Category Archives: Neurology & Psychiatry

Man’s best friend

I usually pay little attention to animal models of neurologic disease. After all, our brain is what separates us from animals (recent human behavior excepted). Neuromuscular disease is different because our peripheral nerves and muscles work the same way as animals. An astounding paper from Harvard and Brazil, gives us an entirely new angle to treat muscular dystrophy, particularly the Duchenne form. I ran a muscular dystrophy clinic for 15 years in the 70s and 80s and haplessly watched young boys deteriorate and die from Duchenne. The major therapeutic advance during that time was — hold your breath — lighter weight braces, allowing the boys to stay out of wheelchairs a bit longer.

Some background for those who don’t know, the molecular defect in Duchenne was found in ’87. Interestingly Kunkel, one of the authors on the original paper [ Cell vol. 51 pp.; 919 – 928 ’87 ] is an author on the present one [ Cell vol. 163 pp. 1204 – 1213 ’15 ]. Duchenne dystrophy affects only males, as the gene for the protein (dystrophin) is found on the X chromosome, so women with a normal X and a mutant X escape. To show how pathetic things were back then, we tried to find out if a sister of a patient was a carrier. How did we do it. By measuring an enzyme released by damaged muscle (CPK) on several occasion. Carriers often showed an elevation.

The mutated protein is called dystrophin. It hooks the contractile apparatus of a muscle cell to the membrane. Failure of this makes muscle cells more fragile when they contract resulting in eventual loss. From a molecular biological point of view the protein is fascinating. The gene is one of largest known, stretching over 2,220,233 positions (nucleotides) on the X chromosome and containing 79 exons. Figuring a transcription rate of 100 nucleotides a second, it takes 6 hours to make the messenger RNA (mRNA) for it. The protein has 3,685 amino acids and figuring a translation rate of 3 – 6 amino acids/second it takes 10 minutes for the ribosome to make it. Given that it takes only 3 nucleotides to code for an amino acid, the protein coding part of the gene takes up only .5% of the gene. Correctly splicing out the introns is a huge task, which we all perform well. This size and complexity of the gene explains why mutations are so common, making it the most common form of hereditary muscular dystrophy (most are).

There are currently all sorts of efforts underway to correct the mutation, particularly in a milder form called Becker dystrophy. Derek has covered them and they constitute a logical direct attack on the pathology.

What is so remarkable about the current Cell paper is that it gives us an entirely new and different way to attack Duchenne (and possible all forms of muscular dystrophy). It involves a colony of dogs in Brazil. They have GRMD (Golden Retriever Muscular Dystrophy) with a mutation in one of the many splice sites in dystrophin (it has 79 exons in man) leading to a premature stop codon and no functional dystrophin in the dogs’ muscles. The animals weaken and become non ambulatory with a shortened lifespan. However, a few of the dogs in the colony seemed pretty normal. So they went to work. The obvious reason was that gene was in some way repaired so the animals had normal amounts of dystrophin. Not so, even though ambulatory, the animals’ muscles had no dystrophin. So the whole genome was sequenced. What they found was that a mutation at an upstream site of a protein called Jagged1 lead to increased transcription of the gene and increased levels of the protein.

Jagged1 is a protein ligand for the Notch system of receptors. The Notch system is important in muscle regeneration. The myoblasts of the animals had more proliferative capacity. The Notch system is far too complicated to go into here —, but expect to see a lot more research money pumped into it.

What I find so fabulous about this paper, is that it gives us an entirely new way of thinking about Duchenne, totally unrelated to the genetic defect, which had been our focus up to now. It also rubs our noses in how little we understand about our molecular biology and cell physiology. If we really understood things, we’d have been focused on Notch years ago. Yet another reason drug discovery is so hard. We are trying to alter a system we only dimly understand.

Facilitated communication

Amidst the ads in the Sunday Magazine largely targeted to the 1% that the New York Times claims to hate is an article on facilitated communication. I had a clinical experience with it 30 years ago that you might be interested in.

As a neurologist I was asked to do an Independent Medical Evaluation (IME) on an unfortunate man who was electrocuted at work (he worked on high voltage transmission lines). He went into cardiac arrest and sustained severe brain damage. The issue was not fault, which the power company readily admitted, but whether in what appeared to be a vegetative state, with no visible response to verbal commands, he was in fact conscious but unable to respond. In the latter case the reward to the family would have been substantially larger (for pain and suffering in addition to loss of consortium, etc. etc.). It was claimed that facilitated communication showed that he was able to write the answer to simple calculations given verbally, not visually.

Reviewing the chart before seeing the man, showed that he and his wife were admirable individuals, adopting children that no one else wanted and raising them despite limited income. He was seen at the rehab facility, with attorneys for the insurer for the power compony and his family present. It was apparent that the people caring for him were quite devoted, both to him and his wife and were very sincere, especially one of his young therapists.

The neurologic exam showed that although he did react to deep pain (sternal compression), he did not follow simple commands (e.g. blink). He appeared to be in a coma. Following the neurologic examination the young therapist then demonstrated how when he held the man’s hand to which a pencil was attached, the man could actually perform calculations — add 2 and 2 produce a 4, etc. etc. Several such calculations were produced all with correct answer.

What do you think I did next?

No peeking. Think about it.

I took the first sheet of paper away, placed a clean sheet under the man’s hand and asked for a repeat (this time with the therapist’s eyes closed).

