Has Stanford University found a cure for Alzheimer's disease?

[JPV]

Progression of alot of neurological disorders seems to come down to increasing inflammation.

More and more I am of the opinion that inflammation, though not the root cause, is the prime mitigating factor in numerous health conditions. We live in a very toxic world these days and controlling inflammation seems to help ease the symptoms of virtually every health problem.

 

[anciendaze]

@JPV

I think you mean "aggravating" rather than "mitigating" factor.

@heapsreal

A few years ago we found out that one SSRI, fluoxetine (Prozac) strongly inhibited Coxsackie B, an enterovirus. This was especially interesting from a medical standpoint because doctors had no specific medications to treat enterovirus infections. We now appear to be seeing that all SSRIs have effects on enteroviral infections. This suggests to me that many depressed patients who respond are actually suffering from undetected enteroviral infections.

Why don't ME/CFS patients respond? First, because they can't tolerate these drugs. The standard explanation for how SSRIs improve mood has to do with blocking reuptake of serotonin at synapses in the brain, allowing the molecules to bounce around in the synaptic cleft until they have been captured by receptors many times. The problem with this is that most of these receptors are outside the brain, and most of those in the brain are blocked by glial cells.

The vast majority of open serotonin receptors are in and around the gut. They are associated with a large part of the autonomic nervous system which has even been called a "second brain". (This is inaccurate, because in evolutionary terms the autonomic nervous system has been around longer than the CNS. If it is a brain, it is the first.)

If anyone had been paying attention to what ME/CFS patients were reporting they would have noticed a great deal of symptomology associated with dysautonomia. Specifically, they would have noticed that the sympathetic branch of the autonomic nervous system was overactive, and the parasympathetic branch could not control it when patients needed to sleep. This would have naturally led to the idea that it would be a very bad idea to further stimulate the sympathetic nervous system. Understanding better how SSRIs worked would have had them listed as contraindicated in ME/CFS.

I think this illustrates the extent to which doctors fail to learn from experience.

 

[adreno]

This would have naturally led to the idea that it would be a very bad idea to further stimulate the sympathetic nervous system. Understanding better how SSRIs worked would have had them listed as contraindicated in ME/CFS.

I don't see how they would be contraindicated in that case, as 5-HT inhibits NE.

 

[Marco]

@anciendaze

Coincidentally in the last few days I've been reading up on autonomic dysfunction as measured by reduced heart rate variability in schizophrenia, the manic phase of bipolar disorder and in depression and anxiety disorders.

I have never tried SSRIs so can't comment but tricyclics messed me up big time. According to the following, tricyclics reduce HRV while there is some evidence that SSRIs do the opposite :

http://www.ncbi.nlm.nih.gov/pubmed/11011352

In the context of 'pyschiatric' disorders one proposed mechanism for autonomic dysfunction is dysfunction of the pre-frontal cortex. As SSRIs are also anti-inflammatory (and more specifcally attenuate microglial activation) they may help normalise grey matter function.

http://www.ncbi.nlm.nih.gov/pubmed/22251606

Given that the 'serotonin hypothesis' of depression doesn't fit with the delayed response to treatment any benefits from SSRIs may be due to top down rather than bottom mechanisms. Gastro symptoms in ME/CFS may not be due to infection but through serotonin degradation via the TryCat pathway due to neuroinflammation.

 

[anciendaze]

I don't see how they would be contraindicated in that case, as 5-HT inhibits NE.

That may be more relevant to SNRIs. There are a lot of different biochemical feedback paths related to 5-HT/serotonin, norepinephrine, dopamine and histamine, which could cause mental state to change in just about any direction. (Epinenephrine is also called adrenalin, and many of us are already "running on adrenalin" just to get to the doctor's office, not that doctors are likely to notice.)

