Latest / Pharmacy Podcast Network / Desmosterol, Statins, and Cognition | Geriatric Pharmacy Focus

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Desmosterol, Statins, and Cognition | Geriatric Pharmacy Focus · Pharmacy Podcast Network

0:05
Speaker 1: You are listening to the global network of podcasters dedicated
0:09
Speaker 1: to the pharmacy profession. Welcome to the Pharmacy Podcast Network.
0:27
Speaker 1: We have an aging population taking more medications than ever before.
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Speaker 1: On this podcast, I will interview experts in geriatric medicine
0:34
Speaker 1: to gain insights so we can provide optimal care to
0:37
Speaker 1: patients in their golden ears. I'm your host, doctor Tammar Ruggles,
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Speaker 1: and this is the Geriatric Pharmacy Focus.
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Speaker 2: Hello and welcome to.
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Speaker 3: The Geriatric Pharmacy Focus. I'm your host, doctor Tamar Reuels,
0:52
Speaker 3: and with me is doctor Lippett himself, doctor Thomas day Spring.
0:56
Speaker 3: We're so excited to have him back. Thank you for
0:59
Speaker 3: joining us. Doctor day Spring is a Fellow of the
1:02
Speaker 3: American College of Physicians and a Fellow of the National
1:05
Speaker 3: Lippid Association. He practiced in New Jersey nearly forty years
1:09
Speaker 3: and now is retired but staying very busy because he's
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Speaker 3: the social media ambassador for both the European Athrosclerosis Society
1:17
Speaker 3: and the National Lippet Association, giving thousands of lectures, interviews
1:22
Speaker 3: on podcasts, and just staying very busy. If you're not
1:25
Speaker 3: following him, you need to be doctor lippid on X
1:28
Speaker 3: and doctor Thomas day Spring on LinkedIn. So welcome doctor
1:31
Speaker 3: day Spring.
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Speaker 4: Good to be with you again, Tamara, and I guess
1:35
Speaker 4: I qualify as a geriatric person night. Your podcast is
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Speaker 4: entitled so Perfect.
1:42
Speaker 3: That's right, that's right, this is perfect. So we've had
1:45
Speaker 3: you on two different episodes. One was just kind of
1:48
Speaker 3: a generic lipid podcast, the Lipid Lowdown. The next one
1:52
Speaker 3: we dove into lipoprotein little A. And since meeting you
1:56
Speaker 3: and learning so much more about lipids, now I can
2:00
Speaker 3: you come back and talk about does moosterol because I
2:02
Speaker 3: think it's something not a lot of people know about,
2:05
Speaker 3: but I do think it's important for pharmacists to know
2:08
Speaker 3: about doesmostral because of medications and how they can affect
2:12
Speaker 3: does moosterol and what that means for our patients. So
2:16
Speaker 3: thank you for coming to talk about this very complex topic.
2:20
Speaker 3: But if you can first teach us a little bit
2:23
Speaker 3: about exactly what doesmosterol is.
2:26
Speaker 4: Yes, a little bit of biochemistry will be involved in
2:30
Speaker 4: today's talk, but doesmosterol if you look at the last
2:33
Speaker 4: five letters as a stoll. Stoll are a group of
2:37
Speaker 4: cyclic lipid molecules that are the basic structure of all
2:44
Speaker 4: of the steroid hormones and everything. But of course the
2:48
Speaker 4: stromost everybody has heard about is colesterol. That is one
2:54
Speaker 4: of the stol family, has probably one hundred different starols
2:59
Speaker 4: in it, and very few people are cognizant of anything
3:03
Speaker 4: else other than cholesterol. So we're not going to discuss
3:07
Speaker 4: every sterol in this podcast, thank god. But to understand
3:11
Speaker 4: what you're interested in desmosterol, we have to basically understand
3:16
Speaker 4: the cholesterol synthetic pathways, and it's a very complex pathway.
3:21
Speaker 4: It's not a plus B equal C ce being cholesterol.
3:25
Speaker 4: There's over thirty steps in the synthesis of a single
3:28
Speaker 4: cholesterol molecule. It basically starts with either a three carbon
3:32
Speaker 4: molecule acetate acetic acid or a five carbon molecule citric
3:37
Speaker 4: acid a citrate, and that of course comes out of
3:39
Speaker 4: the CREB cycle. Now, through many stepwise modifications, those three
3:44
Speaker 4: or five carbon molecules become longer, longer longer. They're adding
3:50
Speaker 4: carbon hydrogen atoms. Everybody like. The third step is the
3:54
Speaker 4: creation of mevylonic acid, and most people are a little
3:57
Speaker 4: bit familiar with that because the the enzyme that causes
4:02
Speaker 4: that to be generated as hmg CoA reduct case, and
4:07
Speaker 4: of course that's the enzyme that if we inhibit with statins,
4:10
Speaker 4: we slow down the cholesterol synthetic pathway. But mevalonic acid
4:16
Speaker 4: becomes longer, longer, longer, and it becomes the longest still
4:20
Speaker 4: linear molecule called scaling. That is thirty carbon molecules long.
4:25
Speaker 4: It's a gigantic molecule and you really can't have things
4:28
Speaker 4: getting much longer than that. And what happens is it
4:32
Speaker 4: starts to turn on itself, its cyclicizes, it becomes a
4:36
Speaker 4: cyclical molecule. So the thirty carbon squaling turns into a
4:40
Speaker 4: twenty seven carbon stol called lenosterol. And the sterol structure
4:47
Speaker 4: is basically four rings, three six carbon rings and one
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Speaker 4: five carbon ring, and on the fifth carbon happens to
4:55
Speaker 4: be carbon seventeen. If you count all the carbons, there's
4:59
Speaker 4: a that sticks up off of it, and that tail
5:03
Speaker 4: is pretty much what differentiates the different stols. Cholesterol has
5:07
Speaker 4: an eight carbon saturated tail, and that's cholesterol. Now on
5:11
Speaker 4: the first ring at the third position, there's a hydroxy
5:15
Speaker 4: molecule on virtually all of the stols, and that's what
5:19
Speaker 4: gives sterols their interesting physical a thing that makes it
5:26
Speaker 4: so functional in cell membranes. One side, the hydroxy side,
5:30
Speaker 4: is soluble in water, and the other side with that
5:33
Speaker 4: eight carbon tail, is lipiphilic. It's hydrophobic. So that's what
5:37
Speaker 4: we call an antipathic molecule. One side water soluble, one
5:41
Speaker 4: side lipid cyble. And that's why stols are particularly well
5:45
Speaker 4: positioned to align themselves between phospholipids and cell membranes. The
5:50
Speaker 4: hydroxy group sticks out and interacts with the water and
5:53
Speaker 4: the plasma, and the lipid n interacts with the lipids
5:56
Speaker 4: and the cell membrane or the cell structure in the
6:01
Speaker 4: same way. On the structure of lipoproteins stols, that's a unilayer,
6:05
Speaker 4: not a bilayer, but its sterols between phospholipids. So lnosterol
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Speaker 4: is the first stol that's going to become cholesterol, and
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Speaker 4: interesting evolution has given it two pathways from which to
6:20
Speaker 4: become cholesterol. The first many steps where citratee acetate becomes squaling,
6:28
Speaker 4: that's it. There's one pathway. But then linosterol and here's
6:31
Speaker 4: where lnosterol can go. There's two separate pathways, and the
6:36
Speaker 4: one which is the more common pathway. It is used
6:39
Speaker 4: primarily by all the peripheral cells in the body, goes
6:43
Speaker 4: through several more steps. But that what we call the
6:46
Speaker 4: penultimate next to the last sterol that through one further
6:50
Speaker 4: ensmetic action becomes cholesterol is lathosterol la thho strol. So,
6:58
Speaker 4: by the way, if we measure lithosterol in the blood
7:01
Speaker 4: stream and it's high, we know the cells that use
7:05
Speaker 4: that pathway are oversynthesizing cholesterol. That pathway, by the way,
7:10
Speaker 4: was discovered and it now carries the name of the
7:13
Speaker 4: two discoverers, the Tan Dutch Russell pathway. So not that
7:19
Speaker 4: anybody's ever heard of that, but I like to give
7:21
Speaker 4: credit to the geniuses who discovered these pathways. But there's
7:25
Speaker 4: another pathway that lenosterol can become cholesterol by, and it
7:30
Speaker 4: goes through several sterol intermediates. But the penultimate, the next
7:34
Speaker 4: to the last sterol that will become cholesterol is what
7:38
Speaker 4: we're talking about today. Does mosterol desmo sterol? And interesting
7:45
Speaker 4: that pathway is pretty much used by the brain and
7:49
Speaker 4: maybe in the adrenal cortical cells in the gonads. So
7:55
Speaker 4: in the periphery, does mosterol pathway by the way which
7:59
Speaker 4: is named the Block Pathway after Conrad Block, who actually
8:02
Speaker 4: got the Nobel Prize for discovering this pathway is kind
8:09
Speaker 4: of very important. So that's the Block pathway that goes
8:12
Speaker 4: through desmostral. Likewise, if I measured desmosterol in the blood,
8:16
Speaker 4: I have a handle on synthesis of cholesterol, but pretty
8:21
Speaker 4: much in the brain because in the periphery it's lithosterol.
