Improved cognitive performance after dietary supplementation with a pinus radiata bark extract formulation

Improved Cognitive Performance after Dietary
Supplementation with a Pinus radiata
Extract Formulation

Andrew Pipingas1*, Richard B. Silberstein1, Luis Vitetta2, Cindy Van Rooy1, Elizabeth V.
Harris1, Joanna M. Young3, Christopher M. Frampton4, Avni Sali5 and Joseph Nastasi1
1Brain Sciences Institute, Swinburne University of Technology, Melbourne, Australia
2School of Medicine, University of Queensland, Queensland, Australia
3Lipid and Diabetes Research Group, Christchurch Hospital, New Zealand
4Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand
5National Institute of Integrative Medicine, Melbourne, Australia
Dietary interventions may have the potential to counter age-related cognitive decline. Studies have demon-
strated an improvement in age-related cognitive impairment in animals after supplementation with plant
extracts containing flavonoids but there are few human studies. This double-blind, controlled study examined
the effects on cognitive performance of a 5 week supplementation with Enzogenol® Pinus radiata
bark extract
containing flavonoids, in 42 males aged 50–65 years, with a body mass index
>25. Participants were supple-
mented for 5 weeks either with Enzogenol® plus vitamin C, or with vitamin C only. A battery of computerized
cognitive tests was administered, and cardiovascular and haematological parameters were assessed prior to
and following supplementation. The speed of response for the spatial working memory and immediate
recognition tasks improved after supplementation with Enzogenol® plus vitamin C, whereas vitamin C alone
showed no improvements. A trend in a reduction of systolic blood pressure was observed with Enzogenol®
plus vitamin C, but not with vitamin C alone. The blood safety parameters were unchanged. The findings
suggest a beneficial effect of supplementation with Enzogenol® on cognition in older individuals. Larger
studies are needed to ascertain its potential as a preventive treatment for age-related cognitive decline.
Copyright 2008 John Wiley & Sons, Ltd.

Keywords: Pinus radiata; pine bark extract; Enzogenol; vitamin C; cognition; cognitive decline.
benefits have been demonstrated in older individuals INTRODUCTION
after supplementation with vitamin E (Sano et al., 1997),soya extract (Duffy et al., 2003) and Ginkgo biloba Our cognitive abilities decline with age (Christensen, extract (Mix and Crews, 2002). Recently there has been 2001) and age-related neurodegenerative disorders such interest in the possible nootropic effects of the many as Alzheimer’s dementia or Parkinson’s disease can different flavonoids that are consumed as part of our greatly exacerbate this decline (Savla and Palmer, 2005).
diet. Flavonoids show very high antioxidant activities, A number of studies indicate that performance in exert neuroprotective effects in vitro and may play memory tests is predictive of the later development of a role as neuroprotective agents in vivo (Youdim dementia (Small et al., 2000), even up to 10 years prior et al., 2002). Feeding studies in rats have demonstrated to onset (Elias et al., 2000), suggesting that the patho- that supplementation with extracts high in flavonoid logical process begins early. If cognitive decline can compounds can delay or even reverse age-related be treated in the early stages more serious cognitive cognitive deficits in animals (Joseph et al., 1998, 1999).
impairment may be prevented or delayed. Concerns However, few human studies have investigated the about such age-related decline in cognitive function have led to a growing public interest in dietary measures The present study investigated the effects of supple- such as antioxidants and plant extracts that hold pro- mentation with a commercially available flavonoid mise to both preserve cognitive abilities with age and antioxidant formula, containing a Pinus radiata bark to improve cognitive performance (Martin et al., 2002; extract branded Enzogenol®, which is particularly rich in proanthocyanidins, plus vitamin C; compared with There is an increasing number of human interven- vitamin C alone, on cognitive performance, blood pres- tion studies examining the effects of dietary supple- sure and standard haematological safety parameters in ments on cognition are scarce. For example, cognitive a group of older adults. Previous studies using the samepine bark extract in combination with vitamin C have * Correspondence to: Andrew Pipingas, Brain Sciences Institute, shown potential improvements in the parameters of Swinburne University, 400 Burwood Rd, Hawthorn, Victoria 3122 oxidative stress and cardiovascular health. An uncon- Australia.
E-mail: [email protected] trolled, open label study showed potential benefits for Contract/grant sponsor: ENZO Bioactives Pty Ltd.
endothelial function, systolic blood pressure and plasma Copyright 2008 John Wiley & Sons, Ltd.
