1230 replies to this topic

[Ark]

The immune system attacking the brain is just another piece of the puzzle.

[resveratrol_guy]

The immune system attacking the brain is just another piece of the puzzle.

 

Nice find! C1q and ANX-005 represent a completely novel attack pathway against synapse destruction. The problem is that if ANX-005 ever evolves into a drug, it will be too expensive and administered too late. (The best thing about the FDA is that it has made pharmaceutical failure very predictable.) So baesd on your paper, if the theory works (and it sounds like it would), what we really need is gene therapy to knock out C1q. I hate to say this, but that's going nowhere, either. (Imagine the approval process!) So all in all, this is more Alzheimer's research that will pretty much never benefit anyone. I'm not being pessimistic. I'm just looking at the history of these approaches, even where they've actually worked in humans. For instance, we were sprouting new axons in Alzheimer's brains via intracranial NGF injection back in 2000. The science is solid and proven by autopsy. But where has that gone? What do we have in 2016? Donepezil.
 

[corb]

 

The immune system attacking the brain is just another piece of the puzzle.

 

Nice find! C1q and ANX-005 represent a completely novel attack pathway against synapse destruction. The problem is that if ANX-005 ever evolves into a drug, it will be too expensive and administered too late. (The best thing about the FDA is that it has made pharmaceutical failure very predictable.) So baesd on your paper, if the theory works (and it sounds like it would), what we really need is gene therapy to knock out C1q. I hate to say this, but that's going nowhere, either. (Imagine the approval process!) So all in all, this is more Alzheimer's research that will pretty much never benefit anyone. I'm not being pessimistic. I'm just looking at the history of these approaches, even where they've actually worked in humans. For instance, we were sprouting new axons in Alzheimer's brains via intracranial NGF injection back in 2000. The science is solid and proven by autopsy. But where has that gone? What do we have in 2016? Donepezil.
 

 

 

Recently I read a news article about an implant that secrets antibodies capable of tagging abeta and tau for destruction by the imune system in mice.

I don't see why the same implant method can't be used with ANX-005.

 

As you say the technology is there, whether it goes somewhere in the next decade or two is a different question.

[Logic]

http://www.sciencema...=alzhapses-3369

 

Alzheimer’s may be caused by haywire immune system eating brain connections

 

• More than 99% of clinical trials for Alzheimer’s drugs have failed...Most new Alzheimer’s drugs aim to eliminate β amyloid...more plaques don’t always mean more severe symptoms such as memory loss or poor attention...
• What does track well with the cognitive decline seen in Alzheimer’s disease...is a marked loss of synapses, particularly in brain regions key to memory...
• a normal immune mechanism...prunes weak or unnecessary synapses as the brain matures from the womb through adolescence, allowing more important connections to become stronger. In this process, a protein called C1q sets off a series of chemical reactions that ultimately mark a synapse for destruction. After a synapse has been “tagged,” immune cells called microglia—the brain’s trash disposal service—know to “eat” it...When this system goes awry during the brain’s development, whether in the womb or later during childhood and into the teen years, it may lead to psychiatric disorders such as schizophrenia...
• ...the same mechanism goes awry in early Alzheimer’s disease, leading to the destruction of good synapses and ultimately to cognitive impairment. Using two Alzheimer’s...models...[found] elevated levels of C1q in brain tissue. When they used an antibody to block C1q from setting off the microglial feast, however, synapse loss did not occur...
• that suggests that the normal mechanism for pruning synapses during development somehow gets turned back on again in the adult brain in Alzheimer’s, with dangerous consequences. “Instead of nicely whittling away [at synapses], microglia are eating when they’re not supposed to...
• a drug that blocks C1q slows their cognitive decline...
• In addition, microglia only went after synapses when β amyloid was present, suggesting that the combination of protein and C1q is what destroys synapses, rather than either element alone...
• The findings contradict earlier theories which held that increased microglia and C1q activity were merely part of an inflammatory reaction to β amyloid plaques. Instead, microglia seem to start gorging on synapses long before plaques form...
• Stevens...will soon start testing the safety of a human form of the antibody the team used to block C1q, known as ANX-005, in people.

