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Joined: 12/12/2011
Posts: 4855
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I have a research friend in Brazil who has done a great deal of research on the use of glucuronolactone and its metabolite glucaric acid in the treatment of behavioral problems for Alzheimer's disease. He has given me permission to share part of his research here.
For two years, he has given his aunt with Alzheimer's disease glucuronolactone powder and after about thirty minutes her hallucinations, delusions, yelling, and agitation are under control. None of the other supplements, he is using (extra virgin coconut oil, carnosine, and carnitine) work to produce this effect.
My friend says that glucuronolactone is a powerful liver detoxifier and that it does not work well with certain other medications that require liver detoxification or with a diet high in saturated fats (he also pointed out to me that extra virgin coconut oil will even help those with the APOE4 gene as long as they do not consume many other saturated fats). The detoxification process limits the availability of glucuronolactone elsewhere in the body.
One source of glucaric acid is apple juice. In one study, apple juice did not improve cognition but significantly reduced behavioral problems.
Abstract
Preclinical studies demonstrate that apple juice exerts multiple beneficial effects including reduction of central nervous system oxidative damage, suppression of Alzheimer’s disease (AD) hallmarks, improved cognitive performance, and organized synaptic signaling. Herein, we initiated an open-label clinical trial in which 21 institutionalized individuals with moderate-to-severe AD consumed 2 4-oz glasses of apple juice daily for 1 month. Participants demonstrated no change in the Dementia Rating Scale, and institutional caregivers reported no change in Alzheimer’s Disease Cooperative Study (ADCS)-Activities of Daily Living (ADL) in this brief study. However, caregivers reported an approximate 27% (P < .01) improvement in behavioral and psychotic symptoms associated with dementia as quantified by the Neuropsychiatric Inventory, with the largest changes in anxiety, agitation, and delusion. This pilot study suggests that apple juice may be a useful supplement, perhaps to augment pharmacological approaches, for attenuating the decline in mood that accompanies progression of AD, which may also reduce caregiver burden.
Glucuronalactone and glucaric acid may help reduce dopamine levels (which contribute to hallucinations) by lowering myo-inositol levels which are often high in individuals with Alzheimer's disease (and even higher in those with behavioral probems).
Elan’s Gene Kinney recounted how falling myoinositol levels were discovered when company researchers used NMR to confirm scyllo-inositol had made its way into the brain. The researchers noticed that, as brain scyllo-inositol rose, its myo-isoform fell. Going back to animal models, they found that the myo isoform dropped by as much as 70 percent when the animals imbibed drinking water laced with scyllo-inositol. Why is this important? Previously, researchers had reported elevated brain myoinositol in patients with AD, Down's syndrome, and bipolar disorder, said Kinney (see Miller et al., 1993). More recently, a group in Japan correlated elevated brain myoinositol with behavioral and psychological problems in AD patients. Lithium, which has been used for many years to treat neuropsychiatric disorders, may work in part by reducing myoinositol. In fact, a 30 percent reduction of myoinositol is predictive of lithium efficacy, said Kinney. By reducing myoinositol, could scyllo-inositol treat neuropsychiatric symptoms in AD patients?
http://www.alzforum.org/new/detail.asp?id=3184
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1970.tb56424.x/abstract
[scyllo-inositol resulted in deaths in clinical trials for Alzheimer's disease and lithium is a very difficult drug, so glucarates may provide a safer alternative].
When combined with more powerful peroxynitrite scavengers such as various essential oils and heat-processed ginseng, glucuronolactone/glucaric acid may lead to improvements in both behavior and cognition.
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Joined: 12/12/2011
Posts: 4855
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Researching this disease is like going from one box to another. My friend from Brazil has informed me that the use of glucuronolactone powder in conjunction with methxoyphenols such as curcumin or various essential oils cancels all the benefits of glucuronolactone in stopping hallucinations, anxiety, and agitation. Indeed, they often make the situation worse. So once again compounds that improve cogniton worsen behavior when the behavioral problems are the result of high levels of adrenaline and dopamine (because many phenolic compounds increase adrenaline and dopamine levels).
One essential oil--lemon balm--has compounds that both increase cognition (eugenol) and reduce agitation and anxiety (linalool).
http://mt.china-papers.com/?p=51999
http://www.ncbi.nlm.nih.gov/pubmed/19962290
Whether lemon balm essential oils in conjunction with glucuronolactone powder would improve cognition and improve behavior is unknown at this point.
