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Understanding Chemobrain

Compiled by John G. Connor. M.Ac., L.Ac.

01-03-11

 

1.      Introduction

2.      Factors Involved in Cognitive Impairment

3.      Natural Compounds that May Alleviate the Symptoms of Chemobrain

4.      Natural Compounds that Lower Homocysteine

5.      Natural Compounds that Lower C-Reactive Protein

6.      Natural Compounds that Suppress TNF-alpha

7.      References

 

Introduction:

An unknown, but significant subgroup (perhaps the majority), of patients who have undergone chemotherapy treatment for their cancer report a subsequent decline in cognitive performance (e.g., difficulty in balancing a checkbook; forgetting or mixing up names of friends or relatives, etc.). The condition has been termed chemo fog, chemo brain, or some similar term to reflect the fact that the symptoms are usually difficult to describe and involve domains of cognition such as attention, concentration, memory, speed of information processing, multitasking, or ability to organize information. The deficits are reported to persist. The magnitude of the negative impact on quality of life depends, as does the condition itself, on multiple and varied factors. (Raffa & Martin 2010)

 

Mild cognitive impairment following chemotherapy is one of the most commonly reported post treatment symptoms by breast cancer survivors. This deterioration in cognitive function, commonly referred to as “chemobrain” or “chemofog,” was largely unacknowledged by the medical community until recent years. This condition encompasses a range of symptoms such as memory loss, inability to concentrate, difficulty in thinking, and other subtle, cognitive changes.  (Boykoff et al 2009)

 

Current research indicates the cognitive domains that may be most impacted by chemotherapeutic agents are visual and verbal memory, attention and psychomotor functioning.  The potential mechanisms that cause this disruption remain largely unknown, although contributing factors could be vascular injury and oxidative damage, inflammation, direct injury to neurons, autoimmune responses, chemotherapy-induced anemia, and the presence of the apolipoprotein E epsilon4 (APOE epsilon 4) gene. Interventions to help alleviate the symptoms of chemobrain could include nonpharmacologic treatment such as antioxidants and cognitive-behavioral therapy. (Nelson et al 2007)

 

Cognitive dysfunction manifested by severe memory and attention deficits has been reported in up to 70% of cancer patients undergoing chemotherapy, however, the mechanisms of this serious side effect have not been defined. (Konat et al 2008)

 

What Barbara and I are presenting here is a compilation of some of the ways in which we believe natural compounds can help as part of an overall strategy to help prevent and alleviate the symptoms of chemobrain.  Please refer to our Comprehensive Cancer Care Consulting Program article to find out more about how we work with cancer.

 

Factors Involved in Cognitive Impairment

 

Chemotherapy

Chemotherapeutic agents alone, i.e., in the absence of malignancy, damage the brain resulting in memory dysfunction. Moreover, the results strongly indicate that the damaging effect is mediated by oxidative stress, as memory dysfunction is preventable by the co-administration of NAC (N-Acetyl Cysteine). (Konat et al 2008)

           

There is a strong argument that androgen-ablation therapy is linked to subtle but significant cognitive declines in men with prostate cancer. (Nelson et al 2008)

 

Analysis of individual deviation scores revealed that both the patients taking tamoxifen and those taking anastrozole were more likely than healthy controls to show reliable cognitive decline. Processing speed and verbal memory were the cognitive domains most affected. These data suggest that hormonal therapies exert a subtle negative influence on cognition in breast cancer patients.  (Collins et al 2009)

 

Recent studies on breast cancer patients treated with adjuvant chemotherapy have revealed that, relative to controls, patients had slower speeded processing and altered fractional anisotropy (a measure of white matter integrity) in the corpus callosum. It has been suggested that these white matter changes are related to the cognitive deficits that may be associated with treatment with systemic chemotherapy. (Han et al 2008)

 

Reduced numbers of dividing hippocampal neuronal progenitors are also seen in association with exposure to 5-FU, BCNU or cytarabine (cytotoxic chemos), the additional damage to white-matter tracts caused by chemotherapy would be expected to impair normal neuronal impulse conduction in accordance with the changes in ABR (auditory brainstem response) latency seen here and thus might also contribute to alterations in cognition. (Han et al 2008)

 

