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Mayo Clinic Study of Thousands of Brains Reveals Tau as Driver of Alzheimer’s Disease
scma_2007
Posted: Monday, March 30, 2015 7:45 PM
Joined: 9/13/2013
Posts: 112


Note: So Tau could be the main culprit!
http://newsnetwork.mayoclinic.org/blogtag/news-release/

By examining more than 3,600 postmortem brains, researchers at Mayo Clinic's campuses in Jacksonville, Florida, and Rochester, Minnesota, have found that the progression of dysfunctional tau protein drives the cognitive decline and memory loss seen in Alzheimer's disease. Amyloid, the other toxic protein that characterizes Alzheimer's, builds up as dementia progresses, but is not the primary culprit, they say.

The findings, published in Brain, offer new and valuable information in the long and ongoing debate about the relative contribution of amyloid and tau to the development and progression of cognitive dysfunction in Alzheimer's, says the study's lead author, Melissa Murray, Ph.D., a neuroscientist at Mayo Clinic in Jacksonville.

The findings also suggest that halting toxic tau should be a new focus for Alzheimer's treatment, the researchers say.

"The majority of the Alzheimer's research field has really focused on amyloid over the last 25 years," Dr. Murray says. "Initially, patients who were discovered to have mutations or changes in the amyloid gene were found to have severe Alzheimer's pathology -- particularly in increased levels of amyloid. Brain scans performed over the last decade revealed that amyloid accumulated as people progressed, so most Alzheimer's models were based on amyloid toxicity. In this way, the Alzheimer's field became myopic."

But researchers at Mayo Clinic were able to simultaneously look at the evolution of amyloid and tau using neuropathologic measures. "Imagine looking at the rings of a tree -- you can identify patterns, like the changing seasons and the aging of the tree, when viewing the tree's cross-section," Dr. Murray says. "Studying brains at different stages of Alzheimer's gives us a perspective of the cognitive impact of a wide range of both amyloid and tau severity, and we were very fortunate to have the resource of the Mayo brain bank, in which thousands of people donated their postmortem brains, that have allowed us to understand the changes in tau and amyloid that occur over time."

"Tau can be compared to railroad ties that stabilize a train track that brain cells use to transport food, messages and other vital cargo throughout neurons," Dr. Murray says. "In Alzheimer's, changes in the tau protein cause the tracks to become unstable in neurons of the hippocampus, the center of memory. The abnormal tau builds up in neurons, which eventually leads to the death of these neurons. Evidence suggests that abnormal tau then spreads from cell to cell, disseminating pathological tau in the brain's cortex. The cortex is the outer part of the brain that is involved in higher levels of thinking, planning, behavior and attention -- mirroring later behavioral changes in Alzheimer's patients."

"Amyloid, on the other hand, starts accumulating in the outer parts of the cortex and then spreads down to the hippocampus and eventually to other areas," she says. "Our study shows that the accumulation of amyloid has a strong relationship with a decline in cognition. When you account for the severity of tau pathology, however, the relationship between amyloid and cognition disappears -- which indicates tau is the driver of Alzheimer's," Dr. Murray says.

Amyloid brain scanning has been used for only about a decade, and "so there are still many unanswered questions about what it is measuring," she adds. "Investigating what brain pathology underlies the amyloid brain scanning threshold indicative of Alzheimer's can only be addressed in patients who underwent scanning and donated their brain for research."

The study was conducted in two parts. Researchers at Mayo Clinic in Florida examined 3,618 brains in its postmortem brain bank, of which 1,375 brains were Alzheimer's confirmed. These patients died at different ages and different stages of dementia, providing a valuable timeline into disease progression.

The researchers used recommended scoring systems to examine the evolution of amyloid and tau in dissected brain tissue. They found that the severity of tau, but not amyloid, predicted age onset of cognitive decline, disease duration and mental deterioration.

The second part of the study was conducted with their collaborators at Mayo Clinic in Rochester. Together the team examined amyloid brain scans taken of patients prior to death and compared the scans to measures of tau and amyloid brain pathology.

The investigators found that the signal from amyloid brain scans corresponded with amyloid pathology specific to the brain and not amyloid found in vessels, and did not correspond to tau pathology. The brains of some participants had amyloid visible at pathology that did not reach the threshold for what would be found in Alzheimer's brain scans. This is important, as amyloid can be found in brains of older individuals who have not experienced cognitive decline, researchers say.