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Joined: 12/12/2011
Posts: 4855
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This may be a critical factor in why some people with Alzheimer's disease suffer from hallucinations and others don't.
Increased noradrenergic activity has been associated with anxiety and aggression. Postmortem studies have shown that Alzheimer's disease patients exhibiting psychotic behaviors and agitation have higher levels of norepinephrine than AD patients without psychotic symptoms.
http://www.gcrweb.com/PsychosisDSS/clinical/clin-neuro.html
Aluminium fluoride via protein kinase C is one factor in increased noreadrenaline release.
Effect of concurrent chronic exposure of fluoride and aluminum on rat brain.
Source
Department of Biophysics, Panjab University, Chandigarh, India. tanzeercaur@rediffmail.com
Abstract
The present in vivo study was designed to investigate the toxic potential of fluoride alone and in conjugation with aluminum on the rat brain. The region-specific response of both elements was studied in different regions of brain, namely the cerebrum, cerebellum, and medulla oblongata. Following fluoride exposure, oxidative stress increased significantly, estimated by increased lipid peroxidation and a decrease in the activity of the antioxidant enzyme, superoxide dismutase. The neurotransmitter (e.g., dopamine, norepinephrine, and serotonin) content was also altered. However, these aspects were more pronounced in animals given fluoride and aluminum together. Histological evidence showed deprivation of neuronal integrity with higher magnitude in concurrent fluoride and aluminum exposure, as compared to fluoride alone. Thus, it can be concluded that aluminum appears to enhance the neurotoxic hazards caused by fluoride.
What role if any aluminium fluoride plays in hallucinations in Alzheimer's disease has not been determined, but it may be one factor in protein kinase C/noreadrenaline produced hallucinations.
http://www.schizophrenia.com/sznews/archives/001350.html
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Joined: 12/12/2011
Posts: 4855
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It turns out that the same charts that explain Alzheimer's disease explain why some people experience psychosis with Alzheimer's disease and other don't.
In the first chart, myo-inositol is the precursor to phosphatidylinositol 4,5 biphosphate (PIP2). Myo-inositol is a major biomarker for early Alzheimer's disease and limits the phosphatidyinositol 3 kinase/AKT which is neuroprotective. Morevoer, high levels of myo-inositol lead to high levels of protein kinase C which leads to high levels of p38 MAPK which leads to high levels of peroxynitrites which leads to Alzheimer's disease.
In most people with Alzheimer's disease, protein kinase C levels drop as the disease progresses because of the peroxynitrite-mediated oxidation of g-protein coupled receptors (peroxynitrite levels remain high though because peroxynitrites generate p38 MAPK and p38 MAPK generate peroxynitrites). However, g proteins (and protein kinase C) can be activated independently from g-protein coupled receptors. Protein kinase C activation leads to high levels of norepinephrine (noradrenaline) which leads to psychosis. This is likely why some people have psychosis with Alzheimer's disease and others do not.
Compounds that lower myo-inositol such as lithium, scyllo-inositol, and glucuronolactone will also lower protein kinase C activity and should be able to at least partially treat psychosis. Of these only glucuronolactone appears generally safe.
Elan’s Gene Kinney recounted how falling myoinositol levels were discovered when company researchers used NMR to confirm scyllo-inositol had made its way into the brain. The researchers noticed that, as brain scyllo-inositol rose, its myo-isoform fell. Going back to animal models, they found that the myo isoform dropped by as much as 70 percent when the animals imbibed drinking water laced with scyllo-inositol. Why is this important? Previously, researchers had reported elevated brain myoinositol in patients with AD, Down's syndrome, and bipolar disorder, said Kinney (see Miller et al., 1993). More recently, a group in Japan correlated elevated brain myoinositol with behavioral and psychological problems in AD patients. Lithium, which has been used for many years to treat neuropsychiatric disorders, may work in part by reducing myoinositol. In fact, a 30 percent reduction of myoinositol is predictive of lithium efficacy, said Kinney. By reducing myoinositol, could scyllo-inositol treat neuropsychiatric symptoms in AD patients?
http://www.alzforum.org/new/detail.asp?id=3184
The problem is that many of the compounds used to improve cognition in Alzheimer's patients are stimulants and will increase norepinephrine levels and thus increase behavioral problems. There may be two ways around this problem: one is by removing the source of what is causing the hallucination, for example, such as aluminium fluoride in drinking water; the other is by finding compounds that effectively scavenge peroxynitrites and lower norepinephrine levels (lemon balm perhaps).
