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Original Investigation |

Albuminuria and Decline in Cognitive Function:  The ONTARGET/TRANSCEND Studies FREE

Joshua I. Barzilay, MD; Peggy Gao, MSc; Martin O’Donnell, MD, PhD; Johannes F. E. Mann, MD; Craig Anderson, MD, PhD; Robert Fagard, MD, PhD; Jeffrey Probstfield, MD; Gilles R. Dagenais, MD; Koon Teo, MD, PhD; Salim Yusuf, MD, DPhil; the ONTARGET and TRANSCEND Investigators
[+] Author Affiliations

Author Affiliations: Kaiser Permanente of Georgia and Division of Endocrinology, Emory University School of Medicine, Atlanta (Dr Barzilay); Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada (Ms Gao and Drs O’Donnell, Teo, and Yusuf); Schwabing General Hospital, KfH Kidney Centre, Ludwig Maximilians University, Munchen, Germany (Dr Mann); George Institute of International Health, Sydney, Australia (Dr Anderson); Hypertension and Cardiovascular Rehabilitation Unit, KU Leuven University, Leuven, Belgium (Dr Fagard); Clinical Trials Service Unit, Division of Cardiology, Department of Medicine, University of Washington School of Medicine, Seattle (Dr Probstfield); and Institut Universitaire de Cardiologie et Pneumologie de Québec, Québec City, Québec, Canada (Dr Dagenais).Group Information: A complete list of the ONTARGET and TRANSCEND Investigators was published in Am Heart J. 2004;148(1):59-61.


Arch Intern Med. 2011;171(2):142-150. doi:10.1001/archinternmed.2010.502.
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Published online

Background  Microvascular disease of the kidney (manifesting as albuminuria) and of the brain (manifesting as cognitive decline) may share a common pathogenesis. Gaining an understanding of the concomitant history of these 2 conditions may inform clinical practice and lead to novel prevention and treatment approaches.

Methods  A total of 28 384 participants with vascular disease or diabetes mellitus were examined. At baseline and year 5, participants underwent a Mini-Mental State Examination (MMSE) and urine testing for albumin excretion. Multivariable logistic regression was used to determine the association between albumin excretion and MMSE score, cross-sectionally and prospectively, and whether angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker use modified the association.

Results  Compared with participants with normoalbuminuria, those with microalbuminuria (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.11-1.44]) and macroalbuminuria (1.49; 1.20-1.85) were more likely to have a reduced MMSE score (<24). On follow-up, participants with baseline albuminuria had increased odds of cognitive decline (decrease in MMSE score ≥3 points) compared with those with normoalbuminuria (microalbuminuria: OR, 1.22; 95% CI, 1.07-1.38; macroalbuminuria: 1.21; 0.94-1.55). Participants who developed new albuminuria had increased odds of cognitive decline during follow-up compared with those who remained normoalbuminuric (new microalbuminuria: OR, 1.30; 95% CI, 1.12-1.52; new macroalbuminuria: 1.77; 1.24-2.54). Participants with baseline macroalbuminuria treated with an angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker had lower odds of MMSE decline than participants treated with placebo.

Conclusion  Factors that contribute to albuminuria may contribute to cognitive decline, supporting the notion that both conditions share a common microvascular pathogenesis.

Trial Registration  clinicaltrials.gov Identifier: NCT00153101

Figures in this Article

Kidneys that excrete excessive amounts of albumin have many of the same microvascular features that are found in the brains of people with cognitive impairment, eg, capillary basement membrane thickening, luminal narrowing, and leakiness.13 These observations suggest that both conditions may share a common pathogenesis, and they may also share similar natural courses. Recently, several studies demonstrated that microalbuminuria and macroalbuminuria are associated with increased odds or risk of cognitive impairment. Given the cross-sectional nature of some of these studies46 and the inconclusive results of the prospective studies (2 of which had <2 years of follow-up),79 it would be of interest to perform larger studies with longer follow-up to confirm and quantify the prospective relationship between albuminuria and cognitive impairment. If such a relationship does exist, it will contribute to a better understanding of pathways leading to cognitive decline that may facilitate new approaches to prevention and possibly treatment.

The Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET) and the Telmisartan Randomized Assessment Study in ACE [Angiotensin-Converting Enzyme]–Intolerant Subjects With Cardiovascular Disease (TRANSCEND) provide an opportunity to address these questions because both trials included participants with baseline and follow-up measurement of albuminuria and cognitive function.10 A significant proportion of participants had albuminuria. In this study we determined (1) the association between the presence and severity of albuminuria at baseline and cognitive function at baseline and follow-up, and (2) the relationship between an increase in albumin excretion and change in cognitive function during follow-up. Our hypothesis was that the presence and severity of albuminuria and its progression were independently associated with decline in cognitive function. We also examined whether use of ACE inhibitors and/or angiotensin receptor blocker (ARBs) modified the association of albuminuria with cognitive function.