Radiation

It has been recognized for some time that neuronal tissue is susceptible to oxidative stress because of its high oxygen consumption and modest antioxidant defenses. These features are coupled with a high concentration of iron and high concentrations of polyunsaturated fatty acids, which are easily oxidized and known to generate oxygen radicals following oxidation. Reactive oxygen species (ROS), in particular the hydroxyl radical, can lead to functional alterations in lipids, proteins, and nucleic acids, and an accumulation of ROS is considered to be one factor that contributes to neurodegenerative changes, for example in Parkinson's disease and Alzheimer's disease.  An increase in ROS production occurs following irradiation, and therefore, it is not surprising to find that at least some effects of exposure of cells to ROS are mimicked by exposure of cells to ionizing radiation. (Lonergan et al 2002)

 

In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable (by conventional Western medicine – Ed.). This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. (Monje et al 2002)

 

Elevated Homocysteine:

Homocysteine, which damages blood vessels, nerves, and specifically mitochondria, has been linked to heart attacks, strokes, cancer (particularly colon, breast, and prostate cancer), Alzheimer's disease and other neurological diseases, depression, birth defects, gout, cervical dysplasia, erectile dysfunction and rheumatoid arthritis. The optimal lab range for homocysteine is between 5-9.

 

Elevated C-Reactive Protein (CRP):

            The production of C-reactive protein is an essential part of the inflammatory process and the measurement of this substance reflects the level of inflammatory activity deep within the body.  In one study the more CRP that subjects had at the start of the study, the higher their risk of developing Alzheimer's disease. Optimal lab levels for CRP are below 0.8.

 

Advanced Glycation End Products:

The formation of advanced glycation end products happens in everyone and is a major factor in the aging process itself.  Elevated insulin and glucose can lead to the formation of advanced glycation end products.  Advanced glycation end products-induced free radicals activate the pro-inflammatory cytokine TNF-alpha (tumor necrosis factor-alpha), known to be elevated in the elderly.  TNF-alpha is known to be particularly high in inflammatory diseases of the central nervous system (e.g., Alzheimer's disease, multiple sclerosis, ischemia) and is believed to promote neurodegeneration.

 

Tumor Necrosis Factor-Alpha (TNF-alpha)

The activation of inflammatory cascades has been consistently demonstrated in the pathophysiology of Alzheimer's disease (AD). Among several putative neuroinflammatory mechanisms, the tumor necrosis factor α (TNF-α) signaling system has a central role in this process. Recent evidence indicates that the abnormal production of inflammatory factors may accompany the progression from mild cognitive impairment (MCI) to dementia. Abnormal activation of TNF-α signaling system, represented by increased expression of sTNFR1, is associated with a higher risk of progression from MCI to AD. (Diniz et al 2010)

 

Another study found data to be consistent with a growing body of literature that implicates inflammatory cytokines in neural and behavioral processes and further suggests that TNF-α may be involved in the production and/or maintenance of non-motor symptoms in Parkinson’s Disease. (Menza et al 2010)

 

Glutathione Deficiency:  

            Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many neurological diseases, including seizure, Alzheimer's disease, and Parkinson’s disease.  Animal and human studies demonstrate that adequate protein nutrition (non-denatured whey protein concentrate being the best) is crucial for the maintenance of glutathione homeostasis.

 

Surgery

Postoperative cognitive dysfunction is characterized by the progressive deterioration of intellectual/cognitive function following surgery. It has been suggested that the senile brain, which characteristically expresses higher levels of central proinflammatory cytokines, interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α, is more susceptible to additional insult following surgery. (Cao et al 2010)

  

Natural Compounds that May Alleviate the Symptoms of Chemobrain

 

Many phytochemicals simply do not function effectively as single molecules and there are many examples of synergies within and between the chemical groups. (Kennedy and Wightman 2011)  This is important to keep in mind when putting together an effective protocol for the treatment of Chemobrain.  The beauty of using natural compounds is that many of them have pleiotrophic functions and when combined intelligently they work synergistically with one another.  The following is a list of natural compounds and how they can work to alleviate the side effects of Chemobrain.

 

American ginseng:

            American ginseng is a neurological protectant; it improves memory and learning, and has been shown to improve ADHD.  American ginseng extract has also been shown to improve brainstem neuronal activities, insulintrophic effects, free radical quenching activity and cerebral circulation, which contribute to its neuro-protective and anti-aging effects.