"Our findings highlight the need to focus on tau for therapeutics, but it also still indicates that the current method of amyloid brain scanning offers valid insights into tracking Alzheimer's," Dr. Murray says. "Although tau wins the 'bad guy' award from our study's findings, it is also true that amyloid brain scanning can be used to ensure patients enrolling for clinical trials meet an amyloid threshold consistent with Alzheimer's -- in lieu of a marker for tau."


Lane Simonian
Posted: Monday, March 30, 2015 11:32 PM
Joined: 12/12/2011
Posts: 4998


The line between correlation and causation is often a very blury one. Tau tangles (neurofibrillary tangles) may eventually cause the death of brain cells by inhibiting the transport of nutrients in the brain, but the process seems to take a very long time. Hyperphosphorylated and nitrated tau inhibit neurotransmissions which may pose a more immediate and serious problem in regards to cognition.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663562/

Tau nitration can occur as a result of peroxynitrite formation or from transtion metals attracted to amyloid oligomers. Peroxynitrite scavengers (which are also metal chelators) not only reduce the tyrosine nitration of tau they also begin to reverse that nitration.

http://www.ncbi.nlm.nih.gov/pubmed/16816118

It is possible to have amyloid oligomers and plaques and neurofibrillary tangles in the relative absence of peroxynitrites, but in such cases people do not have Alzheimer's disease. On the other hand, it is possible to have Alzheimer's disease with neurofibrillary tangles but few amyloid plaques or vice versa.

http://www.ncbi.nlm.nih.gov/pubmed/25348064

http://www.ncbi.nlm.nih.gov/pubmed/15079014

Oxidants contribute to the formation of oligomers, plaques, and tangles. They are what drive Alzheimer's disease. Find the right antioxidants and you successfully treat Alzheimer's disease.





Lane Simonian
Posted: Tuesday, March 31, 2015 12:16 AM
Joined: 12/12/2011
Posts: 4998


From one of the articles cited above:

2004 Apr 13;62(7):1141-7.

Alzheimer disease without neocortical neurofibrillary tangles: "a second look".


CONCLUSIONS:

Dementing syndromes virtually indistinguishable from each other can, and do, develop in the presence or absence of neocortical NFT. Patients without neocortical NFT are, on average, older at disease onset and death, and show a trend toward a shorter disease duration with somewhat slower deterioration. Although neocortical NFT per se are not obligatory for the development of clinical dementia, more subtle neocortical cytoskeletal tau pathology may contribute to cognitive decline in these subjects.

And the parallel article for amyloid plaques:

Alzheimer’s Disease Without Amyloid Plaques


Amyloid plaques have long been thought to be the cause of neuron loss in Alzheimer’s disease. Now researchers report that excess of mutated amyloid precursor protein (APP) inside the neurons is sufficient to induce neuron death. The report challenges the notion that amyloid deposits outside of the cells are necessary for neuron death in Alzheimer’s disease.

All that is required for Alzheimer's disease is hyperphosphorylated and nitrated tau and the c-terminal fragment of the amyloid precursor protein. Peroxynitrite scavengers inhibit the formation of both and reverse part of the damage done to the brain by oxidation and nitration in Alzheimer's disease.

http://www.ncbi.nlm.nih.gov/pubmed/16816118

http://www.ncbi.nlm.nih.gov/pubmed/11432978

Amyloid plaques likely do no damage to the brain and neurofibrillary tangles likely do relatively little damage to the brain. Alzheimer's researchers need to change their focus from amyloid and neurofibrillary tangles and focus on the role that antioxidants can play in treating Alzheimer's disease. We are as close as that to an effective treatment for the disease.

Lane Simonian
Posted: Friday, April 3, 2015 9:45 AM
Joined: 12/12/2011
Posts: 4998


This quote confused me for awhile:

[Alzheimer's] Patients without neocortical NFT [neurofibrillary tangles] are, on average, older at disease onset and death, and show a trend toward a shorter disease duration with somewhat slower deterioration.

A shorter disease should be the result a faster deterioration one would think. But probably the individuals without neocortical neurofibrillary tangles died from another cause at a relatively early stage of the disease before the tangles formed.