[aaCharley]

MIT Technology Review has a good article on the Barnes and Stevens work on microglia.

 

 

[resveratrol_guy]

 

Recently I read a news article about an implant that secrets antibodies capable of tagging abeta and tau for destruction by the imune system in mice.

I don't see why the same implant method can't be used with ANX-005.

 

As you say the technology is there, whether it goes somewhere in the next decade or two is a different question.

 

 

The tagging approach is more convenient than injections every few weeks or months. Still I'm not sure I like the idea of an implant becoming progressively less reliable over time. Either way, I'd like to see an antibody or ANX005 group buy. (Yeah I know I'm probably dreaming.)

 

Edited by resveratrol_guy, 05 April 2016 - 11:06 PM.

[tunt01]

 

• The findings contradict earlier theories which held that increased microglia and C1q activity were merely part of an inflammatory reaction to β amyloid plaques. Instead, microglia seem to start gorging on synapses long before plaques form..

 

It'd be nice to fully understand how they arrive at that conclusion and if the pruning process involving C1q is also unrelated to phospho-Tau.  I know nothing about C1q, but it just doesn't seem very logical to me that C1q activity is anything more than a downstream event.

 

Nice for nootropic theory, not so much for actual Alzheimer's pathology other than probably a band-aid like Namenda.

 

I think the most elegant ALZ "solution" is going to be an upregulation of LRP1.  Perhaps Ashwagandha should be more closely examined.  Or maybe Ginkgo.

Edited by prophets, 06 April 2016 - 02:38 AM.

[resveratrol_guy]

 

I think the most elegant ALZ "solution" is going to be an upregulation of LRP1.  Perhaps Ashwagandha should be more closely examined.  Or maybe Ginkgo.

 

 

Given that the ashwaganda paper came out in 2012, I would have expected more news on LRP1, had it proven effective. Why are you optimistic about this receptor?

[tunt01]

I think the most elegant ALZ "solution" is going to be an upregulation of LRP1. Perhaps Ashwagandha should be more closely examined. Or maybe Ginkgo.

Given that the ashwaganda paper came out in 2012, I would have expected more news on LRP1, had it proven effective. Why are you optimistic about this receptor?

Look up reviews on alzheimer and or lrp1 by Berislav Zlokovic. His lab is focused on unique lrp1 drugs. Think also that apoe lipid action improves lrp1 mechanism of a beta removal.

Scientists are not focused on ashwagandha, they are focused on drugs that mediate the pathway.

I'm not near my office now to pull specific papers

[tunt01]

What makes the most sense to me as an explanation for the cause of Alzheimer's is the two-hit hypothesis (Amyloid Beta Cascade) put forth by Berislav Zlokovic.  (Zlokovic 2011)

 

 

 

What he explains is that there is typically some cerebrovascular impediment that precedes ALZ in terms of amyloid beta, phospho-tau and other clinical features of ALZ.  It's microvascular health that is the first hit.  The second hit is the accumulation of Abeta that leads to the clinical features of ALZ.  Defective amyloid beta clearance is a consequence of microvascular impairment and the unattractive ApoE4 allele.  The half-life of Abeta is greater in E4, E3, and E2 by order.  Clearance of Abeta is approximately 30% lower in AD patients (5.6% vs. 7.6% in controls). (Bateman 2006)

 

Therefore, the appropriate intervention depends a bit on where an individual is in the process.  Early on, improving cerebrovascular blood flow (Egb 761), PDE-5 inhibitors, etc. might be more attractive.  Ultimately in a later stage intervention, one would need to get accumulated Abeta out of the brain, ideally by enhancing innate clearance methods.  I think that makes LRP-1 an attractive, thoughtful approach relative to the immuno-therapies we are seeing that target Abeta.

