1230 replies to this topic

[ceridwen]

I'm eating some blueberries now and I don't think they do anything for me! Not sure about the other ingredients haven't tried them for long enough.

[Der Springende Punkt]

EIP Pharma announces presentation of new positive clinical data with neflamapimod (VX-745) at Alzheimer's Association International Conference (AAIC)

 

 

The authors reported on further analyses of the episodic memory findings from two phase 2a clinical studies of neflamapimod in patients with early-stage Alzheimer's disease (Study 302 and Study 303).  As reported originally at CTAD meeting in Dec 2016, the two clinical trials met their primary objectives by demonstrating disease-relevant pharmacologic activity; and secondarily demonstrated statistically significant improvement in measures of episodic memory. The new analyses revealed consistent and substantial treatment effects on immediate and delayed recall aspects of episodic memory, as within-subject effect sizes (Cohen's d_avg) were similar between the two studies and ranged between 0.59 and 0.86.

...

Neflamapimod is a brain-penetrant oral small molecule that inhibits the intra-cellular enzyme p38 mitogen activated protein kinase alpha (p38α).

 

 

[Der Springende Punkt]

Positive data from a small safety trial of Leukine (sargramostim / GM-CSF) reported at AAIC in London.

 

 

“This is a short safety trial, lasting just under three weeks for each participant, and we weren’t expecting to see improvements in cognitive testing results,” said Dr. Boyd, who has been working with Dr. Potter on the Alzheimer’s treatment theory involving Leukine® since 2007. “For us to see these kinds of improvements gives us a lot of hope.”

 

Dr. Potter said thinking and memory indicators were tested using the Mini-Mental State Examination (MMSE), a common evaluation tool in dementia diagnostics. At the end of treatment, the participants improved their baseline scores by a statistical measurement considered “significant.”  When the same test was administered weeks after the treatment phases ended, the scores returned to levels closer to baseline.

[Daniel Cooper]

 

Scientists hope they have found a drug to stop all neurodegenerative brain diseases, including dementia.

 

In 2013, a UK Medical Research Council team stopped brain cells dying in an animal for the first time, creating headline news around the world.

But the compound used was unsuitable for people, as it caused organ damage.

Now two drugs have been found that should have the same protective effect on the brain and are already safely used in people.

[...]

Prof Mallucci told the BBC News website: "Both were very highly protective and prevented memory deficits, paralysis and dysfunction of brain cells."

The best known drug of the pair is trazodone, which is already taken by patients with depression.

The other, DBM, is being tested in cancer patients.

[source]

 

 

looks like trazodone is easy to get online and cheap. Assuming you trust the source.

 

 

 

Go to your doc and tell him/her that you are having sleep issues and generally they will be happy to write you a script for trazodone.

Edited by Daniel Cooper, 01 August 2017 - 09:29 PM.

[albedo]

Stop Alzheimer’s before it starts

http://www.nature.co...-starts-1.22274

[resveratrol_guy]

I don't want to interrupt the research discussion, but something's up with this and I'll leave it to y'all to figure out what...

 

I notice that if I eat eggs, eryngii mushroom (specifically, the fruiting body that sticks out of the ground), and a methylcobalamin supplement, I get excellent visual recall hours later.  It then lasts for several hours. (I've mentioned many times before that shiitake-maitake extract is great for visualizing engineering stuff, but this is much more about recall.) Just don't do this before bed or you'll be up all night. The last time I had this experience was in 2006. It was so vivid that I remember it to this day. Milage may vary, and sorry I don't have the ratios down yet.

 

Furthermore I would note that it seems to unlock the read pathway in particular, because I'm often suddenly able to recall visual information from before I ate the meal.

 

That's all. Oh, and please do try this at home!

 

Edited by resveratrol_guy, 20 August 2017 - 03:48 PM.

[albedo]

I don't want to interrupt the research discussion, but something's up with this and I'll leave it to y'all to figure out what...