8:26
Speaker 4: Now that testing is widely available, lithosterol and desmostral can
8:30
Speaker 4: be obtained at the Boston Heart Lab. Lab Core will
8:33
Speaker 4: do it if you request something called plasma sterols, but
8:36
Speaker 4: they ship it out to the Mayo Clinic for analysis,
8:40
Speaker 4: and of course if you have a relationship with the
8:42
Speaker 4: maoclinic the lab, they also will check sterols for you.
8:46
Speaker 4: If there are others, I'm not aware of them, but
8:48
Speaker 4: there is a nice direct to consumer method of getting
8:52
Speaker 4: desmosterol in me fosterol levels as well as the markers
8:56
Speaker 4: of absorption, which we're not talking about today. Those are
8:58
Speaker 4: the phidosterols. It's called empowered d X. If people google that,
9:05
Speaker 4: they'll go to their website. They send you a little
9:07
Speaker 4: mini test tubeno lansy. You prick your finger put a
9:11
Speaker 4: couple of drops of blood in the thing and ship
9:13
Speaker 4: it back to them, and they actually send that tube
9:16
Speaker 4: to the Boston Heart Lab for analysis, and that is
9:20
Speaker 4: probably the lab that's doing the most of these studies nowadays.
9:23
Speaker 4: And the developer of sterols, Ernie Schaeffer, is the director
9:29
Speaker 4: of that lab, and they're quite excellent at doing sterol concentrations.
9:34
Speaker 4: So the real reason to measure desmostol ethostel is we're
9:37
Speaker 4: looking for hypersynthesizers of cholesterol. Because if we see, hey,
9:42
Speaker 4: somebody's got a high ldol cholesterol or apo B andlethosterol
9:47
Speaker 4: and desmosterol or elevate it, I know, wow, I have
9:50
Speaker 4: to inhibit synthesis if I'm going to reduce apo B
9:54
Speaker 4: or LDO cholesterol. And of course that's where the statins
9:57
Speaker 4: or ben pedolic acid come into play, the two drugs
10:00
Speaker 4: that are available to us that inhibit cholesterol synthesis. So
10:05
Speaker 4: now that we understand this, we're going to pump up
10:08
Speaker 4: to the brain. Remember, the brain is separated from the
10:11
Speaker 4: plasma by that very tight blood brain barrier. That means
10:15
Speaker 4: lipoproteins carrying cholesterol cannot cross the blood brain barrier and
10:20
Speaker 4: deliver cholesterol to the brain. That's why when we aggressively
10:24
Speaker 4: lower ldol cholesterol in the plasma to reduce athros herotic events,
10:29
Speaker 4: we are influencing the brain to no degree. You can
10:33
Speaker 4: make the eldol cholesterol fifteen with some of the PCSK
10:37
Speaker 4: nine inhibitors and statins and it has no effect on
10:40
Speaker 4: brain function. They've done extensive studies checking that out, and
10:44
Speaker 4: that just tells you the cholesterol, being a maybe the
10:48
Speaker 4: most prominent molecule that is in the brain, is totally
10:52
Speaker 4: synthesized by brain cells because it cannot get cholesterol anywhere else.
10:57
Speaker 4: So the brain cholesterol syentis. This is a very interesting tale.
11:02
Speaker 4: It actually starts in utero and like the second and
11:05
Speaker 4: third trimester. Early on, it's moms cholesterol that is supplying
11:09
Speaker 4: the fetus with their cholesterol needs. But in that second
11:13
Speaker 4: and third trimester they're still getting mom's cholesterol, but they
11:16
Speaker 4: start making in themselves the little fetus. Of course, the
11:19
Speaker 4: second you're born, you're not getting moms cholesterol anymore. The
11:23
Speaker 4: brain has to synthesize all of the cholesterol, and the
11:27
Speaker 4: brain from the day you're born has a lot of
11:29
Speaker 4: growing still to do. In fact, it keeps growing until
11:33
Speaker 4: about the age of ten or very early adolescens. So
11:37
Speaker 4: up until that age from birth till so let's say ten,
11:41
Speaker 4: every cell in the brain is producing cholesterol very aggressively.
11:46
Speaker 4: But there's only a few cells in the brain. We
11:48
Speaker 4: have the neurons, pretty important cells, and a bunch of
11:52
Speaker 4: other cells that are grouped together called gliless and the
11:56
Speaker 4: two the glial cells that produce the cholesterol all are
12:02
Speaker 4: basically oligodendrocytes. Because cholesterol, that's the cell that makes myelin,
12:07
Speaker 4: which coats every axon and dendrite in your body. So
12:11
Speaker 4: throughout life, oligodendrocytes make the most cholesterol in the brain,
12:16
Speaker 4: but they use it by them cells to make myelin.
12:18
Speaker 4: They don't share it with the other cells in the
12:20
Speaker 4: brain to speak of, So the other cells would be
12:24
Speaker 4: the neurons and astrocytes. Now, up until age ten, both
12:28
Speaker 4: neurons and astrocytes are making a lot of cholesterol, and
12:32
Speaker 4: because the neuron needs a lot. The neuron works because
12:35
Speaker 4: of its functional cell membranes, and what are the two
12:39
Speaker 4: components of cell membranes, phospholipids and cholesterol, So the neuron
12:44
Speaker 4: absolutely has to have the proper amount of cholesterol. So
12:48
Speaker 4: up until age ten it's making it. But around that
12:51
Speaker 4: age the neuron says, I'm gonna stop making cholesterol. And
12:54
Speaker 4: here's why I've told you that over thirty step process
12:59
Speaker 4: of synthesized cholesterol. It's incredibly energy requiring. To synthesize one
13:05
Speaker 4: molecule cholesterol, it requires over thirty molecules of ATP, and
13:10
Speaker 4: the neuron doesn't want to waste ATP on making cholesterol
13:13
Speaker 4: because the neuron needs APT to make all its synapses
13:17
Speaker 4: fire off the impulses that make our body function, so
13:21
Speaker 4: it would rather conserve ATP and do what neurons do,
13:25
Speaker 4: generate action potentials. So once the neuron says I'm not
13:29
Speaker 4: making cholesterol anymore, it becomes the job of the astrocytes
13:33
Speaker 4: to make cholesterol and then ship it over to the neurons.
13:37
Speaker 4: And they do that not through the plasma. The neurons.
13:41
Speaker 4: All the glial cells they exist in brain interstitial connective
13:46
Speaker 4: tissue that is called the matrisome and they all life
13:50
Speaker 4: very close to each other. All these cells are pretty
13:52
Speaker 4: much touching each other. So if an astrocyte synthesizes cholesterol,
13:57
Speaker 4: it wraps it in a brain licoprotein, which has the
14:01
Speaker 4: buoyancy and density of a plasma HDL particle, except its
14:05
Speaker 4: protein is apoe, not apo a one as is on
14:09
Speaker 4: the HDLs in the plasma. So the neuron makes an
14:13
Speaker 4: APOEHDL particle, ships it into the a matrisome and it
14:17
Speaker 4: sort of floats over and goes to the neuron, and
14:20
Speaker 4: the neuron has receptors that can either internalize that particle
14:24
Speaker 4: getting cholesterol, or it can delipidate it using a different receptor,
14:28
Speaker 4: again getting the cholesterol it needs to function. So that's
14:34
Speaker 4: pretty much brain cholesterol synthesis. By the way, the half
14:37
Speaker 4: life of cholesterol molecule in the brain is five years.
14:41
Speaker 4: The half life in plasma is about three days. So
14:44
Speaker 4: this shows you the brain really conserves and reutilizes all
14:48
Speaker 4: of its cholesterol and then keeps synthesizing whatever it has to.
14:53
Speaker 4: But here's where the story comes back to desmosterol. The astrocyte,
14:58
Speaker 4: which in adults is producing most of the cholesterol that
15:01
Speaker 4: neurons are going to use, uses the block pathway through
15:04
Speaker 4: desmostral It does not use the can Dutch rustle pathway
15:08
Speaker 4: through lithosterol. So researchers who started to understand this. I
15:14
Speaker 4: think around twenty twelve comes the best study that's going
15:17
Speaker 4: to support what I'm about to espouse as a theory
15:21
Speaker 4: is that if the doesmostral is the marker we can
15:28
Speaker 4: measure for brain synthesis, can we prove that?