This produced a bunch of random lines, nothing more.  When the therapist opened his eyes and saw the results, he was visibly shaken and close to tears.

Was he faking the whole time? At any time? I seriously doubt it. A faker could have produced a reasonable number with his eyes shut. Try it. He didn’t.

“You can’t con an honest man” —

True, but you certainly can con yourself.

For another example, this time perpetrated by nurses, see how an 11 year old girl (Emily Rosa) put a definitive end to “Therapeutic Touch” and became the youngest co-author ever of an article in the Journal of the American Medical Association —

A new kid on the Alzheimer’s block

There’s a new kid on the Alzheimer’s block, and it may explain why the huge sums thrown at beta-secretase inhibitors by big pharma has been such an abject failure. First, a lot of technical background.

The APP (for amyloid precursor protein) contains anywhere from 563 to 770 amino acids in 5 distinct transcripts made by alternate splicing of the single gene. The 3 main forms contain 695, 751 and 770 amino acids. The 695 amino acid form is found only in brain and peripheral nerve where it predominates, while the transcripts containing 751 and 770 amino acids are found everywhere but predominate in other tissues. The A4 peptides (Abeta peptides) which are the major components of the Alzheimer senile plaque are derived from from the carboxy terminal end of APP (beginning at amino acid #597 ) and contain only 39 – 43 amino acids. About 1/3 of the 39 – 43 amino acid amyloid beta peptide (A beta peptide) is found within the transmembrane segment of APP the other two thirds being found just outside the membrane.  So to get A beta peptides the APP must be cut (more than once) at its carboy terminal end.

For Abetaxx (xx between 39 and 43) to be formed, cleavage must occur outside the membrane in which APP is embedded by beta secretase. This produces a soluble extracellular fragment, with the rest embedded in the membrane (this is called C99). Then gamma secretase (another enzyme) cleaves C99 within the membrane forming the Abeta peptides, which constitute much of the senile plaque of Alzheimer’s disease.

Alpha secretase (yet another enzyme) also cleaves the APP in its carboxy terminal extramembranous part, but does so closer to the membrane, so that part of the protein which would form the aBeta peptide is removed.

R. Scheckman personal communication (2012) — The Abeta peptide is appears to be cleaved by gamma secretase from the fragment generated by beta secretase. However, this happens well inside the cell in the last station of the Golgi apparatus. Then Abeta is swept out of the cell by the secretory pathway. So all this happens INSIDE the cell, rather than at the neuron’s extracellular membrane (which is what I thought).

Remarkably it is very difficult (for me at least) to find out just at what amino acids of the amyloid precursor protein(s) the 3 secretases (alpha, beta, gamma) cleave.

[ Nature vol. 526 pp. 443 – 447 ’15 ] describes a totally new kid on the block, which (if replicated) should make us rethink everything we thought we knew about the amyloid precursor protein and the Abeta peptide. Another set of carboxy terminal fragments (CTFs) called CTFneta is formed from the amyloid precurosr protein (APP). Formation is mediated (in part) by MT5-MMP, a matrix metalloprotease. (In grad school neta is how we pronounced the Greek letter eta, which looks like a script N). The authors call the enzymatic activity forming them neta-secretase (clearly not all the enzymes which do this have been identified at this point). At least the authors tell you where the neta secretases cleave APP695 (between amino acids #504 – #505) . This is amino terminal to the beta and alpha sites (which are at higher amino acid numbers and the gamma site which is at a higher number still).  Alpha and beta secretase then work on CTFneta to produce shorter peptides, called Aneta-alpha, and Aneta-beta.

This isn’t idle chatter as Aneta-alpha, and Aneta-beta are found in the dystrophic neurites in an Alzheimer mouse model (human work is sure to follow). Inhibition of beta secretase activity results in accumulation of CTFneta and Aneta-alpha.

Aneta-alpha itself lowers long term potentiation (LTP) in hippocampal slices (LTP is considered by most to be the best molecular and physiological model we have of learning). As judged by intracellular calcium levels, hippocampal neuronal activity is also inhibited by Aneta-alpha.

What’s fascinating about all this, is that the work possibly explains why the huge amount of money big pharma has spend on beta secretase inhibitors has been such a failure.

Maybe chemistry just isn’t that important in wiring the brain

Even the strongest chemical ego may not survive a current paper which states that the details of ligand receptor binding just aren’t that important in wiring the fetal brain.

The paper starts noting that there isn’t enough information in our 3.2 gigaBase genome to specify each and every synapse. Each cubic milliMeter of cerebral cortex is stated to contain a billion of them [ Cell vol. 163 pp. 277 – 280 ’15 ].

If you have enough receptors and ligands and use them combinatorially, you actually can specify quite a few synapses. We have 70 different protocadherin gene products found on the neuronal surface. They can bind to each other and themselves. The fruitfly has the dscam genes which guide axons to their proper position. Because of alternative splicing some 38,016 dscam isoforms are possible.

It’s not too hard to think of these different proteins on the neuronal surface as barcodes, specifying which neuron will bind to which.

Not so, says [ Cell vol. 163 pp. 285 – 291 ’15 ]. What is important is that there are lot of them, and that a neuron expressing one of them is unlikely to bump into another neuron carrying the same one. Neurons ‘like’ to form synapses, and will even form synapses with themselves (one process synapsing on another) if nothing else is around. These self synapses are called autapses. How likely is this? Well under each square millimeter of cortex in man there are some 100,000 neurons, and each neuron has multiple dendrites and axons. Self synapse formation is a real problem.

