Alzheimer's disease

Alzheimer's disease (AD), also called Alzheimer disease, senile dementia of the Alzheimer type, primary degenerative dementia of the Alzheimer's type, or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Most often, it is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.

Although the course of Alzheimer's disease is unique for every individual, there are many common symptoms. The earliest observable symptoms are often mistakenly thought to be 'age-related' concerns, or manifestations of stress. In the early stages, the most common symptom is inability to acquire new memories, observed as difficulty in recalling recently observed events. When AD is suspected, the diagnosis is usually confirmed with behavioural assessments and cognitive tests, often followed by a brain scan if available.

As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline. Gradually, bodily functions are lost, ultimately leading to death. Individual prognosis is difficult to assess, as the duration of the disease varies. AD develops for an indeterminate period of time before becoming fully apparent, and it can progress undiagnosed for years. The mean life expectancy following diagnosis is approximately seven years. Fewer than three percent of individuals live more than fourteen years after diagnosis.

The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain. Currently used treatments offer a small symptomatic benefit; no treatments to delay or halt the progression of the disease are, as of yet, available. As of 2008, more than 500 clinical trials have been conducted for identification of a possible treatment for AD, but it is unknown if any of the tested intervention strategies will show promising results. A number of non-invasive, life-style habits have been suggested for the prevention of Alzheimer's disease, but there is a lack of adequate evidence for a link between these recommendations and reduced degeneration. Mental stimulation, exercise, and a balanced diet are suggested, as both a possible prevention and a sensible way of managing the disease.

Because AD cannot be cured and is degenerative, management of patients is essential. The role of the main caregiver is often taken by the spouse or a close relative.  Alzheimer's disease is known for placing a great burden on caregivers; the pressures can be wide-ranging, involving social, psychological, physical, and economic elements of the caregiver's life. In developed countries, AD is one of the most costly diseases to society.

Characteristics

The disease course is divided into four stages, with progressive patterns of cognitive and functional impairments.

Pre-dementia

The first symptoms are often mistakenly attributed to aging or stress. Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of AD. These early symptoms can affect the most complex daily living activities. The most noticeable deficit is memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.

Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of AD. Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease. term corresponds to a different diagnostic stage or identifies the first step of AD is a matter of dispute.

Early

In people with AD the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small portion of them, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems.  AD does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a lesser degree than new facts or memories.

Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, which lead to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is usually capable of adequately communicating basic ideas. While performing fine motor tasks such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present but they are commonly unnoticed. As the disease progresses, people with AD can often continue to perform many tasks independently, but may need assistance or supervision with the most cognitively demanding activities.

Moderate

Progressive deterioration eventually hinders independence; with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases.  During this phase, memory problems worsen, and the person may fail to recognise close relatives.  Long-term memory, which was previously intact, becomes impaired.

Behavioural and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Sundowning can also appear. Approximately 30% of patients develop illusionary misidentifications and other delusional symptoms.  Subjects also lose insight of their disease process and limitations (anosognosia).  Urinary incontinence can develop. These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from home care to other long-term care facilities.

Advanced

During this last stage of AD, the patient is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, patients can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results. Patients will ultimately not be able to perform even the simplest tasks without assistance.  Muscle mass and mobility deteriorate to the point where they are bedridden, and they lose the ability to feed themselves. AD is a terminal illness, with the cause of death typically being an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself.

Causes

Several competing hypotheses exist trying to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinflammation.

In 1991, the amyloid hypothesis postulated that amyloid beta (Aβ) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid beta precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age. Also APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD. Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.

An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia. Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication. One receptor for Aβ oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt-Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease.

In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by aging-related processes in later life to cause the neuronal withering of Alzheimer's disease. N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21). DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the aging brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.

A 2004 study found that deposition of amyloid plaques does not correlate well with neuron loss. This observation supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade.[36] In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.  Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene. 

Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain. Demyelination leads to axonal transport disruptions, leading to loss of neurons that become stale. Iron released during myelin breakdown is hypothesized to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as amyloid-beta and tau.

Oxidative stress and dys-homeostasis of biometal (biology) metabolism may be significant in the formation of the pathology.

AD individuals show 70% loss of locus coeruleus cells that provide norepinephrine (in addition to its neurotransmitter role) that locally diffuses from "varicosities" as an endogenous antiinflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus. It has been shown that norepinephrine stimulates mouse microglia to suppress Aβ-induced production of cytokines and their phagocytosis of Aβ. This suggests that degeneration of the locus ceruleus might be responsible for increased Aβ deposition in AD brains.