15:32
Speaker 2: And here's what they did.
15:34
Speaker 4: They had a bunch of patients, like one hundred of them,
15:36
Speaker 4: and they did spinal taps on everybody, and of course
15:39
Speaker 4: they drew blood in the plasma through the antracubital vein,
15:43
Speaker 4: and they checked asmostral in the spinal fluid, and they
15:46
Speaker 4: checked desmostral in the peripherallycoproteins that are floating around, and
15:51
Speaker 4: they have a high correlation. And that established the fact
15:55
Speaker 4: that we can actually measure desmosterol in the plasma and
15:58
Speaker 4: it tells us what's going on in the cerebral spinal fluid,
16:01
Speaker 4: which certainly tells us what is going on in the brain,
16:04
Speaker 4: because the brain and cerebral spunal fluid exchanged things all
16:08
Speaker 4: day long. So these researchers then went on and looked
16:13
Speaker 4: further and they said, oh my god, look what we've discovered.
16:17
Speaker 4: People who have low desmosterol builth in the cerebral spinal fluid.
16:22
Speaker 4: But equally so in the plasma are prone to cognitive impairment.
16:26
Speaker 2: And Alzheimer's disease.
16:28
Speaker 4: So Bingo they discovered a plasma biomarker that we can
16:33
Speaker 4: use to estimate somebody's risk for developing cognitive impairment or
16:38
Speaker 4: Alzheimer's disease. And that's important to know because there are
16:42
Speaker 4: many therapies you can introduce early in life, many of
16:47
Speaker 4: them lifestyles, some particular supplements that will probably less than
16:51
Speaker 4: the onset or delay the onset of Alzheimer's disease for
16:54
Speaker 4: those who are so prone to get it. We often
16:58
Speaker 4: checked APOE four genotype is a good way to see
17:02
Speaker 4: who's going to get Alzheimer's disease. But we can now
17:05
Speaker 4: add as amosterol to that list as a plasma biomarker.
17:09
Speaker 4: And if you ever have a patient who had a
17:11
Speaker 4: family history of dementia or they tell you i'm a
17:14
Speaker 4: little I'm not thinking right anymore, or people have noticed
17:18
Speaker 4: that of them, or for sure if they carry an
17:20
Speaker 4: apo E four or LEO, you might want to check
17:23
Speaker 4: dysmosterol as one of the tests to help you say, wow,
17:26
Speaker 4: I think there's something going on here and get them
17:29
Speaker 4: to people who are preventive neurologists and know what to
17:33
Speaker 4: do on this. So there's the other side of the
17:36
Speaker 4: story though too. Alzheimer's disease is related to too much
17:39
Speaker 4: cholesterol in the brain. When that neuron membrane starts to
17:43
Speaker 4: acquire extra cholesterol, that's when a lot of things go
17:49
Speaker 4: on interplay and they start producing amyloid beta and taal,
17:52
Speaker 4: which are too great biomarkers to tell us somebody is
17:56
Speaker 4: going to get Alzheimer's disease, and they are actually involved
17:59
Speaker 4: with the development of Alzheimer's disease. So this would at
18:03
Speaker 4: least raise to the theory that why, my god, if
18:06
Speaker 4: I'm worried about somebody getting Alzheimer's disease uh or strong
18:11
Speaker 4: family history apoe four leos blah blah blah, maybe I
18:14
Speaker 4: want to lower brain cholesterol a little bit, so then
18:18
Speaker 4: neuron does not get cholesterol toxicity. Now, how can we
18:22
Speaker 4: lower cholesterol synthesis in the brain. Well, we do have
18:26
Speaker 4: a lot of cholesterol lowering drugs that we use to
18:28
Speaker 4: lower cholesterol in the plasma, but of all of them,
18:31
Speaker 4: only one can cross the blood brain barrier, and that
18:34
Speaker 4: is statins. And forget the lipophilic hydrophilic stuff. Yes, a
18:41
Speaker 4: lipophilic might get in a little easier than hydrophilic, But
18:44
Speaker 4: if you're on a statin that's in steady state, they
18:47
Speaker 4: all get in. I mean, if you take one statin today,
18:51
Speaker 4: resume statin hydrophilic, and another tomorrow a sembustat the stemba
18:55
Speaker 4: statin will get in quicker if you look at those
18:57
Speaker 4: type of pharmacokinetics. But if we're looking at steady state,
19:00
Speaker 4: you're on a statin, you to a certain degree are
19:03
Speaker 4: going to inhibit cholesterol synthesis in the brain. And since
19:07
Speaker 4: Alzheimer's is becoming an epidemic and so many people are
19:11
Speaker 4: getting it and other types of dimension cognitive impairment, it
19:14
Speaker 4: actually makes perhaps a little sense to somewhat lower cholesterol.
19:18
Speaker 2: Synthesis in the brain.
19:20
Speaker 4: We have numerous statin trials done over time, got thirty
19:24
Speaker 4: of them, and some of them have actually looked never
19:27
Speaker 4: as a primary outcome but secondary outcomes. Do statins help cognition?
19:34
Speaker 4: And if you do a meta analysis of those studies
19:38
Speaker 4: that actually looked at at least some feature of cognitive impairment,
19:42
Speaker 4: the conclusion is statins are null on Alzheimer's disease. They
19:46
Speaker 4: don't hurt anybody or cause Alzheimer's disease. So anybody spouting
19:50
Speaker 4: that on the internet reject them because there's no evidence
19:53
Speaker 4: that that is true. But there are actually where a
19:55
Speaker 4: few studies that suggested statins do improve the development or
19:59
Speaker 4: less in the development of Alzheimer's disease and cognitive impairment,
20:03
Speaker 4: which would make sense if hey, we do lower cholesterol
20:07
Speaker 4: synthesis a little bit, and somebody who Alzheimer's is a
20:10
Speaker 4: disease of too much cholesterol in the cell membrane, That
20:13
Speaker 4: at least makes sense.
20:15
Speaker 2: It's a good theory right now.
20:18
Speaker 4: But then I raised the theory that that's great, but
20:21
Speaker 4: what if somehow we over suppress the synthesis of cholesterol
20:27
Speaker 4: in the brain, with the caveat that the brain only
20:31
Speaker 4: can get cholesterols through synthesis. So I think it's certainly
20:36
Speaker 4: plausible that we do not want to suppress cholesterol synthesis.
20:40
Speaker 2: In the brain.
20:41
Speaker 4: And this is where monitoring desmosterol might be come into play.
20:45
Speaker 2: Now, this is.
20:46
Speaker 4: Totally a theoretical supposition. Now nobody's done a trial to say, geez,
20:51
Speaker 4: what Tom is saying now is absolutely true. But we
20:54
Speaker 4: certainly know as mosterl in the CSF or the plasma
20:57
Speaker 4: is a mile marker of Alzheimer's disease. We know too
21:01
Speaker 4: much cholesterol causes or degenerates the things that cause Alzheimer's disease.
21:07
Speaker 4: At least some of the statin data suggests lowering it
21:10
Speaker 4: a bit is going to help some people. But what
21:13
Speaker 4: about lowering does moosterol too much? Then I go back
21:16
Speaker 4: to that study that says low does mostral is causing
21:20
Speaker 4: cognitive impairment in Alzheimer's disease, or is at least associated
21:24
Speaker 4: with it.
21:25
Speaker 2: So I come up with the theory, maybe we do not.
21:28
Speaker 4: Want to oversuppress cholesterol synthesis in the brain. And the
21:32
Speaker 4: number one drug, of course, that can do that is
21:35
Speaker 4: statin therapy. Now listen, this is why I believe it's
21:39
Speaker 4: good to check desmostrol before you start statin therapy, because
21:44
Speaker 4: say you came to me and I know, oh my god,
21:46
Speaker 4: you got a high apo B or something. We got
21:47
Speaker 4: to get you on a statin. But I want to
21:50
Speaker 4: check your both apoe and your desmosterol level at baseline,
21:55
Speaker 4: and if at baseline, well you're not on a stat
21:58
Speaker 4: in your desmosterol is low, especially if you're an apo
22:02
Speaker 4: E four carrier, I know you're heading down the wrong role,
22:06
Speaker 4: and if I have to lower apo B in that patient,
22:09
Speaker 4: maybe I'm going to choose one of the other drugs,
22:12
Speaker 4: none of which do anything to cholesterol synthesis of the brain.