The effects of SSRIs take place below the level of 5-HT synthesis, at specific synapses where there are particular types of serotonin receptors on one side of the synaptic cleft, and reuptake receptors on the other side. This is why they are called "selective". By interfering with reuptake and using the same serotonin molecules repeatedly they get the effect of high levels of 5-HT without any change in actual concentrations of those molecules, except temporarily in specific synapses where reuptake is blocked. This means that the path you describe is more or less out of the picture. It may even be down-regulated by processes which sense excess activity in serotonergic receptors, even though general serotonin levels have not changed at all.

One problem we have is that patients with ME/CFS symptoms are likely to be classified as depressed patients with psychomotor retardation. Naive reasoning about this is that they need something to perk them up, and make them more alert during the day. Some doctors will even prescribe amphetamines. At night they need something different to sleep, which leads to prescriptions for benzodiazapines. I don't think you will have any trouble finding patients on this forum who have been through this mill, sometimes barely escaping with their lives.

 

[Hip]

The actual published study by Stanford University researcher Prof Katrin Andreasson, showing that blocking prostaglandin E2 receptor (EP2 receptor) improve Alzheimer's symptoms, is this one:

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models.
Johansson JU, Woodling NS, Wang Q, Panchal M, Liang X, Trueba-Saiz A, Brown HD, Mhatre SD, Loui T, Andreasson KI.
J Clin Invest. 2014 Dec 8. pii: 77487. doi: 10.1172/JCI77487. PMID: 25485684

Abstract
Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation.

In Alzheimer's disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD.

Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE2 receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits.

Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE2/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.

Full paper here.

Here are some excerpts from the full paper:

Microglial activities represent critical lines of defense against the development of neurodegenerative disease; microglia clear misfolded proteins, elaborate trophic and regenerative factors, and regulate and terminate toxic inflammation.

Recent studies point to a steady decline of these normal microglial functions in aging and in AD. In AD, microglia not only lose their capacity to clear Aβ peptides but also develop a persistent proinflammatory phenotype that does not resolve, accelerating neuronal and synaptic injury.

In conclusion, our data demonstrate that microglial EP2 suppresses multiple beneficial functions that are essential to combat the toxic effects of Aβ42 peptides on synapses and memory function. These findings suggest that microglial EP2 activity hastens pathological progression to AD.

Although the study authors do not mention it explicitly, when they are referring to the anti-inflammatory, regenerative and garbage clearing (clearing proteins) activities of microglia, I believe they are implicitly talking about the alternative neuroprotective mode of microglial activation, which contrasts to the classical neurodestructive mode of microglial activation.

Certainly this study found that EP2 receptor regulates the classical activation of microglia, and this study found that blocking the EP2 receptor led to reduced microglial neurotoxicity.

These two very different mode of microglial activation, neuroprotective and neurodestructive, are detailed at the end of this post here.

As far as I can work out from the study, blocking the EP2 receptor seems to induce activities that are characteristic of the alternative neuroprotective mode of microglia — a mode which does things like garbage clearing (in this case of the Alzheimer's beta amyloid plaque).

This might of course have import for ME/CFS: I guess it's conceivably that there may be too much neurodestructive microglial activity in ME/CFS, and not enough neuroprotective and restorative microglial activity.



There are some EP2 receptor antagonists available for research purposes (like SC-19220 and PF-04418948).

 

[adreno]

@anciendaze, it's hard to find long-term data, but at least acutely SSRIs suppress sympathetic activity:

Short-term sertraline treatment suppresses sympathetic nervous system activity in healthy human subjects.

Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity.

 

[anciendaze]

@adreno

This is surprising to me in view of the effects many ME/CFS patients have experienced from SSRIs: increased anxiety, anorexia, insomnia and even tachycardia. These symptoms all seem closely connected with "flight or fight" responses and epinephrin/adrenalin. (At the other end of the scale, I've heard about patients given Zoloft/Sertraline who stopped getting out of bed entirely.) I think the problem has to do with the fact that we are not "healthy human subjects".

I would also point out that the primary effects of SSRIs as antidepressants do not manifest for about a week or more, i.e. these are not immediate effects of administration of the drug, which changes levels in a matter of hours, but the results of adaptation to the chemical change over a period of days. It is not the direct effect of the chemical, but the body's response to it, which could well be in exactly the opposite direction due to feedback.