The paper says that the structure of all these protocadherins, dscams and similar surface molecules is irrelevant to what program they are carrying out — not synapsing on yourself. If a process bumps into another in the packed cortex with the same surface molecule, the ‘homophilic’ binding prevents self-synapse formation. So the chemical diversity is just the instantiation of the ‘don’t synapse with yourself’ rule — what’s important is that there is a lot of diversity. Just what this diversity is chemically is less important than there is a lot of it.

This is another example of “It’s not the bricks, it’s the plan” in another guise —

Carly’s cancer

Carly Florina had breast cancer surgery (bilateral mastectomy) 2 March 2009 at Stanford University Hospital followed by chemotherapy and radiation. She was given an excellent prognosis for full recovery —

So far so good and it’s coming up on 7 years. But it is reasonable to ask just what her prognosis really is, particularly as she may be our next president. I asked an old friend and colleague who has been involved in research on breast cancer and in many of the clinical trials of therapy over the past 35 years.

So I wrote the following — I’m writing you for some idea what the chances of someone with breast cancer being free for 6+ years (Carly’s surgery was 2/09) will be free for the next 5+? I know that there are all sorts of statistics on survival in breast cancer (because the cohort is so large). If anyone would know them, it would be you.

and got this back

Impossible to answer your question. Too many variables and NO DATA or info. Many people, docs and patients alike call ductal carcinoma in situ,” cancer” but cure rate is 99%. If she was one of those then, of course, she’s likely to be cured . Stage 1 ,luminal A tumors (even though real cancers) have excellent prognoses—probably > 90% cured. For other real cancers Lots depend on stage, hormone receptors ad infinitum. On thin ice lumping anyone into a broad statement without lots more info

just what you’d expect from an circumspect intelligent expert

So I dug a bit more and sent him this

I tried to find out just what type of breast cancer Carly had. No luck, but various newspaper articles show that she did receive postop chemo causing her hair to fall out as well as radiation. Would ductal carcinoma in situ (Dcis) be treated this way? Would stage 1 luminal A tumors be treated this way?

He replied

Dcis definitely no. luminal a probably shouldn’t be. Sounds like a significant cancer. Next issue is did she get antihormonal therapy. Estrogen receptor tumors are the ones that tend to relapse after 5 years. ER neg. tumors while more aggressive overall seldom recur >5 yrs after dx. The radiation part doesn’t mean much unless she had a mastectomy since all lumpectomy patients get radiation. – If she had mastectomy and chemo and radiation it was probably a poorer risk tumor. Even chemo might not be so bad—–we give chemo to node neg tumors which could end up with very good long term prognosis.AMONG RELAPSES in ER pos pts. 15% recur before year 5 and 17% recur after year 5. However overall likelihood of relapse depends on whether or not she had positive or negative nodes and was ER + or Neg. Sorry to be so wordy but prognosis has been improving steadily. I would guestimate that we’re curing about 70% of women with newly diagnosed breast cancer—excluding dcis who are virtually all cured.

I realized that I’d neglected to tell him that she’d had a bilateral mastectomy as well and got the following back after I did.

If she indeed had radiation after a mastectomy as well as chemo it speaks for a more aggressive presentation. Rule of thumb—-post mastectomy xrt reserved for patients with > 4 positive nodes or tumors >5 cm in size. Today, many are giving post mastectomy xrt to 1-3 positive nodes although that was very controversial for years . newer data impies benefit. So, just guessing, but she probably had positive nodes—a poorer prognostic sign for long term—but only if she was estrogen receptor pos. as noted in prior email.

So there you have it — she’s fortunately well presently, but the tumor and prognosis doesn’t sound that good. Still unknown are histologic type of the tumor, presence or absence of spread to lymph nodes (and if so how many), estrogen receptor positivity, which would certainly give us a better idea of her ultimate prognosis (and the country’s should she become president).

I take no pleasure in any of these posts. See Both Carly and Hillary are brilliant women it would be an honor to know and I wish them both the best. FYI Hillary was valedictorian of her class at Wellesley.

So why write about their potential health problems? Look at the sad saga of Hugo Chavez who claimed he was cured in July elected in the fall with death before he could take office in March of the following year — see Also consider the last months in office of Woodrow Wilson and Franklin Roosevelt and the results of the League of Nations and the Yalta conference when they were both impaired.

My wife asked my why I pick on female candidates, and I’ll address Christie’s massive obesity should he rise in the polls.

The amount of BS you can get published about the brain

Hype about brain therapies isn’t confined to second rank journals The following is a direct quote from Neuron vol. 87 pp. 940 – 941 ’15.

” When a journal of the standing of Nature carries a headline ‘‘Shocks to the brain improve mathematical abilities’’ (Callaway) concerning two studies, we have to ask how this will be perceived. It is doubtful that the non-scientific reader will note that the studies have not been independently replicated, that only one of them tested mathematics, that the gains are as small as being milliseconds faster at some simple sums, and that only six people were tested in follow-up.

When it is claimed that tDCS (transcranial Direct Current Stimulation) can improve problem-solving abilities (Chi and Snyder, Brain Res. vol. 1353 pp. 168 – 175 ’10), the casual reader will not notice that only one-third of subjects improved, that there is no evidence that effects are sustained beyond 3 min, that there was no active control stimulation, and that there was no control for order effects.”