22:15
Speaker 4: Is that in my bempidolic acid PCSK nine inhbitors some
22:19
Speaker 4: other drugs that are soon to come. So this is
22:23
Speaker 4: a nice theory area that goes on to it. Now,
22:26
Speaker 4: what if you're already on a statin as millions of
22:30
Speaker 4: people are, and they should be because you have to
22:32
Speaker 4: lower apo B. So it's the most widely used. At
22:36
Speaker 4: least the initial drug combination therapy is becoming more common,
22:40
Speaker 4: but the vast majority of clinicians do start with statin therapy.
22:45
Speaker 4: And fine, I got no problems with that, and you're
22:47
Speaker 4: going to see if it works. In a couple of months,
22:49
Speaker 4: you're going to repeat the apo b LDO cholesterol non
22:52
Speaker 4: HDL cholesterol and sees the statin working. But I would
22:56
Speaker 4: suggest at the same time you might want to repeat
22:58
Speaker 4: the desmosterol level even if you do not have a
23:01
Speaker 4: baseline desmosterol, and if on the statin the desmosterol has
23:06
Speaker 4: dropped a low the twentieth percentile, and that would be
23:10
Speaker 4: zero point eight milligrams per leader. If you use these
23:13
Speaker 4: labs that I spoke about, perhaps you have over suppressed
23:17
Speaker 4: cholesterol synthesis.
23:18
Speaker 2: In the brain.
23:19
Speaker 4: And with the information we at least notice studying, linking
23:23
Speaker 4: it to AD is pretty solid. But my theory is
23:27
Speaker 4: if you're lowering desmosterol a marker of brain cholesterol synthesis
23:32
Speaker 4: with a stat and you are likely oversuppressing cholesterol synthesis
23:36
Speaker 4: in the brain, and that's probably not good. Just the
23:41
Speaker 4: theory at the present time, but no other theories, and
23:44
Speaker 4: with the information at load, desmostrol is not a good
23:47
Speaker 4: marker to have, I think it's wise that if on
23:51
Speaker 4: a follow up you see you've suppressed desmosterol too much
23:55
Speaker 4: to perhaps use some of the other APO B lowering therapies. Now,
23:59
Speaker 4: if you jumped in with a high potency statin as
24:03
Speaker 4: many people are nowadays a guideline suggest, and you really
24:08
Speaker 4: suppressed as mostral, maybe you could start reducing the dose
24:12
Speaker 4: of the statin, and on a subsequent blood test, see
24:15
Speaker 4: have you still over suppressed as mostral If you have,
24:18
Speaker 4: keep reducing the dose. Now, you might say, but wait
24:21
Speaker 4: a minute LDL cholesterol or apo B is going to
24:24
Speaker 4: go up. So what then you add a zetimibe empedoic
24:27
Speaker 4: acid or if it's a really nightmare, PCSK nine to
24:31
Speaker 4: the regimen and you can get apo B under control
24:34
Speaker 4: with having no influence on brain cholesterol synthesis. So this
24:39
Speaker 4: is pretty much the whole theory that I put together.
24:43
Speaker 4: Going on with this with the low des mostrol. But
24:46
Speaker 4: I want to end this little speech of mind. What
24:49
Speaker 4: about is it possible to increase dos mostrol in the
24:57
Speaker 4: certainly the cerebral spinal fluid, the brain, or in the plaza,
25:00
Speaker 4: but where we're measuring it And the answer is yes.
25:03
Speaker 4: So to show you why low des mostral is no good,
25:07
Speaker 4: I just explained that. But should we also be worried
25:09
Speaker 4: if for some reason a person has high des mostral?
25:13
Speaker 4: And yes, yes, yes we should. And here's the data.
25:17
Speaker 4: And nobody knows this except geeks like me who've gone
25:20
Speaker 4: back and studied everything ever done at cholesterol. So most
25:24
Speaker 4: people don't know. What is the first drug that got
25:27
Speaker 4: FDA approval to be used by clinicians to lower cholesterol
25:32
Speaker 4: nineteen fifty nine. Even I was like in starting high
25:36
Speaker 4: school lens. I was not aware of this study then,
25:39
Speaker 4: but I've since gone back and visited when I wound
25:42
Speaker 4: up as a lipidologist. So Merk developed a generic drug
25:47
Speaker 4: called triparanol trip A R A n O L. And
25:51
Speaker 4: the brand name it was actually like I believe, the
25:55
Speaker 4: twenty ninth drug they ever invented. So they called it
25:58
Speaker 4: Merk for merk Are twenty nine, and the FDA let
26:03
Speaker 4: it come on the market because Merk showed, hey, it
26:05
Speaker 4: mower's cholesterol and they pretty much were just measuring LDL
26:09
Speaker 4: cholesterol in those days. You know, there was no ldol
26:15
Speaker 4: cholesterol biomarker of available then, so they showed at lower
26:19
Speaker 4: total cholesterol and the FDA said okay, and they you know,
26:23
Speaker 4: and there I don't even think the FDA asked for
26:25
Speaker 4: any adversity studies like they would for today. And back
26:29
Speaker 4: in fifty nine, you didn't need to come with an
26:31
Speaker 4: outcome trial showing your drug works. All you had to
26:33
Speaker 4: do was show it improved a bad biomarker total cholesterol.
26:38
Speaker 2: All right.
26:39
Speaker 4: And then all of a sudden, about two to three
26:41
Speaker 4: years later, Merk, because they knew the FDA was gonna
26:45
Speaker 4: yanke it, told it from the market because they were
26:47
Speaker 4: starting to see adversity. And the adversity number one was
26:51
Speaker 4: the development of cataracts and number two was actually increased
26:56
Speaker 4: carnary artery disease and some other morbidities also. So how
27:00
Speaker 4: in the world did that happen? Well, how did the
27:03
Speaker 4: drug triparanol lower cholesterol? So remember desmosterol becomes cholesterol, there's
27:11
Speaker 4: one enzyme that converts it. It's called DHCR twenty four
27:15
Speaker 4: dehydro cholesterol reductase, and it reduces the double bond at
27:19
Speaker 4: the twenty fourth carb and that's where the twenty fourth
27:22
Speaker 4: and that's in that eight member tail. So now, if
27:28
Speaker 4: you are preventing desmosterol from becoming cholesterol, you're going to
27:32
Speaker 4: reduce cholesterol in the blood. Yay, But wait a minute,
27:35
Speaker 4: what might you be increasing dramatically in the blood? Does
27:39
Speaker 4: moosterol because it's got nowhere to go, it becomes the
27:43
Speaker 4: a predominant sterol in these people, and it's all of
27:46
Speaker 4: a sudden, not cholesterol going into the cell membranes, it's
27:50
Speaker 4: doesmosterol and doesmosterol causes dysfunctional membrane activity. You need your
27:56
Speaker 4: membranes want cholesterol. That's what they're designed through evolution to
28:01
Speaker 4: work with. They don't want other star rolls in there,
28:04
Speaker 4: and that's why desmostrol turned out to be bad news.
28:08
Speaker 4: And I guess the first tissues it impaired is catat
28:11
Speaker 4: the eye, so cataracts, the epithelium over the lens started
28:16
Speaker 4: to get screwed up. So we've known since then and
28:21
Speaker 4: it got yanked because that was nineteen fifty nine nineteen
28:25
Speaker 4: sixty two. Nobody ever is taught about triparanoil anymore, and
28:29
Speaker 4: nobody has ever heard of it except researchers like myself
28:33
Speaker 4: have gone back trying to understand cholesterol and all of
28:37
Speaker 4: the drugs that puts with cholesterol, and you stumble across
28:40
Speaker 4: that if you go back and start to review it.
28:43
Speaker 4: So it's amazing that's basically being hidden from modern cholesterol teaching,
28:47
Speaker 4: and it shouldn't be. So now all we have to
28:50
Speaker 4: worry about is God, is there anything today that can
28:54
Speaker 4: raise desmostral in the blood, because it's inhibiting DHCR twenty four.
28:59
Speaker 4: It's causing by the way, if you have genetic total
29:02
Speaker 4: loss of function of DHCR twenty four, those little babies
29:08
Speaker 4: either die in utero because they can make very little
29:11
Speaker 4: cholesterol in their brain, and they are if they don't
29:15
Speaker 4: die in utero, they are born with severe neurologic impairment
29:19
Speaker 4: and they die pretty early in life. That disease is
29:22
Speaker 4: called desmosterolosis. Now they have massive increases in desmosterol because
29:27
Speaker 4: they can't change any desmostrol for cholesterol. The drugs that
29:32
Speaker 4: we now are aware of that can increase desmostol, they
29:36
Speaker 4: only partially inhibit that enzyme, so they don't totally shut
29:40
Speaker 4: down cholesterol production, and they don't send desmostrol through the roof,
29:45
Speaker 4: but they send it pretty high enough that once we
29:48
Speaker 4: know desmostral can cause cataracts and perhaps other morbidities. If
29:54
Speaker 4: you're going to take a drug that does that, you
29:56
Speaker 4: better take it transiently and not chronically, so you're walking
30:00
Speaker 4: around with high desmosterone. And the most common drug that
30:04
Speaker 4: does that is a drug that's used for a lot
30:06
Speaker 4: of things, sometimes transiently but unfortunately sometimes long term, and
30:11
Speaker 4: it's clomathene. Of course, clomaphine is used in reproductive endrochronology
30:16
Speaker 4: to help fertility in everything, but that's a transient use.