Copyright 2008 John Wiley & Sons, Ltd.
viscosity. This study also found reductions in plasma of the data. Participants assigned to the treatment group protein carbonyl concentration and leukocyte DNA received a daily dose of four capsules of a commerci- strand breakage, indicating possibly reduced levels of ally available supplement containing in total 960 mg of oxidation (Senthilmohan et al., 2003). A second study Enzogenol® and 120 mg of vitamin C. Enzogenol® is an in smokers that included a vitamin C control group aqueous extract from the bark of New Zealand grown confirmed the reduction of protein carbonyls, reported Pinus radiata trees containing approximately 80% total reduced fibrinogen levels in a subset of heavy smokers proanthocyanidins and other water-soluble flavonoids, and noted a possible trend to lower systolic blood pres- flavonoid-conjugates and phenolic acids. Participants assigned to the control group received four capsules For the present study, it was hypothesized that per- daily containing in total 120 mg of vitamin C only. Both formance in cognitive tasks that are most sensitive to capsule types were identical in appearance. Both groups age related cognitive impairment would improve with the present flavonoid supplementation. Specifically, theprimary outcome measures were performance in the Study measures. Participants were assessed at the be-
spatial working memory and immediate recognition ginning and end of the 5-week supplementation period.
tasks. Spatial working memory was previously shown Participants were asked not to consume alcohol within by this group to be the most sensitive measure of 24 h, or tea or coffee within 2 h prior to their scheduled age-related cognitive decline comparing young, middle appointment. During the testing session personal details and older age individuals (Tournier et al., 2004). More were collected, followed by blood pressure measure- recently, regression analysis applied to the same data ment, computerized cognitive testing, brain electrical set indicated that both spatial working memory and activity measurement and blood sampling. This study immediate recognition measures showed the greatest reports the results of computerized cognitive testing, decline in performance with increased age (unpublished blood pressure measurements and standard blood safety observation, A. Pipingas, 2006). Therefore these two tasks were considered the most likely to improve with Diastolic and systolic blood pressure was measured whilst the participants were seated upright and relaxedin a chair. Blood pressure was measured using an elec-tronic, self-inflating sphygmomanometer cuff.
Blood sampling via venous puncture was conducted at local pathology clinics. In accordance with a previ-ous open label study (Shand et al., 2003), and as part of Study population. Participants were recruited by way
the safety assessment, the blood markers measured in of newspaper advertisements, posters and e-mails.
this trial included liver function tests, urea and electro- Advertisements asked for male non-smokers aged 50– lytes, a full blood cell and differential count and blood 65 years, who were right handed and did not exercise much. Interested participants were screened via tele- Participants performed eight computer-based cogni- phone and invited to participate if they met the more tive tasks designed to test aspects of spatial and object specific inclusion and exclusion criteria. Criteria included memory, executive processes, attention and processing having a sedentary occupation, a body mass index (BMI) speed using tasks similar to those used in a previous greater than 25, not taking any form of vitamin or herbal study by this group (Tournier et al., 2004), with the supplementation and not suffering from any neurologi- exception of the contextual memory task, which was a cal disorder or epilepsy. These criteria were chosen to new version. Participants made responses to trials for select for participants that are potentially at a higher each task using a hand-held button box. For both test- risk of cognitive decline due to their age and sedentary ing sessions, the participants were given instructions on lifestyle. The age span was restricted to 15 years in how to perform each task and completed a practice order to avoid too great a variation in the cognitive task prior to performing the main task used for ana- lysis. Each of the eight cognitive tasks is described One hundred and six prospective interested par- in turn, in the order that they were administered to ticipants responded to advertisements. Of those, 45 participants met the telephone screening criteria andunderwent a medical examination to obtain medical Contextual memory. This task used a variation on a
history and to ensure that they were generally in good previous task, which used everyday images. Participants health and fit to participate. Forty two prospective initially watched a series of abstract images presented participants passed the examination and gave written in one of four locations on the computer screen (top, informed consent to be enrolled into the program. Ap- bottom, left and right). In the second part of the task proval for the study was obtained from the Swinburne the same abstract images were again presented in the University Human Research Ethics Committee.
centre of the screen. Participants were required torecollect the location where each image was initially Treatment. The study was a randomized, double-blind,
presented and thus recall the context of presented vitamin C controlled study. Participants were randomly information. Participants responded by pressing one of allocated to one of two groups, hereafter referred to as four buttons corresponding to the four screen locations.
the treatment group or the control group. Participantswere assigned to either the treatment or control groups Immediate recognition. Participants initially viewed a
using a random permuted block procedure with block series of abstract images presented in the centre of the size of four, by a study investigator who was not in- screen. On completion of the series, a second series of volved in any aspect of recruitment, testing or analysis abstract images were presented. Half of these images Copyright 2008 John Wiley & Sons, Ltd.
