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posted by martyb on Friday August 19 2016, @09:52AM   Printer-friendly
from the finally-some-good-news dept.

Submitted via IRC for cmn32480 with a story that appeared in ScienceAlert:

Australian researchers have come up with a non-invasive ultrasound technology that clears the brain of neurotoxic amyloid plaques - structures that are responsible for memory loss and a decline in cognitive function in Alzheimer's patients.

If a person has Alzheimer's disease, it's usually the result of a build-up of two types of lesions - amyloid plaques, and neurofibrillary tangles. Amyloid plaques sit between the neurons and end up as dense clusters of beta-amyloid molecules, a sticky type of protein that clumps together and forms plaques.

Neurofibrillary tangles are found inside the neurons of the brain, and they're caused by defective tau proteins that clump up into a thick, insoluble mass. This causes tiny filaments called microtubules to get all twisted, which disrupts the transportation of essential materials such as nutrients and organelles along them, just like when you twist up the vacuum cleaner tube.

[...] Publishing in Science Translational Medicine , the team describes the technique as using a particular type of ultrasound called a focused therapeutic ultrasound, which non-invasively beams sound waves into the brain tissue. By oscillating super-fast, these sound waves are able to gently open up the blood-brain barrier, which is a layer that protects the brain against bacteria, and stimulate the brain's microglial cells to activate. Microglila cells are basically waste-removal cells, so they're able to clear out the toxic beta-amyloid clumps that are responsible for the worst symptoms of Alzheimer's.

The team reports fully restoring the memory function of 75 percent of the mice they tested it on, with zero damage to the surrounding brain tissue. They found that the treated mice displayed improved performance in three memory tasks - a maze, a test to get them to recognise new objects, and one to get them to remember the places they should avoid.

[...] The team says they're planning on starting trials with higher animal models, such as sheep, and hope to get their human trials underway in 2017.

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  • (Score: 3, Informative) by slash2phar on Friday August 19 2016, @12:48PM

    by slash2phar (623) on Friday August 19 2016, @12:48PM (#390041)
    The linked paper/story is from March 2015, but it doesn't seem like the researchers [] have published any follow up since.
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  • (Score: 5, Interesting) by Anonymous Coward on Friday August 19 2016, @02:16PM

    by Anonymous Coward on Friday August 19 2016, @02:16PM (#390077)

    There are more issues than that:

    neurotoxic amyloid plaques - structures that are responsible for memory loss and a decline in cognitive function in Alzheimer's patient

    This is hardly established. All we know is people with memory problems are likely to have more stuff in their brain that stains for this. Also, the neurotoxicity depends on dose and context so it isn't clear the plaques can't be benign or even protective under conditions in the brain. Sorry, I'm too lazy for references right now, but may add some later in the day. Instead anyone interested can search around on pubmed [] for this stuff.

    Some comments on the paper:

    1) Apparently they were not blinded while analyzing the data:

    The treatment condition was kept blinded until the analysis

    This is dangerous because it introduces all sorts of opportunities to look at different outcomes and cherry pick etc. For example when choosing which brain sections to look at, etc. Obviously you need to be unblinded when making the final group comparisons, but if that is what they did I don't see why they would mention "until the analysis".

    2) They collected histological/molecular data for the same mice for which they had behavioral data. A major part of their narrative is that the plaques they measured are related to memory deficits. However, THEY DO NOT PLOT ONE AGAINST THE OTHER. This is a really idiotic practice that is standard in neuroscience research, and yes I checked the supplementary materials.

    3) Basic statistical misunderstandings:

    spontaneous alternation (calculated by the number of complete alternation sequences divided by the number of alternation opportunities) in APP23 mice treated with SUS, but not in sham-treated animals,was restored to wildtype levels [P [less than] 0.05, one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison] (Fig. 1E). Total entries into the Y-maze arms did not differ between groups (Fig. 1F).

    First, they twice commit the error of "accepting the null hypothesis". Second, no hypothesis about "restoration" was tested. They are comparing different groups of mice at a single timepoint.