One conclusion from this study is that tau neurofibrillary tangles do no drive Alzheimer's disease, but they may make the progression more rapid as they further decrease the transport of nutrients in the brain and further inhibit neurotransmissions.





Lane Simonian
Posted: Friday, April 3, 2015 9:59 AM
Joined: 12/12/2011
Posts: 4998


I will add this one too in regards to amyloid:

Although familial Alzheimer disease (AD)-associated autosomal dominant mutants have been extensively studied, little is known about the underlying molecular mechanisms of neurodegeneration induced by these mutants in AD. Wild-type, Swedish or London amyloid precursor protein (APP) transfection in primary human neurons induced neuritic beading, in which several co-expressed proteins, such as enhanced green fluorescent protein, red fluorescent protein (RFP)-tau and RFP-ubiquitin, accumulated. APP-induced neuritic beading was dependent on caspase-6 (Casp6), because it was inhibited with 5 μM z-VEID-fmk or with dominant-negative Casp6. Neuritic beading was independent from APP-mediated amyloid β-peptide (Aβ) production, because the APPM596V (APPMV) mutant, which cannot generate Aβ, still induced Casp6-dependent neuritic beading. However, the beaded neurons underwent Casp6- and Aβ-dependent cell death. These results indicate that overexpression of wild-type or mutant APP causes Casp6-dependent but Aβ-independent neuritic degeneration in human neurons. Because Casp6 is activated early in AD and is involved in axonal degeneration, these results suggest that the inhibition of Casp6 may represent an efficient early intervention against familial forms of AD. Furthermore, these results indicate that removing Aβ without inhibiting Casp6 may have little effect in preventing the progressive dementia associated with sporadic or familial AD.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032318/

http://www.ncbi.nlm.nih.gov/pubmed/15640150

So just like tau tangles, amyloid (oligomers in particular) may contribute to cell death but are not the primary cause of cell death. Cell death can occur with caspase activation and with hyperphosporylated and nitrated tau and peroxynitrites are one of the main causes of both.

Just to reemphasize the finding above:

Furthermore, these results indicate that removing Aβ without inhibiting Casp6 may have little effect in preventing the progressive dementia associated with sporadic or familial AD.



onward
Posted: Friday, April 3, 2015 12:45 PM
Joined: 12/20/2011
Posts: 217



Below is linked an article listing many natural products that are believed to target tau.

But, obviously, assuming Lane's analysis is right, as it very well may be, tau targeting is the wrong route.


Natural products as a rich source of tau-targeting drugs for Alzheimer’s disease

(Scroll down to section entitled "Natural products as tau targeting agents.")

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575183/


Lane Simonian
Posted: Friday, April 3, 2015 5:39 PM
Joined: 12/12/2011
Posts: 4998


Great article, Onward. Nearly all of the natural products listed in the article are peroxynitrite scavengers. This is important because peroxynitrites are one of the routes to the hyperphosphorylation and nitration of tau proteins (another route is via amyloid oligomers and transition metals, but most peroxynitrite scavengers are also metal chelators and most peroxynitrite scavengers inhibit the formation of amyloid oligomers in the first place).

Hyperphosphorylated and nitrated tau play a role in Alzheimer's disease by inhibiting the transport of nutrients and neurotransmissions. Neurofibrillary tau tangles may somewhat increase these problems, but are not required for the progression of Alzheimer's disease (in other words, they may speed the progression, but the disease will progress with just hyperphosphorylated and nitrated tau itself). This is the critical article on the subject:

2006 Jul;20(9):1431-42.

Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.

Abstract

To investigate the upstream effector that led to tau hyperphosphorylation, nitration, and accumulation as seen in Alzheimer's disease brain, and the underlying mechanisms, we bilaterally injected SIN-1, a recognized peroxynitrite donor, into the hippocampus of rat brain. We observed that the level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h after drug administration, and these alterations were prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. Concomitantly, we detected a significant activation in glycogen synthase kinase-3beta (GSK-3beta) and p38 MAPKs, including p38alpha, p38beta, and p38delta, but no obvious change was measured in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, in which the activity of 20S proteasome was significantly arrested in SIN-1-injected rats. Further studies demonstrated that the hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis. These results provide the first in vivo evidence showing that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation. Our findings reveal a common upstream stimulator and a potential therapeutic target for Alzheimer-like neurodegeneration.