COGNITIVE EFFECTS OF PINUS RADIATA BARK EXTRACT were identical to the original images presented, the other Statistical analysis. For each of the eight cognitive tasks,
half were new images. Participants indicated with a left the mean accuracy and response time scores were cal- or right button press whether the image was old or culated for each participant for Session 1 and Session 2 new. This task is designed to probe cognitive processes (prior to and following supplementation). The accu- involved in visual recognition memory. Abstract images racy was calculated as the percentage of correct re- were used to reduce the likelihood of verbalizing the sponses. The mean response time was calculated as the information and to make this task more challenging.
average response time in milliseconds for all correctresponses.
Simple reaction time. Participants responded as quickly
The primary outcome measures were performance as possible by pressing the right button to a series of on the spatial working memory and immediate recogni- white squares that appear at the centre of the screen at tion tasks. These tasks were analysed individually using random intervals. This task is designed to probe speed repeated measures analysis of variance (ANOVA), with of information processing and speed of motor response.
the aim of detecting group (treatment, control) by time(Session 1, Session 2) interactions. Accuracy and re- Choice reaction time. Participants responded as quickly
sponse time were analysed separately. Secondly, with as possible to a series of blue triangles and red squares the aim of investigating the effects of supplementation that appeared at the centre of the screen at random on cognition in a more general sense, the remaining intervals. This task is designed to probe the speed of an tasks were included in two multivariate analysis of vari- accurate choice and subsequent motor response.
ance (MANOVA) models, for accuracy and responsetime data.
Visual vigilance. Participants were required to respond
All statistical analyses were performed using SPSS as quickly as possible to the appearance of a target digit in a series of rapidly presented digits. This tasktests the ability to maintain visual vigilance during thecourse of a task as assessed through speed of response.
Complex visual vigilance. This task is a more challenging
version of the previous visual vigilance task. Partici-
Demographic characteristics for the treatment and pants responded to a sequence of three numbers in a control groups are shown in Table 1. The two groups row, requiring maintained focused attention and rapid appeared to be well matched on all measures. There were no significant differences between the treatmentgroups in age, years of education, height, weight or Spatial working memory. A 4 × 4 grid was presented
BMI (p > 0.1). Seven participants in the control group on a black background with some of the locations in were taking medication for hypertension compared the grid filled with a white square. Participants memo- with four participants in the treatment group. There rized which grid locations were filled. They were then were no significant differences between the groups in presented with a series of images of the same grid, haematological indices at the start of the treatments however, with only one square filled. Participants re- (p > 0.1). Similarly, there were no significant differ- sponded with a left or right button press to indicate ences between the groups in performance on the cog- whether the filled grid location matched any of the pre- nitive tasks at baseline (p > 0.1).
viously presented filled grids. Four locations were tested Means and standard deviations of the cognitive meas- in each of 14 trials. The process of holding the set of ures for the treatment and control groups for Session 1 filled grid squares in memory, spanning the time that and Session 2 are shown in Table 2. For the spatial judgments of individual grid locations had to be made, working memory task, analysis of response time data using repeated measures ANOVA revealed a signifi-cant group by time interaction (F(1,40) = 4.59, p = 0.038, Delayed recognition memory. This task is a repeat of
partial η2 = 0.103). This reflected a decrease in response the second task, using the abstract images studied time of 64 ms or 6.4% for participants in the treatment approximately 30 min earlier. This task is designed to group, with a small increase in the control group probe cognitive processes involved in visual recogni- (Fig. 1). Although the mean score for the treatment tion memory and is considered to be a test of short to group was higher than the control group at baseline, this difference was not significant (p > 0.1). Post hoc Table 1. Demographic characteristics of participants assigned to treatment and control groups
Copyright 2008 John Wiley & Sons, Ltd.
Table 2. Means and standard deviations of cognitive task measures for treatment and control groups
higher than the control group at baseline, this differ-ence was not significant (p > 0.1). Post hoc t-tests showedthat the change was significant in the treatment group(t(21) = 2.63, p = 0.016) but not in the control group(t(19) = − 0.396, p = 0.696).
Repeated measures ANOVA revealed that there was no group by session interaction for performance accu-racy on either task. However, for the spatial workingmemory task both treatment and control groups weresignificantly more accurate in Session 2 (F(1,39) = 11.99,p = 0.001) reflecting either a general learning effect inall participants from Sessions 1 to 2, or an effect ofvitamin C.
