 (aka Integral Transmembrane protein 2B (ITM2B), a 266 amino acid type II transmembrane protein. Bri2 contains a carboxy terminal domain Bri23 released by proteolytic processing between amino acids #243 #244 by furinlike proteases. Different missense mutations at the stop codon of Bri2 cause extended carboxy terminal peptides called  Abri or Adan to be released by the proteases. Abri produces Familial British Dementia (FBD) and Adan produces Familial Danish Dementia (FDD). Both are associated with amyloid deposition in blood vessels, and amyloid plaques throughout the brain along with neurofibrillary tangles.

What is fascinating (to me) is that the cause and cure are both present in the same molecule Bri2 also contains a BRICHOS domain.  This implies (to me) that possibly the segment possibly forming amyloid is being used by the cell in some other fashion.

Bri2 is found in the beta cell of the pancreas (produces insulin).  The beta cell also produces Islet Amyloid PolyPeptide (IAPP  aka amylin ) one of the most potent amyloid forming proteins known.  Nonetheless the pancreas makes tons of it, and like insulin, is secreted by the beta cell in response to elevated blood glucose.  The present work shows that Bri2 is what keeps IAPP from forming amyloid.  The BRICHOS segment (amino acids #130 – #231) is released from Bri2 by ADAM10 (you don’t want to know what the acronym stands for).

How many of the 300 or so human proteins containing the BRICHOS domain also have amyloid forming segments.  If they do, this implies that the amyloid forming segments are doing something physiologically useful.

 

 

Stephen Hawking R. I. P.

Stephen Hawking, brilliant mathematician and physicist has died.  Forget all that. He did something for my patients with motor neuron disease that I, as a neurologist, could not do.  He gave them hope.

What has chemistry done for them?  Quite a bit, but there’s so much left.

Chemistry, when successful, just becomes part of the wallpaper and ignored. All genome sequencing depends on what some chemist did.

For one spectacular example of what, without chemistry, would be impossible is Infantile Spinal Muscular Atrophy (Werdnig Hoffmann disease).  For the actual molecular biology behind it — please see — https://luysii.wordpress.com/2016/12/25/tidings-of-great-joy/.   Knowing the cause has led to not one but two specific therapies — an antisense oligonucleotide and a virus which infects neurons and actually changes the gene.

So knowing what the cause of a disease is should lead to a treatment, shouldn’t it?  Hold that thought.  Sometimes one form of motor neuron disease (amyotrophic lateral sclerosis or ALS) can be hereditary.  Find out what is being inherited to find how ALS is caused.

Well, the first protein in which a mutation is associated with familial ALS (FALS) was found exactly 25 years ago.  It is called superoxide dismutase (SOD1).  Over 150 mutations have been found in the protein associated with FALS, and yet despite literally thousands of papers on the subject we don’t know if the mutations cause a loss of function, a gain of function (and if so what that function is), an increased tendency to fold incorrectly, and on and on and on.  It’s a fascinating puzzle for the protein chemist and over the years my notes on the papers I’ve read about SOD1 have ballooned to some 25,000 words.

If you’re tired of working on SOD1, try a few of the other proteins in which mutations have been associated with FALS — Alsin, TAF15, Ubiquilin, Optineurin, TBK1 etc. etc.  The list is long.

Now it’s biology’s turn.  Motor neurons go from the spinal cord (mostly) and brain to produce muscle contraction.  Why should only this tiny (but crucial) minority of cells be affected.  The nerve fibers leave the spinal cord and travel to muscle in nerves which contain sensory nerve fibers making the same long trip, yet somehow these nerves are spared.

More than that, why should these mutations affect only these neurons, and that often after decades.  Also why should great athletes (Lou Gehrig, Ezzard Charles, etc. etc. ) get the disease.

One closing point.  Hawking shows why, in any disease median survival (when 50% of those afflicted die) is much a more meaningful statistic than average duration of survival.  Although he gave my patients great hope, they all died within a few years even as he mightily extended average survival.

 

Hillary Clinton’s latest health event

On a recent trip to India Hillary clearly had difficulty placing her left foot and nearly fell down a set of stairs twice.  You can watch the video on the following website http://dailycaller.com/2018/03/12/hillary-falls-down-stairs-india/.  Please ignore all the snarkiness of the commentary and just look at the video over and over.  She comes out of an old building and starts going down some worn stone steps linking her left arm into that of a large man.  Stop the video when she begins to fall and notice how she placed her left foot.  Fortunately you can go back and forth as many times as you wish.  It clearly wasn’t where it should have been. The same thing happened with her second near fall.  Then watch the way she places her left leg as she walks to the car.  It’s as though she doesn’t really know where it is.

This all fits with my opinion that she suffered a stroke in December of 2012.  The press bought what I thought was a rather hokey explanation that it was traumatic in origin.  At any rate we do know that she had a blood clot in a vein and had double vision lasting for several weeks.  You can read the reasoning behind this here — https://luysii.wordpress.com/2012/12/31/medical-tribulations-of-politicians-degrees-of-transparency/

Then during the campaign in 2016 at an event to commemorate 9/11 she fainted.  The press cast this as a stumble, but I don’t think it was. Once again you have a video of the event with a link to it in a post about the event — https://luysii.wordpress.com/2016/09/13/hillarys-fainting-spell/.  As Richard Pryor famously said when his wife caught him with another woman. He denies anything is going on, and asks his wife, “Who you gonna believe, me or your lying eyes?”

So what does this retired neurologist and former board examiner think is going on?  Given the little released about her health there are many possibilities.  Statistically people who have had one stroke have around a 6% chance of another one in a given year (each and every year).  Given the way she didn’t seem to know where her left foot was, a stroke in the right parietal region is a possibility.

It is clear that the original area of neurologic deficit in 2012 – 13 was in the brainstem, as it affect the nerves to her eyes.  This is an area intimately involved in coordination, but (fortunately) not in thinking.  So she may have suffered a further stroke in this area.  We don’t know if she’s still taking a blood thinner.

She did look pretty frail, and it’s fortunate for her health that she doesn’t have the stresses of the presidency to deal with.

Addendum 14 March: Apparently she tripped/fell/passed out while on a tour in England breaking a toe 6 months ago http://www.foxnews.com/politics/2017/10/16/hillary-clinton-book-tour-stumbles-after-ex-candidate-falls-and-hurts-foot.html

You don’t have to go to medical school or take a neurology residency to know that a 70 year old woman with 4 neurological events in the past 5 years and 3 months is not in good shape.

Addendum 15 March: Unfortunately she’s had another fall, resulting in a fractured wrist since the episode on the stairs. Here’s the report — https://timesofindia.indiatimes.com/india/hillary-clinton-injured-during-rajasthan-visit/articleshow/63290246.cms

It all adds up to a significant neurological problem with balance.