30:20
Speaker 4: I don't think you're going to give any mom trying
30:21
Speaker 4: to get pregnant cataracts because you're raising clomaphine for a
30:25
Speaker 4: few months or whatever you're doing it for. But what
30:28
Speaker 4: is colomafine also used? Especially in men who have gonatlin
30:33
Speaker 4: sufficiency low testosterone, they're prescribed various types of testosterone, but
30:38
Speaker 4: they're often given clomaphine which enhances the testosterone level and
30:42
Speaker 4: they stay on it chronically. So, believe it or not,
30:47
Speaker 4: the drugs that manufacture clomaphine nowadays have been advised to
30:53
Speaker 4: they FDA wants a reporting on they have to follow
30:57
Speaker 4: up with cataract development in their patients. So if anybody
31:02
Speaker 4: is using cloma theme chronically, and pharmacists are the best
31:06
Speaker 4: to know that because they're filling NIP scripts all the time,
31:09
Speaker 4: they might at least want to mention do some research
31:12
Speaker 4: on elevate it does mostrol caused by cloma theme and
31:17
Speaker 4: cataracts is going to be the first possibility. I would
31:20
Speaker 4: contend that if they did it long enough, they're going
31:23
Speaker 4: to get other morbidities related to cell membranes, red blood
31:27
Speaker 4: cell cell membranes, possibly anemias. So that's the desmostral story
31:33
Speaker 4: in a nutshell. You can whip questions at me to
31:36
Speaker 4: try and unconfuse what I've said.
31:39
Speaker 3: Oh, I think you did a great job explaining. I
31:41
Speaker 3: think cholesterol in the brain is so fascinating to me.
31:45
Speaker 3: In the fact that we can now measure does mostral
31:49
Speaker 3: and the periphery and I'll correlate to does mostral levels
31:52
Speaker 3: in the brain. What a gift for us to be
31:54
Speaker 3: able to have that and use that in our practice.
31:56
Speaker 3: And so I just wanted to say this because when
31:59
Speaker 3: I I first got my does moosterol levels from the
32:02
Speaker 3: Boston Heart Lab, they can kind of report it goofy,
32:05
Speaker 3: But what you want to look at is the absolute value.
32:09
Speaker 3: And so that's what you've taught me. Look at the
32:11
Speaker 3: absolute value when you look at the report of does
32:14
Speaker 3: MOSTERL levels, and too low would be anything less than
32:18
Speaker 3: zero point eight milligrams per leader, and right now we
32:21
Speaker 3: would define too high as greater than one point five
32:24
Speaker 3: milligram per dest leader. Looking at the trails and the
32:27
Speaker 3: data that we currently have.
32:30
Speaker 4: Let me just mention that was a great point for
32:32
Speaker 4: people who are going to get the Boston Heart Lab,
32:35
Speaker 4: either because they use that or they go through that
32:37
Speaker 4: empowered DX and get the Boston Heart Lab. Boston Heart
32:41
Speaker 4: Lab reports STUO concentrations via two methodologies. Well, the methodology
32:46
Speaker 4: is same, it's liquor chromatography mass spectrometry, but they report
32:50
Speaker 4: the results as a ratio of this STOL level in
32:54
Speaker 4: this case does mostral to total cholesterol, and they call
32:58
Speaker 4: that the normalized value. But also, and you got to
33:02
Speaker 4: look at the right side of the report form, you
33:04
Speaker 4: will see a column that says absolute concentrations, and that's
33:07
Speaker 4: where you'll see the concentrations. You just elaborate it. Here's
33:11
Speaker 4: the problem with the ratio. That's basically a tool for
33:15
Speaker 4: epidemiologists who want to compare groups of people, and this
33:18
Speaker 4: way you're adjusting for something that both groups might have.
33:22
Speaker 4: But imagine, if you're on a lipid lowering drugs, you're
33:25
Speaker 4: going to lower total cholesterol significantly, and that screws up
33:28
Speaker 4: that total ry because you're not the lipid drugs aren't
33:31
Speaker 4: doing much that it does nosterol. So the ratio becomes
33:34
Speaker 4: goofy and you'll see nice color bars in their report,
33:38
Speaker 4: which are color bars representing the normalized ratio. So I
33:42
Speaker 4: always advise pay people to ignore the color bars, ignore
33:47
Speaker 4: the ratio, and skip over to look to the absolute concentration. Now,
33:54
Speaker 4: the bad news is bosston does not tell you an
33:57
Speaker 4: absolute concentration. Is it at the twentieth thirtieth, fortieth eightieth percentile?
34:02
Speaker 2: You have to have that data.
34:04
Speaker 4: I've tweeted it out and put it on LinkedIn many times.
34:07
Speaker 4: You have it, maybe you could share it. Maybe I'll
34:10
Speaker 4: post it again today on x so people who are
34:13
Speaker 4: listening to this podcast can print it out. It's just
34:17
Speaker 4: a nice color table and you will see all the
34:19
Speaker 4: values of the desmostl in the lithosterol, the lithosterol you
34:24
Speaker 4: use for evaluating peripheral cholesterol synthesis, and that can actually
34:30
Speaker 4: tell you how is the statin working because you should
34:32
Speaker 4: see a nice suppression of lithosterol. And there's no worries
34:36
Speaker 4: suppressing cholesterol synthesis in the peripheral cells because even if
34:40
Speaker 4: you did reduce plasma cholesterol, every cell in the body
34:44
Speaker 4: can make all the cholesterol it needs, so you're not
34:46
Speaker 4: screwing up any cells by lowering litosterol too much or
34:50
Speaker 4: altering peripheral cholesterol synthesis. But we have a big study
34:55
Speaker 4: that lowering doesmosterol in the brain, or having low desmostol
34:59
Speaker 4: in the brain, it is a biomarker of ad incognitive impairment.
35:04
Speaker 4: So you got to understand how to interpret every blood
35:07
Speaker 4: test you get back. Your podcast goes out to pharmacist too,
35:12
Speaker 4: so I want to warm them. You guys and galas
35:15
Speaker 4: can be looking at this, but understand. I would say
35:18
Speaker 4: ninety nine percent of physicians in America are unaware of
35:22
Speaker 4: cholesterol synthesis and the biomarkers of cholesterol synthesis. And if
35:27
Speaker 4: you tell a patient maybe your doc should measure des mosterol,
35:31
Speaker 4: you might get an angry call from the doc. Stop
35:34
Speaker 4: telling my patients things that I don't know about. And
35:37
Speaker 4: then that's why it's good to have some of the
35:39
Speaker 4: references around that you can share.
35:41
Speaker 3: Yeah, that happened. I mean with my own dad because
35:43
Speaker 3: he was started on a stat and for his high
35:45
Speaker 3: CAx score and him and I both have high lightfel
35:48
Speaker 3: protein little A and I asked his cardiologist if he
35:52
Speaker 3: would measure des mosterol and they weren't happy with me.
35:56
Speaker 3: They called me the helicopter daughter. I'm going to get
36:00
Speaker 3: checked anyway, because I don't want him to get you know,
36:03
Speaker 3: cognitive decline from being on a statin and he needs
36:06
Speaker 3: to be on you know, lipid lurering medication because of
36:10
Speaker 3: his high CAC and his lipoprotein little ad but I
36:13
Speaker 3: would like to keep his desmosterol between point, what.
36:16
Speaker 4: Is the harm of checking this and then being at
36:19
Speaker 4: least aware of the data. I think you can make
36:21
Speaker 4: your own decision, but at least knowing we don't necessarily
36:25
Speaker 4: need statins to lower cholesterol.
36:27
Speaker 2: We have several good.
36:29
Speaker 4: Other drugs, and even if you had to make the
36:31
Speaker 4: case for a more potent one with a third party payer,
36:34
Speaker 4: basically that's a statin intolerance if you're lowing this moosterol,
36:38
Speaker 4: which might qualify you for other type drugs to ben Oh.
36:41
Speaker 3: Yeah, that's a great point with the prior off paperwork.
36:44
Speaker 3: So yes, and I wanted to say too. I started
36:48
Speaker 3: rosuvastatin about three months ago. My does mosterol levels went
36:52
Speaker 3: from the fiftieth percent out to the fourtieth percentile, but
36:55
Speaker 3: we're still above point eight. So I'm happy with that.