 

 

 

 

Bateman, R., Munsell, L., Morris, J., Swarm, R., Yarasheski, K., & Holtzman, D. (2006). Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nature Medicine, 12(7), 856-861. doi:10.1038/nm1438

 

Zlokovic, B. (2011). Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders.Nature Reviews Neuroscience. doi:10.1038/nrn3114

 

 

 

 

 

 

Edited by prophets, 06 April 2016 - 10:48 AM.

[albedo]

Also here, wondering if similarly to the previous Prophets's post on the two hit hypothesis, ALZ seems starting earlier that one would expect, possibly leading to more preventive actions?

 

New Clues Show Out-of-Control Synapse Pruning May Underlie Alzheimer's

http://www.scientifi...=SA_MB_20160406

 

"...In a study published this week in Science, a team of researchers led by neurologist Beth Stevens at Boston Children’s Hospital has found evidence that such synapse loss may in fact occur much earlier in Alzheimer’s disease. Rather than being a secondary effect of these protein pathologies, as experts had previously thought, this process may begin well before plaques form..."

[resveratrol_guy]

All the abeta clearance drugs -- even those which worked as advertised -- have completely failed to ameliorate dementia, and have in some cases accelerated it. It's possible that using them in the preclinical phase would have different results, although Longvida is safer and cheaper and has been shown to clear abeta significantly in rodents, so there's little financial justification for such trials.

 

The two-hit process may very well be an accurate description of Alzheimer's evolution. And most likely there's an overactive immune component, as albedo's article hypothesized.

 

But the question is, what we can do on a practical level to arrest this process? (We don't need reversal, at least in the early stages, as neuroplasticity could address the functional deficits provided that neurodegeneration were brought to a halt. So NGF may be unnecessary in that context, for all its promise.) It seems to me that the best approaches involve interruption of the protein misfolding duplication process. In other words, if we can only stop the misfolded proteins from begetting more of themselves by infecting neighbors, then we can survive plenty of ordinary insults, such as those involving abeta oligomers, plaque nucleating metal ions, microvascular lesions, etc. The best drug I know of in this regard, which is easily obtained from EVOO, is oleocanthal. Does anyone know anything more effective?

 

It's downright sad how little research has gone into correlating olive oil consumption to dementia. There are plenty of claims and a few studies supporting the notion that olive oil is neuroprotective, but I don't see anything correlating dose to effect. This is unfortunately unsprising, given that olive oil is not patentable.

 

The problem I have with LRP1, based on my crude understanding, is that it can assist with amyloid, but not phosphotau, clearance. It's unlikely that such a solution could actually arrest a disease process which is increasingly dominated by the latter.

 

Edited by resveratrol_guy, 06 April 2016 - 11:51 PM.

[tunt01]

The two-hit process may very well be an accurate description of Alzheimer's evolution. And most likely there's an overactive immune component, as albedo's article hypothesized.

 

 

 

I can't speak to this C1q issue.  It seems like it has to be a downstream event.  An ALZ brain is in a state of metabolic hypoxia where neurons are starving.  The fact that they undergo a pruning process, may just be a natural biproduct and evolution of an underlying disease pathology.

 

 

But the question is, what we can do on a practical level to arrest this process? (We don't need reversal, at least in the early stages, as neuroplasticity could address the functional deficits provided that neurodegeneration were brought to a halt. So NGF may be unnecessary in that context, for all its promise.) It seems to me that the best approaches involve interruption of the protein misfolding duplication process. In other words, if we can only stop the misfolded proteins from begetting more of themselves by infecting neighbors, then we can survive plenty of ordinary insults, such as those involving abeta oligomers, plaque nucleating metal ions, microvascular lesions, etc. The best drug I know of in this regard, which is easily obtained from EVOO, is oleocanthal. Does anyone know anything more effective?

 

 

It's downright sad how little research has gone into correlating olive oil consumption to dementia. There are plenty of claims and a few studies supporting the notion that olive oil is neuroprotective, but I don't see anything correlating dose to effect. This is unfortunately unsprising, given that olive oil is not patentable.

 

The problem I have with LRP1, based on my crude understanding, is that it can assist with amyloid, but not phosphotau, clearance. It's unlikely that such a solution could actually arrest a disease process which is increasingly dominated by the latter.