Diagnosis

Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia. Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease.

Assessment of intellectual functioning including memory testing can further characterise the state of the disease.  Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process for practicing physicians. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.

Prevention

At present, there is no definitive evidence to support that any particular measure is effective in preventing AD.[111] Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results. However, epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether these factors can help to prevent AD.

Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,  statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease. The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease.  Its beneficial cardiovascular effect has been proposed as the mechanism of action.  There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD.

Reviews on the use of vitamins have not found enough evidence of efficacy to recommend vitamin C, E, or folic acid with or without vitamin B12, as preventive or treatment agents in AD. Additionally vitamin E is associated with important health risks. Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline. Docosahexaenoic acid, an Omega 3 fatty acid, has not been found to slow decline.

Long-term usage of non-steroidal anti-inflammatory drug (NSAIDs) is associated with a reduced likelihood of developing AD. Human postmortem studies, in animal models, or in vitro investigations also support the notion that NSAIDs can reduce inflammation related to amyloid plaques. However trials investigating their use as palliative treatment have failed to show positive results while no prevention trial has been completed. Curcumin from the curry spice turmeric has shown some effectiveness in preventing brain damage in mouse models due to its anti-inflammatory properties. Hormone replacement therapy, although previously used, is no longer thought to prevent dementia and in some cases may even be related to it. There is inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and dementia, and a recent study concludes that it has no effect in reducing the rate of AD incidence. A 21-year study found that coffee drinkers of 3–5 cups per day at midlife had a 65% reduction in risk of dementia in late-life.

People who engage in intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction show a reduced risk for Alzheimer's disease. This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations. Education delays the onset of AD syndrome, but is not related to earlier death after diagnosis. Learning a second language even later in life seems to delay getting Alzheimer disease. Physical activity is also associated with a reduced risk of AD.

Medical marijuana appears to be effective in delaying Alzheimer's Disease. The active ingredient in marijuana, THC, prevents the formation of deposits in the brain associated with Alzheimer's disease. THC was found to inhibit acetylcholinesterase more effectively than commercially marketed drugs. THC was also found to delay amylogenesis.

Some studies have shown an increased risk of developing AD with environmental factors such the intake of metals, particularly aluminium, or exposure to solvents. The quality of some of these studies has been criticised, and other studies have concluded that there is no relationship between these environmental factors and the development of AD.

While some studies suggest that extremely low frequency electromagnetic fields may increase the risk for Alzheimer's disease, reviewers found that further epidemiological and laboratory investigations of this hypothesis are needed. Smoking is a significant AD risk factor. Systemic markers of the innate immune system are risk factors for late-onset AD

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Curcumin

Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family (Zingiberaceae). The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols and are responsible for the yellow color of turmeric. Curcumin can exist in at least two tautomeric forms, keto and enol. The enol form is more energetically stable in the solid phase and in solution.

Curcumin can be used for boron quantification in the curcumin method. It reacts with boric acid forming a red colored compound, known as rosocyanine.

Curcumin is brightly yellow colored and may be used as a food coloring. As a food additive, its E number is E100.

Chemistry

Curcumin incorporates several functional groups. The aromatic ring systems, which are polyphenols are connected by two α,β-unsaturated carbonyl groups. The diketones form stable enols or are easily deprotonated and form enolates, while the α,β-unsaturated carbonyl is a good Michael acceptor and undergoes nucleophilic addition. The structure was first identified in 1910 by J. Miłobędzka, Stanisław Kostanecki and Wiktor Lampe.

Curcumin is used as a reagent for boron in EPA Method 212.3.

Biosynthesis

The biosynthetic route of curcumin has proven to be very difficult for researchers to determine. In 1973 Roughly and Whiting proposed two mechanisms for curcumin biosynthesis. The first mechanism involved a chain extension reaction by cinnamic acid and 5 malonyl-CoA molecules that eventually arylized into a curcuminoid. The second mechanism involved two cinnamate units being coupled together by malonyl-CoA. Both mechanisms use cinnamic acid as their starting point, which is derived from the amino acid phenylalanine. This is noteworthy because plant biosyntheses employing cinnamic acid as a starting point are rare compared to the more common use of p-coumaric acid. Only a few identified compounds, such as anigorufone and pinosylvin, use cinnamic acid as their start molecule. An experimentally backed route was not presented until 2008. This proposed biosynthetic route follows both the first and second mechanisms suggested by Roughley and Whiting. However, the labeling data supported the first mechanism model in which 5 malonyl-CoA molecules react with cinnamic acid to form curcumin. However, the sequencing in which the functional groups, the alcohol and the methoxy, introduce themselves onto the curcuminoid seems to support more strongly the second proposed mechanism. Therefore, it was concluded the second pathway proposed by Roughly and Whiting was correct.

