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Institute of Medicine (US) Committee on Nutrition, Trauma, and the Brain; Erdman J, Oria M, Pillsbury L, editors. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington (DC): National Academies Press (US); 2011.

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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel.

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9Choline

Choline has multiple roles as an essential nutrient. A major dietary component found in eggs and liver, its absorption in the intestine is mediated by choline transporters. The majority of choline is used to synthesize phosphatidylcholine, the predominant lipid in cell membranes. As well as being essential in the synthesis of membrane components, choline accelerates the synthesis and release of acetylcholine, an important neurotransmitter involved in memory storage and muscle control. Choline is an essential element in neurodevelopment. As a major dietary source of methyl groups, choline also participates in the biosynthesis of lipids, regulation of metabolic pathways, and detoxification in the body.

Health outcomes associated with choline involve memory, heart disease, and inflammation, which also explain the consideration of choline as a plausible intervention in traumatic brain injury (TBI). Although there are no human studies examining the effect of supplementation during pregnancy on enhanced memory of the newborn, there are animal studies showing that choline supplementation provided during hippocampal development has an effect on maintaining memory in older age. This effect appears to involve changes in gene expression via gene methylation. Changes in homocysteine due to choline supplementation are also hypothesized to reduce cardiovascular disease (CVD) risk. In the Framingham Offspring Study, combined dietary intakes of choline and betaine were associated with lower concentrations of homocysteine, a marker for inflammation. During the ATTICA study, a cross-sectional survey (1,514 men and 1,528 women with no history of CVD) of health and nutrition being carried out in the region of Attica, Greece, the association between inflammatory markers and choline intakes was measured. Participants who consumed higher levels of choline (> 310 vs. < 250 mg/day) had lower concentrations of C-reactive protein, interleukin-6, and tumor necrosis factor-alpha (Detopoulou et al., 2008). For an overview of the metabolism, functions, and health effects of choline, the reader is referred to previous reviews (IOM, 1998; Zeisel, 2006; Zeisel and da Costa, 2009; Zeisel et al., 1991).

Because of its undesirable organoleptic characteristics when administered in doses that exceed the capacity of the small intestine to absorb it, choline is not readily accepted by patients. The most common form of choline in the diet is phosphatidylcholine, an ester of choline that is not used as a substrate by gut bacteria and does not result in fishy body odor (Zeisel et al., 1983). Most studies reviewed in this chapter used an intermediary in the synthesis of phosphatidylcholine, CDP-choline. CDP-choline is composed of cytidine and choline and is hydrolyzed in the small intestine before absorption as citidine and choline. After absorption, citidine and choline are rephosphorylated and then CDP-choline is resynthesized again. CDP-choline also serves as a donor of choline in the synthesis of acetylcholine. This chapter includes evidence for the potential use of CDP-choline in TBI.

CHOLINE AND THE BRAIN

Choline has a critical role in neurotransmitter function because of its impact on acetylcholine and dopaminergic function. Studies in animals suggest that CDP-choline supplements increase dopamine receptor densities and can ameliorate memory impairment. In Parkinson’s disease, for example, CDP-choline may increase the availability of dopamine. A Cochrane review of randomized trials testing the efficacy of CDP-choline in the treatment of cognitive, emotional, and behavioral deficits associated with chronic cerebral disorders in the elderly revealed no evidence of a beneficial effect on attention, but some evidence of benefit on memory function and behavior (Fioravanti and Yanagi, 2005). The brains of those with Alzheimer’s disease have decreased phosphatidylcholine and phosphatidylethanolamine, and it has been suggested that CDP-choline may provide benefit by repairing cell membrane damage and enhancing acetylcholine synthesis. Both sphingomyelin and phosphatidylcholine, major constituents of brain membranes, are synthesized from the precursor choline (Zeisel, 2005). The role of choline in regulating the synthesis of phospholipids (e.g., phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and sphingomyelin) as constituents of cell membranes is reviewed in Saver (2008). This review also includes a discussion of the evidence showing that choline promotes rapid repair of injured cell surfaces and mitochondrial membranes as well as maintenance of cell integrity and bioenergetic capacity. Increases in biomarkers representative of CDP-choline activity, such as phosphodiesters, were observed on proton magnetic resonance spectroscopy and were associated with improvements in verbal memory in humans (Babb et al., 2002; Fioravanti and Yanagi, 2005).

