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Influence of antihypertensive therapy on cerebral perfusion in patients with metabolic syndrome: relationship with cognitive function and 24‐h arterial blood pressure monitoring

ORIGINAL RESEARCH ARTICLE Influence of Antihypertensive Therapy on Cerebral Perfusion inPatients with Metabolic Syndrome: Relationship with CognitiveFunction and 24-h Arterial Blood Pressure Monitoring Nataliya Y. Efimova,1,2 Vladimir I. Chernov,1,2 Irina Y. Efimova1 & Yuri B. Lishmanov1,2 1 Federal State Budgetary Scientific Institution, Research Institute for Cardiology, Tomsk, Russia2 National Research Tomsk Polytechnic University, Tomsk, Russia Antihypertensive treatment; Brain perfusion; Aims: To investigate the regional cerebral blood flow, cognitive function, and parame- Circadian rhythm of blood pressure; Cognitive ters of 24-h arterial blood pressure monitoring in patients with metabolic syndrome function; Metabolic syndrome.
before and after combination antihypertensive therapy. Methods: The study involved 54 patients with metabolic syndrome (MetS) investigated by brain single-photon emission Nataliya Efimova, Federal State Budgetary computed tomography, 24-h blood pressure monitoring (ABPM), and comprehensive neu- Scientific Institution, Research Institute for ropsychological testing before and after 24 weeks of combination antihypertensive therapy.
Cardiology, 111a Kievskaya Street, Tomsk Results: Patients with metabolic syndrome had significantly poorer regional cerebral blood 634012, Russia.
flow compared with control group: by 7% (P = 0.003) in right anterior parietal cortex, by Tel.: +7-3822-558298; 6% (P = 0.028) in left anterior parietal cortex, by 8% (P = 0.007) in right superior frontal Fax: +7-3822-555057; lobe, and by 10% (P = 0.00002) and 7% (P = 0.006) in right and left temporal brain regions, correspondingly. The results of neuropsychological testing showed 11% decrease in mentation (P = 0.002), and 19% (P = 0.011) and 20% (P = 0.009) decrease in immedi-ate verbal and visual memory in patients with MetS as compared with control group. Rela- tionships between the indices of ABPM, cerebral perfusion, and cognitive function were found. Data showed an improvement of regional cerebral blood flow, ABPM parameters, and indicators of cognitive functions after 6 months of antihypertensive therapy in patients with MetS. Conclusion: The study showed the presence of diffuse disturbances in cerebralperfusion is associated with cognitive disorders in patients with metabolic syndrome. Com- bination antihypertensive treatment exerts beneficial effects on the 24-h blood pressure profile, increases cerebral blood flow, and improves cognitive function in patients with later-life hypertension and subsequent cognitive impairment were Over the last years, scientific community has recognized a signifi- It is known that focal and diffuse ischemic brain injury may lead cance of the problem of metabolic syndrome (MetS). This condi- to the development of vascular dementia. However, the available tion is associated with substantially elevated risks of type 2 literature presents only a few works where the main goal was to diabetes (5-fold), cardiovascular diseases (2-fold to 3-fold), and study the cerebral perfusion in patients with MetS and AH [7–10].
stroke (2-fold) [1]. The incidence rate of MetS is expected to Prevention of vascular dementia represents a challenging problem increase by 50% in the next 25 years [1].
in the treatment of these patients.
Arterial hypertension (AH) is one of the components of MetS. It At the same time, it has not been proved yet that the decrease is also one of the major causes of chronic cerebrovascular insuffi- in arterial blood pressure (BP) reduces the risk of vascular demen- ciency, cognitive function (CF) decline, hemorrhagic stroke, and tia. Indeed, several studies showed that treatment of hypertension ischemic stroke [2]. Moreover, there is a relationship between AH prevented cognitive dysfunction [2,11], whereas other authors and vascular dementia resulting in noticeable neurocognitive and did not find any correlations [12].
social dysfunction of patients. Studies of patients with normal cog- The aim of this study was to estimate brain perfusion, cogni- nitive function or minor cognitive impairment showed that neu- tive function, and parameters of 24-h arterial blood pressure ropsychological tests can predict whether patients are likely to monitoring in patients with MetS before and after antihyperten- proceed to dementia [3]. The associations between midlife and sive therapy.