 

 

I think Phospho-tau is usually a downstream event from Amyloid Beta accumulation or at best concurrent.  ABeta accumulation and aggregation is the primary event.  Cells become hypoxic and insulin resistant.  Insulin signalling normally inhibits GSK3b (and is prevented in this ALZ case).  Tau gets phosphorylated.

 

Oleocanthal upregulates LRP-1 and improves Abeta removal.

 

 

 

 

 

[resveratrol_guy]

 

It's downright sad how little research has gone into correlating olive oil consumption to dementia. There are plenty of claims and a few studies supporting the notion that olive oil is neuroprotective, but I don't see anything correlating dose to effect. This is unfortunately unsprising, given that olive oil is not patentable.

 

The problem I have with LRP1, based on my crude understanding, is that it can assist with amyloid, but not phosphotau, clearance. It's unlikely that such a solution could actually arrest a disease process which is increasingly dominated by the latter.

 

I think Phospho-tau is usually a downstream event from Amyloid Beta accumulation or at best concurrent.  ABeta accumulation and aggregation is the primary event.  Cells become hypoxic and insulin resistant.  Insulin signalling normally inhibits GSK3b (and is prevented in this ALZ case).  Tau gets phosphorylated.

 

Oleocanthal upregulates LRP-1 and improves Abeta removal.

 

Impressive study. (I'm blind to most of the Longecity commentary on it at the moment, which I believe was also posted in the oleocanthal thread, because the internal search is 403ing me. Very annoying!)

 

Anyway, I agree that phosphotau is largely downstream of abeta. My only point was that LRP1 doesn't seem to address the former. Oleocanthal, however, does. I would hope to identify an even more effective antifibrilization agent which could be acquired with practical amounts of money and effort. Meanwhile, I continue to scavenge the local grocery stores for cheap liter bottles of EVOO...

 

Here is another 2015 study on EVOO's role in the prevention of dementia, beyond the mere question of oleocanthal. The abstract sounds intriguing but I can't get the full text.

 

On another topic, the TOAD study is still recruiting patients in the hope that oxaloacetate will slow disease progression. If you live near Kansas City and have a relative afflicted with AD, you might want to contact them.

[tunt01]

Anyway, I agree that phosphotau is largely downstream of abeta. My only point was that LRP1 doesn't seem to address the former. Oleocanthal, however, does. I would hope to identify an even more effective antifibrilization agent which could be acquired with practical amounts of money and effort. Meanwhile, I continue to scavenge the local grocery stores for cheap liter bottles of EVOO...

 

 

It's a good point.  I have been thinking about this a bit.  I think the best bet is to look at it through inhibiting GSK-3B activity.

 

 

 

The body fluctuates on a circadian rhythm between fasted and fed states.  In the fed state, protein transcription occurs via insulin and GSK-3B gets phosphorylated, preventing it from being active and phosphorylating Tau.

 

In the nutrient deprived state (fasted), GSK-3B is activated and tau becomes phosphorylated.  The problem in ALZ pathology is that neurons are always starving, they are always nutrient deprived and that's why GSK-3B activation is out of control.  How the pathology gets to this point relates to Abeta and our prior discussion.

 

Therefore, how do we prevent GSK-3B and phospho-Tau?  I would say things like lithium and ppar-gamma activators (Telmisartan, Exercise, AICAR, Resveratrol, etc.).  Again, from a circadian rhythm standpoint, I think we should be exercising in-between meals and that would mean upregulation of AMPK/ppar-y.

 

 

 

 

 

 

Pang T, e. (2014). Telmisartan protects central neurons against nutrient deprivation-induced apoptosis in vitro through activation of PPARγ and the Akt/GSK-3β pathway. - PubMed - NCBI .Ncbi.nlm.nih.gov. Retrieved 7 April 2016, from http://www.ncbi.nlm....pubmed/24793312

[resveratrol_guy]

In reference to your first image above, could you please post a web link instead? I can't respond to something I can't see. These Longecity errors lately are getting ridiculous:

 

"Sorry, you don't have permission for that!