It is hypothesized that CDP-choline may exert neuroprotective effects in an injured brain through its ability to improve phosphatidylcholine synthesis (Adibhatla and Hatcher, 2002). In addition to its neuroprotective capability, CDP-choline potentiates neurorecovery, which has led to its evaluation as treatment for both stroke and TBI in animal models and in human clinical trials (Cohadon et al., 1982; Levin, 1991; Warach et al., 2000). The positive effects seen in models of ischemia and hypoxia may be explained by increased Bcl-2 expression, decreased apoptosis, and reduced expression of pro-caspase. Inhibiting caspase activity may decrease apoptotic activity and calcium-mediated cell death. Supporting these ideas, in vitro studies have also revealed that choline deficiency induces apoptosis in the liver by mechanisms independent of protein 53, which likely involve abnormal mitochondrial membrane phosphatidylcholine, leakage of oxygen radicals, and activation of caspases (Albright and Zeisel, 1997; Albright et al., 1996, 1998, 1999a, 199b, 2003; Chen et al., 2010). In humans, a choline-deficient diet also causes DNA damage and apoptosis (da Costa et al., 2006).

In addition, CDP-choline is hypothesized to attenuate the loss of phospholipid and increase in fatty acids after global and focal cerebral ischemia by preventing activation of phospholipase A2. CDP-choline may also act to protect against oxidative stress since it has been shown to increase total glutathione levels, glutathione reductase activity, decreased oxidized glutathione, and glutathione oxidation ratio (Adibhatla and Hatcher, 2005).

In rat models, the availability of choline to the fetus influences neurogenesis in the fetal brain (Craciunescu et al., 2003), and choline status in early life influences neurogenesis rates in the adult hippocampus (Glenn et al., 2007), an area of the brain that is often dysfunctional in TBI. Additionally suggesting choline mechanisms of action relevant to TBI are the fact that in rodents, choline deficiency is associated with lipid peroxidation in liver (Ghoshal et al., 1984, 1990) and that deletion of a choline metabolism gene results in mitochondrial dysfunction in the liver, sperm, testis, heart, and kidney (Johnson et al., 2010). A list of human studies (years 1990 and beyond) evaluating the effectiveness of CDP-choline in providing resilience or treating TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy) in the acute phase in humans is presented in Table 9-1; this also includes supporting evidence from animal models of TBI. The table includes the occurrence or absence of adverse effects in humans.

TABLE 9-1. Relevant Data Identified for Citicoline/CDP-Choline.

TABLE 9-1

Relevant Data Identified for Citicoline/CDP-Choline.

USES AND SAFETY

In 1998, the Institute of Medicine (IOM) recognized choline as an essential nutrient (IOM, 1998; Zeisel and da Costa, 2009) and set the Adequate Intake (AI) for choline at 550 mg/day and 425 mg/day for men and women 19 years of age and older, respectively. These levels were set based on the dietary intakes of the U.S. population, and on the development of liver damage seen with lower intake. The Tolerable Upper Intake Level (UL) for choline is 3.5 g/day for adults 19 years of age or older, based on fishy body odor and hypotension (IOM, 1998).

Choline is found in a variety of foods including eggs and liver. Deficiency has been clearly linked to atherosclerosis, neurodevelopmental diseases, and liver disease (Penry and Manore, 2008). The human body is unable to synthesize sufficient choline via direct methylation of phosphatidylethanolamine to phosphatidylcholine, so choline must also be acquired via the diet. Analysis of choline intake has suggested a high level of deficiency in the U.S. population (Fischer et al., 2005; Jensen et al., 2007). Choline deficiency has been linked to a variety of secondary disease processes, such as liver disease; cardiac, neurodegenerative and neurodevelopmental problems; and breast cancer (Li and Vance, 2008; Zeisel, 2006). In addition, it is estimated that up to 50 percent of the population carries genetic variations that require increased choline intake (Zeisel and da Costa, 2009).

Direct choline therapy, when administered in doses higher than the intestine can absorb, often leads to malodor that is unacceptable to participants. The use of forms of choline that are efficiently absorbed and avoid this problem is desirable. All the studies reported by the committee have used CDP-choline, an endogenous compound and intermediary of the synthesis of phosphatidylcholine. CDP-choline was originally identified as the key intermediary in the biosynthesis of phosphatidylcholine by Kennedy in 1956 (2003), and is now also sold as a dietary supplement. However, there is no evidence that CDP-choline is the most effective form, and other forms of choline could be tested in future TBI studies.

CDP-choline has been used in the treatment of cerebrovascular disorders for many years, under a variety of protocols and to ameliorate various conditions. In several European countries, for example, CDP-choline is frequently prescribed for cognitive impairment and in the treatment of Parkinson’s disease.

CDP-choline is generally considered safe; the side effect most noted in clinical trials has been mild diarrhea, with leg edema, back pain with headache, tinnitus, insomnia, vision problems, and dizziness reported much less frequently (Adibhatla and Hatcher, 2002; Clark et al., 1997; Levin, 1991). There were no adverse events reported even with doses as high as 4,000 mg/day (Calatayud Maldonado et al., 1991). It is notable that in a study by Clark and colleagues (2001), a dose of 2,000 mg/day by enteral administration did not induce severe adverse events at a rate any higher than placebo in the 899 patients.