36:58
Speaker 3: I'm happy that you've trained my physician to monitor.
37:02
Speaker 4: Yeah, regardless of what your risk for Alzheimer's disease is,
37:07
Speaker 4: lowering your cholesterol in the brain a little bit it
37:10
Speaker 4: is probably good because too much cholesterol in the neurons
37:14
Speaker 4: is a precursor of you're gonna get neuronal injury as
37:19
Speaker 4: time goes on.
37:21
Speaker 3: Right, So we talked about stantons and how they can
37:23
Speaker 3: lower it as mosterral. We've talked a little bit about
37:25
Speaker 3: chlomaphine and how they can increase does mosterol. What are
37:29
Speaker 3: some other commonly prescribed medications that can either lower or
37:33
Speaker 3: increase does mosterol levels.
37:36
Speaker 4: The one that can be involved with as mosterol is trazodone.
37:43
Speaker 4: It's the use for depression or for sleep that can
37:46
Speaker 4: also screw up as mosterol and even litosterol because they've
37:50
Speaker 4: checked that in the brain on some people, the people
37:54
Speaker 4: who did the study.
37:55
Speaker 2: With that drug. So that's another one you want to
37:58
Speaker 2: keep an eye on it.
37:59
Speaker 4: Or so and see what's happening to desmosterol and in
38:03
Speaker 4: the checking latosterol in the peripheral because trazodone in the
38:08
Speaker 4: study was reported and I think it was autopsy studies
38:11
Speaker 4: where they could measure tresdone in the brain tissue. Checking
38:16
Speaker 4: ltosterol in the periphery tells you nothing about the brain
38:19
Speaker 4: because ninety five percent of it is coming from peripheral cells,
38:23
Speaker 4: whereas desmosterol, most of it is coming from the brain cells.
38:27
Speaker 4: So that's why latosterol doesn't become that useful other than hey,
38:31
Speaker 4: the stat in is working because it's lowering litosterol and
38:33
Speaker 4: the liver and where I wanted to But it's the
38:37
Speaker 4: desmosterol that tells us about going on the brain. So
38:40
Speaker 4: that's the other drug where that is more commonly used,
38:45
Speaker 4: and you know it's used for a lot of reasons.
38:50
Speaker 4: You know, sleep and depression.
38:54
Speaker 3: Two of the medication or medication classes. I was surprised
38:57
Speaker 3: to see on that you sent over a nice report
38:59
Speaker 3: which I will attached to the show notes, but they
39:02
Speaker 3: mentioned antipsychotic medications such as erapippersol, halo paradol, and then
39:07
Speaker 3: they also mentioned some commonly prescribed beta blockers such as metaprolol.
39:12
Speaker 3: So how do those affect does MONSTERL levels?
39:14
Speaker 4: I have no idea, but since they've done the studies
39:19
Speaker 4: and they've checked the levels and a lot of people
39:21
Speaker 4: on a lot of drugs, I would suggest if you've
39:24
Speaker 4: got a load as mostral level back, remember I told
39:26
Speaker 4: you please, if possible, check it before you start a
39:30
Speaker 4: statin and it's low there, you know they're at risk
39:33
Speaker 4: for ad But then you want to pull that article
39:35
Speaker 4: and start, oh, you're on this drug, so maybe we
39:39
Speaker 4: have to play with that drug if possible or so.
39:41
Speaker 4: So I think it's a very useful reference to keep
39:44
Speaker 4: around because the list is long. It's easy for me
39:47
Speaker 4: to tell you how the lipid modulating drugs do it,
39:50
Speaker 4: but how these other drugs do it. Whether it's true
39:53
Speaker 4: agenrsic effects with a beta blocker that's somehow affecting the
39:58
Speaker 4: production of it in the brain, I don't know.
40:00
Speaker 2: You know, there's another.
40:01
Speaker 4: Biomarker which unfortunately we can't get. Evolution new Too much
40:06
Speaker 4: cholesterol in the neurons is bad news. So the evolution
40:10
Speaker 4: actually gave the neurons an enzyme that no other glial cell,
40:14
Speaker 4: including astrocytes, have, and it converts cholesterol to an oxysterol
40:20
Speaker 4: called twenty four S hydroxy cholesterol. That means it not
40:25
Speaker 4: only has a cholesterol at the third carbon, as all
40:28
Speaker 4: sterols do, it has a hydroxy molecule on the twenty
40:31
Speaker 4: fourth carbon. And that's these oxysterols are actually basically they're bioacids.
40:37
Speaker 4: Free cursors deliver makes changes cholesterol into oxysterols, and they
40:43
Speaker 4: go through several other steps and become a bioacid, which
40:46
Speaker 4: then becomes a biosal. So the brain is actually creating
40:50
Speaker 4: like early biosals. And because it has a hydroxy group
40:55
Speaker 4: on each end of the molecule, it's actually a hydrophilic
40:59
Speaker 4: lipid molol. Very unusual. So when the neuron changes cholesterol
41:05
Speaker 4: to twenty four S hydroxy cholesterol, it can pass through
41:09
Speaker 4: the neuron cell membrane into the matrosome, and it can
41:12
Speaker 4: pass right through the blood brain barrier where it jumps
41:15
Speaker 4: on an albumin that's cruising by or a lipoprotein that's
41:19
Speaker 4: cruising by, and they bring that oxysterol to the liver,
41:23
Speaker 4: which says, hey, thank you for supplying with you with
41:26
Speaker 4: some bioacid precursors, and it changes them into bio acids
41:29
Speaker 4: and they get excreted in the bio and efeically if
41:32
Speaker 4: the body so desires that. So I kind of laugh. Hey,
41:36
Speaker 4: nobody knew the brain cells are connected to the small intestine,
41:40
Speaker 4: but they are. And the neuron is the only cell
41:44
Speaker 4: that contains the enzyme that converts cholesterol to twenty four
41:50
Speaker 4: S hydroxy cholesterol. Now, in research studies, people doing neurologic
41:55
Speaker 4: studies always measure twenty four S hydroxy cholesterol because if
41:59
Speaker 4: it's your plasma and that's where they're measuring it, of
42:02
Speaker 4: course the only source is the brain. Other cells don't
42:05
Speaker 4: make twenty four S hydroxy cholesterol, so it's a good marker.
42:10
Speaker 4: And if it's high in the blood, it tells you
42:13
Speaker 4: the brain has too much darn cholesterol and the neuron
42:15
Speaker 4: is trying to get rid of it. So that's another
42:18
Speaker 4: biomarker that is used as it's a precursor of Alzheimer's
42:23
Speaker 4: disease too, because it's an indication the neuron has too
42:26
Speaker 4: much cholesterol. Now interesting statins which slow the synthesis of
42:31
Speaker 4: cholesterol in the brain. Therefore, the astrocytes will make less cholesterol,
42:36
Speaker 4: ship less cholesterol to the neurons, the neurons will stop
42:40
Speaker 4: making twenty four S hydroxy cholesterol. So a good biomarker.
42:45
Speaker 4: If you test it twenty four S hydroxy cholesterol in
42:48
Speaker 4: the plasma and it's high, you worry. But if all
42:51
Speaker 4: of a sudden it goes down, you say, I'm probably
42:54
Speaker 4: helping that patient. But then I would tell you go
42:57
Speaker 4: back and make sure you didn't lower it desmosterol because
43:01
Speaker 4: you've over yes, twenty four S hydroxic cholesterol will be low,
43:05
Speaker 4: but that's because you've over suppressed cholesterol synthesis. So I
43:09
Speaker 4: wish we could actually get both of those biomarkers, because
43:12
Speaker 4: then we would have even a more thorough analysis of
43:16
Speaker 4: cholesterol homeostasis in the brain. Right now, it's a research tool,
43:20
Speaker 4: and maybe one day it'll become available, but I don't know.
43:25
Speaker 4: It would take a lot of studies. Labs don't want
43:27
Speaker 4: to do it because they can't get reimbursed for doing it,
43:30
Speaker 4: So that's your problem.
43:32
Speaker 3: Sure, So yes, as far as does mosterol goes? One
43:37
Speaker 3: thing I did want to point out is the lowering
43:40
Speaker 3: or probably increasing is dose dependent. So it doesn't mean
43:44
Speaker 3: if you're on a STAT and does mostral goes too low,
43:46
Speaker 3: it doesn't mean you have to stop it. You can
43:48
Speaker 3: lower it and then recheck does mosterol levels and see
43:51
Speaker 3: where they're at, And then if they are still low
43:54
Speaker 3: and you're on the lowest dose, yeah, maybe it's time
43:56
Speaker 3: to stop the STAT and go to a PSK nine
43:58
Speaker 3: inhibitor or something else. But it is dependance. I think
44:00
Speaker 3: that's one thing for pharmacists to keep in mind. Like
44:03
Speaker 3: most side effects are don't repentant, you know, and then
44:07
Speaker 3: one other thing I wanted, Well, I have two more questions.