 

Eleuthero:

            Eleuthero demonstrates favorable effects on various human functions, including visual acuity, color differentiation, hearing, fatigability, thinking association with motor activity.  It also possesses a capacity of displaying a normalizing effect regardless of the physiological abnormalities caused by damaging influences, e.g. normalization of blood pressure in patients with both elevated or lowered blood pressure; normalization of blood sugar levels in hyper-or hypoglycemia.

 

Eleuthero has been shown to improve learning and memory.  Several animal and human studies have demonstrated that eleuthero preserves neurological health, inhibits oxidative damage and extends life span.

 

Rhodiola:

            Rhodiola rosea extract enhances immunity, increases capacity for exercise, increases the activity of superoxide dismutase, decreases serum lipids and modulates the ratio of cAMP and cGMP.  It also has antimutagenic and antioxidant properties, enhances memory and is an antidepressive agent.

 

            Rhodiola rosea extract has also been shown to enhance central nervous system activity, improve learning and memory, improve mood, act as a neuro-enhancer and inhibit aging of the brain.

 

Ashwagandha:

            Ashwagandha root has been shown to enhance learning and memory.  Withanolide A (WL-A), isolated from ashwagandha root, regenerates neuritis and reconstructs synapses in severely damaged neurons.

 

            Ashwagandha root extract has been shown to increase acetylcholine receptor capacity, which might partly explain the cognition-enhancing and memory-improving effects of extracts observed in animals and humans.

 

            Combined with ginseng, it improves psychomotor skills, protects cognition, and, combined with mumie, inhibits dementia/Alzheimer's disease.  Ashwagandha and mumie together showed a GABA-like effect, as well as an acetylcholine receptor enhancing effect. These effects explain how ashwagandha may enhance memory and inhibit age-related mental decline

 

Rhaponticum:

            Rhaponticum carthamoides extract (RCE) improves sleep, appetite, moods, mental and physical state, and the functional ability of humans under working conditions.  It builds lean muscle, reduces body fat, improves mental acuity, relieves depression, and delays the effects of aging.

            RCE helps prevent loss of lean muscle tissue during the time of intensive training, thereby enhancing middle and long distance runner’s performance.  This same effect is vitally important for the prevention of age-related catabolic increases that contribute to mental decline.

 

Schisandra seed and fruit:

            It has recently been demonstrated that Schisandra berry fortifies mitochondrial antioxidant status. Given the indispensable role of the mitochondrion in generating cellular energy, the linking of Schisandra to the safeguarding of mitochondrial function provides a biochemical explanation for its Qi invigorating action.

 

            Schisandra seed improves reading comprehension, aptitude and speed.  Schisandra fruit possesses therapeutic potential against oxidative neuronal damage induced by excitotoxin.

 

            The results of another study suggest that Schisandra based herbal preparations have some protective characteristics against neuronal cell death and cognitive impairments often observed in Alzheimer's disease, stroke, ischemic injury and other neurodegenerative diseases.

 

            Other primary adaptogens that have been shown to improve memory and learning and to inhibit neurological aging, include Aralia manchuria root (In Vital Adapt) and mumie (In Botanabol).

 

Panax ginseng:   

            Panax ginseng improves overall mental performance, particularly during prolonged stress and helps with poor concentration due to fatigue or old age.  It is also considered a general anti-aging tonic for the elderly.

 

            Panax ginseng was recently shown to possess neurotrophic (improves neurological health) and neuroprotective properties, which may be useful in preventing various forms of neuronal cell loss, including the degeneration seen in Parkinson’s disease.

 

            In one animal study ginseng and schisandra extracts taken together suggested that they might be useful for treating physiological aging and age-related memory deficits in humans.

 

            Panax ginseng possesses a strong protective effect against neurotoxicity by preventing carboxyl-terminal fragments-induced neurofibrillary tangles.  These fragments have been found in plaques, microvessels and the neurofibrillary tangles in the brains of Alzheimer's disease patients.

