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Arterial Stiffness and Cognition in Elderly Persons With Impaired Glucose Tolerance and Microalbuminuria

Departments of ¹ Geriatric Medicine and Metabolic Diseases and ² General Pathology, Second University of Naples, Italy.
³ Department of Medical and Surgical Sciences, University of Padova, Italy.

Address correspondence to Giuseppe Paolisso, MD, Second University of Naples, Italy, Piazza Miraglia 2, I-80138 Naples, Italy. E-mail: giuseppe.paolisso{at}unina2.it

	Abstract

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Background. Cognitive decline that occurs frequently in impaired glucose tolerance (IGT) may be largely due to endothelial dysfunction. We assessed: (i) the relationships between impact of urinary albumin excretion rate (UAER), as marker of generalized endothelial dysfunction, and cognition; (ii) if cognitive decline could be explained by arterial stiffening using pulse wave velocity (PWV).

Methods. One hundred forty older patients (age range 70–85 years) with IGT and no dementia were selected. Patients were classified according to 24-hour UAER: normoalbuminuric (NA) (UAER < 20 µg/min) or microalbuminuric (MA) (UAER between 20 and 199 µg/min). Cognitive abilities were assessed by the Mini-Mental State Examination (MMSE) and a composite score of executive and attention functioning (CCS) at baseline and after 12 months of follow-up.

Results. In MA patients (n = 80), increased UAERs correlated with intimal media thickness (IMT) (r = 0.268; p =.02) and PWV (r = 0.310; p =.004). In the same group, increased UAERs were correlated with MMSE and CCS even after adjusting for age and mean arterial blood pressure (MABP). After adding PWV, the associations among UAERs, MMSE, and CCS were no longer significant. In MA patients, PWV correlated with IMT, MMSE, and CCS. In NA patients, no significant correlations were found among UAERs, MMSE, and CCS. At follow-up, baseline UAERs predicted an approximately 20% risk of poor cognition (according to MMSE and CCS) after adjusting for confounders. After adding PWV, UAERs no longer predicted cognitive performance.

Conclusions. MA older persons with IGT showed a decline in cognition performance that may be partially explained by arterial stiffness.

Key Words: Cognitive decline • Microalbuminuria • Arterial stiffness • Pulse wave velocity • Aging

Older persons with IGT are a selective group of individuals at significantly higher risk of cognitive impairment (8) and endothelial dysfunction (9–11) compared to those with normal glucose tolerance (NGT). Due to the fact that endothelial dysfunction, especially in the presence of microalbuminuria, may be largely correlated to cognitive impairment (12), diverse mechanisms explaining such an important clinical entity could be operating in concert. One cannot rule out that an important role played by arterial stiffness on cognitive impairment may be occurring in the presence of microalbuminuria.

We hypothesize that: (i) increased urinary albumin excretion rate (UAER), as a marker of endothelial damage, in older patients with IGT and microalbuminuria, may be associated with impaired cognitive functioning; and (ii) that such a decline may be mediated by an increase in arterial stiffness, using the pulse wave velocity (PWV) measurement.

	METHODS

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Study Population
One hundred forty older persons with IGT and an age range of 70–85 years volunteered for the study. Data collection started in September 2003 and was completed in September 2006. Participants were selected from a group of approximately 220 individuals with IGT or probable IGT from university outpatient offices. Persons with type 2 diabetes mellitus, chronic renal or liver disease, congestive heart failure, history of stroke, presence of carotid plaques with severe hemodynamic impairment, dementia, or UAER > 200 µg/min were excluded from the study. All participants underwent an initial 75-g oral glucose tolerance test (OGTT) screening procedure after fasting for at least 12 hours, and blood glucose levels were determined every 30 minutes up to 180 minutes. Persons with IGT had a 2-hour postchallenge result between 140 and 199 mg/dL (7.8–11.0 mmol/L) according to World Health Organization (WHO) criteria (13).

All patients were asked whether they were undergoing any antiplatelet treatment and then were categorized as drug intakers (patients currently in antiplatelet therapy) or not drug intakers (patients not undergoing any antiplatelet therapy). All patients with microalbuminuria were already undergoing treatment with an angiotensin-converting enzyme inhibitor or an angiotensin II receptor antagonist. Smoking status was categorized according to cigarette use as current smoker or never smoked. All participants gave their written informed consent before participating in the study, which the ethical committee of our institution approved.