ª 2015 John Wiley & Sons Ltd Cardiovascular Therapeutics 33 (2015) 209–215 Antihypertensive Therapy in Metabolic Syndrome Patients N. Y. Ef imova et al.
period lasting for 10–14 days when patients did not receive any Material and Methods antihypertensive, vascular, and nootropic therapy. Target value of Patient Population and Clinical Assessment BP was 130/80 mmHg. The protocol to lower BP to target value was based on the 2013 ESH/ESC Practice Guidelines for the The study involved 54 patients with MetS (20 men and 34 Management of Arterial Hypertension [13]. In three patients, women, mean age 52.0  5.6 years) (Table 1). According to the target BP was not achieved, but there was a tendency to BP reduc- IDF consensus worldwide definition of the metabolic syndrome tion. In these patients, the third antihypertensive drug (indapa- (2005), MetS was diagnosed if patient had central obesity (waist mide, 1.5 mg once daily) was administered according to the same circumference >94 cm in males and >80 cm in females) plus any two of the following four factors: raised triglycerides (>1.7 mmol/L), reduced HDL cholesterol (<1.03 mmol/L in males, <1.29mmol/L in females), increased blood pressure (systolic BP >130 or diastolic BP >85 mm Hg), elevated fasting plasma glucose All patients received perfusion brain SPECT with 99mTc-HMPAO, (≥5.6 mmol/L), or previously diagnosed type 2 diabetes. The pres- comprehensive neuropsychological testing and arterial blood pres- ence of hypertension was required for the inclusion of patients in sure monitoring before and after 24 weeks of combination antihy- pertensive therapy with verapamil and enalapril.
Criteria of excluding patients from the study were as follows: target organs damage (myocardial infarction, stroke, stenosing coronary or carotid atherosclerosis, and chronic renal insuffi- ciency), psychiatric illnesses (including drug abuse and chronic 99mTc-HMPAO was prepared according to manufacturer's instruc- alcoholism), craniocerebral injury and neuroinfection in the past tion and was used within 5 min after labeling. Perfusion brain and severe concomitant diseases.
SPECT was performed 10–12 min after the injection of 99mTc- Fifteen patients of similar age (six men and nine woman; mean HMPAO at a dose of 740 MBq. SPECT studies were performed age: 54.5  4.5 years) without signs of carotid atherosclerosis, using a rotating dual head gamma-camera ("Forte," Philips, coronary artery disease, AH, neurological diseases, and psychiatric Amsterdam, The Netherlands) supplied with a high-resolution disorders were investigated as control group (Table 1).
low-energy collimator (140 keV) and interfaced with a dedicated Informed consent was obtained from each patient. The study computer system for scintigraphic data processing (Skylight). Data was approved by the Ethics Committee of the author's institution.
were acquired using 128 9 128 matrix in 64 projections with anexposure of 20 seconds per frame over 360°. Image acquisition and processing were performed using JetStream computer system The therapy included sustained-release calcium channel blocker verapamil (Isoptin SR) at a dose of 240 mg per day and angioten- sin-converting enzyme inhibitor (iACE) enalapril at an average dose of 12.2  5.9 mg. Interventions treatment course with Brain SPECT images were divided into 14 symmetrical (right and selected doses of drugs lasted for 24 weeks followed by control left) regions of interest per patient: inferior and superior frontal lobes, temporal lobes, anterior and posterior parietal lobes, occipi- tal lobes, and cerebellar hemispheres. To calculate the regional Table 1 Patient characteristics cerebral blood flow (rCBF, mL/100 g/min), we used a three-com- ponent model of 99mTc-HMPAO kinetics according to Lassen et al.
[14] modified by Yonekura et al. [15]. The dynamics of rCBF was Sex (male/female) defined as the difference between the rCBF values measured before and after treatment.