POPULATION

The ONTARGET was a double-blind, randomized cardiovascular outcome study of 25 620 participants with vascular disease or diabetes mellitus (DM) with end-organ damage, randomly assigned to receive the ARB telmisartan (80 mg/d), the ACE inhibitor ramipril (10 mg/day), or their combination. It reported that the 2 medications were equal in terms of cardiovascular and renal outcomes, whereas their combination was associated with more adverse effects and offered no benefit other than reducing the level of albuminuria.11,12 A parallel study, the TRANSCEND, determined whether telmisartan was superior to placebo in 5926 patients who had the same eligibility criteria as in ONTARGET but were intolerant of ACE inhibitors. It demonstrated that telmisartan had no statistically significant effect on the primary cardiovascular outcome (cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure), but it reduced the risk of the secondary composite outcome of cardiovascular death, myocardial infarction, and stroke. It had no effect on cardiovascular or total mortality.13,14 The median follow-up of both studies was 56 months. Nested within these studies was a cognition study with serial assessment of Mini-Mental State Examination (MMSE). Repeated measurements of albuminuria were also obtained. All participants signed informed consent on study entry.

OUTCOME MEASURES

Cognitive function was ascertained by use of the MMSE at baseline and at the penultimate study visit. The MMSE includes 10 domain items, which relate to orientation to time (5 points), orientation to place (5 points), registration of new information (3 points), attention and calculation (5 points), recall (3 points), naming and repetition (3 points), items assessing language skills (8 points [2 naming items, repeating a phrase, following a 3-step command, reading and following a written command, and writing a sentence]), and design copy (1 point), the last being a brief measure of visual construction. The MMSE scale ranges from 0 to 30, with higher scores indicating better cognitive performance. The MMSE is a screening instrument to discriminate cognitive impairment and dementia.15 Contextually appropriate translations of the MMSE were used in several countries (Austria, Belgium, Czech Republic, Germany, Greece, the Netherlands, Finland, Norway, Sweden, South Africa, United Arab Emirates, and South Korea).

A decrease of 3 points or more in the MMSE score was considered a significant change in cognitive function and is a cutoff point that has been used previously.16 An MMSE score of less than 24 has been used as a conventional cutoff point for clinically significant cognitive impairment.14

MEASUREMENT OF ALBUMINURIA AND OTHER LABORATORY TESTING

Albuminuria was measured as urine albumin to creatinine ratio before run-in and at the penultimate visit. A value between 30 and 299 mg per gram of creatinine (to convert to milligrams per millimole, multiply by 0.113) was defined as microalbuminuria. A value of 300 mg or more per gram of creatinine was defined as macroalbuminuria. Urine albumin was measured centrally by a turbidimetric method (Unicel DxC600 Synchron Systems; Beckman Coulter, Brea, California). The coefficient of variation was 4.4% at 32.2 mg/L and 2.4% at 105.5 mg/L. A human serum pool at a concentration of 10.9 mg/L gave a coefficient of variation of 9.2%, and at 159.8 mg/L gave a coefficient of variation of 2.7%. Creatinine in urine was measured centrally by a modified Jaffe method (Unicel DxC600 Synchron Systems). The coefficient of variation was 2.9% at 7.9 mg/L and 2.8% at 23.1 mg/L. A human serum pool at a concentration of 10.8 mg/L gave a coefficient of variation of 2.6%, and at 103 mg/L gave a coefficient of variation of 1.8%.

Serum creatinine was measured before run-in, 6 weeks after randomization, after 2 years, and at study conclusion. Serum creatinine was measured locally at study sites. From these values, the estimated glomerular filtration rate (eGFR) was calculated by means of the 4-item Modification of Diet in Renal Disease formula.17

BASELINE AND INCIDENT COVARIATES

Baseline characteristics were obtained through questionnaires and clinical assessment. Fasting glucose and lipid values were obtained locally. Depression was considered present if the participant answered positively to the questions “Have you felt sad, in low spirits or depressed for the past 2 weeks or more?” and “Have you thought of death or required treatment for depression?” Regular alcohol use was defined as 3 or more drinks per week; binge drinking was defined as more than 5 drinks per day. Being physically active was defined as doing exercise 2 to 4 times a week or more. Education level was categorized by the highest attained level. Data were sought regarding prevalent and incident cardiac events (myocardial infarction, angina, hospitalization for heart failure), stroke/transient ischemic attacks, peripheral artery disease, coronary artery bypass grafting, and percutaneous coronary intervention, as well as medication use.