The geometric mean of three 24-hour urinary collection samples was obtained to determine UAER. UAER was analyzed by a solid-phase enzyme immunoassay (Microalbuminuria-ELISA; DRG Diagnostics, Marburg, Germany). Patients were classified according to mean 24-hour UAER: normoalbuminuric (NA) (UAER < 20 µg/min) or microalbuminuric (MA) (UAER between 20 and 199 µg/min). All participants were asked to maintain a standardized diet and liquid consumption 2 days prior to urinary test sampling as well as during the three 24-hour urinary collections to maintain consistent urinary volumes. Glomerular filtration rate (GFR) was determined using the Modification of Diet in Renal Disease formula (13).

For study protocol purposes and after training on a self-blood-glucose-monitoring instrument, participants were asked to record the self-monitoring of blood glucose levels at fasting and 2 hours, after lunch and dinner. Each participant recorded his or her blood glucose levels in a glucose diary 3 days a week, 2 weeks before baseline and follow-up. Baseline blood pressure was recorded by standard mercury sphygmomanometer on three occasions separated by intervals of 2 minutes, and the average of the last two measurements was used in the analysis. Hypertension was defined according to the following criteria: systolic blood pressure (SBP) > 140 mmHg and diastolic blood pressure (DBP) > 90 mmHg and/or taking antihypertensive medication (14).

Stiffness over the carotid-femoral portion of the arterial tree was assessed by measuring carotid-femoral PWV using the Pulse trace 6000 Micro Medical (Kent, U.K.). Electrocardiogram-referenced sequential carotid and femoral tonometry was used to measure carotid-femoral transit time, and PWV was calculated from the carotid-femoral path length divided by transit time. Path length was estimated as linear distance from the sternal notch to the femoral artery at the point of applanation. PWV of an arterial segment is inversely related to the square root of the distensibility of that segment and is considered the most reliable measure of large artery stiffness (15). All of the measurements were made by an experienced physician who was unaware of study protocol.

Plasma insulin was determined by a commercial double-antibody, solid-phase radioimmunoassay (Sorin Biomedica, Milan Italy, intra-assay coefficient of variation [CV] 3.1 + 0.3%, cross-reactivity vs proinsulin = 0.9%). Serum glucose, hemoglobin A1c (HbAlc), serum lipid and serum lipoprotein were quantified from fresh samples drawn after participants had been fasting for a least 12 hours.

All participants underwent the following tests of cognitive performance at baseline and at the 12th month of follow-up: Mini-Mental State Examination (MMSE), the Verbal Fluency (VF), Digit Span (DSp) forward and backward, Trail Making Test A (TMT-A), and Trail Making Test B (TMT-B). All cognitive evaluations were made by physicians who were unaware of both study design and albuminuric status.

The MMSE was assessed for global cognitive function (16). This cognitive test covers many cognitive skills, and scores range from 0 to 30. The TMT is visuomotor speed task that consists of two parts: TMT-A and TMT-B. TMT-A, visual scanning test, requires one to draw a line connecting consecutive numbers from 1 to 25. TMT-B adds cognitive flexibility to TMT-A and requires one to draw a line connecting numbers and letters in alternating sequence (17). Although time to completion scores are typically used to examine aspects of attention and executive function (16), the difference between the two scores, TMT-B minus TMT-A, provides a measure of cognitive efficiency (18). The VF test requires participants to generate as many words as possible in 1 minute for a given letter (F,A,S) (19).

The Wechsler Adult Intelligence Scale-Revised Digit Span is a measure of mental tracking as well as brief storage and mental manipulation (16). Depression was evaluated using the Center for Epidemiological Studies Depression Scale (CES-D) (20).

Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. Carotid ultrasound evaluation examining the common carotid artery, the carotid bulb, and the internal and external carotid arteries was performed in all patients. The carotid arteries were carefully examined for wall changes from different longitudinal and transverse views (21). A region about 1.5 cm proximal to the carotid bifurcation was identified, and the intimal media thickness (IMT) of the far wall was evaluated as the distance between the luminal-intimal interface and the medial-adventitial interface. One transversal and two longitudinal measurements of IMT were obtained from 10 contiguous sites at 1-mm intervals, and the average of the 10 measurements was used for the analysis. All measurements were performed at baseline and at the end of the follow-up by two trained investigators who were unaware of study protocol.