Education (years) Arterial hypertension (n) 24-h Ambulatory Blood Pressure Monitoring Central obesity (n) Triglycerides ≥1.7 Automated 24-h blood pressure devices (Model 90207; SpaceLabs Medical, Inc., Issaquah, WA, USA) were used to measure blood pressure and heart rate with intervals of 15 min during daytime <1.03 mmol/L for male, (from 6 a.m. to 10 p.m.) and 30 min during the night (10 p.m. to <1.29 mmol/L for 6 a.m.). For each 24-h measurement, the values of arterial blood pressure were evaluated separately for daytime and nighttime.
Fasting plasma glucose Daytime arterial hypertension was diagnosed according to the cri- ≥5.6 mmol/L (n) teria of the European Society of Hypertension (systolic blood pres- sure ≥40 mmHg and/or diastolic blood pressure ≥90 mmHg).
Interpretations of ambulatory blood pressure (ABP) profile data MetS, metabolic syndrome; NS, not significant; P, significance of differ- were based on the mean daytime, nighttime (sleep), and 24-h val- ences MetS versus control group.
ues of blood pressure, diary notes, and times of drug intake.
210 Cardiovascular Therapeutics 33 (2015) 209–215 ª 2015 John Wiley & Sons Ltd N. Y. Ef imova et al.
Antihypertensive Therapy in Metabolic Syndrome Patients Reports also included ABP "loads" (percentage area under the in left posterior parietal region, by 8% (P = 0.007) in right blood pressure curve above set limits) for daytime and nighttime superior frontal lobe, by 10% (P = 0.00002) in right temporal periods, day–night differences, and blood pressure variability. A brain regions, by 7% (P = 0.006) in left temporal brain nondipping blood pressure profile was detected when the noctur- regions, by 9% (P = 0.00002) in left occipital cortex, and by nal blood pressure fall was <10% of daytime values. Night-peakers 8% (P = 0.0003) in right occipital cortex (Table 3).
had nighttime blood pressure values higher than daytime values.
The results of neuropsychological testing showed 11% decrease in mentation (P = 0.002), 19% decrease in immediate verbalmemory (P = 0.011), 13% decrease in learning (P = 0.003), as well as 20% decrease in immediate visual memory (P = 0.009) in We assessed the patients' cognitive status using seven neuropsy- pts with MetS as compared with control group (Table 4).
chological tests (Table 2) [16]. To reduce the "test–retest" effects, Furthermore, data showed 20% reduction in delayed visual different versions of neuropsychological tests were used [17].
memory (P = 0.009) and psychomotor speed (P = 0.022). We alsofound a decrease by 24% (P = 0.016) in the spatial optical gnosisand by 7% (P = 0.04) in visuoconstruction (Table 4).
Statistical Analysis According to the results of ambulatory blood pressure monitor- Data were statistically processed using "STATGRAF" software ing (ABPM), patients with MetS had an increase in mean values package. Between-group comparisons were performed using the of daytime systolic blood pressure (SBP) and diastolic blood pres- Mann–Whitney U-test and Pearson's chi-squared test. Data are sure (DBP), as well as in the levels of daytime and nighttime SBP expressed as mean  standard deviation. Assuming non-Gaussian and DBP compared with control group (Table 5).
distribution, the effects of the treatment on rCBF, cognitive tests In addition, there was an increase in SBP and DBP "pressure scores, and hemodynamic parameters were analyzed by Wilcoxon load" during daytime, nighttime, and 24 h. The study demon- test. Linear regression analysis was performed to calculate the strated an increased variability in blood pressure during daytime relationships between rCBF, cognitive tests scores, and ABP and nighttime. The analysis of daily blood pressure profile in parameters. Values were considered statistically significant when patients with MetS showed abnormal circadian rhythm of blood P was <0.05. The study was approved by the local ethics commit- pressure. According to the results of ABPM, 22 patients (41%) tee of the authors' institute.