The new version of the contextual memory task demonstrated a baseline performance close to chanceand was excluded from further analyses. Analysis ofthe remaining tasks together using MANOVA showedno group by time interaction for either response timeor accuracy measures, indicating either that the treat-ment effect was specific to the spatial working memoryand immediate recognition tasks, or that the other tasksare less sensitive in detecting changes in cognitiveperformance.
Figure 1. Mean change in response time (ms) for spatial work-
There was no significant change in systolic or diastolic ing memory ( ) and immediate recognition ( ) tasks for treat- blood pressure measures for either group. However, ment and control groups. Error bars show ± 1 standard error.
there was a trend of reduced systolic blood pressure(Table 3). Interestingly, a reduction of systolic bloodpressure had previously been reported in an open label t-tests were conducted for each group separately and study using the same pine bark extract (PBE) with revealed that the change in response time from Session vitamin C (Shand et al., 2003). Furthermore, a recent 1 to Session 2 was significant in the treatment group vitamin C controlled study by Young et al. (2006) also (t(21) = 3.21, p = 0.004) but not in the control group (t(19) found a trend of reduced systolic blood pressure using the same PBE with vitamin C (Table 3). As a post hoc For the immediate recognition task, repeated meas- measure, the systolic blood pressure data from the ures ANOVA indicated there was a significant group present study and the study by Young et al. were pooled by time interaction (F(1,40) = 5.25, p = 0.027, partial and repeated measures ANOVA conducted for the η2 = 0.116) reflecting an improvement in the response combined group. Although Young et al. were studying time of 60 ms or 5.4% in the treatment group, com- smokers, the treatment was very similar to the present pared with a small increase in the control group (Fig. 1).
study, but used half the dose and supplemented for Although the mean score for the treatment group was 12 weeks. The results from this meta-analysis indicated Copyright 2008 John Wiley & Sons, Ltd.
COGNITIVE EFFECTS OF PINUS RADIATA BARK EXTRACT Table 3. Individual and combined analyses of systolic blood pressure data from the present study and a double-blind, controlled trial by
Young et al.
(2006), comparing supplementation with Enzogenol® and vitamin C against vitamin C alone
Present study and Young et al. 6 weeks n = 39/35 Present study and Young et al. 12 weeks n = 39/35 there was a significant decrease in systolic blood pres- cognitive impairment (Nicholl et al., 1995). Furthermore, sure in the treatment group compared with the control a recent study that also used a computerized battery to group, regardless of whether the present 5 week data assess cognitive effects following supplementation with were combined with the 6 or 12 week time points by plant extracts found that ‘speed of memory’ improved with supplementation (Tildesley et al., 2005). Thus the The biochemical and haematological analyses of the findings of the current study advocate speed of response venous blood samples, including liver function tests, as an important measure when assessing outcomes of full blood cell and differential counts, and blood interventions that are designed to counteract cognitive lipid profiles showed no significant changes in either treatment or control groups. No adverse events were The present treatment used a Pinus radiata bark reported by participants in this study.
extract, Enzogenol®, with high antioxidant capacity(Wood et al., 2002), in combination with vitamin C.
PBEs are rich in proanthocyanidins and contain a rangeof flavonoids including catechin, epicatechin, quercetin, DISCUSSION
dihydroquercetin, taxifolin and phenolic acids (Woodet al., 2002). Here we discuss a number of possible In the present study, a short term supplementation over mechanisms by which the treatment may exert its 5 weeks with combined PBE and vitamin C improved positive effects on cognitive performance including the speed of response on spatial working memory and antioxidant action, improvements of cerebral blood immediate recognition tasks, whereas supplementation supply and circulation, and influences on neuronal with vitamin C alone showed no improvements. A trend towards reduced systolic blood pressure was noted in Oxidative damage has been observed in the aging the current study, and while not statistically significant, brain, and antioxidants may play a role in protecting this decrease was of the same magnitude as demon- the brain from reactive oxygen species (Halliwell, 2001).
strated in a previous open-label study (Shand et al., However, accumulation of oxidative damage in the brain 2003). A combined analysis of data from the present is likely to manifest in cognitive decline only over long study and a recent vitamin C controlled study in periods of time. The present antioxidant supplementa- smokers (Young et al., 2006) indicated that systolic tion was able to improve significantly cognitive perfor- blood pressure may indeed be reduced with this com- mance over a short period of only 5 weeks, suggesting bined PBE and vitamin C treatment. However, this that other mechanisms may at least in part account for conclusion has to be taken with caution, and needs verification in a larger study since the two studies are Improved blood circulation to the brain might also not of identical design and the study by Young et al. have contributed to enhanced cognition and would also was in smoking subjects. The supplementation was be consistent with our findings of improved systolic notably safe without adverse events or any indications blood pressure. Previous research indicates that hyper- of changes in any blood safety parameters.
