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From the Townsend Letter
April 2015

Integrative Treatment Considerations for Cancer–Treatment Related Cognitive Dysfunction
by Lise Alschuler, ND, FABNO
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Cancer-related cognitive dysfunction – commonly referred to as "chemo brain" – is a common side effect of chemotherapy, yet many integrative practitioners are unaware that it exists in their cancer-survivor patients. Presently in conventional oncology, due to the still emerging understanding of the condition as well as due the lack of evidence-based therapies, not much is being offered to patients to either prevent or treat this cognitive dysfunction. Although there have not been any scientific studies to validate the use of an integrative approach to reversing chemo brain, given the significant impairment on quality of life imposed by this condition and the high benefit to risk ratio for indicated integrative therapies, an empiric integrative approach is warranted. This approach is buttressed by an understanding of the pathophysiology of chemo brain and utilization of targeted botanicals and nutrients that address aspects of this pathophysiology. Specifically, agents that improve connectivity, ease neurological inflammation, and enhance nerve growth factor are highly indicated in an integrative approach to chemo brain.

Estimates indicate that up to 75% of patients diagnosed with cancer experience chemotherapy-related cognitive impairment, often referred to as "chemo brain," and in about 35% the condition persists for years following treatment.1 In one study involving breast cancer patients, significant impairment was reported even 20 years after completion of chemotherapy, with symptoms similar to those found shortly after treatment, indicating the persistence of this chemotherapy-induced sequela.2
The existence of chemo brain in the medical literature is a fairly new phenomenon, as it has only been scientifically validated within the last decade.3 Symptoms of chemo brain can include:
•    memory lapses
•    trouble concentrating
•    taking longer to complete tasks
•    inability to multitask
•    difficulty remembering common words or details
•    struggle learning new things
Clinically, patient self-reported symptoms consistent with chemo brain can be used to establish the presence of this condition in much the same manner that cancer patients self-report symptoms of fatigue, anorexia, and pain. Symptoms can be subtle and cognitive function may be in the normal range while functioning is still noticeably reduced. It was previously believed that cognitive changes were strictly related to psychological factors such as depression or anxiety, or cancer-related fatigue.4 However, newer evidence refutes this assertion. In a commentary in the Journal of the National Cancer Institute, Karyn Hede makes a case that "chemo brain" should be called "cancer brain" because some research indicates poor cognitive function prior to treatment in patients with invasive cancers.5 Illustrating this very point is a 2014 study which found that people diagnosed with colorectal cancer, including those with localized disease, have a higher incidence of cognitive impairment prior to receiving chemotherapy than do age-matched healthy controls (45% vs. 15%, p < 0.001).6 This suggests that the presence of malignancy per se may predispose to cognitive impairment. This, in turn, creates an even greater susceptibility to the additional cognitive impairment effects caused by chemotherapy. Of note, this study also found that women were more likely to have cognitive impairment than men, and that the cognitive impairment did not correlate with cytokine levels or anxiety or depression. Hede and other experts argue that there are likely several underlying factors that may be contributing to cognitive impairment in patients diagnosed with cancer.7
While clinical data that involve substances – natural or pharmaceutical – to reduce or reverse cancer-related cognitive dysfunction are limited, identification of underlying pathophysiological mechanisms provides reasonable targets for a therapeutic approach.

Potential Pathophysiological Mechanisms
The proposed mechanisms for chemotherapy-induced cognitive dysfunction are numerous. The prevailing emphasis is being placed on impaired connectivity, neurological inflammation, and alterations in neuronal signaling via nerve growth factor (NGF) deficiency. A 2014 longitudinal study was the first to demonstrate reduced connectivity between regions in the brain directly associated with multitasking, attention, and short-term memory in patients who had been treated with chemotherapy.8 A previous 2012 longitudinal study by the same lead researcher demonstrated changes in cerebral white matter integrity after chemotherapy in patients with breast cancer.9 As white matter mediates communication among different brain regions, a compromise in its integrity leads to changes in cognitive performance. This same effect has been observed in the cognitive decline associated with age, neurodegenerative disease, diabetes, and alcohol neurotoxicity. The connectivity tracts most affected by chemotherapy were those involved in processing speed, working and verbal memory, and attention. The mechanism of the decreased connectivity is not known, but is surmised to be the result of demyelination of white matter axons or axonal injury.
Research demonstrates that many chemotherapeutic agents can in fact cross the blood–brain barrier and cause potential harm to the central nervous system.10 One of the effects of chemotherapy agents is elevation of pro-inflammatory cytokines.11 Many studies have demonstrated a link between cognitive dysfunction and an increase in inflammatory markers, particularly IL-6.12 Neuroinflammation affects neurotransmitter levels and causes direct oxidative damage to white matter and to neurons.
Neurotrophins are a family of proteins that control survival, development, and function of neurons. Specifically, neurotrophins control synaptic function and neuroplasticity and sustain neuronal cell survival, morphology, and differentiation. Neurotrophins include nerve growth factor (NGF) and brain-derived nerve factor (BDNF), among others. Neurotrophins are important to the functional integrity of neurons and are specifically associated with attention and memory, which are areas negatively affected by chemotherapy.13 In a prospective controlled trial of patients with B-cell non-Hodgkin lymphoma, postchemotherapy cogni­tive impairments were more severe than in healthy controls and this impairment was associated with lower BDNF levels.14
Other factors that may contribute to chemo brain include oxidative damage, genetic predisposition, HPA axis damage/dysfunction, and altered blood flow. While of interest, data supporting a direct link between dysfunction in one or more of these areas and chemotherapy-induced cognitive dysfunction are still considered preliminary.
Nutritional and Botanical Considerations
While there are many natural substances that can affect proposed mechanisms underlying chemo brain, this article will focus on several agents that show particular promise and are perhaps less familiar to many integrative practitioners. Specifically, the therapeutic possibilities of lion's mane, acetyl-L-carnitine, citicoline, curcumin, and rosemary for the management of chemo brain will be discussed.