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Joined: 12/12/2011
Posts: 4855
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Ah yes, my brilliant friend from Brazil has it figured out. He has been giving his aunt with Alzheimer's disease glucuronolactone, acetyl-l-carnatine, and L-carnosine (along with extra virgin coconut oil via massage) with dramatic improvements in mood and behavior (greatly reducing hallucinations, crying, yelling, agitation, aggression and anxiety) as well as major improvements in cognition. The reduction in behavioral problems is due to the ability of many of these compounds to reduce protein kinase C activity. They all also improve cognition by scavenging peroxynitrites.
If behavioral problems are not an issue (except for delusions which the following will help), such things as essential oils high in eugenol (bay laurel, clove, cinnamon leaf, basil, nutmeg, etc.), steamed ginseng, boiled curcumin, ginger, etc. will significantly help with mood and cognition. Don't use these (except perhaps lemon balm essential oil) if agitation, hallucinations, and aggression are problems as they may worsen such problems.
With great help from my friend, I now see an end to this disease in its current form.
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Joined: 12/12/2011
Posts: 4855
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Further evidence that the pathway in the post above leads to Alzheimer's disease. I would not recommend lithium for the prevention of Alzheimer's disease largely because it has a poor safety profile. However, people who take lithium (or valporic acid) for bipolar disorder appear to be at much less risk for Alzheimer's disease.
Lithium and valporic acid lower myo-inositol levels. This increases phosphatidylinositol 3 kinase activity which is neuroprotective and decreases phospholipase C activity which lowers the production of peroxynitrites, the formation of amyloid plaques, the hyperphosphorylation of tau proteins. and in those Alzheimer's patients in which protein kinase C activity remains high may lower hallucinations.
BACKGROUND:
Lithium and valproate (VPA) are used for treating bipolar disorder. The mechanism of mood stabilization has not been elucidated, but the role of inositol has gained substantial support. Lithium inhibition of inositol monophosphatase, an enzyme required for inositol recycling and de novo synthesis, suggested the hypothesis that lithium depletes brain inositol and attenuates phosphoinositide signaling. Valproate also depletes inositol in yeast, Dictyostelium, and rat neurons. This raised the possibility that the effect is the result of myo-inositol-1-phosphate (MIP) synthase inhibition.
http://www.ncbi.nlm.nih.gov/pubmed/15576064
Med Hypotheses. 2008 Dec;71(6):948-51. doi: 10.1016/j.mehy.2008.03.049. Epub 2008 Aug 28.
Lithium may be useful in the prevention of Alzheimer's disease in individuals at risk of presenile familial Alzheimer's disease.
Source
Department of Family Medicine, Taipei Veterans General Hospital, Taiwan.
Abstract
Alzheimer's disease (AD) is the most common form of dementia among older people. Presenile familial AD (FAD) and sporadic Alzheimer's disease (SAD) have identical brain lesions, containing senile plaques with beta-amyloid (Abeta) peptide and neurofibrillary tangles formed by hyperphosphorylation of a microtubule-associated protein known as tau. However, FAD and SAD differ in onset and genetic transmission. Unlike SAD, presenile FAD is transmitted as a pure autosomal dominant trait. The authors suggest that lithium could be used for AD prevention, particularly in individuals at risk of presenile FAD, which has early onset. Evidence supporting this hypothesis suggests that lithium decreases Abeta peptide production and inhibits the activity of glycogen synthase kinase-3 which induces aggregation of tau protein into tangles, and tau hyperphosphorylation. Prevalence of AD is lower in patients with chronic lithium treatment, which also increases brain-derived neurotrophic factor activity, so might prevent onset in patients at risk for AD. Several considerations are suggested for prevention trials: the effect of lithium could be evaluated in young animal models that express presenile FAD mutant genes; the time, dose, duration and monitoring of lithium therapy are considered; early phenotypes could be monitored for treatment effect; and some other agents, like valproic acid, could also be candidates for prevention.
http://www.ncbi.nlm.nih.gov/pubmed/18760542
For individuals with Alzheimer's disease without behavioral problems some combination of p38 MAPK inhibitors (which contribute to peroxynitrite formation) such as salvianolic acid, reishi mushrooms, and astragalus with effective peroxynitrite scavengers (such as clove, bay laurel, basil, rosemary, and lemon balm essential oils, steamed ginseng, boiled curcumin, and ginger) should lead to significant improvements in cognition.