EVIDENCE INDICATING EFFECT ON RESILIENCE

The committee found no clinical or animal trials that have tested the potential benefits of choline or CDP-choline in TBI or in other diseases or conditions included in the reviews of the literature (subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy).

EVIDENCE INDICATING EFFECT ON TREATMENT

Human Studies

In human studies, patients who were administered CDP-choline early in the postischemia recovery process demonstrated improved levels of consciousness (Tazaki et al., 1988) as well as improvements in the modified Rankin scale (a measure of function after stroke) (Clark et al., 2001). Consistent with this observation, magnetic resonance imaging data show a decrease in lesion volume with CDP-choline compared to placebo in a preliminary trial (Warach et al., 2000). A meta-analysis was conducted of four randomized clinical trials of CDP-choline in stroke in the United States (Davalos et al., 2002). Although the conclusion from pooling the data in the meta-analysis was positive and the authors concluded that oral CDP-choline increases the probability of recovery, the results of the individual studies are ambiguous. CDP-choline improved functional outcome and reduced neurological deficit in one of those studies (Clark et al., 1997); however, two subsequent studies failed to demonstrate improvement, although a post hoc analysis showed improvements in moderate to severe stroke cases (Clark et al., 1999, 2001). One of the studies (Clark et al., 2001) showed a beneficial effect of CDP-choline as measured by the Rankin scale, a secondary outcome metric in these trials. A separate meta-analysis of acute and subacute stroke, published in abstract form only, suggested a positive treatment effect of CDP-choline precursors on rates of death and disability (Saver et al., 2002).

In early randomized clinical trials of CDP-choline in TBI, it was associated with faster recovery from focal motor deficits in patients with severe TBI (Cohadon et al., 1982); improved recall design (a measure of memory) (Levin, 1991); a reduction of postconcussion symptoms following mild TBI (Levin, 1991); and reduced inpatient hospital stay and requirement for outpatient follow-up (Calatayud Maldonado et al., 1991). CDP-choline has also been shown to enhance cerebral blood flow. Among patients with TBI and very severe memory deficits, hypoperfusion of the inferior left temporal lobe normalized after administration of CDP-choline (Leon-Carrion et al., 2000).

Clinical trials of CDP-choline in TBI have demonstrated efficacy in secondary outcome measures but not in primary measures. These ambiguous results of some of the human trials in the United States may be due to a combination of causes. Many of the trials used doses substantially lower than may be optimal for highest efficacy (Agut et al., 1983; Clark et al., 1997). Also, this failure may have been due to substantial weaknesses in study designs, such as insufficient sample size (Calatayud Maldonado et al., 1991; Cohadon et al., 1982; Tazaki et al., 1988) or lack of sensitivity of the chosen outcomes measure (Glasgow Outcome Scale) (Clark et al., 2001). For example, Clark’s study of patients with stroke did not show a significant difference in the primary outcome measure (an improvement of total score by > 7 in the National Institutes of Health Stroke Scale), but post hoc analysis using a standard of “excellent recovery” showed a possible treatment effect. In this study, the primary outcome measure may have been too stringent (Clark et al., 2001). Differences in outcomes also may have been due to the route of administration of CDP-choline. Although bioavailability data suggest that enteral and intravenous routes are similar, brain uptake of CDP-choline may vary depending on the route of administration (Adibhatla and Hatcher, 2002; Grotta, 2002; Secades and Frontera, 1995). Theoretically, it is possible that intravenous administration may yield higher brain delivery (Agut et al., 1983; Secades and Frontera, 1995).

Animal Studies

In animal models, CDP-choline has been demonstrated to exert acute neuroprotection, as well as positive effects in chronic brain injury and stroke and in epilepsy.

A major mechanism of secondary injury in TBI is the formation of reactive oxygen species and lipid peroxidases, which cause significant tissue damage. Animal models of TBI support a key role for oxidative stress (Ikeda and Long, 1990; Kontos et al., 1992). The exogenous administration of CDP-choline or its precursors significantly increased levels of glutathione (Adibhatla et al., 2001; Barrachina et al., 2003; De la Cruz et al., 2000), a powerful endogenous antioxidant. CDP-choline also attenuates release of arachidonic acid, cardiolipin, and sphingomyelin (Adibhatla and Hatcher, 2002). Studies in animal models of ischemia and hypoxia also found that CDP-choline treatment improves concentration of free fatty acids, decreases neurological deficits, and improves behavioral performance on learning and memory (Rao et al., 2001). Increased expression of B-cell lymphoma 2, a regulator of apoptosis; decreased apoptosis; and reduced expression of both pro-caspase (Krupinski et al., 2002) and cleaved caspase-3 (Mir et al., 2003) also may explain the functional find ings. Inhibiting caspase activity may decrease apoptotic activity and calcium-mediated cell death.