We have multiple clues that various kinds of feedback are broken in ME/CFS, so depending on this to provide desired drug response is unwise. We seem to experience the side effects without the intended primary effect. General rule about antidepressants: the side effects come first.

I will stand by my claim that dysautonomia is prevalent in ME/CFS patients, and that it is unwise to try to manipulate the autonomic nervous system when you don't even realize that is what you are doing, and are not measuring anything which might tell you whether you are making the problem better or worse.

 

[alex3619]

Receptor isoforms (alternative forms with alternative functions) are important in regulating impact of hormones. Different tissues will have different receptor combinations. That means a cell can regulate how it responds to a hormone in different ways. So it can amplify one response or suppress another.

Identifying a specific isoform is a big step in restricting the range of side effects from a drug. Vioxx or Celebrex would probably have an impact on PGE2 mediated responses, but the side effects would be broad and dangerous. That does not mean though that isolating the effect to one receptor type will eliminate side effects.

One of the first things I would like to know is what is the tissue distribution of EP2. What else besides the microglia is this isoform expressed in?

 

[lansbergen]

One of the first things I would like to know is what is the tissue distribution of EP2. What else besides the microglia is this isoform expressed in?

For one: dentric cells. http://www.ncbi.nlm.nih.gov/pubmed/12773508

And http://www.nextprot.org/db/entry/NX_P43116
Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. The subsequent raise in intracellular cAMP is responsible for the relaxing effect of this receptor on smooth muscle.

and: http://jpet.aspetjournals.org/content/336/2/391.full
EP1, EP2, EP3, and EP4 were expressed on human platelets and megakaryocytes. PGE2 through different EPs finely modulates human platelet responsiveness

And http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113270
It has been known that EP2 receptor is differentially over-expressed in epithelia of inflamed human colonic mucosa

 

[natasa778]

@adreno

This is surprising to me in view of the effects many ME/CFS patients have experienced from SSRIs: increased anxiety, anorexia, insomnia and even tachycardia. These symptoms all seem closely connected with "flight or fight" responses and epinephrin/adrenalin. (At the other end of the scale, I've heard about patients given Zoloft/Sertraline who stopped getting out of bed entirely.) I think the problem has to do with the fact that we are not "healthy human subjects".

Low dose SSRIs are part of Dr Goldberg's NIDS autism treatment protocol (he started off looking into and trying to find treatments for CFS/ME for personal reasons, long story). The focus however is on 'low', ie tweaking the dosage. Sympthetic overactivation is well documented in asd, and increased anxiety and insomnia is almost the norm. Different patients react differently but I have seen reports of massively different reactions in same kids to same SSRIs depending on dosages, ranging from 'horrible - severe anxiety and irritability' to 'life-changing, stunning improvements in overall functioning' after changing dose. As far as I know those are often less than half of the normal dosages used for antidepressant effects, per weight of course. Often a lot less than half.

Not trying to advocate for this for ME but wondering if similar experiences have been reported?

 

[natasa778]

PS another central feature of that NIDS protocol are antivirals, mostly acycolvir. Which reminds me of that recent fibro/CFS study that combined an antiviral (was it famvir) with a COX-2 inhibitor... btw chronic microglial overactivation is also a feature of asd - a thread was posted recently on something called M2 pathway of chronic microglial activation.

 

[anciendaze]

@natasa778

What you describe indicates strongly non-linear response, which is another gap in medical reasoning, after we get past misunderstanding of systems with feedback. This makes me wonder just what such people are doing in medicine, where nonlinearity and feedback are the norm.

 

[anciendaze]

natasa778 has raised an interesting question: do ME/CFS patients have a dramatically different response to very low doses of SSRIs? I've heard of doctors starting with low doses and titrating up to "therapeutic levels", but I've never heard of anyone staying at a very low level. The doctors involved were convinced they were treating depression, and when the fatigue did not go away they assumed a higher dose was needed.