STATISTICAL METHODS

Continuous data were summarized by means and standard deviations, and the comparison across normoalbuminuria, microalbuminuria, and macroalbuminuria was performed via analysis of variance method. Categorical data were presented as frequencies and percentages and then compared with the χ2 test. Multivariable logistic regression was used to determine (1) the association between presence and severity of albuminuria (at baseline) and cognitive function at baseline and at follow-up and (2) the association between an increase in albumin excretion during follow-up and decline in cognitive function during follow-up (Figure 1). Only participants with available urine albumin to creatinine ratio and MMSE scores at baseline or baseline and 5 years were included in the corresponding regression analyses. The characteristics of included patients and other participants were compared by unpaired, 2-tailed t tests for continuous variables and χ2 test for categorical variables. Multivariate analyses were also used to examine whether ACE inhibitor and/or ARB use modified the association of albuminuria with cognition change.

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Figure 1.

Flow diagram of study participants in whom the relationship of Mini-Mental State Examination (MMSE) scores and change in MMSE scores with baseline albuminuria and change in albuminuria was analyzed.

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All models were adjusted for demographic factors (age, sex, and ethnicity [European, Arab, African, native or aboriginal, and other]) and level of education [none, 1-8 years, 9-12 years, trade/technical school, and college/university]), previous cardiovascular disease (CVD), and risk factors, including the following: history of myocardial infarction, angina, coronary artery bypass grafting, and stroke/transient ischemic attacks; eGFR as a continuous variable; hypertension and baseline systolic blood pressure; smoking (never, former, or current); body mass index; lipid levels; and DM and fasting glucose levels. Other factors affecting or possibly affecting cognition were also adjusted for: (1) alcohol use (none, binge [>5 drinks/d], once a week, 2-4/wk, 5-6/wk, or every day); (2) depression (yes/no); and (3) use of medications: statins, β-blockers, antiplatelet agents, calcium-channel blockers, and anticoagulants. For incident changes in MMSE, additional adjustment was made for incident CVD events and for change in eGFR. A 2-tailed P < .05 was considered statistically significant. Analyses were performed with SAS version 8.2 (SAS Institute, Inc, Cary, North Carolina).

In total, 28 384 participants with baseline albuminuria levels and MMSE scores were included, of whom 84.0% had normoalbuminuria, 12.5% microalbuminuria, and 3.5% macroalbuminuria (Table 1). Compared with participants with normoalbuminuria, those with albuminuria were older; had higher blood pressure, body mass index, and waist circumference; had higher glucose and creatinine levels, lower eGFR, increased low-density lipoprotein cholesterol levels, and reduced high-density lipoprotein cholesterol levels; were less likely to be of European ethnicity; were more likely to currently smoke; more frequently had a history of hypertension, left ventricular hypertrophy, and DM; had less clinical vascular disease; drank alcohol less often; had lower attained levels of education; and were less physically active at baseline. Those with microalbuminuria or macroalbuminuria were also less likely to be taking a statin, a β-blocker, or aspirin but were more likely to be taking a diuretic, calcium-channel blocker, or anticoagulant.

Table Graphic Jump LocationTable 1. Baseline Characteristics of the ONTARGET/TRANSCEND Cohorts Included in the Cognition Evaluation Study Categorized as Having Normoalbuminuria, Microalbuminuria, or Macroalbuminuriaa
BASELINE ALBUMINURIA AND COGNITIVE FUNCTION

Mean (SD) baseline MMSE scores were 27.8 (2.7), 27.2 (3.3), and 26.8 (3.7) in participants with normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively (Table 2; eFigure). There was a graded increase in MMSE score less than 24 with increasing severity of albuminuria. On multivariable analyses (Table 3), the presence of albuminuria was associated with impaired cognitive function (MMSE score <24), with odds ratios (ORs) of 1.27 (95% confidence interval [CI], 1.12-1.45) for microalbuminuria and 1.51 (1.22-1.87) for macroalbuminuria. When these analyses were repeated (eTable 1), categorized by sex, English or non-English speaker, white or nonwhite, or highest level of attained education, a similar effect was noted. There was no relationship between baseline MMSE scores and quartiles of urine albumin in participants with albuminuria levels less than 30 mg/g of creatinine (data not shown).

Table Graphic Jump LocationTable 2. Distribution of MMSE Scores and Mean MMSE Scores Categorized by Baseline Level of Albuminuria
Table Graphic Jump LocationTable 3. Logistic Regression Models of Odds of MMSE Score Less Than 24 at Baseline in Participants With Microalbuminuria or Macroalbuminuria vs Without Albuminuriaa

Compared with participants with baseline albuminuria and MMSE values, participants who did not have measured baseline albuminuria and/or MMSE scores had a greater burden of CVD risk factors, lower levels of achieved education, and lower activity levels (eTable 2).