    4) More confusion about what hypothesis was actually being tested here:

    Our results revealed that the degree of Ab reduction achieved by SUS treatment was

    They did not measure any "reduction", they compared different groups of mice. If they want to measure "reduction" or "restoration" they would need to figure out a way to measure A-beta multiple times in living mice. Just because this may be hard/impossible doesn't mean they get to leap to claims of "reduction".

    5) These tests of memory may not correspond to what is seen in Alzheimer's, or even be measuring memory. The first one is the Y-maze [] :

    The Y-maze was made of clear Plexiglas and had three identical arms (40 x 9 x 16 cm) 120° apart. The center platform was a triangle with 9 cm side-length. The room was illuminated by 70 lux. Mice were habituated to the testing room and the apparatus 24 h prior to testing by being in the maze for 5 min. On the day of testing mice were placed in one of the arms and allowed to explore the maze for 8 min. Arm entry was defined as having all four limbs inside one of the arms. Mice were videotaped and the videos were analyzed blind. The maze was cleaned with 70% ethanol between animals. The sequence of arm entries was used to obtain a measure of alternation, reflecting spatial working memory. The percentage alternation was calculated by the number of complete alternation sequences (i.e., ABC, BCA, CAB) divided by the number of alternation opportunities (total arm entries minus two).

    They saw the normal/treated mice averaged 60% alternations and the untreated averaged 50%. So this test assumes if a mouse goes in arm A of the maze, then arm B, then goes back to arm A, it must be because it didn't remember what it did a bit earlier. For some reason it is supposed to go to arm C before going again to arm A. There are tons of other explanations for this behavior (maybe the untreated mice were more stressed by bright light, so they tended to avoid the side near the light, maybe their sense of smell was a little worse so they had to go further into each arm (rather than just peeking in) to check for food than the normal mice, maybe they left behind less of a scent).

    I've spent too much time already but maybe this will give someone an idea of what to look for in these papers.

  • (Score: 2) by bzipitidoo on Friday August 19 2016, @02:54PM

    by bzipitidoo (4388) on Friday August 19 2016, @02:54PM (#390097) Journal

    Yes this is the ultrasound therapy I read about earlier this year and mentioned in the previous Alz story on mefenamic acid: []

    Nice, but I fear it's too late to do my mother much good now, and they say this won't be available until 2017 at the earliest. Particularly frustrating is hearing that the researcher who stumbled upon the M13 virus did that way back in 2004, and just sat on the discovery for the better part of a decade. We really need to change our laws and customs to get more experimental treatments-- ones that have a real chance of helping, and are not solely for gathering data-- to people who have nothing to lose. If by just asking, the family could get these treatments to mother today, we'd do it. She's 86, in great physical shape, able to wander away, fast, the moment your back is turned, but doesn't know her own name or who anyone is and is in a nursing home. We couldn't handle her ourselves any more. But it's not so easy to get in an experimental treatment. Around 5 years ago, I looked into getting her into whatever ones were available, but there wasn't much and she didn't qualify for most, in many cases didn't live close enough, and would have required constant travel to and from a distant hospital.

    It's not just practical concerns, have to watch out for the sort of moralists who think they have the right to dictate their ideas of morality to everyone else regardless of general agreement, and get the heebie jeebies at the mere thought of death, insisting that living as long as possible is the only socially acceptable goal and doing anything else, taking the slightest medical risk, is tantamount to murder. Euthanasia and the likes of Dr. Kevorkian are beyond the pale, but the death penalty is acceptable. They are of course "pro-life" to the extreme, and want to criminalize not just abortions but even miscarriages, probably on the idea that women might try to dodge abortion restrictions by relabeling them as miscarriages. They badly embarrassed themselves over the Terri Schiavo case, but that's been over a decade ago, and they have short memories.

    One experiment was this idea that high altitudes with their thinner air are healthier environments, and to expose patients to that through use of an air tent through the night, but with oxygen levels boosted. It didn't sound anywhere near as hopeful as these others. Heck, some years ago, reading that cell phone radiation actually does affect the brain despite telecoms' protestations to the contrary, and that it might be beneficial, I seriously considered slipping one in her pillow.