Caveat emptor. The quote is from an excellent review about brain stimulation with either magnetic fields or electrical current (direct, alternating or random) — Neuron vol. 87 pp. 932 – 944 ’15 — e.g. Non-invasive human brain stimulation, by 3 of the adults in the room.

It gets worse — here’s part of an older post — with a link to the whole thing —

How badly are thy researchers, O default mode network

If you Google “default mode network” you get 32 million hits in under a second. This is what the brain is doing when we’re sitting quietly not carrying out some task. If you don’t know how we measure it using functional mMRI skip to the **** and then come back. I’m not a fan of functional MRI (fMRI), the pictures it produces are beautiful and seductive, and unfortunately not terribly repeatable.

If [ Neuron vol. 82 pp. 695 – 705 ’14 ] is true than all the work on the default network should be repeated.


Because they found that less than half of 71 subjects studied were stably awake after 5 minutes in the scanner. E.g. they were actually asleep part of the time.

How can they say this?

They used Polysomnography — which simultaneously measures tons of things — eye movements, oxygen saturation, EEG, muscle tone, respiration pulse; the gold standard for sleep studies on the patients while in the MRI scanner.

You don’t have to be a neuroscientist to know that cognition is rather different in wake and sleep.


Reproducibility and its discontents

A widely cited (but unreproducible) therapeutic study caused the most difficult moral choice I ever faced in decades of neurologic practice. Lack of reproducibility is currently in the news big time thanks to the work of 270 or so volunteer psychologists [ Science vol. 349 pp. 910 – 911, 943, aa47161 to 8 ’15 (28 August) ]. They tried to reproduce 100 significant studies appearing in 3 high level psychology journals in 2008. They had the cooperation of the original authors. Sadly, they were only replicate slightly over 1/3, and the effect sizes of the original 100 were half that on replication, and in a few cases, the effects were opposite.

In what follows you will encounter reasoning of almost talmudic intricacy. Don’t give up. The real world effects were far from trivial, and undoubtedly some died of therapeutically induced intracerebral hemorrhage.

The study was large and done under NIH auspices [ New England J. Med. vol. 333 pp. 1581 – 1587 ’95 ] and had an extremely logical basis — if some strokes are due to blood clots blocking vessels, administer an agent to break up the clot and restore circulation, before the part of the brain lacking circulation irreversibly dies. The agent was Tissue Plasminogen Activator (tpa).

624 patients were studied (so it had significant statistical power to detect an effect) . Treatment had to be initiated within 3 hours (about this more later) As compared with patients receiving placebo, patients with tPA were 30% more likely to have minimal or no disability at 3 months (the absolute increase in good outcome was 11 – 13%) — e.g. without tpa roughly 30% of the placebo group had good outcomes at 3 months, with tpa the figure was 41 – 43%. So the therapy was no guarantee of success.

There was a huge amount of interest in the paper and letters to the NEJM soon followed. One from Mass. General noted that rapid neurologic improvement expected after recanalization was rare in the treated group (there were few differences at 24 hours between the two groups ). This surprised my cardiologist friends, long used to giving clot busting (thrombolytic) agents to patients with acute heart attacks (myocardial infarctions) due to coronary occlusion and watching EKG changes vanish before their eyes along with improved cardiac function.

Followup of the 624 was impressive (609), and results one year out showed that the 11 – 13% absolute increase in good outcome persisted [ New England J. Med. vol. 340 pp. 1781 -1787 ’99 ]. Of interest was the risk of another stroke during this time — was 6% in both treated and untreated. Hopefully that figure is lower now (I don’t know as I’m no longer in practice and reading the literature).

There are a variety of scales to measure stroke severity and stroke outcome. The tpa and placebo groups had the same average National Institutes of Health Stroke Severity scores (NIHSS scores) on entry to the study — the higher the number the more severe the stroke. The authors used something called the modified Rankin score to measure outcome (here lower is better).

There was a huge push to get everyone to use tpa for stroke hitting the ER in the first few hours. The evidence seemed pretty flimsy and the effect pretty minimal to me (and to most clinical neurologists that I talked to). Hospitals used it as an advertising tool. The legal profession geared up to sue docs who didn’t use it. Fortunately the criteria for use were quite strict (within 3 hours of stroke, no hypertension, etc. etc.). The academic industrial complex weighed in, with the author of one of the subsequent studies threatening to testify in malpractice cases against docs who didn’t use it.

There was a lot of resistance on the part of clinicians and ER docs to using the therapy, but we had no blogosphere then.

Results when the therapy was adopted in the community were not happy ones. Here’s just one example [ Stroke vol. 30 pp. 34 – 39 ’99 ] A study of 138 patients treated in Houston and Calgary from 12/95 to 7/98 showed a much higher rate of symptomatic intracerebral hemorrhage (9 % == 13/138) and the any hemorrhage rate was also high (30% — 42/138). The only predictor was blood glucose. 7/13 symptomatic hemorrhage patients died and the rest were severely disabled.

This was not a therapy to be undertaken lightly, particularly if you thought the evidence was flimsy.

A technique was available (TransCranial Doppler) to actually look at blood flow inside the head in someone with a stroke, and this was later applied to patients receiving tpa. It involved continuous ultrasound monitoring, which one plucky neurologist actually thought was breaking up the clot (rather than the tpa) Robinson, L. Clototripsy? Stroke 2000; 31 2024. Clototripsy is a play on lithotripsy a therapy in widespread use to focus sound energy on kidney stones to break them up.