Lane Simonian
Posted: Friday, April 3, 2015 5:52 PM
Joined: 12/12/2011
Posts: 4998


Another way of looking at this is to target what is causing tau hyperphosphorylation, nitration, and tangles, because what is causing all of this (i.e, oxidants especially peroxynitrites) are doing other damage to the brain that can also be partially reversed by peroxynitrite scavengers. Take the example of panax ginseng, mentioned in the article found by Onward.

The steroid glycoside ginsenoside Rd (22) from Asian ginseng, Panax ginseng, shows in vivo and in vitro reduction of neurotoxicity and tau hyperphosphorylation by enhancing the activities of PP-2A []. [the ginsenosides are less important than other compounds in Panax ginseng and de-nitration is more important that de-phosphorylation via PP-2A]


2009 Feb;12(1):124-30. doi: 10.1089/jmf.2007.0646.

Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng.

Abstract

To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.

2012 Jul 9. [Epub ahead of print]

Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease.

Abstract

OBJECTIVES:

Ginseng has been reported to improve cognitive function in animals and in healthy and cognitively impaired individuals. In this study, we investigated the efficacy of a heat-processed form of ginseng that contains more potent ginsenosides than raw ginseng in the treatment of cognitive impairment in patients with moderately severe Alzheimer's disease (AD).

METHODS:

Forty patients with AD were randomized into one of three different dose groups or the control group as follows: 1.5 g/day (n = 10), 3 g/day (n = 10), and 4.5 g/day (n = 10) groups, or control (n = 10). The Alzheimer's Disease Assessment Scale (ADAS) and Mini-Mental State Examination (MMSE) were used to assess cognitive function for 24 weeks.

RESULTS:

The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.

DISCUSSION:

These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.

onward
Posted: Friday, April 3, 2015 8:12 PM
Joined: 12/20/2011
Posts: 217


Lane, thanks as always.

I know you've posted about this before - but have you come across any new info on availability of heat-processed ginseng - or any other particular type of ginseng product that seems likely to produce a notable cognitive improvement?

If I remember right, a while back you reported that the heat-processed ginseng (that proved effective in the clinical trial) was only available from one source and was extremely expensive.

Yet it would seem that if there really are specific ginseng products that can produce a very notable cognitive improvement, there ought to be supplement manufacturers jumping on this to make it more widely available.

Also - do you (or anyone reading this) know of anyone who's gotten really positive results (i.e., notable memory improvement) from any particular ginseng product?

I'd love to think that this is a possibility.

Thanks.


Lane Simonian
Posted: Saturday, April 4, 2015 12:48 AM
Joined: 12/12/2011
Posts: 4998


I keep looking, but as of yet I have not found another supplier of heat processed ginseng. The below study for red Korean ginseng seems to indicate you can achieve improvements in cognition albeit at higher dose than for heat processed ginseng (as I understand it red Korean ginseng is produced through pressure cooking/steaming whereas heat processed ginseng is produced through repeated steaming and dry heat).

A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer’s disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer’s Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer’s disease.

I am trying to find out from Life Extension how much it would cost to run a 24 week trial with 100 participants--50 individuals receiving 4.5 grams of red Korean ginseng and clove, bay laurel, and lemon balm essential via direct inhalation and 50 people receiving a sugar pill and some type of perfume. Once I know the dollar number, I am going to try to run down who in the world might be willing to finance such a trial. I figure that I will never know a good answer to the questions of efficacy unless I try to move this forward.

Lane Simonian
Posted: Saturday, April 4, 2015 1:13 AM
Joined: 12/12/2011
Posts: 4998


I think that I have incorrectly remembered the process by which red ginseng and heat-processed ginseng (also know as sun ginseng) are produced. Red ginseng is heated at 100 degrees celsius whereas heat-processed ginseng is heated at 120 degrees celsius. The big partially unanswered question is what difference does that 20 degrees make in the antioxidant capacity of ginseng for the treatment of Alzheimer's disease.



onward
Posted: Saturday, April 4, 2015 9:05 AM
Joined: 12/20/2011
Posts: 217


Lane, thanks very much for the additional info. The lack of clinical trials is certainly a concern and a big challenge.