BASELINE ALBUMINURIA AND DECLINE IN COGNITIVE FUNCTION ON FOLLOW-UP

For this analysis, 22 507 participants who had albuminuria and MMSE values at baseline and at follow-up were examined (Table 4). A decrease in MMSE score of 3 points or more occurred in 11.0% of participants without albuminuria, 14.5% with microalbuminuria, and 15.0% with macroalbuminuria. On multivariable analyses, baseline microalbuminuria (OR, 1.23; 95% CI, 1.08-1.39), but not macroalbuminuria (OR, 1.25; 95% CI, 0.98-1.59), was significantly associated with a 3-point or greater decline in MMSE score compared with those without albuminuria. When these analyses were repeated (eTable 3), categorized by sex, English or non-English speaker, white or nonwhite, or highest level of attained education, a similar effect was noted. Compared with participants with baseline and follow-up MMSE values, participants without follow-up MMSE values had higher levels of CVD risk factors, more prevalent CVD, lower renal function, higher levels of albuminuria, and lower levels of attained education (eTable 4).

Table Graphic Jump LocationTable 4. Logistic Regression Model of Odds of a 3-Point or Greater Decrease in MMSE Score From Baseline to Year 5 of Follow-up in Participants With Microalbuminuria or Macroalbuminuria vs Without Albuminuriaa

We further examined whether the use of medications (telmisartan from ONTARGET and TRANSCEND, n = 8240; ramipril from ONTARGET, n = 6184; and the combination of ramipril and telmisartan from ONTARGET, n = 6027) vs placebo (TRANSCEND, n = 2056) modified the association of albuminuria with cognitive decline (Table 5). In unadjusted analyses, there was no overall effect in each treatment group. However, when groups were subdivided by albuminuria status, there was a decrease in the odds of MMSE decline in participants with macroalbuminuria, especially with telmisartan. The overall interaction term of treatment on the odds of MMSE decline approached statistical significance (P = .055) and was significant with adjustment (P = .02).

Table Graphic Jump LocationTable 5. Odds Ratios (ORs) (Logistic Regression Analyses) of a 3-Point or Greater Decline in MMSE Score From Baseline to the Penultimate Visit by Treatment in the ONTARGET and TRANSCEND Studies Combineda
CHANGE IN URINARY ALBUMIN EXCRETION AND DECLINE IN COGNITIVE FUNCTION ON FOLLOW-UP

This analysis included 19 544 participants with both urine albumin and MMSE measurements at baseline and at follow-up. During follow-up, 83.0% (16 216 of 19 544 participants) had no change in albuminuria status (normoalbuminuria, 15 022 participants; microalbuminuria, 924; and macroalbuminuria, 270); 5.9% (1155 of 19 544) had improvement in albuminuria status (macroalbuminuria to microalbuminuria, 131 participants; macroalbuminuria to normoalbuminuria, 94; and microalbuminuria to normoalbuminuria, 930); and 11.1% (2173 of 19 544) had worsening (normoalbuminuria to microalbuminuria, 1642 participants; normoalbuminuria to macroalbuminuria, 224; and microalbuminuria to macroalbuminuria, 307). Among those with normoalbuminuria at baseline who progressed to microalbuminuria or macroalbuminuria, there was a stepwise increase in the odds of a 3-point or greater MMSE score decrease compared with those who remained normoalbuminuric (OR [95% CI], 1.30 [1.12-1.52] and 1.77 [1.24-2.54], respectively) (Table 6 and Figure 2). Compared with those whose microalbuminuria regressed to normoalbuminuria, those who remained microalbuminuric or had progression to macroalbuminuria had an increased odds of a 3-point or greater decrease in MMSE score (OR [95% CI], 1.33 [1.00-1.78] and 1.57 [1.07-2.32]). Last, compared with those whose macroalbuminuria regressed to normoalbuminuria, those who remained with macroalbuminuria or had regression to microalbuminuria were 1.50 (95% CI, 0.65-3.50) and 1.73 (0.70-4.29) more likely to have a 3-point or greater decrease in MMSE score.

Place holder to copy figure label and caption
Figure 2.

Odds ratios (ORs) and 95% confidence intervals (CIs) of developing a 3-point or greater decrease in Mini-Mental State Examination (MMSE) score during 5 years categorized by baseline normoalbuminuria (normal), microalbuminuria (micro), and macroalbuminuria (macro) and the change in albuminuria status during 5 years of follow-up.

Graphic Jump Location
Table Graphic Jump LocationTable 6. Logistic Regression Model of the Odds of a 3-Point or Greater Decrease in MMSE Score From Baseline to Year 5 of Follow-up in Participants Whose Albuminuria Status Changeda

Compared with participants with baseline and follow-up albuminuria and MMSE values, those without either or both of these values had a higher burden of CVD risk factors, more prevalent CVD, lower renal function, higher levels of albuminuria, and lower levels of attained education (eTable 5).

This is, to our knowledge, the first study to report both a cross-sectional and a prospective, graded association between a marker of microvascular disease—albuminuria—and the development of cognitive decline. Importantly, this association was independent of clinical cardiovascular and renal disease (prevalent and incident) and cardiovascular risk factors, which cluster with albuminuria. These results are consistent with the notion that albuminuria and cognitive decline may share a common microvascular pathogenesis and progression.