 

...

 

Hi Resveratrol_guy. I hazard an hypothesis...

 

Assuming causation limited to the 2 foods and one micronutrient you mention, I would guess the effect is more likely to be found into the mushroom chemicals and the methylcobalamine, maybe in that order. Both are known to influence the brain activity. Even if the same can be said for the phosphatidylcholine in the eggs, I would guess its main effect here is as excipient and increasing bioavailability of the other chemicals.

 

Just my 2 cents …

 

To which extent all this connects to AD is probably another topic for another thread. 

 

[albedo]

This looked to me interesting:

 

"Conclusions: We observed significant improvements in the prediction of cognitive impairment by adding one-carbon metabolites. This is partially explained by associations with CSF tau and p-tau181, suggesting a role for one-carbon metabolism in the aggregation of tau and neuronal injury. These metabolites may be particularly critical in APOE ε4 carriers."

 

Dayon L, Guiraud SP, Corthésy J, et al. One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: homocysteine and beyond. Alzheimers Res Ther. 2017;9(1):43.

[albedo]

24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial

 

http://www.thelancet...0332-0/fulltext

 

The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed.

 

[ta5]

Front Aging Neurosci. 2017 Oct 6;9:324.

Hyperhomocysteinemia, Suppressed Immunity, and Altered Oxidative Metabolism Caused by Pathogenic Microbes in Atherosclerosis and Dementia.

McCully KS1,2.

Many pathogenic microorganisms have been demonstrated in atherosclerotic plaques and in cerebral plaques in dementia. Hyperhomocysteinemia, which is a risk factor for atherosclerosis and dementia, is caused by dysregulation of methionine metabolism secondary to deficiency of the allosteric regulator, adenosyl methionine. Deficiency of adenosyl methionine results from increased polyamine biosynthesis by infected host cells, causing increased activity of ornithine decarboxylase, decreased nitric oxide and peroxynitrate formation and impaired immune reactions. The down-regulation of oxidative phosphorylation that is observed in aging and dementia is attributed to deficiency of thioretinaco ozonide oxygen complexed with nicotinamide adenine dinucleotide and phosphate, which catalyzes oxidative phosphorylation. Adenosyl methionine biosynthesis is dependent upon thioretinaco ozonide and adenosine triphosphate (ATP), and the deficiency of adenosyl methionine and impaired immune function in aging are attributed to depletion of thioretinaco ozonide from mitochondrial membranes. Allyl sulfides and furanonaphthoquinones protect against oxidative stress and apoptosis by increasing the endogenous production of hydrogen sulfide and by inhibiting electron transfer to the active site of oxidative phosphorylation. Diallyl trisulfide and napabucasin inhibit the signaling by the signal transducer and activator of transcription 3 (Stat3), potentially enhancing immune function by effects on T helper lymphocytes and promotion of apoptosis. Homocysteine promotes endothelial dysfunction and apoptosis by the unfolded protein response and endoplasmic reticulum stress through activation of the N-methyl D-aspartate (NMDA) receptor, causing oxidative stress, calcium influx, apoptosis and endothelial dysfunction. The prevention of atherosclerosis and dementia may be accomplished by a proposed nutritional metabolic homocysteine-lowering protocol which enhances immunity and corrects the altered oxidative metabolism in atherosclerosis and dementia.