[#10744.1]

Sorry, but that does not appear to be a valid image. If you arrived at this screen by following a link on this site, please notify a system administrator"

[tunt01]

I honestly do not remember where I grabbed this from.  Hopefully this image translates better.

 

http://i.imgur.com/SNz0PVD.jpg

 

[tunt01]

 

In the nutrient deprived state (fasted), GSK-3B is activated and tau becomes phosphorylated.  The problem in ALZ pathology is that neurons are always starving, they are always nutrient deprived and that's why GSK-3B activation is out of control.  How the pathology gets to this point relates to Abeta and our prior discussion.

 

Therefore, how do we prevent GSK-3B and phospho-Tau?  I would say things like lithium and ppar-gamma activators (Telmisartan, Exercise, AICAR, Resveratrol, etc.).  Again, from a circadian rhythm standpoint, I think we should be exercising in-between meals and that would mean upregulation of AMPK/ppar-y.

 

 

 

Speak of the devil....

 

Fruit flies live longer on lithium
Date:  April 7, 2016

Fruit flies live 16% longer than average when given low doses of the mood stabiliser lithium, according to a UCL-led study.  How lithium stabilises mood is poorly understood but when the scientists investigated how it prolongs the lives of flies, they discovered a new drug target that could slow aging -- a molecule called glycogen synthase kinase-3 (GSK-3).

 

SOURCE

 

 

From the original study.  Dosage between 1 - 25 mM extended lifespan while 50 - 100 shortened (Figure 1A).  Best appears to be ~5 mM.

 

 

 

 

Castillo-Quan, J., Kinghorn, K., Ivanov, D., Tain, L., Slack, C., & Kerr, F. et al. (2016). Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis. Cell Reports, 0(0). doi:10.1016/j.celrep.2016.03.041

Edited by prophets, 07 April 2016 - 10:44 PM.

[resveratrol_guy]

I honestly do not remember where I grabbed this from.  Hopefully this image translates better.

 

http://i.imgur.com/SNz0PVD.jpg

 

Much better! So this is complicated by the empirical fact that fasting improves cognition. Yet, as Lostfalco has discussed at length, so does intranasal insulin, which is progrowth and almost certainly progeriatric.

 

Telmisartan, for its part, does not seem to have been very effective at achieving its intended endpoints with respect to the avoidance of cardiovascular events. It also has some potentially hazardous side effects. But perhaps it's more effective at AD prevention, if for no other reason than that it seems to lower blood pressure relatively effectively. From your study, it seems like we want to inhibit GSK3B in the most narrowly targetted manner possible.

[tunt01]

 

Much better! So this is complicated by the empirical fact that fasting improves cognition. Yet, as Lostfalco has discussed at length, so does intranasal insulin, which is progrowth and almost certainly progeriatric.

 

Telmisartan, for its part, does not seem to have been very effective at achieving its intended endpoints with respect to the avoidance of cardiovascular events. It also has some potentially hazardous side effects. But perhaps it's more effective at AD prevention, if for no other reason than that it seems to lower blood pressure relatively effectively. From your study, it seems like we want to inhibit GSK3B in the most narrowly targetted manner possible.

 

 

I think this dichotomy fundamentally exists in biology (fasting/catabolism -- vs. -- insulin secretion/protein synthesis), because the body operates along a continuum of a circadian rhythm.  I think it's critical to have periods of deprivation/stress (exercise) followed by quality meals.  It's the constant snacking (excessive PI3K/Akt activity) or the constant deprivation (neuronal starvation, overactive GSK3b) that leads to problems.

 

It is simplistic, but I think just good cardiovascular health, proper diet, and a good night's sleep are probably the cornerstones of avoiding alzheimer's at the molecular level.  Maybe a supplement or two to tweak things further.

Edited by prophets, 08 April 2016 - 05:53 PM.