It is hypothesized that changes in the cerebral microcirculation contribute to cognitive changes. Owing to the difficulty of studying such changes ante mortem and the lack of specific symptoms referable to them, most evidence for their role is indirect. Such evidence includes magnetic resonance imaging–defined silent strokes, white matter lesions, and white matter hyperintensity in the absence of clinical stroke events18 and the presence of microvascular risk factors (such as hypertension, DM, and smoking) in people with cognitive impairment. Further evidence comes from cross-sectional studies of the retinal vasculature. Retinal arterioles share common anatomical and physiological characteristics with cerebral arterioles and are affected by hypertension and age. In the Atherosclerosis Risk in Communities Study, any form of retinopathy was associated with increased odds of cognitive impairment.19 The greater the severity of the retinopathy (microaneurysms, hemorrhages, and exudates), the greater were the odds of impaired cognition. Similar findings were observed in the Cardiovascular Health Study in an older cohort.20 One study demonstrated retinopathy to be associated with brain white matter hyperintensity.21 Finally, 3 cross-sectional studies of albuminuria have shown it to be associated with dementia, white matter hyperintensity on magnetic resonance imaging, or poor executive functioning.46

Additional evidence of an association of microvascular disease and cognitive change comes from several cross-sectional studies of albuminuria. In a study of 2316 adults 65 years or older, drawn from the Cardiovascular Health Study, the risk of mild cognitive impairment was increased by 10% and that of dementia by 22% in univariate analysis for each doubling of the urine albumin to creatinine ratio.4 The association of albuminuria with dementia remained significant in multivariate analysis. In a different study,5 of 335 elderly participants, the presence of albuminuria was associated with worse executive functioning. In both studies the degree of albuminuria was associated with a graded increase in white matterhyperintensity score. A third study, based on the National Health and Nutrition Examination Survey III data set, also reported an association between albuminuria and cognition but only in people with peripheral artery disease.6

Three studies have prospectively assessed the association of baseline albuminuria with cognitive change. A study from Australia found that cognitive decline in 204 older diabetic individuals was predicted across 1.5 years by increased urinary albumin excretion.7 In a study of 140 elderly participants with impaired glucose tolerance, baseline urine albumin to creatinine ratio was associated with a 10% to 20% increased risk, during 1 year, of developing poor cognitive function.8 Another report9 showed no cross-sectional association between albuminuria and low cognitive scoring in older adults but a statistically significant prospective (6.6 years) association in men. In the largest of these studies,9 there were only 90 participants with albuminuria. None had the ethnic and geographic diversity of our cohort or the large number of participants, with or without DM and CVD; nor were as many adjustments for covariates done as in our study.

A causal relationship between albuminuria and the development of cognitive change cannot be derived from our study. It is likely, however, that the 2 disorders arose concomitantly. The cerebral and renal circulations are characterized by high flow and low impedance. Autoregulation of the microvasculature serves to bring blood flow to these organs, at the same time limiting excess pressure exposure in the capillaries (reviewed by Mitchell22). Endothelial dysfunction and loss of microvascular autoregulation can disrupt the normal milieu within the extracellular matrix of the brain and kidney.23 Strain in the microcirculation, for example, can increase the generation of reactive oxygen species.22

With regard to the modification of study drug on the association of albuminuria with MMSE decline, lower odds of MMSE decline compared with placebo were found with all treatments, especially telmisartan, in the presence of macroalbuminuria. These results are in keeping with our previous analyses that showed renin angiotensin system (RAS) blockade to be consistently effective in lowering proteinuria only in participants with greater than 1 g of protein per gram of creatinine in the urine.14 The results suggest that, in this relatively small subgroup of study participants, RAS blockade may have been protective of cognitive function. Given the nonrandomized, observational nature of our analyses, such a conclusion should be viewed with caution. However, there is indirect support for our findings. A retrospective analysis of the Cardiovascular Health Study has shown that certain RAS blockers are protective of cognitive decline in people with hypertension. The effect was hypothesized to be due to decreased brain RAS activity.24 A small, prospective study reported that patients treated with a combination of telmisartan and hydrochlorothiazide showed improvement in cognitive function compared with those treated with a combination of lisinopril and hydrochlorothiazide.25 The Observational Study on Cognitive Function and Systolic Blood Pressure Reduction demonstrated antihypertensive therapy based on ARB use to be associated with preservation of cognitive function.26 On the other hand, in the Study on Cognition and Prognosis in the Elderly, ARB use was not associated with lower rates of cognitive decline compared with placebo.27 None of these studies examined albuminuria and cognition.