 

N-Acetyl Cysteine

Chemotherapeutic agents alone, i.e., in the absence of malignancy, damage the brain resulting in memory dysfunction. Moreover, the results strongly indicate that the damaging effect is mediated by oxidative stress, as memory dysfunction is preventable by the co-administration of NAC (N-Acetyl Cysteine). (Konat et al 2008)

 

Glutathione:

            Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many disease including Alzheimer's disease and Parkinson’s disease. 

 

Undenatured whey protein (In Beyond Whey), rich in cysteine, (In Cell Guardian), along with magnesium-glutamine chelates, lipoic acid, N-Acetyl Cysteine (In Cell Guardian), isothiocyanates (In Cell Guardian), selenium schisandrins in Schisandra and silibinin in milk thistle (In Immucare II), all play a role in enhancing healthy cellular glutathione levels in the body.

 

Poria cocus:

            Poria cocus, used in combination with other herbs, recently demonstrated an ability to improve learning and memory, and inhibit dementia in animals.

He shou wu:

            Many studies have verified the brain protecting and enhancing effects of he shou wu, as well as lipid modulating and age reducing effects.

 

 

Ginkgo biloba:

            Ginkgo biloba extract suppresses amyloid-beta toxicity, which initiates synaptic loss and the subsequent neuronal degeneration seen in Alzheimer’s disease.

 

Bacopa:

            Bacopa has been clinically proven to improve memory and mood in Alzheimer’s disease, possessing antidepressant and antioxidative actions.  Bacopa recently demonstrated an ability to prevent aluminum neurotoxicity, a known contributor to dementia and Alzheimer’s disease.

 

            Cigarette smoke induces hsp70 expression and decreases neurons in the brain.  Administration of bacoside A (which is found in Bacopa) prevented expression of hsp70 and neuronal apoptosis during cigarette smoking, protecting the brain from the toxic effects of cigarette smoking.

 

Gotu kola:

            Gotu kola improves memory and inhibits the uptake of glutamate by the brain, a known causative factor in dementia.

 

Companion adaptogens such as turmeric, ginger, rosemary, and grape seed and skin extract (resveratrol), contain high amounts of phenolic compounds, such as anthocyanidins, which inhibit aging of the brain by reducing amyloid plaque formation and affording protection from oxidative damage.  Also bilberry which is rich in anthocyanins, has demonstrated neuron protection.

 

Curcumin:

            Curcumin has been shown to prevent the accumulation of amyloid beta, and to reduce heavy metal toxicity in the brain.  When curcumin was studied in vitro it was found to inhibit amyloid beta aggregation better than ibuprofen or naproxen, which are being evaluated in the treatment of Alzheimer’s disease.

 

Resveratrol, grape seed and skin:

            Moderate intake of red wine, rich in many polyphenols, including resveratrol, has demonstrated significant protection against Alzheimer’s disease, neuropathology, and cognitive deterioration in general.  Resveratrol may also be effective in fighting other human amyloid-related diseases, such as Huntington’s and Parkinson’s disease.

.

Quercetin:

            Quercetin is a flavone found in apples, onions, broccoli, eucalyptus, green, black and red tea, and blue-green algae.  It possesses anti-oxidative, anti-inflammatory, anti-allergenic, and anti-cancer actions, and appears to protect brain cells against oxidative stress, a tissue-damaging process associated with Alzheimer’s and other neurodegenerative disorders.  A new study showed that brain cells treated with quercetin had significantly less damage than those treated with vitamin C or not exposed to any antioxidants.

 

Green Tea: 

            A recent study found that elders who drink green tea regularly may have sharper minds than those who don’t drink green tea.  Those who reported drinking the most green tea were least likely to show cognitive impairment based on their test scores.

 

            Epigallocatechin-3-gallate (EGCG) is a major antioxidant in green tea..  EGCG decreases production of the protein beta-amyloid, which is related to Alzheimer's disease and can accumulate abnormally in the brain, leading to nerve damage and memory loss.  EGCG’s ability to prevent beta-amyloid buildup requires much higher amounts than what would normally be consumed, so drinking green tea alone may be insufficient.  In addition, the amount of EGCG a patient needs to fight Alzheimer's disease is much higher than that found in green tea.

 

Grape seed and skin and  pomegranate juice:

Certain herb and fruit concentrates rich in polyphenols, e.g. grape seed and skin pomegranate extract provide neuroprotection in adult animal models of ischemia and Alzheimer's disease. 