It was suggested that a 3 pronged study be done on patients with acute stroke due to arterial occlusion (1) tpa alone (2) TransCranial Doppler alone (3) Tpa + TransCranial doppler. This was never done.

A later study [4] Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford, SR, Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moye LA, Hill MD, Wojner AW. Ultrasound-Enhanced Systemic Thrombolysis for Acute Ischemic StrokeN. Engl. J. Med. 2004; 351: 2170 – 2178
was devastating (although the authors didn’t realize it). Why?

29% of patients receiving tPA alone had a modified Rankin score of 0 – 1 at 3 months (e.g. a good result). But 29% is practically the same as 26% — the percentage of good outcome in patients in the original 1995 study who received no tPA whatsoever. A mere difference of 3 points on the initial NIHSS score between the two groups is not explanatory.  The 41 – 43% good outcome of the original study was nowhere in sight.

So tpa was actually no better than placebo when retested 9 years later. The authors had failed to replicate the original work.

I tried to get the following letter in the New England Journal back then.

To the editor:

The initial results of continuous 2 MHz transcranial Doppler (TCD) monitoring during tPA infusion for acute ischemic stroke were exciting and unprecedented. [1] Since no study up to then had replicated the NINDS results [2], I argued that the dramatic results with continuous TCD were probably real, and quite likely independent of tPA [3]. I urged that a three-pronged study (tPA alone, TCD alone, and tPA plus TCD) should be carried out.

The recent two-pronged study [4] also fails to replicate the NINDS study. Only 29% of patients receiving tPA alone had a modified Rankin score of 0 – 1 at 3 months. Even worse, 26% of patients in the NINDS study receiving no tPA whatsoever had this outcome. A mere difference of 3 points on the initial NIHSS score between the two groups is not explanatory. After 9 years our diagnostic techniques have improved and we are presumably smarter about whom to treat. It’s time to do the study I suggested and to stop regarding tPA for stroke as ‘standard of care’.

[1] Alexandrov AV, Demchuk AM, Felberg RA, Christou I, Barber PA, Burgin WS, Malkoff M, Wojner AW, Grotta JC. High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuously monitored with 2-MHz transcranial Doppler monitoring. Stroke. 2000; 31: 610 – 614.

[2] The National Institutes of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 1995; 333: 1581 – 1587

[3] Robinson, L. Clototripsy? Stroke 2000; 31 2024

[4] Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford, SR, Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moye LA, Hill MD, Wojner AW. Ultrasound-Enhanced Systemic Thrombolysis for Acute Ischemic Stroke
N. Engl. J. Med. 2004; 351: 2170 – 2178

It was not published.

Thank God for the blogosphere. Often irritating and irascible but extremely useful.

So what do you think I did faced with a patient satisfying the criteria for tpa, knowing that the therapy could (and had) killed, and not thinking that it was much good. Satisfy my conscience and my responsibility to the patient by not giving it and risk financial destruction, or do what I thought was wrong and  protect my family with the full weight of medical legal precident to back me up.

What would you do in this situation?

It’s important to realize, that all this took place a decade ago, and that new information and studies may have come out, showing that tpa actually is of use in acute stroke.  I wouldn’t rely on meta-analyses of the old studies however.

Nonetheless, the above reasoning is still valid.  Docs do the best they can with the information available to them at the time (which is NEVER enough) and this was the state of play when I was in practice.

The elegance of metabolism control in the cell.

The current two pronged research effort on the possible use of Gemfibrozil (Lopid) to treat Alzheimer’s disease now has far wider implications than Alzheimer’s disease alone. As far as I’m aware, the combination of mechanisms described below to control a cellular pathway as never been reported before.

A previous post has the story up to 3 August — — you can read it for the details, but here’s some background and the rest of the story.

Background: One of the two pathologic hallmarks of Alzheimer’s disease is the senile plaque (the other is the neurofibrillary tangle). The major component of the plaque is a fragment of a protein called APP (Amyloid Precursor Protein). Normally it sits in the cellular membrane of nerve cells (neurons) with part sticking outside the cell and another part sticking inside. The protein as made by the cell contains anywhere from 563 to 770 amino acids linked together in a long chain. The fragment destined to make up the senile plaque (called the Abeta peptide) is much smaller (39 to 42 amino acids) and is found in the parts of APP embedded in the membrane and sticking outside the cell.

No protein lives forever in the cell, and APP is no exception. There are a variety of ways to chop it up, so its amino acids can be used for other things. One such chopper is called ADAM10 (aka Kuzbanian). ADAM10breaks down APP in such a way that Abeta isn’t formed. A paper in the 7 July PNAS (vol. 112 pp. 8445 – 8450 ’15 7 July ’15) essentially found that Gemfibrozil (commercial name Lopid) increases the amount of ADAM10 around. If you take a mouse genetically modified so that it will get senile plaques and decrease ADAM10 you get a lot more plaques.

I wrote the author (Dr. Pahan) to ask how they came up with Gemfibrozil (Lopid). He told me that a transcription factor (PPARalpha) helps transcribe the ADAM10 gene into mRNA, and that Gemfibrozil makes PPARalpha a better transcription factor.

I told him to datamine from HMOs to find out if people on Lopid had less Alzheimer’s, he said it would be hard to get such as grant to do this as a basic researcher.