Of interest is to view our findings from a population perspective. Studies from the United States estimate that 14.6% to 32.7% of adults 60 years to 80 years or older have microalbuminuria or macroalbuminuria.28 Among similarly aged adults with DM, the rates are 37.6% to 48.6%. Assuming that the presence of microalbuminuria or macroalbuminuria increases the odds of cognitive impairment by 22% to 44%, it follows that 3.2% to 14.4% of diminished cognitive function is associated with or explained by microalbuminuria or macroalbuminuria and in 8.3% to 21.4% of those with DM. Likewise, assuming that microalbuminuria or macroalbuminuria increases the risk of a decrease in cognitive function by approximately 18%, we estimate that 2.6% to 5.9% of cases of cognitive decline in the general population, and 6.8% to 8.7% in those with DM, are associated with microalbuminuria or macroalbuminuria. These estimates are in accord with estimates of cognitive decline in association with high white matter intensity scores.29 It should be noted that our estimates apply to a population whose mean age is approximately 10 years younger than the “usual” age at which cognitive impairment appears.

There are several limitations to this study. First, participants in ONTARGET and TRANSCEND had vascular disease or were at high risk for it. These characteristics by themselves can increase the risk of cognitive disease.2 Our results, therefore, may not be applicable to people with albuminuria without known vascular disease. Second, the MMSE is a general test of cognition, weighted mostly to memory and orientation; it does not capture deficiencies in various domains of cognitive function, nor can it detect subtle changes in frontal lobe executive function, a common early feature of vascular-related cognitive impairment. A simple screening tool such as the MMSE is used in large trials to minimize cost and to lessen inconvenience to the participant. Last, the cohorts for each of the 3 sets of analysis were healthier than those excluded from the analyses for lack of albuminuria or MMSE values. This makes our estimates conservative.

Our findings have clinical implications. They suggest that, among people with macrovascular disease, microvascular disease in one organ system may reflect microvascular disease in another. This may explain why dementia and mild cognitive impairment are more common in people with DM,30 who have a high prevalence of albuminuria. Our findings offer a possible avenue for screening of people at risk for cognitive impairment. Our findings regarding treatment require confirmation by a dedicated prospective study.

Correspondence: Joshua I. Barzilay, MD, Kaiser Permanente of Georgia, 200 Crescent Center Pkwy, Tucker, GA 30084 (Joshua.barzilay@kp.org).

Accepted for Publication: June 18, 2010.

Author Contributions:Study concept and design: Barzilay, Anderson, and Yusuf. Acquisition of data: Barzilay, Mann, Anderson, Fagard, Probstfield, Dagenais, Teo, and Yusuf. Analysis and interpretation of data: Barzilay, Gao, O’Donnell, Mann, Anderson, Teo, and Yusuf. Drafting of the manuscript: Barzilay, Gao, Mann, and Teo. Critical revision of the manuscript for important intellectual content: Barzilay, O’Donnell, Mann, Anderson, Fagard, Probstfield, Dagenais, Teo, and Yusuf. Statistical analysis: Barzilay, O’Donnell, and Gao. Obtained funding: Anderson and Yusuf. Administrative, technical, and material support: Mann, Anderson, Probstfield, Dagenais, and Teo. Study supervision: Anderson, Probstfield, Teo, and Yusuf.

Financial Disclosure: None reported.

Funding/Support: This study was supported by Boehringer Ingelheim, Ingelheim, Germany.

Role of the Sponsor: Boehringer Ingelheim had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Independent Statistical Analysis: The studies were coordinated and the results analyzed independently by the Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. The database was transferred to the sponsor at the end of the study.