 

Isothiocyanates:

Isothiocyanates from cabbage sprouts, were also recently shown to inhibit neurological disease as well.  This most likely occurred through the enhancement of the brain levels of glutathione, reducing oxidative stress and inhibiting amyloid protein A-beta.

 

Common Sage:

            The results of one study indicate the efficacy of Common sage (S. officinalis) extract in the management of mild to moderate Alzheimer's disease. 

 

High fruit and vegetable intake:

            Higher intake of fruits, vegetables and omega-3 rich fish protect against oxidative damage, thus lower the risk of cancer, cardiovascular disease and the occurrence of Alzheimer's disease.  One study found that fruit and vegetable juices appear to play a significant role in delaying the onset of Alzheimer's disease, particularly among those who are at high risk for the disease. Another recent study confirmed that increased vegetable consumption is protective against cognitive decline.

 

The Mediterranean diet:

            One study found that close adherence to the Mediterranean diet was significantly associated with a reduced incidence of Alzheimer's disease.

 

EPA and DHA fatty acids:

            Clinical studies with DHA/EPA have shown improvement in Alzheimer's disease, senile dementia, cerebral thrombosis and many cardiovascular diseases.  They have also been shown to prevent hyperlipidemia, hypertension and cancer. Boosting levels of DHA in the blood either by eating about three fish-meals each week and/or supplementing the diet with a DHA/EPA-rich fish oil, can reduce the risk of Alzheimer's disease by one-half in elderly men and women. 

 

Creatine:

            A recent human study found that creatine supplementation (5 gm/day) given to people suffering from Alzheimer's disease showed significant enhancement in brain energy capacity, improving brain performance.

 

Lipoic acid and Carnosine:

            Both lipoic acid and carnosine have been shown to rejuvenate aging cells, causing them to regain their youthful state.  Glycosylation, one of the cardinal processes of aging, is inhibited by both lipoic acid and carnosine.

 

            Lipoic acid (alpha-lipoic acid) (In Amino-Max Beyond) has several beneficial effects on the whole body, especially for the liver, eyes, brain, pancreas, kidneys and skin.  Its function as a coenzyme is essential for ATP production and cell efficiency.  Another important benefit of its use is that lipoic acid chelates heavy metals such as aluminum.

 

Alpha Glyceryl Phosphoryl Choline (A-GPC):

            Choline, an essential component of phospholipids, is a building block for acetylcholine; a major neurotransmitter of the central nervous system, its decline is believed to be a contributing cause of Alzheimer's disease.

 

Carnitine and Acetyl l-carnitine:

            Both carnitine and acetyl l-carnitine (ALC) enhance energy production by facilitating the transport of fatty acids into the energy-producing units in the cells.  In two animal studies acetyl l-carnitine significantly reversed age-associated mitochondrial decay.  It increased cellular respiration, membrane potential, cardiolipin levels, and mitochondrial health.

 

CoQ10:

            CoQ10 has been shown to improve learning and memory deficits by inhibiting oxidative stress and improving levels of ATP.

 

Boron:

Boron may play a role in human brain function and cognitive performance.

 

Natural Compounds that Lower Homocysteine

 

1.       Betaine,

2.       Choline,

3.       Creatine,

4.       Folic acid,

5.       Magnesium,

6.       Resveratrol,

7.       Riboflavin,

8.       SAMe

9.       Trimethyl Glycine.

10.   Vitamin B12,

11.   Vitamin B-6,

12.   Zinc,

Efficient conversion of homocysteine requires certain nutrients, which neutralize homocysteine’s toxicity by transforming it into useful substances.  The most well-studied nutrients are folic acid, vitamin B12, and vitamin B6.  Choline, betaine (TMG), creatine, riboflavin, zinc, magnesium and other nutrients also help detoxify homocysteine.

 

Studies show that folate supplements (1-5 mg/day) have a significant impact on reducing homocysteine levels.  Increasing your intake of fruits and vegetables, which has numerous other benefits, and/or supplementing with B vitamins, can help convert homocysteine to other amino acids that are not harmful.  Homocysteine levels can rise when people eat a diet heavy in animal protein and/or few fruits or leafy vegetables.