KEYWORDS: allylsulfides; atherosclerosis; dementia; furanonaphthoquinones; homocysteine; oxidation; thioretinaco ozonide

PMID: 29056905 

 

The last paragraph includes a proposed treatment protocol:

 

Treatment of the metabolic abnormalities produced by pathogenic microbes in atherosclerosis or AD, including hyperhomocysteinemia, increased biosynthesis of polyamines, decreased NO biosynthesis, and impaired oxidative metabolism from depletion of thioretinaco ozonide, may be accomplished by a proposed plasma homocysteine-lowering protocol. The protocol consists of thioretinamide, B vitamins, including methyl-cobalamin, methyl-folate, pyridoxal phosphate, and nicotinamide riboside, ascorbate, Coenzyme Q10, adenosyl methionine, menoquinone, cod liver oil, vitamin D3, pancreatic enzymes, and dietary improvement to minimize consumption of processed foods and to provide adequate dietary protein for prevention of subclinical protein energy malnutrition (Ingenbleek and McCully, 2012; McCully, 2016a). Because of their powerful digestive activity against the polysaccharides, proteins, and nucleic acids of biofilm matrix, pancreatic enzymes, including amylase, trypsin, ribonuclease, and deoxyribonuclease, may disperse biofilms in atherosclerotic plaques and cerebral plaques in AD, increasing susceptibility of the pathogens within biofilms of plaques to antibiotic therapy (Allen, 2016). In addition to these measures, meticulous oral hygiene, antibiotic therapy of dental procedures, consumption of dietary monolaurin and other anti-microbial nutrients, consumption of adequate dietary protein, and avoidance of neurotoxins from foods, vaccines, or environmental contaminants may also decrease the progression of mild cognitive impairment to dementia. The efficacy of this proposed protocol requires validation by a properly designed clinical trial.

 

The author has a patent on Compositions and method for utilization of thioretinamide in therapy of degenerative diseases of aging.

 

Edited by ta5, 05 November 2017 - 11:45 PM.

[tunt01]

McCully has some further explanation in his post here.  The biochemistry is above my paygrade.  He seems to be suggesting the deficiencies of thioretinamide are driven by microbial exposures, which partly explains the 2nd set of remarks you highlight.  I'm not sure how one would test for thioretinamide deficiency other than to watch homocysteine and vitamin A levels themselves.

[mag1]

hey, res could you help us out with sourcing the King Trumpet mushrooms?

 

Just don't think it's fair to put out such a super cool experience without detailing how we could try it out.

iherb?

 

eryngii mushroom

 

Perhaps you could use a standard online product for the King Trumpet and report back on what happens.

I would really love having such an experience!

Could be helpful before an exam.

Edited by mag1, 07 November 2017 - 02:47 AM.

[aribadabar]

hey, res could you help us out with sourcing the King Trumpet mushrooms?

 

I buy them in Chinese or even regular grocery store here in Canada.

 

What I found strange is that their marshmallow-like texture never gets digested by my GI tract and comes out almost intact.

Hope I retain the beneficial compounds

[ceridwen]

Not sure how to get Thioretinamide.

[mag1]

ari, thanks for the suggestion!

I am not a big mushroom person, though if I could have a similar response as res, than I'm in.

Anyone also experience this memory effect with mushrooms?

 

I really can't believe it but it looks like LMTX is back for another round.

After what has already happened with LMTX, I am now quite weary of making any

comments about it. Wonder how the trial extension has worked out?

 

When the results came out at ICAD Toronto, it all seemed to turn into a bad dream.

They seemed to do an unblinded after the fact treatment comparison between those

who were taking AD drugs (because they had dementia) and were likely progressing

and those who were not taking AD drugs but were taking LMTX (because they probably

did not have dementia) and they were likely not progressing. No great surprise that

LMTX was found effective under these conditions.

 

Yet, now they are reporting the second phase 3 and are suggesting that brain atrophy

greatly reduced with LMTX even at a 4 mg dose. They now intend to bring this back

into a phase 3 trial. Not sure if they really intended to have AD patients in the control arm

on placebo. How will they have a blinded trial if LMTX turns pee blue? (That's why

they went with a 4 mg LMTX placebo dose!)

 

 

https://content.iosp...sease/jad170560

http://taurx.com/upl...ase_website.pdf

 

[mag1]

Looks like Methylene Blue / LMTX is the cure for AD.