44:10
Speaker 3: What is have you noticed a difference in does moster
44:13
Speaker 3: all lowering? I know we talked a little bit about
44:15
Speaker 3: hydrophilic lip both feel extents, but does say a torvostat
44:18
Speaker 3: and lower that? Does moster all a little more than
44:20
Speaker 3: we're all subastatin? Or haven't you seen that? In practice?
44:24
Speaker 4: There's no studies on it that I know of, so
44:27
Speaker 4: in practice it would be anecdotal data.
44:30
Speaker 2: So and I've never.
44:32
Speaker 4: Kept track of people who are on the various drugs
44:35
Speaker 4: with respected Maybe I should have in retrospect, but it
44:38
Speaker 4: would still be anecdotal data of lipid profiles. I'm on
44:43
Speaker 4: patients I've been involved with, or lots of docs are
44:46
Speaker 4: always sending me, hey, here's what went on with my patients,
44:50
Speaker 4: And they those who follow me are starting to check
44:54
Speaker 4: that a lot. But now, so I can't answer that question.
44:56
Speaker 4: I believe once they're in steady state, they're all going
44:59
Speaker 4: to to suppress cholesterol synthesis in the brain. Yes, if
45:03
Speaker 4: I had two people and I'm doing a single dose
45:07
Speaker 4: pharmakinetic study, the reserve of might getting quicker and you
45:12
Speaker 4: might start a suppressed cholesterol synthesis sooner than the ATRBN does.
45:16
Speaker 4: But once you're on it for a couple of weeks,
45:18
Speaker 4: I think you're suppressing cholesterol synthesis in the brain, so
45:22
Speaker 4: I don't Again, there's no all of the statin studies
45:26
Speaker 4: that have looked at a where they're either no on
45:30
Speaker 4: cognition or a lower that they You know, you might
45:33
Speaker 4: have to go back and look at which statin was
45:35
Speaker 4: used in that study, But you're all you're going to
45:37
Speaker 4: see is that stat and improve dementia. Remember, and you
45:41
Speaker 4: know this, and I think pharmacists know it. A lot
45:44
Speaker 4: of people who start statins come back and they might
45:47
Speaker 4: first complain to the pharmacists before they complain to the duck.
45:51
Speaker 4: Since I started this statin, I'm not thinking right. I
45:54
Speaker 4: can't add as well as I used to. I'm confused.
45:57
Speaker 4: That's called brain fog. It's actually listed as a minor
46:00
Speaker 4: side effect in the package inserts. And my total theory
46:04
Speaker 4: is those are the people that are super sensitive to statins,
46:07
Speaker 4: or maybe they got way too big of those of
46:09
Speaker 4: the stand and you really oversuppressed cholesterol synthesis right away
46:13
Speaker 4: in those people. Now, most people don't get the brain
46:17
Speaker 4: fog when they start a stand. But my worry would
46:19
Speaker 4: be Okay, they're feeling great on their stand. But if
46:23
Speaker 4: for years upon years they're desmostral, they're cholesterol synthesis in
46:28
Speaker 4: the brain is low. Uh oh, what is the long
46:31
Speaker 4: term ramifications of that? Again, just I'm theorizing things. And
46:35
Speaker 4: that's why even if the patient says, oh, I'm anasymptomatic
46:39
Speaker 4: my brain is working, well, I'm taking this stat and
46:41
Speaker 4: a stand that the big dose, whatever dose, I would
46:45
Speaker 4: like to also follow desmostral. Why do we follow lipids,
46:49
Speaker 4: carnage diseases and asymptomatic disease. We don't wait and say,
46:52
Speaker 4: get the heart attack and then we'll decide whether the
46:54
Speaker 4: stat and we were using with good or not. We
46:56
Speaker 4: follow biomarkers to judge the statfficacy. Well, now we have
47:01
Speaker 4: a plausible biomarker to perhaps follow brain health in our patients.
47:06
Speaker 4: And with the epidemic of Alzheimer's disease, why not you know,
47:12
Speaker 4: all it takes is yeah, you're going to confuse a
47:14
Speaker 4: lot of people, but they don't have to read twenty
47:17
Speaker 4: two articles on this. There's a handful of articles in
47:20
Speaker 4: just a one big study at least telling its low
47:22
Speaker 4: des mosterol is bad. So I think it'd be a
47:25
Speaker 4: great research study for somebody to do, even in a
47:28
Speaker 4: small cohort of people on various stands or on any
47:32
Speaker 4: stands at different doses. I'll bet well the stating trials,
47:36
Speaker 4: the blood still exists, they could go back and measure
47:38
Speaker 4: does moosterol in their bloods and see what nobody's going
47:42
Speaker 4: to do that probably, but look that those are all
47:45
Speaker 4: they're generic. That that is available now, I think it'd
47:48
Speaker 4: be a great research project for somebody to go and die.
47:51
Speaker 3: I agree, I would love to read it. So Okay,
47:54
Speaker 3: as far as lifestyle modifications and does moster al levels,
48:00
Speaker 3: what do we know about do we know anything about that?
48:02
Speaker 3: If you get a baseline dosmosterol and it's lows, there
48:05
Speaker 3: lifestyle modifications that can increase it. Or is this all
48:08
Speaker 3: just dependent on your brain's you know, production of cholesterol
48:12
Speaker 3: and this is without any medications. I'm talking if your
48:15
Speaker 3: does mosterols.
48:16
Speaker 4: Well no, certainly in the periphery. There are diets, especially
48:21
Speaker 4: getting rid of saturated fat, where obviously we know we
48:24
Speaker 4: can lower ildo cholesterol apo B and in those studies
48:27
Speaker 4: there's a few reasons why they do that. But saturated
48:31
Speaker 4: fat can cause hypersynthesis of cholesterol.
48:34
Speaker 2: So since you're it's.
48:36
Speaker 4: The peripheral cells that are doing most of that, you
48:38
Speaker 4: can follow litosterol if you want to see is how
48:41
Speaker 4: why is saturated fat screwing up my ildo cholesterol? Or
48:45
Speaker 4: is that check litosterol? But I don't since the plasma
48:50
Speaker 4: cholesterol levels have nothing reflecting.
48:52
Speaker 2: On the brain.
48:54
Speaker 4: Uh, there's no diet I know that specifically as engineered
48:59
Speaker 4: to lower dosmostral I would tell you, as we do
49:01
Speaker 4: with all people, go on a very heart healthy diet,
49:04
Speaker 4: and you're probably helping your brain in a lot of
49:06
Speaker 4: ways aside from even cholesterol homeostasis. But no, I can't
49:12
Speaker 4: have an answer for you on lowering brain cholesterol.
49:17
Speaker 3: Yeah, well you're so sharp, doctor day Spring. What do
49:21
Speaker 3: you do to protect your brain? I'm curious?
49:24
Speaker 4: Remember what I have for breakfast this morning? Said so,
49:29
Speaker 4: and all listen a couple of things. Number one being
49:34
Speaker 4: totally stating as that of my been tolerant person, serious
49:38
Speaker 4: side effects with those drugs with respect to the muscles.
49:41
Speaker 4: I require a PCSK nine inhibitor to and it's got
49:45
Speaker 4: my apo B in the high forties, low fifties consistently
49:49
Speaker 4: luckily with just monotherapy, so I have a good response
49:52
Speaker 4: to that. But I've also since I met my buddy
49:57
Speaker 4: doctor Ta many years ago and he put me on
49:59
Speaker 4: the Initially it was a hypochloric diet with intermittent fasting, and.
50:04
Speaker 2: It was low fat. I blew away all my abnormal.
50:08
Speaker 4: Bio markers, and since then where I did that for
50:13
Speaker 4: four years, but that's a tough diet to stay on forever.
50:17
Speaker 4: I started to gain weight again and now I use
50:19
Speaker 4: the Semba glue tide where I've lost an equal amount
50:23
Speaker 4: of weight and I have all my other biomarkers that
50:26
Speaker 4: can measure in excellent control. So I got to presume
50:31
Speaker 4: that's helping the brain. Also, there have certainly been analysis
50:35
Speaker 4: of some of the GOLP one receptor studies where their
50:39
Speaker 4: deuce does seem to be lowered dementia in these people,
50:43
Speaker 4: and I think sooner or later that's going to be
50:45
Speaker 4: proven as an endpoint. Just like almost every day you
50:48
Speaker 4: pick up an article and you find out some other
50:50
Speaker 4: thing that gop one is doing beneficially. Most recent would
50:54
Speaker 4: be faty liver, which is hardly a stretch. We can
50:57
Speaker 4: believe that we know it reduces mace and certainly helps
51:01
Speaker 4: the insulin sensitivity and the diabetic control. So I am
51:06
Speaker 4: on high dose zempic and I'm on PCST nine inhibitors.