were "dippers," 24 patients (44%) were "nondippers," and eight patients (15%) were "night-peakers." "Night-peakers" had a decrease in visual short-term memory by 30.4% (P = 0.017) com- pared with group of "dippers." Moreover, "nondippers" had reduction in attention by 13% (P = 0.037) and in psychomotor Brain Perfusion and Cognitive Function in speed by 17% (P = 0.036) compared with "dippers." Patients with Metabolic Syndrome Relationships between the indices of ABPM, cerebral perfusion, The results of 99mTc-HMPAO SPECT showed that brain perfu- and cognitive function were found. Data showed an inverse corre- sion was significantly poorer in all regions of MetS patients in lation between mean values of daytime diastolic blood pressure comparison with control group (Table 3). Compared with con- and rCBF in left occipital lobe (R2 = 0.10, P = 0.033) in patients trol group, MetS patients had rCBF values lower by 7% with MetS. Diastolic blood pressure "loads" for nighttime period negatively correlated with rCBF in right posterior parietal region, (P = 0.028) in left anterior parietal cortex, by 6% (P = 0.024) in right and left temporal cortex (R2 = 0.12, P = 0.011; R2 = 0.10,P = 0.027; R2 = 0.08, P = 0.04; R2 = 0.11, P = 0.016, respec-tively), with mentation, psychomotor speed, and attention Table 2 Neuropsychological tests used to assess cognitive deficits (R2 = 0.08, P = 0.046; R2 = 0.10, P = 0.032; R2 = 0.14, P = 0.008,respectively).
After 24-week treatment, we observed a statistically significant Immediate verbal memory, delayed reduction in the main parameters of systolic and diastolic blood Verbal Learning Test (AVLT) memory, learning, attention (trial 1) pressure assessed by ABPM (Table 5).
Digit span forward backward Immediate verbal memory, attention The study revealed a significant decrease in day–night differ- Verbal comprehension ences for SBP and DBP. The number of "dippers" decreased, Digit Symbol Test Psychomotor speed, attention, whereas the number of "night-peakers" increased (P < 0.05) both immediate non-verbal memory for systolic and diastolic values of blood pressure. Data showed an The Bourdon—Wiersma Psychomotor speed, sustained and improvement of rCBF, 24-h blood pressure monitoring parame- Dot Cancellation Test (DCT) activity visual attention, concentration ters, and cognitive function scores after 6 months of antihyperten- The Trail Making Test (TMT) Volume and sustained attention, sive therapy in patients with MetS.
psychomotor speed Combination antihypertensive treatment (verapamil with ena- The Trail Making Test (TMT) Volume and shift attention, psychomotor lapril) led to perfusion improvement over many areas of the brain.
speed, mental flexibility Antihypertensive 24-week therapy resulted in rCBF increase in The Complex Figure Test Visuoconstruction (copy), immediate the right inferior frontal, right temporal, and right anterior parie- visual memory, delayed memory, tal regions and in the posterior parietal lobes on both sides spatial optical gnosis compared with baseline (Table 3).
ª 2015 John Wiley & Sons Ltd Cardiovascular Therapeutics 33 (2015) 209–215 Antihypertensive Therapy in Metabolic Syndrome Patients N. Y. Ef imova et al.
Table 3 Regional cerebral blood flow (mL/100 g/min) in patients with MetS MetS pts baseline (n = 54) MetS pts after treatment (n = 54) Anterior parietal Posterior parietal MetS, metabolic syndrome. Values are mean  standard deviation. *P < 0.05; **P < 0.01; ***P < 0.001: significance of differences versus controlgroup. #P < 0.05, ##P < 0.01, ###P < 0.001: significance of differences versus before treatment.
Table 4 Parameters cognitive function in patients with the metabolic syndrome MetS pts baseline (n = 54) MetS pts after treatment (n = 54) Digit Span Forward The number of digits Digit Symbol Test The Bourdon—Wiersma Dot Cancellation Test (DCT) Number of mistakes The Trail Making Test (TMT) The Trail Making Test (TMT) The Rey Auditory Verbal The number of words Learning Test (AVLT) reproduced after the firstpresentation Number reproduced words 30 min The total number of words reproduced in 8 repetitions The Complex Figure Test The number of graphic figures, reproduced after the firstpresentation Number of played figures in 30 min Mets, metabolic syndrome. Values are mean  standard deviation. *P < 0.05; **P < 0.01: significance of differences versus control group. #P < 0.05:significance of differences versus before treatment.