tension (Brady et al., 2005) and cardiovascular risk Our previous research has indicated that the spatial factors (Barnes et al., 2006) are associated with cogni- working memory and immediate recognition tasks are tive decline. Furthermore, bioflavonoid consumption has the most sensitive to the effects of aging compared with been reported to improve cardiovascular risk factors the other tasks used in this test battery. It was conse- (Caccetta et al., 2001) and to promote relaxation of quently hypothesized that in this group of cognitively vascular smooth muscle (Stein et al., 1999) indicating a intact older males, these tasks would be the most likely possible contribution of improvements in blood circu- to reveal any cognitive benefits that the PBE supple- lation to better cognitive functions. Previous studies mentation may afford, and this was demonstrated in using the same PBE plus vitamin C supplementation have shown the potential for cardiovascular benefits Improvements in cognition after supplementation including improved endothelial function, reduced with PBE plus vitamin C were demonstrated for speed plasma fibrinogen concentrations (Young et al., 2006), of response but not for performance accuracy, which is and reduced plasma viscosity and systolic blood pres- consistent with cognitive aging studies which suggest sure (Shand et al., 2003). An effect of lowering systolic that accuracy is preserved at the expense of speed of blood pressure has been corroborated here by our response, both with age (Brebion, 2001) and in mild pooled analysis, which indicated a significant reduction Copyright 2008 John Wiley & Sons, Ltd.
with the PBE plus vitamin C treatment over vitamin C combined with vitamin C. Furthermore, accuracy meas- ures for spatial working memory demonstrated an Another mechanism that may play a role in the effects improvement in both treatment and control groups and of the present treatment on cognitive performance is it cannot be certain whether this improvement was due the direct influence of flavonoids or their metabolites to practice or to a beneficial effect of vitamin C. How- in the brain. Although only a few studies have pro- ever, the vitamin C dosage was 120 mg, a much lower duced evidence of flavonoid uptake into the brain, one dosage than has been used in other studies which have study found epicatechin metabolites formed in rat brains used, for example, 500 mg (Yaffe et al., 2004) or 1500 mg after oral ingestion of epicatechin, indicating the possi- (Baker et al., 1999) with no demonstrated cognitive bility of PBE constituents entering the brain and directly benefit. Given that with age, the response time tends to affecting neurological signalling (Abd El Mohsen et al., decline before accuracy and that there was no benefit 2002). Studies of dietary supplementation with berry in the response time for the vitamin C group, it is likely and spinach extracts in rats have been shown to pre- that the improvement reflects practice effects rather than vent onset (Joseph et al., 1998) and reverse (Joseph the benefits of vitamin C. Nevertheless, the above limita- et al., 1999) age-related deficits in cognitive behaviour, tions should be assessed in a larger study that includes and to normalize cognitive performance deficits in an a treatment group receiving only the pine bark extract.
amyloid plaque transgenic mouse model (Joseph et al., This randomized, double-blind, vitamin C controlled 2003). Interestingly, blueberry supplementation in these study has demonstrated the potential to improve both studies caused significant increases in indices of neuronal cognitive and cardiovascular functions prone to decline signalling in the brains of the animals, indicating mecha- with age after a relatively short duration of supple- nistic actions beyond the antioxidant activity of the mentation with Enzogenol® plus vitamin C in a group flavonoids. In addition, a study using the same PBE of older men that may be at risk of cognitive decline.
supplement as the present study has demonstrated a Larger studies in men and women of different age reduction in the duration and severity of migraines in groups are necessary to ascertain its potential as a human migraine sufferers, possibly suggesting that this preventive treatment to fight age-related or neurode- supplementation may have effects that affect the brain There are a number of limitations to this study.
Although there was no response time effect in the con-trols taking vitamin C only, it is unclear whether the ENZO Bioactives Pty Ltd provided partial funding for this study and PBE alone would have demonstrated the same positive provided all supplements used in the study. There are no conflicts of effects or whether there is a synergistic benefit when REFERENCES
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VERTRAULICH Studientitel: Multizentrische, randomisierte, doppelblinde, placebokontrollierte Dosisfindungsstudie zur Bewertung der Sicherheit und Wirksamkeit von GSK2586184 bei Patienten mit chronischer Plaque-Psoriasis INFORMATIONSBLATT UND EINWILLIGUNGSERKLÄRUNG FÜR DIE TEILNEHMER AN DER KLINISCHEN PRÜFUNG, NR: JAK116679 Studie zur Untersuchung der Wirksamkeit und Sicherheit vo


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