If I'm understanding right, the higher dose of Korean red ginseng (9 g) boosted MMSE scores by about 3 points, and at the lower dose (4.5 g) by about 2 points (according to the chart in the article). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/

Chart: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/figure/F001/

I wonder how many points the 4.5 g Sun ginseng boosted the MMSE. Do you know? The abstract doesn't say, and I can't find the full article free online.

I'm wondering if the Sun ginseng was able to boost the MMSE higher than the Korean red ginseng did.

It seems many times an abstract of a study may report that a certain product produced "significant" improvement, but when we look at the actual data on memory improvement, it's so small that it might be barely noticeable even to a caregiver, for example.


Lane Simonian
Posted: Saturday, April 4, 2015 10:35 AM
Joined: 12/12/2011
Posts: 4998


These test results can be misleading. Supposedly, the ADAS-cog scores are more accurate than the MMSE scores, but even then it is hard to know how (or if) the numbers translate into visible improvement. One potentially positive aspect of the study is that no significant worsening occurred in nearly two years.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/figure/F002/

I am going to check on Monday to see if my school can get me the full text article (only four pages long) through interlibrary loan. That would help to answer the question as to whether heat processed/sun ginseng really is more effective than red Korean ginseng for the treatment of Alzheimer's disease.



onward
Posted: Saturday, April 4, 2015 10:56 AM
Joined: 12/20/2011
Posts: 217


Thanks, Lane!
scma_2007
Posted: Sunday, April 5, 2015 9:22 PM
Joined: 9/13/2013
Posts: 112


The two year study did not mention of any side effects except that it improved MMSE scores. Is that a continous intake?

WebMD has some warning about Korean panax ginseng. Not to be taken for more than six months as it has a hormone like effect in the body, could possibly be unsafe as it has hormone like action in the body.

http://www.webmd.com/vitamins-supplements/ingredientmono-1000-ginseng%20panax%20%28ginseng,%20panax.aspx?activeingredientid=1000&activeingredientname=ginseng%20panax%20%28ginseng,%20panax

Here's an article that says something about dosage. Not a scientific article, but summarizes dosage usage and warnings that I know of. It suggest not to take in continously.

What Is the Daily Recommended Intake of Korean Red Ginseng? 4/17/2014
http://www.livestrong.com/article/508471-what-is-the-daily-recommended-intake-of-korean-red-ginseng/


.

Lane Simonian
Posted: Monday, April 6, 2015 10:21 AM
Joined: 12/12/2011
Posts: 4998


I did find these short-term side effects mentioned in the study:

Five patients in the low-dose KRG group, six patients in the high-dose KRG group, and twelve patients in the control group reported adverse effects and withdrew from the study during the first 24 wk. Participants reported mild symptoms of heat sensation, nausea, diarrhea, and headache, and all subjects who reported adverse events withdrew from the study.

But you are right, no long term side effects were mentioned in the trial. The drop outs in the control group may have been due to Alzheimer's medications. In any case, heat sensation, nausea, diarrhea, and headaches are all potential side effects of ginseng use and it would have been interesting to know from the study how many of these effects were seen after 24 weeks and how many in the 4.5 gram and 9 gram groups.

The main cautions that I have seen for panax ginseng are elevations in blood pressure at least in the short-term and interactions with other drugs (such as blood thinners).

It is estimated that more than 6 million people ingest ginseng regularly in the United States. There have been few reports of severe reactions and a very low incidence of adverse events has been reported in clinical trials. Hypersensitivity and anaphylaxis have been reported. Inappropriate use of P. ginseng or ginseng abuse syndrome includes symptoms such as hypertension, diarrhea, sleeplessness, mastalgia, skin rash, confusion, and depression.

http://www.drugs.com/npp/ginseng.html

The dose and length of usage may cause severe adverse effects in some people.

scma_2007
Posted: Monday, April 6, 2015 1:56 PM
Joined: 9/13/2013
Posts: 112



Thanks for pointing out about the side effects. I scanned through the report and missed it. I was more interested in the charts.

Yes, I am surprised that 6 million people in US consumed this regularly. What I can think of is the difference in body size may matter on how much one can take. Americans are taller and bigger than Asians. This is where dosage, I believe, can make a difference - My 2 cents.