 

http://taurx.com/phase-3-trx-007.html

Edited by mag1, 03 December 2017 - 08:27 PM.

[albedo]

I did not read the paper but it looks very interesting. It is from the same team at EPFL (Prof. Auwerx) who worked a lot on NR (Nicotinamide Riboside) and Urolithins. I understand one of the pharmacological intervention mentioned in the abstract is NR and a specific antibiotic (doxycycline) to reinforce mitochondria stress response.

 

See:

 

https://actu.epfl.ch...op-alzheimer-s/

 

and:

 

Sorrentino V, Romani M, Mouchiroud L, et al. Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature. 2017

https://www.nature.c...les/nature25143

 

"Alzheimer’s disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer’s disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer’s disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer’s disease."

https://www.nature.c...les/nature25143

Edited by albedo, 08 December 2017 - 03:07 PM.

[albedo]

Pioneering Alzheimer’s study in Colombia zeroes in on enigmatic protein

"Researchers tracking a genetic mutation that causes an early-onset form of the disease hope to uncover new drug targets."

[tunt01]

AAV to overexpress CYP46A1 appears to prevent familial (early onset) alzheimer's with excessive APP.  It is also preventative of Huntington's.

 

I think this is the human AAV-CYP46A1.

[ihatesnow]

https://www.facebook...18593302/?t=105

[ta5]

J Alzheimers Dis. 2018 Jul 20. doi: 10.3233/JAD-180184.

Improvement of Main Cognitive Functions in Patients with Alzheimer's Disease after Treatment with Coconut Oil Enriched Mediterranean Diet: A Pilot Study.

de la Rubia Ortí JE1, García-Pardo MRIP2, Drehmer E1, Cantus DS3, et al.

BACKGROUND:

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder (mainly in women), and new therapies are needed. In this way, ketone bodies are a direct source of cellular energy and can be obtained from coconut oil, postulating that coconut oil could be a new non-pharmacological alternative in AD patients.

OBJECTIVE:

The aim of this study is to detect changes in the main cognitive functions of patients with AD after following a coconut oil enriched Mediterranean diet, and to determine whether there are differences in function of stage or sex.

METHODS:

A prospective, longitudinal, qualitative, analytic, experimental study was carried out in 44 patients with AD, who were randomly divided into two homogenous groups of 22 patients each: an experimental group of patients who followed a coconut oil enriched Mediterranean diet for 21 days and a control group. In order to determine the cognitive changes after the intervention, we carried out the 7 Minute Screen, which analyses temporal orientation, visuospatial and visuoconstructive abilities, and semantic and episodic memory.

RESULTS:

After intervention with coconut oil, improvements in episodic, temporal orientation, and semantic memory were observed, and it seems that the positive effect is more evident in women with mild-moderate state, although other improvements in males and severe state were also shown.

CONCLUSIONS:

The isocaloric coconut oil enriched Mediterranean diet seems to improve cognitive functions in patients with AD, with differences according to patient sex and degree of severity of the disease, although more studies in this line are needed.

PMID: 30056419

[APBT]

 

PODCAST

Richard Isaacson, M.D.: Alzheimer’s prevention (EP.18

 

In this episode, Richard Isaacson, a neurologist and director of the Alzheimer’s Prevention Clinic at Weill Cornell Medicine and New York-Presbyterian, discusses strategies for staving off Alzheimer’s disease. Richard shares a wealth of insight for people who want to know more about Alzheimer’s and what you can do to help yourself and your loved ones — starting today and continuing throughout the entire lifespan.

 

https://peterattiamd...ichardisaacson/

 

 

[MikeDC]

New hope for Alzheimer’s is not a drug. It is a new vitamin B3.
https://www.biospace...es-and-new-hope

[MikeDC]

New hope for Alzheimer’s is not a drug. It is a new vitamin B3.
https://www.biospace...es-and-new-hope

The link no longer work. Harvard Professor Rudy Tanzi designed a clinical using Niagen to treat early Alzheimer’s patients. He said plague starts to form 15 years before symptoms. The accumulation of plague eventually cause inflammation and axon death. In mice models, Niagen has cleared plague and protected axons from death by increasing NAD+ levels in axons.