    • (Score: 0) by Anonymous Coward on Friday August 19 2016, @03:12PM

      by Anonymous Coward on Friday August 19 2016, @03:12PM (#390113)

      I used to feel similar to you (I would try the experimental treatment, etc) but not after doing medical research myself". Even most well established treatments are pretty questionable when it comes to effectiveness, even questionable when it comes to chronic side effects and harm. But usually they are pretty safe in the short term. Trying anything called "experimental" in this context is worse than hoping to win the lottery. Your normal pocket calculator doesn't have enough digits to show the probability of success, it is too small.

      Think about it this way. If you are tinkering around with something you have no understanding of, probing it with concentrated chemicals and sharp objects, is it going to be easier to break it or make it work better? It is definitely easier to break things you don't understand than fix/improve them.

      • (Score: 2) by bzipitidoo on Friday August 19 2016, @05:21PM

        by bzipitidoo (4388) on Friday August 19 2016, @05:21PM (#390170) Journal

        Yes, certainly dishonesty in medicine is a major problem. In the US, concerns of profit warp our whole medical system. Even doctors who mean well are swayed by sophisticated marketing campaigns that play upon uncertainty and hope, and subtle pressures like the old "end justifies the means" thinking that if you do a deal with the Devil, as long as it's for enough money, you will be able to keep your practice open and help more people. Thanks to the pernicious influence of Big Pharma, it's very hard to get the best estimates what the risks and odds, and alternatives really are. Making an informed choice is harder than it should be.

        The best they can do for mother are these various drugs marketed as if they are wonder drugs, but which have nothing wonderful to boast about, they offer only some straws to grasp at, in exchange for piles of money. They say right on the packaging that they do not cure or even slow down Alz. They don't even guarantee a short term improvement in functioning if taken daily as recommended, they say only that those drugs may do that, in some people. And they cause troublesome side effects. I certainly haven't been able to tell whether they helped. They could have slipped us placebos for all I know. Given all that, we don't think they're worth it, but have had to fight the doctors to stop pushing them. This ultrasound therapy couldn't help but be better than that. If ultrasound did absolutely nothing, that would still be better than these drugs that do nothing good while causing bad side effects. There is of course always some risk of damage, but if it didn't do so in mice, and there's reason to think that lack of harm would carry over to humans, then why not give it a try?

        When my time draws near, I would like nothing better than to serve science a final time by taking chances with at least good odds that no harm will come of it. Your mention that many treatments have high uncertainty and terrible odds of doing anything good shows that it won't be easy, there's a lot of bull to dig through. And if it does go badly wrong and kills me, then fine, especially if that saved me from a slow, lingering, decade long dignity destroying decline into raving senility in a nursing home. But, I don't wish to make such a choice blindly (or to have anyone do that on my behalf), with anything less than the best information we have.

        • (Score: 0) by Anonymous Coward on Friday August 19 2016, @06:28PM

          by Anonymous Coward on Friday August 19 2016, @06:28PM (#390209)

          dishonesty in medicine is a major problem

          It really isn't dishonesty for the most part. The biggest problem is that people are not really interested in doing a good job when it comes to medical research. They think they are getting away with half-assing it only because they do not know what their p-values mean. The public also doesn't seem interested in funding the basic science that needs to be done so we can start moving forward, they would prefer funding a million monkeys doing a million random things to 20 million rodents.

          If ultrasound did absolutely nothing, that would still be better than these drugs that do nothing good while causing bad side effects.

          Well, the way it is supposed to work is by "opening the blood brain barrier". They show evidence of this: blue dye they injected into the tail vein collected in the brain underneath where they did the ultrasound, apparently none would normally be found in the brain. I'd just say there is probably a reason your body normally prevents stuff like that blue dye from collecting in the brain. Then they say the next step to it working is that the microglia (immune cells of the brain) become activated. If that is correct, we need to expect that one type of side effect will be brain inflammation and development of autoimmune disorders to nervous system tissues.

          They say it was safe... but is 1.5 months (the duration of this study) long enough for such things to show up? I dunno, I'm just saying that based on their description this does not sound particularly unlikely to be free of side effects or at all safe.

  • (Score: 0) by Anonymous Coward on Saturday August 20 2016, @12:18AM

    by Anonymous Coward on Saturday August 20 2016, @12:18AM (#390355)

    The linked paper/story is from March 2015, but it doesn't seem like the researchers [] have published any follow up since.

    Maybe they forgot.