51:12
Speaker 4: I take culture load DOS culture scene, which is approved
51:15
Speaker 4: to stabilize chronic stable chronic carnary artery disease. So I
51:22
Speaker 4: went on that I don't know that likely lowers some
51:25
Speaker 4: inflammatory markers, but I don't know what that, if anything,
51:30
Speaker 4: does brain. I don't even know if culture scene can
51:32
Speaker 4: cross the barrier, but that's what I do. I take
51:37
Speaker 4: because I am under care of an excellent preventive neurologist.
51:40
Speaker 4: I take a couple of supplements which are involved with
51:44
Speaker 4: brain health. I make sure my Omega three index is
51:47
Speaker 4: quite good. They're big believers that DHA is crucial for
51:51
Speaker 4: brain functioning, so I make sure my DH levels are good,
51:57
Speaker 4: and I take some of the B vitamins which they
52:00
Speaker 4: use early in the cases on because there's some other
52:03
Speaker 4: evidence that that might help brain function. So I'm doing
52:06
Speaker 4: what I can with some expert neurologic advice. Kelly and
52:11
Speaker 4: the otis Richard Isaacson as to how to keep my
52:14
Speaker 4: brain going. And I do think I'm certainly more cognitive impaired.
52:19
Speaker 4: That AJD than I would with the recent memory. I
52:22
Speaker 4: see all these movie stars, I can't remember their names anymore,
52:26
Speaker 4: you know, remembering old tan Yankee baseball players.
52:29
Speaker 2: I used to be so fluent. I have to think
52:31
Speaker 2: hard to remember.
52:32
Speaker 4: So Kelly Anne has done pretty extensive testing on me
52:35
Speaker 4: and has come to the conclusion with all the crazy
52:38
Speaker 4: tests that she did, that I'm not showing the impairment
52:42
Speaker 4: of some of the neurologic cognitive things that would indicate AD.
52:46
Speaker 4: She says, Tom, you just got a seventy nine year
52:49
Speaker 4: old brain, So that explains some of the recent memory
52:54
Speaker 4: issues that you're having and stuff. But you know, dementia,
52:57
Speaker 4: you have to be the activities of daily living. You
53:00
Speaker 4: don't know how to button your shirt, you don't know
53:02
Speaker 4: how to cook anything, turn on the tap, put on
53:05
Speaker 4: your clothes. I'm still functioning pretty good, but all and
53:08
Speaker 4: telling you, and says Tom, you're doing the type of
53:10
Speaker 4: lectures and podcasts you're doing, you don't have Alzheimer's disease.
53:15
Speaker 3: You're absolutely amazing. I love learning from you. I will
53:18
Speaker 3: say too, my OMEGA index is checked. And when I
53:22
Speaker 3: first had mind checked, I was critical low with the
53:25
Speaker 3: DHA And yeah, that was surprising to me, so I
53:29
Speaker 3: did start. I have take quite a bit of fish
53:32
Speaker 3: oil every day, and now it's normal. So I'm thankful
53:35
Speaker 3: we have that checked. We do. I mean, there's still
53:38
Speaker 3: a lot we don't know about cognitive decline, but there's
53:41
Speaker 3: a lot we do know quite a bit now. You
53:43
Speaker 3: could look at does moster al omega indexes a POE
53:47
Speaker 3: if you're an E four carrier so.
53:50
Speaker 4: And there are several other things they're measuring now, some
53:53
Speaker 4: of the tawl and ameloid. There are numerous biomarkers that
53:57
Speaker 4: prevent the neurologists understanding use and really everyday docs could
54:02
Speaker 4: use them too, but it requires a little study. If
54:04
Speaker 4: you're going to order this test, you better know what
54:06
Speaker 4: it's going to mean when it comes back. But all
54:10
Speaker 4: there's great podcasts, there's obviously articles that you can be
54:13
Speaker 4: referred to to learn about that. Most recently with an
54:17
Speaker 4: up and coming lipid modulating drug which I've likely spoken
54:21
Speaker 4: about with you before, cald Obi cetropib. It's the next
54:26
Speaker 4: CETP inhibitor that so far dramatically lowers apo BLDO cholesterol
54:31
Speaker 4: non HDL cholesterol, even more so if you combine it
54:34
Speaker 4: with a statin or a zamide. But it also lowers
54:37
Speaker 4: LP LITLEA by upwards of forty to sixty percent. Wow.
54:41
Speaker 4: And it's a little oral tablet at ten milligrams a day.
54:44
Speaker 4: Would that be beneficial for patients like that? It seems
54:48
Speaker 4: that people who take it, unlike the statins, there's a
54:51
Speaker 4: lesser incidence of the onset of diabetes. So it may
54:54
Speaker 4: be protecting eyelid cells there. But their biggest hope is
54:58
Speaker 4: and they just present is at the recent Alzheimer's Disease
55:02
Speaker 4: conference and it's in publication now that it significantly improves
55:08
Speaker 4: some of the towel markers in beta amyloid in the blood.
55:11
Speaker 2: Now wow.
55:12
Speaker 4: Then now that's a big step, say hey, we make
55:14
Speaker 4: them better and we're going to prevent Alzheimer's disease. That
55:17
Speaker 4: will require a lot further study, but that's tremendous biomarker
55:22
Speaker 4: data to see on this incredible little drug that's coming along.
55:25
Speaker 4: It's like the little engine that could.
55:30
Speaker 3: I love that at Laura's lipoprotein little ad because you
55:32
Speaker 3: know statins can increase it a little bit. So this
55:34
Speaker 3: sounds amazing. When is what phase trial is it in?
55:38
Speaker 4: It's in phase three outcome trial now a big one
55:41
Speaker 4: called Prevail, but it's not supposed to print out till
55:44
Speaker 4: late twenty six, early twenty seven. They actually just published
55:48
Speaker 4: their Broadway trial, which is a trial of FH people
55:52
Speaker 4: and very high risk people that if you add obset
55:56
Speaker 4: your trip to high potency statin or maximumly tolerated stat
56:00
Speaker 4: you can more suppress APO bld L cholesterol than this.
56:04
Speaker 4: I go Staton could buy itself. That alone could actually
56:08
Speaker 4: I believe, get them an indication to come on the
56:10
Speaker 4: market as an ADJUNCTI of statin therapy. But I believe
56:15
Speaker 4: that the new Amsterdam farm is going to wait till
56:19
Speaker 4: the prevailed style concludes showing does it reduce mace or
56:23
Speaker 4: not before they apply to get an indication. But I
56:26
Speaker 4: also understand it's coming on the market in Europe pretty
56:29
Speaker 4: quickly things get on the market I guess, more easily
56:32
Speaker 4: or whatever over there. So Europeans will be able to
56:36
Speaker 4: use obi such a PIB long before we do. Maybe
56:39
Speaker 4: if you have an uncle who lives in England or someplace.
56:42
Speaker 2: They can ship it.
56:43
Speaker 3: Yeah right. I love some of the things that Europe
56:47
Speaker 3: does as far as their guidelines, and yeah, it seems
56:50
Speaker 3: like as far as lipids go, their guidelines are a
56:52
Speaker 3: little bit more up to date or.
56:54
Speaker 2: Yeah they really are.
56:56
Speaker 3: Yeah. Well, it's been such a pleasure having you on
56:59
Speaker 3: doctor Day Spring. I always learned so much. Thank you
57:01
Speaker 3: for all you do for educating all of us and pharmacists.
57:05
Speaker 3: Educate your patients. We can check as mosterol levels, we
57:08
Speaker 3: can know if they're getting too low or if they're
57:10
Speaker 3: too high. Good counseling and get your own levels checked
57:14
Speaker 3: if you want to at empower Lab.
57:16
Speaker 4: Yeah, and remember it's pretty solid that it is a
57:20
Speaker 4: biomarker for AD and cognitive impairment. All of this stuff
57:23
Speaker 4: about lowering and increasing it is plausible theory at this time,
57:28
Speaker 4: but the data is really good, so make of it
57:32
Speaker 4: what you will. You can totally ignore it. But I
57:35
Speaker 4: think if I was able to tolerate a stat and
57:37
Speaker 4: I would do what you're doing, Tamara, I would keep
57:40
Speaker 4: an eye periodically on my dismosterol.
57:43
Speaker 3: Absolutely all right, thanks so much everyone, have a great day.