Since the evidence of cognition benefit is strong from the clinical trials for Korean red ginseng, maybe it is worth a try in lower dosage as the cognitive improvement is only one point difference between a low and a high dosage. The study is not clear though in drop out rates due to side effects within the 2 years. And having the side effect after two years data would be even more helpful. A blanket statement of side effects was stated.




Lane Simonian
Posted: Monday, April 6, 2015 9:17 PM
Joined: 12/12/2011
Posts: 4998


Only one more person dropped out of the 9 gram group compared to the 4.5 group at 26 weeks, but this says nothing about the severity of the side effects. And there is indeed not much difference between the 4.5 gram group and the 9 gram group at 2 years. Given the limited access to information, a 4.5 dose might be relatively safe and relatively effective for most people. It would be good to know however the adverse affects that may have manifested themselves between 26 weeks and two years in both groups.

I ordered the heat processed ginseng article via intralibrary loan today. Hopefully, the librarian can track it down. It will be interesting to compare effects (on cognition and side effects) of heat processed ginseng versus red Korean ginseng. I will include the results in this thread if I receive the full article.

Lane Simonian
Posted: Tuesday, April 7, 2015 11:14 PM
Joined: 12/12/2011
Posts: 4998


I just got the estimate tonight for how much it would cost to do a 24 week trial with 50 participants using 4.5 grams of panax ginseng a day and daily aromatherapy with clove, bay laurel, and lemon balm and fifty on placebo: $325,000 to $350,000. Oh man, the mountain just got that much higher. I was expecting about $200,000. It is times like this where it would be nice to be a millionaire. I don't have much hope but I am going to see what I can turn up in the way of organizations that might have an interest in expending that kind of money on unconventional treatments for Alzheimer's disease.
Lane Simonian
Posted: Wednesday, April 8, 2015 2:30 PM
Joined: 12/12/2011
Posts: 4998


The great librarian at my school found the heat-processed ginseng article through one of the health databases. I am going to read through the article and post what I believe is the most important information as I go along:

Sun ginseng is a new ginsenoside complex that is formed by heat treatment of raw ginseng at high temperature (120 degrees Celsius for 3 hours).

The major ginsenosides...have been shown to have memory-enhancing effects in an experimental model of alcoholic dementia. They also attenuate excitotoxic neuronal cell damage or oxidative neuronal damage by inhibiting glutamate and N-methyl-D-aspartate (NMDA)-induced Ca2+ influx in cortical cells.

There was no significant difference in adverse events between the four groups at 12 weeks and 24 weeks. At the 24-week follow-up, four patients in each group complained of adverse events [four out of 10], including urticaria [hives], headache, palpitation, and irritability. Urticaria, headache, palpitation, irritrability were noted in the sun ginseng group, and headache, nausea were in control group. All the patients who reported adverse events withdrew from the study. However, the adverse events experienced by these patients were tolerable and subsided without specific treatment.

The authors note the limitations of the study: open label, small number of participants, and short duration.

Here is the statistical data with just the mean (I left out the standard deviation but that is important in regards to statistical significance):

Group Baseline 12 weeks 24 weeks

ADAS-cog 1.5 grams 48.3 44.3 29.0
3 grams 40.3 44.3 35.1
4.5 grams 41.3 27.4 28.5
Control 30.2 29.0 26.1

ADAS-non-cog 1.5 grams 8.9 6.2 2.8
3 grams 9.4 8.7 3
4.5 grams 11.6 4.3 3.5
Control 10.9 5.1 6

MMSE 1.5 grams 12.1 10 14.4
3 grams 11.6 10.8 13.7
4.5 grams 14.6 20.8 17
Control 16.4 17 20.0

Statistical significant improvement was seen only in the 4.5 gram group in ADAS-cog, ADAS-non-cot, and MMSE at 12 and 24 weeks.






onward
Posted: Wednesday, April 8, 2015 2:57 PM
Joined: 12/20/2011
Posts: 217


Lane, thanks very much for going to the trouble of locating the article and reporting back to us so quickly.

So... if I've got this right...

The heat-processed ginseng at 4.5 grams daily -
boosted the MMSE by 6 points at 3 months,
but then the MMSE dropped back to a 3 point gain at 6 months.