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Mann  JFESchmieder  REDyal  L  et al. TRANSCEND (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease) Investigators, Effect of telmisartan on renal outcomes: a randomized trial. Ann Intern Med 2009;151 (1) 1- 10, W1-2
PubMed Link to Article
Folstein  MFFolstein  SEMcHugh  PR “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12 (3) 189- 198
PubMed Link to Article
Tzourio  CAnderson  CChapman  N  et al. PROGRESS Collaborative Group, Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003;163 (9) 1069- 1075
PubMed Link to Article
Stevens  LACoresh  JGreene  TLevey  AS Assessing kidney function—measured and estimated glomerular filtration rate. N Engl J Med 2006;354 (23) 2473- 2483
PubMed Link to Article
Schmidt  RPetrovic  KRopele  SEnzinger  CFazekas  F Progression of leukoaraiosis and cognition. Stroke 2007;38 (9) 2619- 2625
PubMed Link to Article
Wong  TYKlein  RSharrett  AR  et al.  Retinal microvascular abnormalities and cognitive impairment in middle-aged persons: the Atherosclerosis Risk in Communities Study. Stroke 2002;33 (6) 1487- 1492
PubMed Link to Article
Baker  MLMarino Larsen  EKKuller  LH  et al.  Retinal microvascular signs, cognitive function, and dementia in older persons: the Cardiovascular Health Study. Stroke 2007;38 (7) 2041- 2047
PubMed Link to Article
Wong  TYKlein  RSharrett  AR  et al. ARIC Investigators, Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 2002;288 (1) 67- 74
PubMed Link to Article
Mitchell  GF Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage. J Appl Physiol 2008;105 (5) 1652- 1660
PubMed Link to Article
Zipser  BDJohanson  CEGonzalez  L  et al.  Microvascular injury and blood-brain barrier leakage in Alzheimer's disease. Neurobiol Aging 2007;28 (7) 977- 986
PubMed Link to Article
Sink  KMLeng  XWilliamson  J  et al.  Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. Arch Intern Med 2009;169 (13) 1195- 1202
PubMed Link to Article
Fogari  RMugellini  AZoppi  A  et al.  Effect of telmisartan/hydrochlorothiazide vs lisinopril/hydrochlorothiazide combination on ambulatory blood pressure and cognitive function in elderly hypertensive patients. J Hum Hypertens 2006;20 (3) 177- 185
PubMed Link to Article
Hanon  OBerrou  JPNegre-Pages  L  et al.  Effects of hypertension therapy based on eprosartan on systolic arterial blood pressure and cognitive function: primary results of the Observational Study on Cognitive Function and Systolic Blood Pressure Reduction open-label study. J Hypertens 2008;26 (8) 1642- 1650
PubMed Link to Article
Lithell  HHansson  LSkoog  I  et al. SCOPE Study Group, The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003;21 (5) 875- 886
PubMed Link to Article
Garg  AXKiberd  BAClark  WFHaynes  RBClase  CM Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III. Kidney Int 2002;61 (6) 2165- 2175
PubMed Link to Article
Frisoni  GBGalluzzi  SPantoni  LFilippi  M The effect of white matter lesions on cognition in the elderly—small but detectable. Nat Clin Pract Neurol 2007;3 (11) 620- 627
PubMed Link to Article
Cukierman  TGerstein  HCWilliamson  JD Cognitive decline and dementia in diabetes—systematic overview of prospective observational studies. Diabetologia 2005;48 (12) 2460- 2469
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Flow diagram of study participants in whom the relationship of Mini-Mental State Examination (MMSE) scores and change in MMSE scores with baseline albuminuria and change in albuminuria was analyzed.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Odds ratios (ORs) and 95% confidence intervals (CIs) of developing a 3-point or greater decrease in Mini-Mental State Examination (MMSE) score during 5 years categorized by baseline normoalbuminuria (normal), microalbuminuria (micro), and macroalbuminuria (macro) and the change in albuminuria status during 5 years of follow-up.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of the ONTARGET/TRANSCEND Cohorts Included in the Cognition Evaluation Study Categorized as Having Normoalbuminuria, Microalbuminuria, or Macroalbuminuriaa
Table Graphic Jump LocationTable 2. Distribution of MMSE Scores and Mean MMSE Scores Categorized by Baseline Level of Albuminuria
Table Graphic Jump LocationTable 3. Logistic Regression Models of Odds of MMSE Score Less Than 24 at Baseline in Participants With Microalbuminuria or Macroalbuminuria vs Without Albuminuriaa
Table Graphic Jump LocationTable 4. Logistic Regression Model of Odds of a 3-Point or Greater Decrease in MMSE Score From Baseline to Year 5 of Follow-up in Participants With Microalbuminuria or Macroalbuminuria vs Without Albuminuriaa
Table Graphic Jump LocationTable 5. Odds Ratios (ORs) (Logistic Regression Analyses) of a 3-Point or Greater Decline in MMSE Score From Baseline to the Penultimate Visit by Treatment in the ONTARGET and TRANSCEND Studies Combineda
Table Graphic Jump LocationTable 6. Logistic Regression Model of the Odds of a 3-Point or Greater Decrease in MMSE Score From Baseline to Year 5 of Follow-up in Participants Whose Albuminuria Status Changeda