CDP-choline was found to be neuroprotective in an animal model of uninterrupted occlusion of the basilar artery after subarachnoid hemorrhage (Alkan et al., 2001). CDP-choline was associated with greater arterial pressure, smaller infarct volumes, and lower mortality than controls. These results also suggest that CDP-choline provides significant neuroprotection during cerebral ischemia.

Dietary choline may promote functional recovery from status epilepticus (Holmes et al., 2002; Wong-Goodrich et al., 2010). Following the status epilepticus, rats given a choline-supplemented diet for four weeks performed better on the Morris water maze test than rats receiving a control diet (Holmes et al., 2002).

Animal studies (Baskaya et al., 2000; Dempsey and Raghavendra Rao, 2003; Dixon et al., 1997) demonstrated the neuroprotective effect of CDP-choline in TBI. The studies showed that CDP-choline had a significant preventive effect on TBI-induced neuronal loss in the hippocampus, decreased cortical contusion volume, and improved neurological recovery. Additionally, there was a dose-dependent attenuation of chronic deficits in motor and spatial performance following CDP-choline administration. Extracellular levels of acetylcholine, a key mediator of memory processes, were increased (Dixon et al., 1997), suggesting that CDP-choline enhances cholinergic transmission and may ameliorate chronic functional deficits. A second mechanism that may explain why CDP-choline improves function in chronically injured animals focuses on observed decreases in dopamine following injury (Yan et al., 2001). In such models, CDP-choline increased dopamine levels (Secades and Frontera, 1995; Yan et al., 2001), which enhanced neurorecovery (Kline et al., 2004).

CONCLUSIONS AND RECOMMENDATIONS

Since 2000, several neuroprotective trials for TBI have failed to show efficacy in any of the interventions tested. One reason may be that many of these agents have targeted one portion of the cascade of injury that occurs after TBI. Such agents have a time-limited opportunity to prevent the secondary brain injury and are rarely involved in the restorative process. An ideal agent would provide both neuroprotection and a means to facilitate the recovery process.

Although clinical trials in stroke and trauma have suggested efficacy in secondary outcome measures related to functional outcome and cognition, design weaknesses in these studies may have affected findings in the primary outcome. Design limitations include insufficient sample size (Tazaki et al., 1988), low dosage (Clark et al., 1997, 1999), variations derived from intravenous versus enteral delivery (Calatayud Maldonado et al., 1991; Clark et al., 2001), and in some cases inadequate outcome measures (Clark et al., 2001).

Preliminary animal data suggest that CDP-choline works via numerous mechanisms to limit the acute secondary injury cascade after ischemic and traumatic injury. In the more chronic setting, CDP-choline appears responsible for an upregulation in acetylcholine synthesis. The diversity of CDP-choline’s mechanisms of action suggests that it may offer neuroprotection and neurofacilitation to patients with TBI through multiple avenues, thereby increasing the possibility of that treatment improving outcome. The optimal clinical dose and duration of treatment of CDP-choline for injured patients is yet unclear.

There is one ongoing human trial on the effect of CDP-choline (Citicoline Brain Injury Treatment [COBRIT] trial) on cognition and functional measures on severe, moderate, and complicated mild TBI being led by a member of the committee (Zafonte et al., 2009). The committee recognizes the significance of this trial in that the findings will reveal more insights about the potential for this nutrient in the treatment of TBI. It was the consensus of the committee to emphasize the importance of monitoring the results of this trial before conducting more human studies. If ongoing trials with CDP-choline and TBI patients show positive results, further studies are warranted to confirm the optimal duration of treatment and clinical dose of choline for injured patients. Likewise, if those studies reveal that choline is a promising intervention, the effect of choline supplementation prior to injury to improve resilience could be explored by conducting animal studies. The impact on neurologic outcome of the choline deficiency observed in the population needs to be explored. Although there are no data regarding supplementation to enhance resilience, choline’s critical role in the maintenance of health suggests that individuals should be cautioned to avoid deficiency. Based on findings from animal studies, it would be prudent to consider potential gender differences in the metabolism of choline when designing studies (Fischer et al., 2007; Resseguie et al., 2007, 2011).

RECOMMENDATION 9-1. DoD should monitor the results of the COBRIT trial, a human experimental trial examining the effect of CDP-choline and genomic factors on cognition and functional measures in severe, moderate, and complicated mild TBI. If the results of that trial are positive, then DoD should conduct animal studies to define the optimal clinical dose and duration of treatment for choline (CDP-choline) following TBI, as well as to explore choline’s potential to promote resilience to TBI when used as a preinjury supplement.

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