For individuals with Alzheimer's disease with behavioral problems glucuronolactones which break down myo-inositol and scavenge peroxynitrites might both reduce anxiety, aggression, and hallucinations while improving cognition.
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Joined: 12/12/2011
Posts: 4855
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Rather that trying to convey my researcher friend's message, you can directly read his very important comments (with caveats).
supplements in an empirical use are controlling "odd" behaviors of my aunt
We are giving the folllowing supplements that are controlling delusions , agressiviness , hallucinations , agitation , depression of my aunt with advanced dementia . Friends of mine are using the same supplements with their relatives with dementia with the same good results to enhances cognition , mood and behavior .
This use of that supplements do NOT have NONE scientific foundation , but it is working for us we observed , in an empirical way , that the enhancings in the mood and behavior disorders starts just in the next day after the patient takes the supplements . and in some cases starts just a couple hours after the patient takes the supplements that I describe bellow,. They stops to have delusions and agressiviness , and starts to be very calm and cooperative.
As I wrote above , it do NOT have none scientific foundation .
Only the MEDICINE DOCTOR OF THE PATIENT can gives permission to use that supplements .
We use (in an empirical mode):
GLUCOSAMIN SULFATE : 200 (two hundred) miligrams four times a day (works as a tau stabilizer and as a alternative fuel to the brain) Based in : J Alzheimers Dis. 2006 Mar;9-Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation-Gong CX, Liu F, Grundke-Iqbal I, Iqbal K.)
Associated to:
L-CARNOSINE (it is NOT L-carnitine) : L-carnosine have antioxidative , antiglycating and have metal chelator propierties , We give 80 (eight) miligrams 3 times a day at meals.
Associated to:
L-GLUCURONOLACTONE : Wer are giving 200 (two hundred) miligrams 3 to 4 times a day . It derivative after liver metabolization it is the GLUCARIC ACID . L-glucuronolactone and glucaric acid (we can find glucaric acid in high amounts in apples too) , are the most powerful detoxyfiers substances , that works as a powerful antioxidative natural supplement and have too peroxinitrite scavengers propierties ,and it is a heavy metal chelator too , and it is a mitochondrial enhancer and works as an alternative fuel to the brain .
Associated to:
Extra virgin coconut oil - 01 TEA SPOON at meals 3 times a day . To patients that have diarrhea with extra virgin coocnut oil we makes massages with a TEA SPOON of coconut oil 4 times a day in the arms of the patient . Extra virgin coconut oil has comproved trans dermal absortion . Based in :Indian Pediatr. 2005 Oct;42 Transcutaneous absorption of topically massaged oil in neonates.Solanki K, Matnani M, Kale M, Joshi K, Bavdekar A, Bhave S, Pandit A. Department of Pediatrics, KEM Hospital, Pune 411 011, India.
As I wrote above , that are ALL EMPIRICAL USE , AND ONLY THE MEDICINE DOCTOR OF THE PATIENTS CAN GIVES PERMISSION TO USE THAT SUPPLEMENTS , and the use have to be under supervison of the medicine doctor of the patient , mainly in patients that are using blood thinners as aspirin (acetyl salcylic acid), once antioxidative supplements can increase the effects of aspirin as a blood thinner.
But it is working to my aunt and to relatives of friends of mine that have advanced dementia with mood and behavior disorders.
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Joined: 12/12/2011
Posts: 4855
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Some information on ferulic acid in the treatment of dementia.
Effect of ferulic acid and Angelica archangelica extract on behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.
Source
Division of Clinical Research, National Hospital Organization Kikuchi Hospital, Kumamoto, Japan. tkimura@kikuti.hosp.go.jp
Abstract
AIM:
The behavioral and psychological symptoms of dementia place a heavy burden on caregivers. Antipsychotic drugs, though used to reduce the symptoms, frequently decrease patients' activities of daily living and reduce their quality of life. Recently, it was suggested that ferulic acid is an effective treatment for behavioral and psychological symptoms. We have also reported several patients with dementia with Lewy bodies showing good responses to ferulic acid and Angelica archangelica extract (Feru-guard). The present study investigated the efficacy of Feru-guard in the treatment of behavioral and psychological symptoms in frontotemporal lobar degeneration and dementia with Lewy bodies.
