Why Cassava’s Simufilam results are not a placebo effect

Any open label study without controls is subject to the reasonable criticism that any benefits seen are due to the placebo effect.  Neurologic and Psychiatric disease trials can have large (33%) placebo effects (e.g. migraine, depression).

This is very unlikely to be the case with the 1 year results of the open label trial of Simufilam in 200 patients with Alzheimer’s disease.  “47% of patients improved on ADAS-Cog over 1 year, and this group improved by 4.7 points”

It is based on my clinical experience with a drug for Alzheimer’s disease released 30 years ago — Tacrine (Cognex).  Initially it was touted as helping Alzheimer’s disease (e.g. improving thinking and memory) although later it was held to slow the decline.   The local medical school advertised it aggressively (primarily as a marketing device).

So I put my Alzheimer patients on Cognex.  I wanted them to get better. They wanted to get better, and their families and caregivers certainly did.  Just about all of them thought it might have helped on followup visits in the first month.  I couldn’t see much difference.  By the second month, they weren’t sure, and later in the first year they didn’t think it helped, and most weren’t using the drug after 1 year.

Not only that, but I was in a call group with 4 other neurologists, and they saw exactly the same thing.  I was practicing in an area with a catchment area of over a million people, and every local neurologist I talked to had the same experience. People thought that “Cognex helped” for a month or two and then they didn’t

This a classic example of a placebo effect.  Moreover it occurred in a therapeutic trial for Alzheimer’s disease.  Crucially, the placebo effect was quite transient and  absent at 1 year.

This is why the Simufilam results mentioned above are not a placebo effect.

Those not interested in neuropharmacology can stop at this point.  There were excellent clinical and theoretical reasons for the use of Tacrine.

Clinically it was apparent that drugs that blocked the effects of the neurotransmitter acetyl choline on one type of its receptors (muscarinic) profoundly impaired memory. Scopolamine is one such drug.  One of the earliest and most invariable symptoms of Alzheimer’s disease is deficient memory.

That’s the clinical part.  Here’s the theory.  So logically, increasing acetyl choline should help memory.  How to do this?  Well there are enzymes that break acetyl choline down (the acetyl cholinesterases).  So by inhibiting cholinesterases, acetyl choline levels in the brain should increase, and memory should be improved.

Impeccable logic and theory.  Unfortunately, like many such it didn’t work.

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.

 

 

Just when you thought you understood neurotransmission

Back in the day, the discovery of neurotransmission allowed us to think we understood how the brain worked. I remember explaining to medical students in the early 70s, that the one way flow of information from the presynaptic neuron to the post-synaptic one was just like the flow of current in a vacuum tube — yes a vacuum tube, assuming anyone reading knows what one is. Later I changed this to transistor when integrated circuits became available.

Also the Dale hypothesis as it was taught to me, was that a given neuron released the same neurotransmitter at all its endings. As it was taught back in the 60s this meant that just one transmitter was released by a given neuron.

Retrograde transmission was just a glimmer in the mind’s eye back then. We now know that the post-synaptic neuron releases compounds which affect the presynaptic neuron, the supposed controller of the postsynaptic neuron. Among them are carbon monoxide, and the endocannabinoids (e. g. what marihuana is trying to mimic).

In addition there are neurotransmitter receptors on the presynaptic neuron, which respond to what it and other neurons are releasing to control its activity. These are outside the synapse itself. These events occur more slowly than the millisecond responses in the synapse to the main excitatory neurotransmitter of the brain (glutamic acid) and the main inhibitory neurotransmitter (gamma amino butyric acid — aka GABA). Receptors on the presynaptic neuron for the transmitter it’s releasing are called autoreceptors, but the presynaptic terminal also contains receptors for other neurotransmitters.

Well at least, neurotransmitters aren’t released by the presynaptic neuron without an action potential which depolarizes the presynaptic terminal, or so we thought until [ Neuron vol. 82 pp. 63 – 70 ’14 ]. The report involves a structure near and dear to the neurologist the striatum (caudate and putamen — which is striated because the myelinated axons of the internal capsule go through its anterior end giving it a striated appearance).

It is the death of the dopamine containing neurons in the substantial nigra which cause Parkinsonism. They project some of their axons to the striatum. The striatum gets input elsewhere (from the cortex using glutamic acid) and from neurons intrinsic to itself (some of which use acetyl choline as their neurotransmitter — these are called cholinergic interneurons).

The paper makes the claim that the dopamine neurons projecting to the striatum also contain the inhibitory neurotransmitter GABA.

The paper also says that the cholinergic interneurons cause release of GABA by the dopamine neurons — they bind to a type of acetyl choline receptor called nicotinic (similar but not identical to the nicotinic receptors which allow our muscles to contract) in the presynaptic terminals of the dopamine neurons of the substantial nigra residing in the striatum. Isn’t medicine and neuroanatomy a festival of terms? It’s why you need a good memory to survive medical school.

These used optogenetics (something I don’t have time to explain — but see http://en.wikipedia.org/wiki/Optogenetics ) to selectively stimulate the 1 – 2% of striatal neurons which use acetyl choline as a neurotransmitter. What they found was that only GABA (and not dopamine) was released by the dopamine neurons in response to stimulating this small subset of neurons. Even more amazing, the GABA release occurred without an action potential depolarizing the presynaptic terminal.

This literally stands everything I thought I knew about neurotransmission on its ear. How widespread this phenomenon actually is, isn’t known at this point. Clearly, the work needs to be replicated — extreme claims require extreme evidence.

Unfortunately I’ve never provided much background on neurotransmission for the hapless chemists and medicinal chemists reading this (if there are any), but medicinal chemists must at least have a smattering of knowledge about this, since neurotransmission is involved in how large classes of CNS active drugs work — antidepressants, antipsychotics, anticonvulsants, migraine therapy. There is some background on this here — https://luysii.wordpress.com/2010/08/29/some-basic-pharmacology-for-the-college-student/