A commenter on the first post gave me a name to contact to try out the idea, but I’ve been unable to reach her. So on 3 August, I wrote an Alzheimer’s researcher at Yale about it. He responded nearly immediately with a link to an ongoing clinical study in progress in Kentucky, actually using Gemfibrozil.

Both researchers (Dr. Jicha and Nelson) were extremely helpful and cooperative. What is so fascinating is that they got to Gemfibrozil by an entirely different route. There are degrees of Alzheimer’s disease, and there is a pathologic grading scheme for it. They studied postmortem brain of 4 classes of individuals — normal nondemented elderly with minimal plaque, non demented elderly with incipient plaque, mild cognitive impairment and full flown Alzheimer’s. They had studied the microRNA #107 (miR-107) in another context. Why this one of the thousand or so microRNAs in the human genome? Because it binds to the mRNA of BACE1 and prevents it from being made. Why is this good? Because BACE1 chops up APP at a different site so the Abeta peptide is formed.

How did Gemfibrozil get into the act? Just as Dr. Pahan did, they looked to see what transcription factors were involved in making miR-107, and found PPARalpha. So to make less BACE1 they give people Gemfibrozil which turns on PPARalpha which turns on miR-107, which causes the mRNA for BACE1 to be destroyed, hopefully making less Abeta. The study is in progress and will last a year, far too short with far too few people to see a meaningful cognitive effect, but not so short that they won’t see changes in the biologic markers  they are studying in the spinal fluids (yes 72 plucky individuals have agreed to take Gemfibrozil (or not) and have two spinal taps one year apart.

The elegance of all this is simply astounding. One transcription factor turns on a gene for a chopper which inhibits Abeta formation, and turns on a microRNA which stops an APP chopper producing Abeta from being made.

So there’s a whole research program for you. Take a given transcription factor, look at the protein genes it turns on. Then look at the microRNA genes it turns on and then see what protein mRNAs they turn off. Then see they affect the same biochemical pathway as do ADAM10 and BACE1.

The mechanism is so elegant (although hardly simple) that I’ll bet the cell uses it again, in completely different pathways.

One problem with PPARalpha is that it is said to affect HUNDREDS of genes (Mol. Metab vol. 3 pp. 354 371 ’14).  So Gemfibrozil is a nice story, but even if it works, we won’t really be sure it’s doing so by ADAM10 and microRNA-107.

Hillary’s stroke – II

On 31 July The Clinton campaign released a letter from Hillary’s personal physician Lisa Bardack, MD, a board certified Internist,  basically saying that her health was excellent.

Well it isn’t and her letter essentially proves that she had a stroke in December of 2012. Here’s why.

First: a timeline.

At some time in the week of 9 December 2012 Mrs. Clinton is said to have fainted suffering a concussion. The New York Times reported on this 13 December.

She remained at home until 31 December at which point she was admitted to New York-Presbyterian Hospital when a blood clot was found in a vein draining the brain. (12 August — correction.  She was admitted 30 December).

Subsequently she had double vision due to her eye muscles not working together for a month or so and had to wear special glasses to correct this.

Second: The following explanation for these events was given by Dr. Bardach. You may read the entire letter at but the relevant paragraph is directly quoted below.

“In December of 2012, Mrs. Clinton suffered a stomach virus after traveling, became dehydrated, fainted and sustained a concussion. During follow up evaluations, Mrs. Clinton was found to have a transverse sinus venous thrombosis and began anticoagulation therapy to dissolve the clot. As a result of the concussion, Mrs. Clinton also experienced double vision for a period of time and benefited from wearing glasses with a Fresnel Prism. Her concussion including the double vision, resolved within two months and she discontinued the use of the prism. She had followup testing in 2013, which revealed complete resolution of the effects of the concussion as well as total dissolution of the thrombosis. Mrs. Clinton also tested negative for all clotting disorders. As a precaution, however, it was decided to continue her on daily anticoagulation.”

Third: Why should you believe what yours truly, a neurologist and not a neurosurgeon says about the minimal likelihood of this clot being due to the head trauma she sustained when she fainted? Neurologists rarely deal with acute head trauma although when the smoke clears we see plenty of its long term side effects (post-traumatic epilepsy, cognitive and coordination problems etc. etc.). I saw plenty of it in soldiers when I was in the service ’68 – ’70, but this was after they’d been stabilized and shipped stateside. However, I had an intense 42 month experience managing acute head injuries.

To get my kids through college, I took a job working for two busy neurosurgeons. When I got there, I was informed that I’d be on call every other night and weekend, taking first call with one of the neurosurgeons backing me up.  Fortunately, my neurosurgical backup was excellent, and I learned and now know far more about acute head trauma than any neurologist should. We admitted some of the head trauma cases to our service, but most cases had trauma to other parts of the body, so a general surgeon would run the show with our group as consultants. I was the initial consultant in half the cases. When I saw them initially, I followed the patients until discharge. On weekends I covered all our patients and all our consults, usually well over 20 people.

We are told that Hillary had a clot in one of the large draining veins in the back of her head (the transverse dural venous sinus). I’d guess that I saw over 300 cases of head trauma,but I never saw a clot develop in a dural sinus due to the trauma. I’ve spoken to two neuroradiologists still in practice, and they can’t recall seeing such a clot without a skull fracture over the sinus. Such a fracture has never been mentioned  at any time about Hillary.