[resveratrol_guy]

Looks like reason also posted the low-dose lithium study here. But it's a nonstarter: "Higher doses reduced lifespan but lower doses prolonged life". How would we have any confidence whatsoever that the human equivalent dose were appropriately "low"? BTW if I recall, lithium upregulates autophagy when delivered at the right dose; I'm not sure if that involves GSK3B.

 

I don't know if I agree that alternating periods of fasting and eating a full-calorie healthy diet is actually superior to continually fasting. There's a lot of evidence on both sides of the issue. In any event you're clearly correct that homeostasis is a big problem when it comes to sustaining the effect of any intervention, be it a drug or a lifestyle change. Personally, I think that slow-and-steady wins the race. I expect to make up for the homeostasis calibration by a lack of systemic stress due to constantly changing interventions. (Having said that, my last couple years has been nothing other than the latter!)

Edited by resveratrol_guy, 08 April 2016 - 09:01 PM.

[mag1]

This one looks large.

It has been something of a mystery how anti-amyloid antibodies ever make through the BBB.

Only a few of them do and they have reduced amyloid somewhat, often at the expense of problems with so called ARIA.

In fact there is some concern that the efficacy signal is being lost because ARIA is subtracting from the gains of treatment.

The ones with ARIA can be the same ones who have the largest amyloid reduction responses. 

 

What if the BBB could be briefly opened to let the antibodies in?

Lower doses, lower side effects, better efficacy?

 

 

https://www.scienced...60408132649.htm

https://www.jci.org/...cles/view/76207

[resveratrol_guy]

This one looks large.

It has been something of a mystery how anti-amyloid antibodies ever make through the BBB.

Only a few of them do and they have reduced amyloid somewhat, often at the expense of problems with so called ARIA.

In fact there is some concern that the efficacy signal is being lost because ARIA is subtracting from the gains of treatment.

The ones with ARIA can be the same ones who have the largest amyloid reduction responses. 

 

What if the BBB could be briefly opened to let the antibodies in?

Lower doses, lower side effects, better efficacy?

 

 

https://www.scienced...60408132649.htm

https://www.jci.org/...cles/view/76207

 

Yeah, that's big, alright. I suspect we could obtain Lexiscan via group buy. Unfortunately, the next logical question is what to do with it, absent the antibodies that we might want to deploy to the brain. So sadly I think this one is going to be buried in the FDA paper mountain for a long time.

Edited by resveratrol_guy, 10 April 2016 - 04:58 PM.

[mag1]

res, thank you for your support.

I was doing a freak out dance in the end zone: I just wanted to make sure the people were with me on this one.

 

In these anti-amyloid antibody trials they have used relatively high doses in order for some of the dosage to get past the

BBB and wind up in the brain. What happens if they could just open the doorway to the brain? Some of the researchers

have done all sorts of crazy things such as open brain surgery to get things into the brain. Lexiscan would make the process

so much easier.

 

My big concern would be that the DIYers out there would give this a try. So if solanezumab made it to market who knows what might

happen if a patient decided to codose with Lexiscan. I think that would be fantastically dangerous. The implications for amping up

ARIA would be significant. Perhaps this could even be a problem with the current trials. It does not seem unreasonable that dosing

studies should be contemplated fairly quickly to try and get ahead of those who might try and experiment.

 

It amazes me how little is known about the consequences of these different interventions. They have been opening the BBB on the patients

receiving Lexiscan and did not even know it? Very scary! Well I guess we can already just accept that opening the BBB is fairly benign, as Lexiscan 

has already received FDA approval.

 

Even though modern medicines are usually reasonably specific there are still

all of these side effects that appear from nowhere? The best policy still seems to be to take as few pharmaceuticals as possible: They 

usually have no clear idea what they are doing.

 

 

Also excited about how opening the BBB might be combined with anti-APOE 4 antibodies.

 

http://www.ncbi.nlm....pubmed/27040139

http://www.alzforum....n-do-without-it

 

 

 

Edited by mag1, 10 April 2016 - 07:55 PM.

[corb]

Even though modern medicines are usually reasonably specific there are still

all of these side effects that appear from nowhere? The best policy still seems to be to take as few pharmaceuticals as possible: They

usually have no clear idea what they are doing.