Lion's mane (Hericium ernaceus) is an edible medicinal mushroom that has been used in Traditional Chinese Medicine for centuries. Preclinical studies have demonstrated the ability of lion's mane extracts to increase NGF.15 This action appears to translate clinically. A 2009 double-blind, placebo-controlled trial demonstrated that 3 g of lion's mane taken daily over 4 weeks improved mild cognitive impairment in adults aged 50 to 80.16 Another randomized, double-blind, placebo-controlled 4-week trial of 30 females found that 2 g of powdered lion's mane reduced depression and anxiety while improving concentration.17 Lion's mane has also been shown to have anti-inflammatory, immune-stimulatory, and other anticancer effects.18
The amino acid acetyl-L-carnitine has been shown to enhance brain function and improve memory. Acetyl-L-carnitine has neuroprotective properties and has been shown, in the presence of NGF, to activate genes involved in the response to neurotoxins.19 Additionally, acetyl-L-carnitine normalizes neuronal concentrations of neurotrophins, further contributing to the neuroprotective effect.20 In a randomized, placebo-controlled trial conducted in 2011, 62 patients with severe hepatic encephalopathy were randomized to receive 4 g of acetyl-L-carnitine or placebo daily for 90 days. 21 At the end of the study, there was a significant difference between the two groups in cognitive function. Additionally, 88% of the acetyl-L-carnitine-treated patients showed favorable modification of EEG vs. 72% of the placebo-treated patients.
is a nutrient that naturally occurs in the body and is the rate-limiting substrate in the synthesis of phosphatidylcholine, a critical component of neuronal cell membranes, thereby increasing neuroplasticity, connectivity, and cognition. A 2013 clinical trial involving 349 elderly adults demonstrated that 500 mg citicoline taken twice daily for 9 months activated the biosynthesis of phospholipids in neuronal membranes, increased brain metabolism, elevated norepinephrine and dopamine levels in the central nervous system, and exerted neuroprotective effects during hypoxia and ischemia.22 A 2012 study showed that 60 healthy women aged 40 to 60 who took 500 mg citicoline had significantly improved attentional performance compared with placebo.23 A 2008 study utilized magnetic resonance spectroscopy to confirm that both 500 mg and 2000 mg doses of citicoline given to 16 adults resulted in improved frontal lobe bioenergetics and phospholipid turnover. This study found that citicoline improves cognition by increasing essential phospholipid membrane components needed to synthesize and maintain cell membranes in the frontal lobe. Interestingly, the lower dose of citicoline exerted changes of a greater magnitude than did the higher dose.24
While many clinicians may not think of curcumin as a brain supportive botanical, its anti-inflammatory affects make it an appropriate herb for this population. A 2008 literature review of curcumin and Alzheimer's disease highlighted many mechanisms underlying its observed cognitive enhancement. Notably, curcumin exerts anti-inflammatory effects, specifically downregulating IL-6, IL-1, and TNF-alpha, all of which have been linked to impaired cognition. In addition, curcumin exerts antioxidant actions, decreases microglia formation, chelates metals, provides neuronal protection, and decreases amyloid-beta plaques.25 A 2014 animal study showed that curcumin reduced inflammation linked to poor cognition, supported axonal regeneration, and enhanced BDNF.26 Human studies have demonstrated an antidepressive effect of curcumin, with a daily dose of 1000 mg showing equivalent effectiveness to 20 mg fluoxetine for individuals with major depressive disorder.27 While depression is distinct from chemo brain, this study demonstrates the clinically relevant neurological activity of curcumin.
Rosmarinic acid from rosemary has been show in animal models to prevent lipid peroxidation and to prevent oxidative damage in the brain.28 The compound 1,8-cineole from rosemary has also been shown to benefit brain health. A 2012 study involving 20 healthy volunteers demonstrated that the participants who had the highest 1,8-cineole concentrations from the aroma of rosemary also had the best cognitive performance.29 This is consistent with similar results from a 2003 study showing that rosemary aromatherapy significantly enhanced cognitive performance and working memory.30
There is often mention of Gingko biloba when it comes to conversations about enhancing cognition. While studies involving general cognition are positive, there was one study in 2012 specifically involving patients diagnosed with breast cancer who had been on chemotherapy. In that study, a dose of 60 mg twice daily of Ginkgo biloba showed no benefit in cognitive performance.31

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