Hillary’s neurologic deficit involved a nerve going to the muscles of her left eye. These start in the brainstem, a part of the brain quite near the site where she is said to have had the clot in her vein. The brainstem is crucial in maintaining consciousness, and it is more likely that the faint earlier in December was a warning sign of the stroke she had subsequently.

Why does the letter essentially prove Hillary had a stroke back then ?

I find it impossible to believe that the double vision occurred when she fainted. No MD in their right mind would not immediately hospitalize a case of head trauma with a neurologic deficit such as double vision. This is just as true for the most indigent patient as for the Secretary of State.

My guess was that the double vision came up later — probably after Christmas. Who gets admitted to the hospital the day of New Year’s Eve? Only those with symptoms requiring immediate attention.  Update 9 August — an alert reader asked how I knew she was admitted during the day and not in the evening.  It made me Google this point further — finding this–politics.html — showing that she was admitted 30 December.  Thanks Joe.

Dr. Bardack’s letter states, “As a precaution,however, it was decided to continue her on daily anticoagulation.” I couldn’t agree more. However, this is essentially an admission that she is at significant risk to have more blood clots. While anticoagulation is not without its own risks, it’s a lot safer now than it used to be. Chronic anticoagulation is no walk in the park for the patient (or for the doctor).   The most difficult cases of head trauma we had to treat were those on anticoagulants. They always bled more.

Dr. Bardack’s letter is quite clever.  She never comes out and actually says that the head trauma caused the clot, but by the juxtaposition of the first two sentences, the reader is led to that conclusion.  Suppose, Dr. Bardack was convinced that the trauma did cause the clot.  Then there would be no reason for her to subject Mrs. Clinton to the risks of anticoagulation, given that the causative agent was no longer present.    In all the cases of head trauma we saw, we never prescribed anticoagulants on discharge (unless we had to for non-neurosurgical reasons). I certainly agree with her use of anticoagulation, as I highly doubt that the trauma had anything at all to do with the blood clot in the transverse sinus. It is even possible that the clot was there all the time and caused the faint in early December.

The really important medical data would be Dr. Bardack’s office notes from December and the consultations of the neurosurgeon and admitting physician at Presbyterian 31 December, but I doubt that we’ll ever see them.

Why does this matter? Fortunately, Mrs. Clinton has recovered. However, statistically a person who has had one stroke is far more likely to have another than a person who has never had one. This is particularly true when we don’t know what caused the first (as in this case).

We’ve had two presidents neurologically impaired by stroke in the past century (Woodrow Wilson after World War I and Franklin Delano Roosevelt at Yalta). The decision they made in that state were not happy for the USA or the world.

Lest you regard this as anti-Hillary, concern for the health of future presidents is not confined to Democratic candidates.  Reagan’s age was raised as a legitimate issue by his opponents  as Christie’s near-morbid obesity should be if he gets the Republican nomination.  The resignation of Thomas Eagleton, the first running mate of George McGovern in 1972 because he had a history of electroshock therapy for depression, again shows that these concerns are not limited to any time or  party.

Addendum 14 Aug ’15: Will be away from the net for several weeks.  If you’ve commented after that, you’ve not been ignored or rejected, just held till I get back.

Addendum 13 Oct ’15:  Watching the debate in real time, not videoed and slowed down.  Her mouth moves symmetrically, although her left cheek appears somewhat swollen and distorted.  On close inspection she rarely moves her left eye to the left fully covering the sclera (white) although I did see it once or twice.  It’s very hard to see if her two eyes are working together at this time.  On gaze to the right she fully buries the sclera of her right eye.  So probably she has fully recovered from the stroke of 2012.

Takes me right back to grad school

How many times in grad school did you or your friends come up with a good idea, only to see it appear in the literature a few months later by someone who’d been working on it for much longer. We’d console ourselves with the knowledge that at least we were thinking well and move on.

Exactly that happened to what I thought was an original idea in my last post — e.g. that Gemfibrozil (Lopid) might slow down (or even treat) Alzheimer’s disease. I considered the post the most significant one I’d ever written, and didn’t post anything else for a week or two, so anyone coming to the blog for any reason would see it first.

A commenter on the first post gave me a name to contact to try out the idea, but I’ve been unable to reach her. Derek Lowe was quite helpful in letting me link to the post, so presently the post has had over 200 hits. Today I wrote an Alzheimer’s researcher at Yale about it. He responded nearly immediately with a link to an ongoing clinical study in progress in Kentucky

On Aug 3, 2015, at 3:04 PM, Christopher van Dyck wrote:

Dear Dr. xxxxx

Thanks for your email. I agree that this is a promising mechanism.
My colleague Greg Jicha at U.Kentucky is already working on this:

Our current efforts at Yale are on other mechanisms:

We can’t all test every mechanism, but hopefully we can collectively test the important ones.

-best regards,
Christopher H. van Dyck, MD
Professor of Psychiatry, Neurology, and Neurobiology
Director, Alzheimers Disease Research Unit

Am I unhappy about losing fame and glory being the first to think of it?  Not in the slightest.  Alzheimer’s is a terrible disease and it’s great to see the idea being tested.

Even more interestingly, a look at the website for the study shows, that somehow they got to Gemfibrozil by a different mechanism — microRNAs rather than PPARalpha.

I plan to get in touch with Dr. Jicha to see how he found his way to Gemfibrozil. The study is only 1 year in duration, and hopefully is well enough powered to find an effect. These studies are incredibly expensive (and an excellent use of my taxes). I never been involved in anything like this, but data mining existing HMO data simply has to be cheaper. How much cheaper I don’t know.