(The ADAS test, which you said is more accurate, I'm not as familiar with.)

It certainly would be interesting to see them do a study that's larger and double-blind. I wonder if that's in the works.



Lane Simonian
Posted: Wednesday, April 8, 2015 5:33 PM
Joined: 12/12/2011
Posts: 4998


You are welcome, Onward. Yes, this is the trouble with very small sample sizes. For the 4.5 gram group there was about a 14 point drop after 12 weeks in ADAS-cog scores (which is indeed a more thorough evaluation than the MMSE test) and then about a 1 point gain (which is not good) at 24 weeks. In the red Korean ginseng study which had just a few more people there was continued improvement in ADAS-cog scores from 12 to 24 weeks. This is what one would expect, but without larger numbers it is hard to say which study was more accurate.


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/figure/F002/


The difference between the 4.5 gram sun ginseng group and 9 gram red Korean ginseng group at 24 months is very close to the same. And after two years, the difference between the 4.5 gram red Korean ginseng group and the 9 gram red Korean ginseng group is also about the same. I have to really focus on the figures more but the short-term use of red Korean ginseng at either the 4.5 gram dose or the 9 gram dose or sun ginseng at 4.5 grams seems to lead to improvements in cognitive function. The improvements in red Korean ginseng are then sustained for two years.


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/figure/F002/


I am not aware of any future trials at this point. To do a double-blinded randomized placebo controlled trial of red Korean ginseng combined with aromatherapy for 100 people (50 on placebo) for 24 weeks in the U.S. would cost about $350,000


Lane Simonian
Posted: Thursday, April 9, 2015 3:14 PM
Joined: 12/12/2011
Posts: 4998


Head to head comparisons between sun ginseng (SG) and Korean red ginseng (KRG). 12 week and 24 week Korean MMSE scores for Korean red ginseng estimated from chart.


Baseline 12 weeks 24 weeks 96 weeks

ADAS-cog SG 4.5 grams 41.3 27.4 28.5 -
ADAS-cog KRG 4.5 grams 19.7 17.8 15.8 9.5
ADAS-cog KRG 9 grams 23.0 19.0 9.2 12.8

MMSE SG 4.5 grams 14.6 20.8 17.0 -
MMSE 4.5 grams 22.1 23.2 23.6 23.7
MMSE 9 grams 21.4 23.8 24.8 24.0

It appears that the more concentrated dose of sun ginseng produces maximum results at 12 weeks, the higher dose of Korean red ginseng produces maximum results at 24 weeks, but the 4.5 gram dose of Korean red ginseng may nearly equal the results of the 9 gram dose of Korean red ginseng at two years. So if you are doing a 24 week trial may be the 9 gram dose of Korean red ginseng is optimal, but for long-term use with fewer and less severe side effects the 4.5 gram dose is probably the best option.

scma_2007
Posted: Thursday, April 9, 2015 10:20 PM
Joined: 9/13/2013
Posts: 112



Thanks for simplifying the comparative stats.

Definitely agree with you!



Lane Simonian
Posted: Thursday, April 9, 2015 11:44 PM
Joined: 12/12/2011
Posts: 4998


You are certainly welcome. Thanks to inquiries and insights from Onward and you it is now much clearer to me. One does not need the very expensive sun ginseng nor does one need the high dose Korean red ginseng to produce the same long-term results (and probably with fewer side effects at the lower dose). What a more concentrated ginseng or a higher dose ginseng does is to produce results sooner. But the long-term results are basically the same. To me, it means that it just takes longer to reverse oxidative damage with lower doses, but eventually the same amount of damage is reversed and then that damage is kept in check from then on out.

Knowing this (or thinking I know this) leaves me with mixed feelings. It says that Alzheimer's disease can be reversed in small part and that it becomes a chronic disease rather than a fatal disease. But it also makes me wonder that if at some point you hit a brick wall, so that any additional antioxidant therapy provides few if any more benefits. I knew this from my mother's own experience with Alzheimer's disease, but I was hoping that more concentrated antioxidants or higher doses of antioxidants would produce better results. Being able to stop the progression of Alzheimer's disease and in small ways reversing it is still a major achievement but not the same as a cure (which may or may not be possible).