Anyone on this forum have experience with maintenance on very low doses of SSRIs?

 

[Sushi]

Not trying to advocate for this for ME but wondering if similar experiences have been reported?

Anyone on this forum have experience with maintenance on very low doses of SSRIs?

My autonomic specialist used to prescribe very low doses of cymbalta (an SNRI) and had good results in a percentage of patients. I did well on it, but he never titrated up--he kept it low. He learned about this method of dosing at a dysautonomia conference, so there is some awareness of this among some specialists.

Sushi

 

[alex3619]

SNRIs may be less problematic than SSRIs. One reason I don't like SSRIs is that we are a high serotonergic disorder .. why do we need more?

 

[natasa778]

I have just posted this as a separate thread. It might have been brought up already on there or elsewhere?

Not sure if this trial has been followed up since by a larger one

Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease

Recent clinical studies point to rapid and sustained clinical, cognitive, and behavioral improvement in both Alzheimer's disease and primary progressive aphasia following weekly perispinal administration of etanercept, a TNF-alpha inhibitor that acts by blocking the binding of this cytokine to its receptors. This outcome is concordant with recent basic science studies suggesting that TNF-alpha functions in vivo as a gliotransmitter that regulates synaptic function in the brain. We hypothesized that perispinal etanercept had the potential to improve verbal function in Alzheimer's disease, so we included several standarized measures of verbal ability to evaluate language skills in a clinical trial of perispinal etanercept for Alzheimer's disease.

... This was a prospective, single-center, open-label, pilot study, in which 12 patients with mild-to-severe Alzheimer's disease were administered etanercept, 25–50 mg, weekly by perispinal administration for six months. Two additional case studies are presented.

 

[adreno]

Anyone on this forum have experience with maintenance on very low doses of SSRIs?

I've taken half the regular dose of fluoxetine for years. Higher dosing is intolerable. SSRIs are normally overdosed IMO. Differences between SSRIs is also important. I tried two others before fluoxetine that I didn't tolerate.

Some say we already have high serotonin levels and don't need more. This I think is oversimplification. A reuptake inhibitor drug will normally increase tonic levels, but reduce phasic levels of neurotransmitters.

There are other advantages of SSRIs. Increasing neurogenesis, curbing excitotoxicity, plus antiviral and anti-inflammatory properties. My symptoms have improved while on it, although I can't specifically attribute it to that.

 

[heapsreal]

Anyone on this forum have experience with maintenance on very low doses of SSRIs?

yes, low doses of zoloft in the past, the first time i used it at very low doses to try and improve brain fog which never left. this was early days of cfs. My wife was on zoloft so i tried 25mg dose, within a few hours my brain fog was totally gone. zoloft kept working for several months. I have used it off and on a few times, like adreno, higher doses just overstimulate the hell out of me and cause insomnia.

recently i have tried low dose 5mg lexapro, mostly to help with orthostatic intolerance, which its worked well, plus im interested in the whole neurogenesis and anti inflammatory thing too. four days ago i increased it to 10mg which is the normal dosage of lexapro and it hasnt been an issue, but i was at 5mg for a couple of month before increasing the dose.. so for me its a very tolerable drug with no bad issues.

for me anything that effects noradrenaline is a night mare. I tried low doses of reboxetine which is a noradrenaline reuptake inhibitor, the first few hours gave me plenty of energy, this was off 1/4 of the normal dose. That night i couldnt sleep a wink and not much improvement in sleep after that, so i didnt last long on this, also perfuse sweating is another side effect i got, probably not good for orthostatic issues??

Any ssri, low and slow is the best way and we dont need the full dose to get good effects. We have to be careful as doctors want to push the doses higher if you still have fatigue issues etc, fine for depression but not for cfs/me.

 

[minkeygirl]

PS another central feature of that NIDS protocol are antivirals, mostly acycolvir. Which reminds me of that recent fibro/CFS study that combined an antiviral (was it famvir) with a COX-2 inhibitor...

I think you're referring to Pridgen's protocol. There's some threads about it here.