 

I'm pretty sure they checked if lexiscan does this quite deliberately because what it is used for generally is similar.

It would have been an unexpected side effect if it was used for something completely different and they just stumbled upon it's property after a wide screening of drugs.

[mag1]

I am just very unclear whether this would have been known before the fact.

The above article seems to imply that this was an unexpected discovery.

In fact there has been ongoing research devoted to try and achieve this very outcome!

 

 

I am sure if I were a biotech company and went to the FDA and asked to do a trial with the stated intent of

opening the BBB, then I would sure hope that the FDA would say, "No way!". As much as I do not agree

with endless delay in advancing drugs through the clinical trial pipeline, it would seem entirely reasonable

to carefully consider what opening the consequences of opening the BBB (even temporarily might be).

 

Perhaps this new research will rapidly change the clinical administration of Lexiscan.

Would you really want to take e.g. a vaccine soon after a Lexiscan dose?

There are now a whole lot of questions.

 

At the same time, since Lexiscan is already FDA approved, to a substantial extent the bridge has already been

crossed. Temporarily opening the BBB has already been proven to be safe in the Lexiscan clinical trials.

[mag1]

Here's what the Lexiscan website has to say:

 

"Lexiscan (regadenoson) injection is a prescription drug given through an IV line that increases blood flow through the arteries of the heart during a cardiac nuclear stress test.

Lexiscan is given to patients when they are unable to exercise adequately for a stress test."

 

https://www.lexiscan.com/

 

 

It does not obviously follow from this description that it would open the BBB, though Lexiscan is an agonist of  A2A adenosine receptor. "The A_2A receptors are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow. In addition, A_2A receptor can negatively regulate overreactive immune cells, thereby protecting tissues from collateral inflammatory damage. " wiki. It looks like it was a happy coincidence that the BBB doubled up on the cardiac functions of the receptor.

 

https://www.jci.org/...cles/view/76207

 

Wonder how the off label argument would play with Lexiscan? "Well, it is always an FDA approved medication. Therefore, QED it is safe." Perhaps, though it was never approved to open

up the BBB and give direct access to one's brain! 

 

This is extremely exciting!

 

Brain entry has been one of the main obstacles to progress in Alzheimer's.

If you can't even get medications to the places in the body that they are needed (here the brain), then it does not matter how effective the treatments you develop

might be. If we have now arrived at a point where the brain is fully accessible, then lowering amyloid or tau or inflammation etc. should be much

easier, more effective and safe. I really wonder whether some of the anti-amyoid antibodies that have been proven in phase 3 trials not to

work might now reenter trials? It is not completely obvious that the currently favored antibodies will remain so with this new development.

Edited by mag1, 10 April 2016 - 10:24 PM.

[corb]

 

In this study, we set out to determine whether activation of A2A AR signaling exerts its effects on the transcellular pathway by way of P-gp modulation. To test this, we used the FDA-approved A2A AR agonist Lexiscan

You see, they didn't stumble upon it, they selected a drug that can prove their theory.

 

Lexiscan, most people probably get a dose or two of it at most in their whole lifetime. And since it's during a medical test I suppose they're rarely taking other medication at the same time, going by the paper they were only able to detect that the BBB has been slightly opened because they were injecting chemo together with the Lexiscan.

 

That being said looking at the adverse effects on the webpage I'd be more worried about what the FDA considers safe (or safe enough anyway) rather than what they miss.

[resveratrol_guy]

Ha! There's another more straightforward way to open the BBB: use a mobile phone right next to your head, ideally an iPhone. Like ultrasound, microwaves can open the BBB, provided they are tuned to the right frequency and have sufficient power to accomplish the task.

 

What Lexiscan adds is predictability because presumably it has been, or soon will have been, studied in detail with regards to this property.

 

But I must admit that I'm not very excited. This is not something we can exploit today, given that the experiments have just started, and we have no antibodies to diffuse anyway.

 

Next idea...

[ceridwen]

Mobile phones can cause brain cancer and Alzheimer's anyway