METHODS:
We designed a prospective, open-label trial of daily Feru-guard (3.0 g/day) lasting 4 weeks in 20 patients with frontotemporal lobar degeneration or dementia with Lewy bodies. Behavioral and psychological symptoms of dementia were assessed at baseline and 4 weeks after the start of treatment, using the Neuropsychiatric Inventory. The Neuropsychiatric Inventory scores were analyzed using the Wilcoxon rank sum test.
RESULTS:
Treatment with Feru-guard led to decreased scores on the Neuropsychiatric Inventory in 19 of 20 patients and significantly decreased the score overall. The treatment also led to significantly reduced subscale scores on the Neuropsychiatric Inventory ("delusions", "hallucinations", "agitation/aggression", "anxiety", "apathy/indifference", "irritability/lability" and "aberrant behavior"). There were no adverse effects or significant changes in physical findings or laboratory data.
CONCLUSION:
Feru-guard may be effective and valuable for treating the behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.
Ferulic acid is highly concentrated in heat-processed ginseng and is a peroxynitite scavenger (it can also be found in coconut oil).
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.
http://www.ncbi.nlm.nih.gov/pubmed/19298205
In one study, ferulic acid in combination with Angelica archangelica had a significant effect on neuropyschiatric problems in dementia with lewy bodies and frontaltemporal lobe dementia. In the other study, ferulic acid in combination with several other phenolic compounds had a major impact on both cognition and non-cognitive functions.
The results of the following study may begin to offer an explanation for the results.
Conclusion: SF [sodium ferulate--the sodium salt of ferulic acid] prevents Aβ-induced neurotoxicity through suppression of p38 MAPK activation and upregulation of phospho-ERK and phospho-Akt/PKB expression.
http://onlinelibrary.wiley.com/doi/10.1111/j.1745-7254.2005.00158.x/abstract
Phospholipase C--Protein kinase C--p38 MAPK--peroxynitrites--p38 MAPK is the likely initiator of Alzheimer's disease. In most people protein kinase C activity declines as the disease progresses due to the oxidation of g-protein coupled receptors, but due to a series of other activators of protein kinase C--aluminium fluoride and sodium fluoride (via water contamination), for instance--protein kinase C levels remain high in some individuals with Alzheimer's disease. This leads to high levels of norepinephrine which can lead to hallucinations. By activating the phosphatidylinositol 3 kinase/AKT pathway ferulic acid lowers protein kinase C levels and should lessen hallucinations. Ferulic acid may also do so by increasing glucose transport and metabolism and by increasing acetylcholine and serotonin levels via its actions as a peroxynitrite scavenger (the latter would also improve memory and mood). Glucuronolactones appear to act in a very similar manner.
The problem with ferulic acid is the opposite of curcumin. It is absorbed easily into the bloodstream but not into the brain. Like curcumin, researchers are working on more available forms of the compound for the treatment of Alzheimer's disease.
https://docs.google.com/a/wnc.edu/viewer?a=v&q=cache:T3vPxmaIr0YJ:www.chem.uky.edu/research/butterfield/dab_pdfs/Marzia%2520FAEE%2520in%2520vivo%2520JNR%2520revised%25202-16-06.pdf+&hl=en&gl=us&pid=bl&srcid=ADGEESgiJEjZdKVFVsdjVOSYe-Q7MCRfmxn5kAU7dxKhFAzAGWmdCbKXCz0sq5zvV4H2XWwhbzRUCJRnAJH5s2CXiCKBJ5_dbCApzLHW_axtncZj7f1ieWxrK29E8SDIpXljVkpE2Di9&sig=AHIEtbSip0bGX2PXFsnAVTupaU0FiwRXkQ
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Joined: 12/12/2011
Posts: 4855
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The key to treating hallucinations, aggression, and anxiety in Alzheimer's patients appears to be limiting the activity of protein kinase C.
http://www.ncbi.nlm.nih.gov/pubmed/18316672
This makes a great deal of sense because protein kinase C activity varies widely among people with Alzheimer's disease. Most of the pathways that lead to its activation are cut off by the disease, but it can be activated independently by such compounds as aluminium fluoride and sodium fluoride in contaminated water supplies.
One compound that inhibits protein kinase C activity is the flavonoid myricitin which can be found in bayberries.
http://www.ncbi.nlm.nih.gov/pubmed/21689712
I am going to add some more about bayberry as a possible treatment for Alzheimer's disease on the peroxynitrite thread.
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