Six-month antihypertensive therapy had positive effect on cog- of psychomotor slowing and changes of rCBF in left anterior parie- nitive function in patients with MetS. These patients demon- tal regions (R2 = 0.50; P = 0.001), as well as with improvement of strated improvement in attention by 13%, immediate and delayed attention and increase in rCBF in right inferior frontal region, and verbal memory by 20%, learning by 14%, and verbal comprehen- in right and left posterior parietal regions (R2 = 0.18; P = 0.005, sion by 10% (P < 0.05) (Table 4).
R2 = 0.10; P = 0.038, R2 = 0.14; P = 0.013, R2 = 0.12; P = 0.023, Relationships between changes in rCBF, 24-h blood pressure monitoring indices, and dynamics of cognitive function were doc- Improvement of immediate verbal memory correlated well with decrease in mean nighttime SBP and DBP (R2 = 0.14; P = 0.018, Improvement of immediate verbal memory strongly correlated R2 = 0.13; P = 0.023); improvement of immediate visual memory with an increase in rCBF in left superior frontal region, left poster- correlated with fall in "loads" for daytime SBP (R2 = 0.093; ior parietal cortex, right temporal lobe, and in right and left occipi- P = 0.049), as well as improvement of spatial optical gnosis with tal regions (R2 = 0.124; P = 0.022, R2 = 0.224; P = 0.002, R2 = decline variability daytime SBP (R2 = 0.110; P = 0.032) and 0.214; P = 0.002, R2 = 0.193; P = 0.004, R2 = 0.968; P = 0.047, "loads" for nighttime SBP and DBP (R2 = 0.122; P = 0.023, correspondingly). Spatial optical gnosis improved due to an R2 = 0.109 P = 0.033, correspondingly). In addition, it revealed increase in cerebral perfusion in left occipital cortex (R2 = 0.197; significant inverse relationship between the dynamics of psycho- P = 0.003). Significant correlation was shown between dynamics motor speed and variability daytime DBP (R2 = 0.116; P = 0.027).
212 Cardiovascular Therapeutics 33 (2015) 209–215 ª 2015 John Wiley & Sons Ltd N. Y. Ef imova et al.
Antihypertensive Therapy in Metabolic Syndrome Patients Table 5 Indicators of 24-h ambulatory blood pressure monitoring in P = 0.035, correspondingly). Diastolic blood pressure "loads" for patients with metabolic syndrome 24-h period was negatively correlated with rCBF in right inferior frontal region (R2 = 0.93; P = 0.039). Increased rCBF in left infe- rior frontal lobe is directly related with lower 24-h mean SBP, mean daytime DBP, and "loads" 24-h DBP (R2 = 0.90; P = 0.042, R2 = 0.85; P = 0.049, R2 = 0.11; P = 0.025).
Our previously published data [18–20] together with the present results suggest that cognitive function of patients with cardiovas- cular diseases is directly related to the parameters of cerebral cir- culation. Our study showed that abnormal cerebral perfusion is one of the major causes of neurocognitive deficits in patients with Available literature suggests that patients with MetS have pronounced initial cerebral perfusion abnormalities affecting the occipital–parietal, temporal, parietal–temporal, frontal–parietal– temporal, parietal, and frontal–parietal regions of the brain [21].
Further degeneration of smooth muscular cells and depositions of hyaline and fibrin occur in vascular walls. Finally, microcir- culation becomes involved via rarefaction of arterioles and/or capillaries within a given vascular region. The changes in micro- circulation in patients with MetsS may be caused by at least three mechanisms. First, abnormalities in vasomotor tone regu- lation may lead to enhanced vasoconstriction or reduced responses to vasodilators [22]. Second, anatomy of the individ- ual precapillary resistance vessels changes due to hypertrophy of smooth muscle cells and accumulation of elastic fibers which is characteristic of adaptive changes in the muscular type arter- ies due to long-term increase in arterial blood pressure. Narrow- ing of lumen and intima thickening occurs in small cerebral arteries and arterioles as a result of media hypertrophy [22,23].