Potential medical uses

Turmeric has been used historically as a component of Indian Ayurvedic medicine since 1900 BC to treat a wide variety of ailments. Research in the latter half of the 20th century has identified curcumin as responsible for most of the biological activity of turmeric. In vitro and animal studies have suggested a wide range of potential therapeutic or preventive effects associated with curcumin. At present, these effects have not been confirmed in humans. However, as of 2008, numerous clinical trials in humans were underway, studying the effect of curcumin on various diseases, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis, and Alzheimer's disease.

In vitro and animal studies have suggested curcumin may have antitumor, antioxidant, antiarthritic, antiamyloid, anti-ischemic, and anti-inflammatory properties. Anti-inflammatory properties may be due to inhibition of eicosanoid biosynthesis. In addition it may be effective in treating malaria, prevention of cervical cancer, and may interfere with the replication of the human immunodeficiency virus (HIV). In HIV, it appears to act by interfering with P300/CREB-binding protein (CBP). It is also hepatoprotective. A 2008 study at Michigan State University showed low concentrations of curcumin interfere with Herpes simplex virus-1 (HSV-1) replication . The same study showed curcumin inhibited the recruitment of RNA polymerase II to viral DNA, thus inhibiting its transcription. This effect was shown to be independent of effect on histone acetyltransferase activities of p300/CBP. A previous (1999) study performed at University of Cincinnati indicated curcumin is significantly associated with protection from infection by HSV-2 in animal models of intravaginal infections.

Curcumin acts as a free radical scavenger and antioxidant, inhibiting lipid peroxidation and oxidative DNA damage. Curcuminoids induce glutathione S-transferase and are potent inhibitors of cytochrome P450.

The Siegel Life Project funded an initial study on curcumin for Alzheimer's in 1997-1998 through the UCLA Center on Aging. UCLA/VA researchers Drs. Cole and Frautschy presented potent anti-Alzheimer's effects in 1997 and 2000 at the Society for Neuroscience. These data were then published in 2001, demonstrating that curcumin was particularly effective in reducing neurodegeneration, oxidative damage, diffuse plaque deposition, aberrant inflammation and impaired inflammatory clearance following beta-amyloid infusion, which was published in 2001. This led to testing in a transgenic animal model where it was shown to dramatically diminish plaque burden and overall inflammation, but also increase plaque associated inflammatory cells suggesting clearance. In 2004 this UCLA/Veterans group demonstrated that the effect was in part to the highly specific binding effects to beta-amyloid, whereby it could break apart amyloid aggregates in vitro, bind to plaques in vivo, and because of its fluroescent properties, it could be determined that plaques of transgenic mice ingesting curcumin fluoresced green, demonstrating brain penetration. A Harvard group showed that 7 days of tail vein injections of curcumin shrunk plaque size and reduced dystrophic neurites. The UCLA group also showed curcumin synerigizing with fish oil working to protect against cognitive deficits in another transgenic model. However humans show much more glucuronidation than rodents, and glucuronidated curcumin does not pass the blood brain barrier (See section on curcumin formulations). Free curcumin but not glucuronidated curcumin readily passes through the barrier. But extensive glucuronidation in humans is the major barrier to translation in neurodegenerative diseases. Human intestinal cells glucuronidate more than rodent intestine (Ireson)

There is also circumstantial evidence curcumin improves mental functions; a survey of 1010 Asian people who ate yellow curry and were between the ages of 60 and 93 showed those who ate the sauce "once every six months" or more had higher MMSE results than those who did not. From a scientific standpoint, though, this does not show whether the curry caused it, or people who had healthy habits also tended to eat the curry, or some completely different relationship.

