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Comment by ninesnines | Hacker News Reader

this above article is kind of inflammatory, however, this paper is incredibly interesting.

I read it this morning and the concept of changing CSF in order to have an increase in oligodendrocyte progenitor cell proliferation and differentiation is such a creative idea; a lot of the idea has focused on increasing flow in order to move waste, etc with csf. I think this concept that CSF is also acting as an important mechanism to moving factors that will cause up regulation, etc, is very novel.

honestly one of my favourite papers in the last five years, I am obsessed.

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Modifying CSF turnover is not particularly novel, but I do think it is generally overlooked. CSF production cycling is greatly reduced in the elderly and and there are a lot of connections to memory diseases such as alzheimers.

A few medical device startups have attacked the problem with promising results. Unfortunately, VC and national funding orgs aren't particularly interested in device based solutions because pills and injections are perpetually 5 years out.

I'm aware of at least one that was able to halt or reverse alzheimers in a 200 patient trial, but folded after they couldnt get funding to move forward.

I remember seeing a drug/substance that potentiated the glymphatic system filtration but I just can't find it again, it's been a year..

sorry! maybe it's just my thoughts on the matter that have changed. i understand that you can have drugs move through the glymphatic system, but maybe i was just unaware that you can move a whole host of other cell proliferation factors through the glymphatic system also!

To be clear I was talking about a drug that increase the fluid movement rate/duration/frequency of the glymphatic filtering, which allow to improve the quantity of cleaning. If you're talking about the effect of the glymphatic system on the repartition of Neurotrophics, I have no idea :)

There's a fair bit of literature suggesting that there's more to it than the production rate. Metabolite delivery and removal also depends on the dynamic pressure and frequency response of the system. That is to say, to get the appropriate pulsatile flow the brain can't be too rigid or too flaccid

Can you share any more information about the medical device that showed efficacy against Alzheimers in the 200-patient trial?

This is one that I thought was compelling.[1] The trial ultimately failed but if you read the results the post-hoc analysis, it showed promise in mild and moderate subgroups of the ITT population. Most drugs today don't even target mild AD, but go after pre-symptomatic patients.

There was also benefit across most measures, but just not of statistical significance.

The trial had some major problems with appropriate controls, and is widely cited as a poster child for why the FDA should not require a control group to undergo invasive brain-surgery, and how this can taint the results.

It also showed a 89% reduction in amyloid Beta, the same proxy measure Biogen's aducanumab was recently approved based on.

https://n.neurology.org/content/neurology/71/3/202.full.pdf

Thanks for checking. Alzheimer Management By Albumin Replacement (AMBAR) treatment has shown efficacy in slowing the progression of moderate & advanced stages disease [0, 1].

[0] https://doi.org/10.1080/14737175.2021.1960823

[1] https://doi.org/10.1002/alz.12137

Yeah, is totally absurd that given the health care and social cost of of Alzheimer's we're not taking Broad shotgun approach to investigating potential remedies.

There are a lot of treatments that's worth dumping several million dollars in even if they are low probability of having durable effects.

It doesn't happen because of the structure of society. Capitalism efficiently allocates capital, but does not maximize citizen quality-of-life.

Either that or bureaucratic NIH grant grant approvers have no balls.

Do you have any evidence to accuse NIH of fault, or is your comment pure speculation?

I have been turned down for a half dozen grants in AD research I think could impact millions of lives, and see them funding bs and no impact projects.

I obviously have biases and an axe to grind, but these are my opinions.

Thanks for explaining. How about publishing those rejected grant proposals?

yes yes I know that increasing CSF flow is not that novel (anymore e.g. last couple of years). you can increase it with cerebral blood flow, and you can do this with sleep, respiration, visual stimuli, etc.

however, the ideas of 1) replacing csf from young to older mice and 2) the idea that there are factors in CSF that are being delivered to other areas of the brain and promoting cell proliferation: that's pretty novel.

all of the literature right now points to csf in terms of waste clearance and csf is painted as almost a river that picks up components and moves waste (e.g. amyloid beta) from the periarterial areas in the parenchyma and then out through the perivenous areas into the lymphatic system. and this means that the idea of delivery of promoting factors is really interesting.

I'm curious, what is your favorite paper of all time (the specification of 'last five years' sounds like it's not this one?)

ah there are a lot of really nice old nature/science neuroscience articles that are really clear! papers were more simple and clear 20 years ago

The papers from the 90s are generally my favorites.

I don't have a favorite but one that stands out is the resuscitation of cryogenized hamsters https://royalsocietypublishing.org/doi/10.1098/rspb.1956.005...

holy cinnamon I've never seen this -- brilliant

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