Further degeneration of smooth muscle cells and depositions of hyaline and fibrin occur in arterial wall. Finally, microvascular network changes due to perhaps a reduction in the density of arterioles or capillaries [24,25]. These mechanisms represent the main causes of ischemic abnormalities in target organs including brain. Experimental modeling suggests that hypertension results in reduction of external diameters of cerebral arteries and thick- ening of arterial walls [26].
It has been known that the combination of arterial hyperten- sion and metabolic syndrome results in pronounced disturbances of cerebral perfusion to the extent of stroke [21]. Metabolic Variability nighttime changes facilitate thrombus formation and lead to abnormal microcirculation in vital organs [27,28]. Additional factors Mets, metabolic syndrome; SBP, systolic blood pressure. Values are contributing to microvascular brain lesions in MetS may be mean  standard deviations, *P < 0.05, **P < 0.01 – reliability of differ- autonomic neuropathy and endothelial dysfunction [29,30].
ences versus control group. #P < 0.05, ##P < 0.01, – reliability of differ- Researcher studying cerebral perfusion considered abnormal cere- ences versus before treatment.
brovascular autoregulation as one of the pathogenic mechanisms of neurocognitive dysfunction in the presence of high blood pres- sure [10]. The results of our study suggested that reduced cerebral Moreover, the results showed that the improvement of cerebral perfusion is one of the major causes of neurocognitive deficit in perfusion is directly related to the degree of blood pressure reduc- patients with MetS and is closely associated with the circadian tion during treatment. Inverse correlation was shown between blood pressure profile. Separate components of the metabolic syn- dynamic variability DBP at night, "loads" 24-h DBP and "loads" drome can exert negative impact on cerebral perfusion and, con- for daytime DBP and changes rCBF in right posterior parietal cor- tex (R2 = 0.93; P = 0.039; R2 = 0.113; P = 0.022; R2 = 0.97, hypertension [10], dyslipidemia [31], and hyperinsulinemia [32] ª 2015 John Wiley & Sons Ltd Cardiovascular Therapeutics 33 (2015) 209–215 Antihypertensive Therapy in Metabolic Syndrome Patients N. Y. Ef imova et al.
increase the risk of dementia and cognitive impairment. More- tors, are able to decrease the media hypertrophy of peripheral over, patients with MetS are prone to thrombogenesis [28].
arteries and increase their luminal diameter [24]. Indeed, accord- This is caused by high level of fibrinogen and increased activity ing to Kuriyama et al. [35], the calcium channel blockers of tissue plasminogen inhibitor (PAI-1) synthesized mainly by vis- increase cerebral blood flow due to the direct effect on the con- ceral adipose tissue; the latter inhibits tissue plasminogen activator stricted cerebral resistance arteries. The antiplatelet activity and and slows down fibrin cleavage [33].
endothelium-protective effect of these drugs likely also improved Differential treatment of cognitive disorders requires good cerebral blood flow [36]. However, no information on combined knowledge of pathogenesis mechanisms and pharmacological use of these drugs is available in the literature in regard to effects of drugs. Our study showed that efficacious antihyperten- patients with MetS.
sive therapy in patients with metabolic syndrome (combination of calcium antagonist and iACE) improves cerebral perfusion and leads to regression of neurocognitive deficits due to positive changes in circadian blood pressure profile. There is evidence Our results suggest that diffuse disturbances of cerebral perfusion that drugs, used in our study, positively affect cerebral blood in different brain regions are associated with cognitive abnormali- flow in hypertensive patients. Chazova et al. [21] demonstrated ties in patients with metabolic syndrome. Combination antihyper- that 6-month perindopril treatment improved brain perfusion in tensive treatment improves the 24-h blood pressure profile, hypertensive patients. Antihypertensive drugs, including ACE increases cerebral blood flow, and corrects cognitive function in inhibitors, can reverse disorders associated with hypertension by patients with metabolic syndrome.
improving the circulation and vascular reserve [34]. There is no direct evidence that antihypertensive therapy beneficially affects Conflict of Interest the remodeling of cerebral arteries in hypertensive patients.