Numerous studies have demonstrated curcumin, amongst only a few other things, such as high impact exercise, learning, bright light, and antidepressant usage, has a positive effect on neurogenesis in the hippocampus and concentrations of brain-derived neurotrophic factor (BDNF), reductions in both of which are associated with stress, depression, and anxiety. Curcumin has also been demonstrated to be a selective monoamine oxidase inhibitor (MAOI) of type MAO-A. Fluorescent imaging in a mouse model of Alzheimer's disease showed that curcumin crosses the blood-brain barrier. Several studies have demonstrated that unlike glucuronidated curcumin, free curcumin, which is lipophilic, readily passes the blood brain barrier

In 2009, an Iranian group demonstrated the combination effect of curcumin with 24 antibiotics against Staphylococcus aureus. In that study, in the presence of a subinhibitory concentration of curcumin, the antibacterial activities of cefixime, cefotaxime, vancomycin and tetracycline were increased against test strain. The increase in inhibition zone surface area for these antibiotics were 52.6% (cefixime), 24.9% (cephotaxime), 26.5% (vancomycin ) and 24.4% (tetracycline). Also it showed curcumin has an antagonist effect on the antibacterial effect of nalidixic acid against the test strain.

Although many preclinical studies suggest curcumin may be useful for the prevention and treatment of several diseases, the effectiveness of curcumin has not yet been demonstrated in randomized, placebo-controlled, double-blind clinical trials.

In 2008 scientists at the Salk Institute (Drs. Dave Schubert and Pam Maher) performed high throughput screening, identifying a curcumin pyrazole derivative, which improved memory, is broadly neuroprotective, stimulates BDNF in vitro and in vivo. This group showed in collaboration with UCLA that it was protective in brain trauma  and in collaboration with Cedars Sinai/UCSD groups that it was protective in stroke.

Anticarcinogenic effects

Its potential anticancer effects stem from its ability to induce apoptosis in cancer cells without cytotoxic effects on healthy cells. Curcumin can interfere with the activity of the transcription factor NF-κB, which has been linked to a number of inflammatory diseases such as cancer.

A 2009 study suggested curcumin may inhibit mTOR complex I via a novel mechanism.

Another 2009 study on curcumin effects on cancer states it "modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK)".

A 2010 study in malignant brain tumors showed curcumin effectively inhibits tumor cell proliferation, as well as migration and invasion, and these effects may be mediated through interference with the STAT3 signaling pathway.

When 0.2% curcumin is added to diet given to rats or mice previously given a carcinogen, it significantly reduces colon carcinogenesis.

Curcumin has recently been shown to have phyto-estrogenic activity that might contribute to activity against breast cancer. In the murine model of breast cancer metastasis, curcumin inhibits the formation of lung metastases  probably through the NF-kappa-B dependent regulation of protumorigenic inflammatory cytokines.

Bioavailability

There have been several commercial products developed to provide an alternate route to curcumin. Several trials with unformulated curcumin show extensive glucuronidation and sulfation and typically undetectable levels of free curcumin. For example, trials show that ingestion from 2 to 10 grams of unformulated curcumin lead to undetectable or very low serum levels of free curcumin. For neurodegenerative diseases, it is important that curcumin is absorbed predominantly as 'free" as opposed to glucuronidated, since glucuronidated curcumin does not penetrate the blood brain barrier, while free curcumin is readily brain penetrant.

The first formulation to improve bioavailability was curcumin supplements with piperine ("bioperine", manufactured by Sabinsa Corp, New Jersey) and distributed by several companies. Co-supplementation with 20 mg of piperine (extracted from black pepper) significantly increased the absorption of curcumin by 2000% in a study funded by the manufacturer of piperine. However, the increase in absorption in plasma only occurred during the first hour, after which the difference between the piperine curcumin and the regular curcumin was almost the same as far as absorption. It is important to recognize that rapid clearance from plasma after acute administration does not necessarily represent levels in tissues such as adispose, breast or brain. Glucuronidation inhibitors should be taken cautiously (if at all) by individuals taking other medications, but whether the doses of piperine used can dramatically alter pharmacokinetics of other drugs is unclear.

The second major commercial innovation of curcumin bioavailability was made in 2006, when UC Regents and the Veterans Administration filed a provisional patent, which led to Longvida Optimized Curcumin. In July 2008, the inventors described a new form of "lipidated curcumin" from Verdure Sciences as "Longvida" that was noted to achieve more than 5 micromolar in the brain in vivo. Pharmacokinetics of Longvida in humans shows superior absorption of free curcumin. Extensive toxicity studies have been performed showing Longvida to have an excellent safety profile. as was found in the NIH cancer toxicity studies with tumeric oleoresin leading it to be placed on the FDA's GRAS (generally recognized as safe) list.

Another method to increase the bioavailability of curcumin was later developed as Meriva, patent pending since 2006 and involves a simple procedure creating a complex with soy phospholipids. However, there was no plasma concentration of free curcumin found in humans. In animals, free curcumin reaching 33.4 nanomolar while in humans, none was detected.