[Engadin]

Cephalosporin antibiotic Cefixime: Promising new Alzheimer’s treatment unexpectedly found in old antibiotic.

 

Yale researchers have identified a drinkable cocktail of designer molecules that interferes with a crucial first step of Alzheimer’s and even restores memories in mice. 

 

The binding of amyloid beta peptides to prion proteins triggers a cascade of devasting events in the progression of Alzheimer’s — accumulation of plaques, a destructive immune system response, and damage to synapses.

“We wanted to find molecules that might have a therapeutic effect on this network,” said senior author Stephen Strittmatter, the Vincent Coates Professor of Neurology, professor of neuroscience, and director of the Yale Alzheimer Disease Research Center.

Strittmatter and research scientist Erik Gunther screened tens of thousands of compounds looking for molecules that might interfere with the damaging prion protein interaction with amyloid beta. They found that an old antibiotic looked like a promising candidate but was only active after decomposing to form a polymer. Related small polymers retained the benefit and also managed to pass through the blood-brain barrier.

They then dissolved the optimized polymeric compound and fed it to mice engineered to have a condition that mimics Alzheimer’s. They found that synapses in the brains were repaired and mice recovered lost memory.

A collaborating team at Dartmouth University reported a positive response when they delivered the same cocktail to cells modeled to have Creutzfeldt-Jakob Disease, a devasting neurological condition caused by infection with misfolded prion protein.

The next step is to verify the compounds aren’t toxic in preparation for translation to clinical trials for Alzheimer’s disease.

Research was funded by grants from the NIA, the NINDS, the Alzheimer’s Association and the Falk Medical Research Trust to Strittmatter.

https://news.yale.ed...ment-alzheimers

https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31932-6#secsectitle0020

 

[davis89x]

25/01/2019 - Bacteria Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

 

 

 

Abstract

Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer’s disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer’s patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1–42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1–42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer’s disease.

 

[albedo]

An interesting approach to reduce risk today in healthy people?

"... beginning in May, they will start testing a novel gene therapy in which people with the unluckiest APOE genes will be given a huge dose to their brain of the low-risk version..."

[capob]

Alzheimer's as a mercury toxicity problem

[mag1]

Phase 3 trial shows 60%+ slowing of progression in moderate AD patients.

This is the most impressive treatment result ever published for Alzheimer's disease (that I am aware of).

 

https://www.prnewswi...-300738956.html

[Phoebus]

Phase 3 trial shows 60%+ slowing of progression in moderate AD patients.

This is the most impressive treatment result ever published for Alzheimer's disease (that I am aware of).

 

https://www.prnewswi...-300738956.html

 

Very interesting. Does anyone know what this means though? 

 

 

 

AMBAR was designed to evaluate whether the progression of Alzheimer's could be stabilized through plasma exchange, a process that entails periodically extracting plasma and replacing it with a specific albumin solution (Albutein®). AMBAR is based on the hypothesis that most of the amyloid-beta protein – one of the proteins accumulated in the brains of Alzheimer's patients – is bound to albumin and circulates in plasma. Extracting this plasma may flush amyloid-beta peptide from the brain into the plasma, thus limiting the disease's impact on the patient's cognitive functions.  Additionally, Albumin may represent a multi-modal approach to the management of the disease due to it's binding capacity, antioxidant, immune modulatory and anti-inflammatory properties.

 

 

why would Extracting the plasma flush amyloid-beta peptide from the brain into the plasma? So they extract albumin from the blood, and theoretically therefore also extract circulating amyloid. So then the brain flushes the amyloid from the brain into the blood in response to this? Why though?