However, some antihypertensive drugs, especially ACE inhibi- The authors declare no conflict of interest.
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Cobre Montana NL POWERING A CLEAN ENERGY FUTURE Presentation to the Annual General Meeting 24 November, 2014 For personal use only DISCLAIMER Cobre Montana NL This presentation is for information purposes only. Neither this presentation nor the information contained in it constitutes an offer, invitation, solicitation or recommendation in relation to the purchase or sale of shares in any jurisdiction. This presentation may not be distributed in any jurisdiction except in accordance with the legal requirements applicable in such jurisdiction. Recipients should inform themselves of the restrictions that apply in their own jurisdiction. A failure to do so may result in a violation of securities laws in such jurisdiction. This presentation does not constitute financial product advice and has been prepared without taking into account the recipients investment objectives, financial circumstances or particular needs and the opinions and recommendations in this presentation are not intended to represent recommendations to particular persons. Recipients should seek professional advice when deciding if an investment is appropriate. All securities transactions involve risks which include, amongst others, the risk of adverse or unanticipated market, financial or political developments. Certain statements contained in this presentation, including information as to the future financial or operating performance of Cobre Montana NL ("Cobre Montana" or "the Company") and its projects, are forward-looking statements. Such forward-looking statements are necessarily based upon a number of estimates and assumptions that, whilst considered reasonable by Cobre Montana, are inherently subject to significant technical, business, economic, competitive, political and social uncertainties and contingencies; involve known and unknown risks and uncertainties that could cause actual events or results to differ materially from estimated or anticipated events or results reflected in such forward-looking statements; and may include, among other things, statements regarding targets, estimates and assumptions in respect of potash and phosphate production and prices, operating costs and results, capital expenditures, ore reserves and mineral resources and anticipated grades and recovery rates, and are or may be based on assumptions and estimates related to future technical, economic, market, political, social and other conditions. Cobre Montana disclaims any intent or obligation to update publicly any forward-looking statements, whether as a result of new information, future events or results or otherwise. The words "believe", "expect", "anticipate", "indicate", "contemplate", "target", "plan", "intends", "continue", "budget", "estimate", "may", "will", "schedule" and other similar expressions identify forward-looking statements. All forward-looking statements made in this presentation are qualified by the foregoing cautionary statements. Investors are cautioned that forward looking statements are not guarantees of future performance and accordingly investors are cautioned not to put undue reliance on forward-looking statements due to the inherent uncertainty therein. Many known and unknown factors could cause actual events or results to differ materially from estimated or anticipated events or results reflected in such forward-looking statements. Such factors include, but are not limited to: competition; mineral prices; ability to meet additional funding requirements; exploration, development and operating risks; uninsurable risks; uncertainties inherent in ore reserve and resource estimates; dependence on third party smelting facilities; factors associated with foreign operations and related regulatory risks; environmental regulation and liability; currency risks; effects of inflation on results of operations; factors relating to title to properties; native title and aboriginal heritage issues; dependence on key personnel; and share price volatility and also include unanticipated and unusual events, many of which are beyond the Company's ability to control or predict. COMPETENT PERSON'S STATEMENT The information in this report that relates to reporting of Exploration Results based on and fairly represents information and supporting documentation prepared by Adrian Griffin, who is a member of

Flourtreatment_pdf.fh8

INFORMATION FOR CUSTOMERS, PARTNERS AND STAFF Flour Treatment in Europe We are doubtless coming closer to a uniform European The present necessity for oxidative treatment might be regarded as definition and regulation of a disadvantage of the fast and gentle processing of grain into flour. chemical flour treatment, but Natural “ageing” of the flour by exposure to the atmosphere alone is