Another curcumin proprietary formulation was introduced in 2008 (BCM-95®, Biocurcumax, Arjuna) mixed with turmeric oils, was shown in human cross-over bioavailability comparison tests to have 8 times the bioavailability and greater blood retention time than standard 95% and up to 5 times more than curcumin combined with lecithin and piperine. This same formula was also shown to remain above 200 ng/g for 12 hours in a human clinical study. Plain curcumin remained above 200 ng/g for less than 2 hours. Two hours after ingestion, BCM-95 levels of free curcumin were 10-fold over that of plain curcumin.However these data were in contrast to a six-month placebo-controlled, double-blind clinical trial for Alzheimer's disease, individuals in the BCM-95 groups even doses as high as 4 g failed to yield any significant free curcumin in the plasma. Interestingly there was a non-significant increase in serum amyloid beta with the high dose, which may relate to some effect on amyloid clearance from the brain.

There are other formulations for curcumin in the pipeline, that have not yet become commercial. In 2007, a polymeric nanoparticle-encapsulated formulation of curcumin ("nanocurcumin"). Nanocurcumin particles have a size of less than 100 nanometers on average, and demonstrate comparable to superior efficacy compared to free curcumin in human cancer cell line models. However, actual in vivo absorption (injected or oral) should be tested with this nanoparticle.

In the year of 2010, a food-grade polymer micellar encapsulation system was shown to increase curcumin's water solubility and in vitro anti-cancer activity. It was found that hydrophobically modified starch, usually used to encapsulate flavors, was able to form polymer micelles. Using a simple high-speed homogenization method, it can load curcumin into its hydrophobic core, and thus solubilize curcumin. Cell culture experiments revealed an enhanced anti-cancer activity on HepG2 cell line. However, more in vivo studies are needed to further prove its efficacy in the aspect of bioavailability.

Populations ingesting high amounts of curcumin in foods may have reduced risk for some diseases (Parkinson's), which may be due to an effect of cooking or dissolution in oil. Some benefits of curcumin, such as the potential protection from colon cancer, may not require systemic absorption. Alternatively, dissolving curcumin in warm oils prior to ingestion increases bioavailability; however, other than abstracts presented at Society for Neuroscience in 2009 "Efficacy of curcumin formulations in relation to systemic availability in the brain and different blood compartments in neuroinflammatory and AD models. Society for Neuroscience, Oct 18. 2009, #211.7, Chicago Ill 36:2009", no manuscripts to date have documented this. The poor stability in aqueous solution as opposed to high stability in lipid solutions argues that cooking with curcumin and oil may increase absorption. Curcumin is not stable in water because it is prone to hydrolysis, that convert it to vanillin and ferulic acid. In addition to curries, one can purchase food products containing turmeric (~5% curcumin) such as Nutmeric, which provide turmeric in an oil-solubilized form similar to Indian curry preparations. But the exact amount of curcumin may be far less than 1% curcumin, questioning health relevance.

Potential risks and side effects

Extensive in vivo toxicity studies have been performed with turmeric Oleoresin (85% curcumin) which led to it being placed on the FDA's GRAS (generally recognized as safe) list . Kawanishi et al. (2005) remarked that curcumin, like many antioxidants, can be a "double-edged sword" where, in the test tube, anticancer and antioxidant effects may be seen in addition to pro-oxidant effects. Carcinogenic effects are inferred from interference with the p53 tumor suppressor pathway, an important factor in human colon cancer. Carcinogenic and LD50 tests in mice and rats, however, have failed to establish a clear relationship between tumorogenesis and administration of curcumin in turmeric oleoresin at >98% concentrations. Other in vitro and in vivo studies suggest that curcumin may cause carcinogenic effects under specific conditions.

Clinical studies in humans with high doses (2–12 grams) of curcumin have shown few side effects, with some subjects reporting mild nausea or diarrhea. More recently, curcumin was found to alter iron metabolism by chelating iron and suppressing the protein hepcidin, potentially causing iron deficiency in susceptible patients. Further studies seem to be necessary to establish the benefit/risk profile of curcumin.

There is no or little evidence to suggest curcumin is either safe or unsafe for pregnant women. However, there is still some concern medicinal use of products containing curcumin could stimulate the uterus, which may lead to a miscarriage, although there is not much evidence to support this claim. According to experiments done on rats and guinea pigs, there is no obvious effect (neither positive, nor negative) on the pregnancy rate or number of live or dead embryos. Curcumin has embryotoxic and teratogenic effects on zebrafishes (Danio rerio) embryos.

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