References

Farkas  ELuiten  PGM Cerebral microvascular pathology in aging and Alzheimer's disease. Prog Neurobiol 2001;64 (6) 575- 611
PubMed Link to Article
de la Torre  JC Alzheimer disease as a vascular disorder: nosological evidence. Stroke 2002;33 (4) 1152- 1162
PubMed Link to Article
Fioretto  PSteffes  MWBrown  DMMauer  SM An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics. Am J Kidney Dis 1992;20 (6) 549- 558
PubMed Link to Article
Barzilay  JIFitzpatrick  ALLuchsinger  J  et al.  Albuminuria and dementia in the elderly: a community study. Am J Kidney Dis 2008;52 (2) 216- 226
PubMed Link to Article
Weiner  DEBartolomei  KScott  T  et al.  Albuminuria, cognitive functioning, and white matter hyperintensities in homebound elders. Am J Kidney Dis 2009;53 (3) 438- 447
PubMed Link to Article
Vupputuri  SShoham  DAHogan  SLKshirsagar  AV Microalbuminuria, peripheral artery disease, and cognitive function. Kidney Int 2008;73 (3) 341- 346
PubMed Link to Article
Bruce  DGDavis  WACasey  GP  et al.  Predictors of cognitive decline in older individuals with diabetes. Diabetes Care 2008;31 (11) 2103- 2107
PubMed Link to Article
Abbatecola  AMBarbieri  MRizzo  MR  et al.  Arterial stiffness and cognition in elderly persons with impaired glucose tolerance and microalbuminuria. J Gerontol A Biol Sci Med Sci 2008;63 (9) 991- 996
PubMed Link to Article
Jassal  SKKritz-Silverstein  DBarrett-Connor  E A prospective study of albuminuria and cognitive function in older adults: the Rancho Bernardo Study. Am J Epidemiol 2010;171 (3) 277- 286
PubMed Link to Article
Teo  KYusuf  SSleight  P  et al. ONTARGET/TRANSCEND Investigators, Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J 2004;148 (1) 52- 61
PubMed Link to Article
Yusuf  STeo  KKPogue  J  et al. ONTARGET Investigators, Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358 (15) 1547- 1559
PubMed Link to Article
Mann  JFESchmieder  REMcQueen  M  et al. ONTARGET Investigators, Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET Study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372 (9638) 547- 553
PubMed Link to Article
Yusuf  STeo  KAnderson  C  et al. Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) Investigators, Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial [published correction appears in Lancet. 2008;372(9647):1384]. Lancet 2008;372 (9644) 1174- 1183
PubMed Link to Article
Mann  JFESchmieder  REDyal  L  et al. TRANSCEND (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease) Investigators, Effect of telmisartan on renal outcomes: a randomized trial. Ann Intern Med 2009;151 (1) 1- 10, W1-2
PubMed Link to Article
Folstein  MFFolstein  SEMcHugh  PR “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12 (3) 189- 198
PubMed Link to Article
Tzourio  CAnderson  CChapman  N  et al. PROGRESS Collaborative Group, Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003;163 (9) 1069- 1075
PubMed Link to Article
Stevens  LACoresh  JGreene  TLevey  AS Assessing kidney function—measured and estimated glomerular filtration rate. N Engl J Med 2006;354 (23) 2473- 2483
PubMed Link to Article
Schmidt  RPetrovic  KRopele  SEnzinger  CFazekas  F Progression of leukoaraiosis and cognition. Stroke 2007;38 (9) 2619- 2625
PubMed Link to Article
Wong  TYKlein  RSharrett  AR  et al.  Retinal microvascular abnormalities and cognitive impairment in middle-aged persons: the Atherosclerosis Risk in Communities Study. Stroke 2002;33 (6) 1487- 1492
PubMed Link to Article
Baker  MLMarino Larsen  EKKuller  LH  et al.  Retinal microvascular signs, cognitive function, and dementia in older persons: the Cardiovascular Health Study. Stroke 2007;38 (7) 2041- 2047
PubMed Link to Article
Wong  TYKlein  RSharrett  AR  et al. ARIC Investigators, Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 2002;288 (1) 67- 74
PubMed Link to Article
Mitchell  GF Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage. J Appl Physiol 2008;105 (5) 1652- 1660
PubMed Link to Article
Zipser  BDJohanson  CEGonzalez  L  et al.  Microvascular injury and blood-brain barrier leakage in Alzheimer's disease. Neurobiol Aging 2007;28 (7) 977- 986
PubMed Link to Article
Sink  KMLeng  XWilliamson  J  et al.  Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. Arch Intern Med 2009;169 (13) 1195- 1202
PubMed Link to Article
Fogari  RMugellini  AZoppi  A  et al.  Effect of telmisartan/hydrochlorothiazide vs lisinopril/hydrochlorothiazide combination on ambulatory blood pressure and cognitive function in elderly hypertensive patients. J Hum Hypertens 2006;20 (3) 177- 185
PubMed Link to Article
Hanon  OBerrou  JPNegre-Pages  L  et al.  Effects of hypertension therapy based on eprosartan on systolic arterial blood pressure and cognitive function: primary results of the Observational Study on Cognitive Function and Systolic Blood Pressure Reduction open-label study. J Hypertens 2008;26 (8) 1642- 1650
PubMed Link to Article
Lithell  HHansson  LSkoog  I  et al. SCOPE Study Group, The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003;21 (5) 875- 886
PubMed Link to Article
Garg  AXKiberd  BAClark  WFHaynes  RBClase  CM Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III. Kidney Int 2002;61 (6) 2165- 2175
PubMed Link to Article
Frisoni  GBGalluzzi  SPantoni  LFilippi  M The effect of white matter lesions on cognition in the elderly—small but detectable. Nat Clin Pract Neurol 2007;3 (11) 620- 627
PubMed Link to Article
Cukierman  TGerstein  HCWilliamson  JD Cognitive decline and dementia in diabetes—systematic overview of prospective observational studies. Diabetologia 2005;48 (12) 2460- 2469
PubMed Link to Article

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