Here’s the previous post —

Could Gemfibrozil (Lopid) be used to slow down (or even treat) Alzheimer’s disease?

Is a treatment of Alzheimer’s disease at hand with a drug in clinical use for nearly 40 years? A paper in this week’s PNAS implies that it might (vol. 112 pp. 8445 – 8450 ’15 7 July ’15). First a lot more background than I usually provide, because some family members of the afflicted read everything they can get their hands on, and few of them have medical or biochemical training. The cognoscenti can skip past this to the text marked ***

One of the two pathologic hallmarks of Alzheimer’s disease is the senile plaque (the other is the neurofibrillary tangle). The major component of the plaque is a fragment of a protein called APP (Amyloid Precursor Protein). Normally it sits in the cellular membrane of nerve cells (neurons) with part sticking outside the cell and another part sticking inside. The protein as made by the cell contains anywhere from 563 to 770 amino acids linked together in a long chain. The fragment destined to make up the senile plaque (called the Abeta peptide) is much smaller (39 to 42 amino acids) and is found in the parts of APP embedded in the membrane and sticking outside the cell.

No protein lives forever in the cell, and APP is no exception. There are a variety of ways to chop it up, so its amino acids can be used for other things. One such chopper is called ADAM10 (aka Kuzbanian). ADAM10breaks down APP in such a way that Abeta isn’t formed. The paper essentially found that Gemfibrozil (commercial name Lopid) increases the amount of ADAM10 around. If you take a mouse genetically modified so that it will get senile plaques and decrease ADAM10 you get a lot more plaques.

The authors didn’t artificially increase the amount of ADAM10 to see if the animals got fewer plaques (that’s probably their next paper).

So there you have it. Should your loved one get Gemfibrozil? It’s a very long shot and the drug has significant side effects. For just how long a shot and the chain of inferences why this is so look at the text marked @@@@


How does Gemfibrozil increase the amount of ADAM10 around? It binds to a protein called PPARalpha which is a type of nuclear hormone receptor. PPARalpha binds to another protein called RXR, and together they turn on the transcription of a variety of genes, most of which are related to lipid metabolism. One of the genes turned on is ADAM10, which really has never been mentioned in the context of lipid metabolism. In any event Gemfibrozil binds to PPARalpha which binds more effectively to RAR which binds more effectively to the promoter of the ADAM10 gene which makes more ADAM10 which chops of APP in such fashion that Abeta isn’t made.

How in the world the authors got to PPARalpha from ADAM10 is unknown — but I’ve written the following to the lead author just before writing this post.

Dr. Pahan;

Great paper. People have been focused on ADAM10 for years. It isn’t clear to me how you were led to PPARgamma from reading your paper. I’m not sure how many people are still on Gemfibrozil. Probably most of them have some form of vascular disease, which increases the risk of dementia of all sorts (including Alzheimer’s). Nonetheless large HMOs have prescription data which can be mined to see if the incidence of Alzheimer’s is less on Gemfibrozil than those taking other lipid lowering agents, or the population at large. One such example (involving another class of drugs) is JAMA Intern Med. 2015;175(3):401-407, where the prescriptions of 3,434 individuals 65 years or older in Group Health, an integrated health care delivery system in Seattle, Washington. I thought the conclusions were totally unwarranted, but it shows what can be done with data already out there. Did you look at other fibrates (such as Atromid)?

Update: 22 July ’15

I received the following back from the author

Dear Dr.

Wonderful suggestion. However, here, we have focused on the basic science part because the NIH supports basic science discovery. It is very difficult to compete for NIH R01 grants using data mining approach.

It is PPARα, but not PPARγ, that is involved in the regulation of ADAM10. We searched ADAM10 gene promoter and found a site where PPAR can bind. Then using knockout cells and ChIP assay, we confirmed the participation of PPARα, the protein that controls fatty acid metabolism in the liver, suggesting that plaque formation is controlled by a lipid-lowering protein. Therefore, many colleagues are sending kudos for this publication.

Thank you.

Kalipada Pahan, Ph.D.

The Floyd A. Davis, M.D., Endowed Chair of Neurology


Departments of Neurological Sciences, Biochemistry and Pharmacology

So there you have it. An idea worth pursuing according to Dr. Pahan, but one which he can’t (or won’t). So, dear reader, take it upon yourself (if you can) to mine the data on people given Gemfibrozil to see if their risk of Alzheimer’s is lower. I won’t stand in your way or compete with you as I’m a retired clinical neurologist with no academic affiliation. The data is certainly out there, just as it was for the JAMA Intern Med. 2015;175(3):401-407 study. Bon voyage.


There are side effects, one of which is a severe muscle disease, and as a neurologist I saw someone so severely weakened by drugs of this class that they were on a respirator being too weak to breathe (they recovered). The use of Gemfibrozil rests on the assumption that the senile plaque and Abeta peptide are causative of Alzheimer’s. A huge amount of money has been spent and lost on drugs (antibodies mostly) trying to get rid of the plaques. None have helped clinically. It is possible that the plaque is the last gasp of a neuron dying of something else (e.g. a tombstone rather than a smoking gun). It is also possible that the plaque is actually a way the neuron was defending itself against what was trying to kill it (e.g. the plaque as a pile of spent bullets).


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