Statistical Analyses
Statistical analyses were performed using SPSS software (version 9.0; SPSS, Inc., Chicago, IL). All data are presented as mean ± standard deviation (SD). Student t tests were used to compare baseline characteristics between groups. Descriptive results of continuous variables are presented as means ± SD. Microalbuminuria values were not normally distributed; therefore, log-transformed values were used in the analysis and back-transformed for data presentation. Pearson product-moment correlations were calculated to test associations among variables. For each individual patient, the CV of postprandial glucose (CV-PPG) was also computed (22).

As previously reported (22), a cluster analysis, using the squared sum of z scores, showed whether an overall value obtained by clustering attention and executive function test results was associated UAERs. To create such cluster analysis, we created a cognition composite score of attention and executive functions (CCS), as sum of the squared z scores of TMT-A, TMT-B, DIFF B-A, Dsp-Forward, Dsp-Backward, and VF. A z score indicates the position of an individual value of a variable in the total distribution of the variable in the population.

Partial correlations were performed at baseline in the entire study group and separately in both groups testing the relationship between cognitive test scores (cognition composite score and MMSE score) and individual UAERs after adjusting for age, MABP, and PWV. Logistic regression models were used to assess the relative risk of developing poor cognitive performance (MMSE score < 24) at follow-up after adjusting for baseline MMSE, age, years of education, BMI, smoking status, depression, drug intake, CV-PPG, SBP, IMT, and PWV. At follow-up, a multivariate linear analysis with CCS as dependent variable, and testing the independent relationship with baseline UAERs, after adjusting for the same multiple confounders, was performed.

	RESULTS

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Baseline Data
At baseline, the mean UAERs were 11.8 ± 8.1 µg/min and 58.3 ± 18.3 µg/min in NA and MA patients, respectively. Clinical characteristics are reported in Table 1. MA patients had slightly higher 2-hour plasma glucose, triglycerides, SBP, IMT, and PWV whereas HbA1c, GFR and indices of cognitive function did not differ between the two study groups. In all patients, we did not find any significant correlations among UAERs and any neuropsychological tests in both unadjusted and adjusted models (data not shown). However, in MA patients, increased UAERs were correlated with worse scores on the MMSE and CCS in an unadjusted model as well as after adjustment for age and MABP (Table 2). After further adjustment for PWV, the associations among UAERs, MMSE, and CCS were no longer significant in MA patients (Table 2). In the same group, increased UAERs correlated with increased IMT (r = 0.268; p =.02) and faster PWV (r = 0.310; p =.004). Furthermore, PWV correlated with IMT (r = 0.389; p <.001), MMSE (r = –0.256; p =.03), and with CCS (r = –0.340; p =.002) only in MA patients.

Follow-Up Data
A total of 75 patients (93.7%) with MA and 53 patients (88.3%) with NA completed study protocol design (Figure 1). At follow up, MA patients did not show any significant variations in glucometabolic parameters (HbA1c) or in indices of cognitive function (data not shown). We found that MA patients had UAERs (48.3 + 18.3 vs 45.9 + 20.4 µg/min; p = not significant), HbA1c (6.9 + 0.3 vs 6.8 + 0.2%; p = not significant), and GFR (74.2 ± 23.2 vs 72.2 ± 21.1 mL/min/1.73 m²) not significantly different from basal ones, whereas a significant increase in PWV (13.7 + 3.1 vs 14.8 + 2.2 cm/s; p <.04) and a worsening degree of cognitive performance were found (MMSE: 26.2 + 1.2 vs 24.3 + 2.2, p <.04; CCS: 0.0455 + 0.075 vs 0.0390 + 0.036, p <.03).

View larger version (25K): [in this window] [in a new window]   Figure 1. Participant categorization and follow-up flow diagram. IGT = impaired glucose tolerance

	DISCUSSION

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The present study provides evidence that increased UAERs, as markers of endothelial damage, are associated with cognitive decline in older microalbuminuric persons with IGT. Furthermore, our findings suggest that such association may be mediated by large arterial stiffening. Our data also demonstrate that increased UAERs are associated with SBP, IMT, and PWV in older microalbuminuric persons with IGT.

At present, cognitive decline represents one of the most difficult and challenging disabilities to overcome in older persons, especially with altered glucose metabolism. The exact mechanisms explaining cognitive performance decline in older persons with altered glucose metabolism have been largely linked to plasma glucose fluctuations (22). In particular, it has been shown that older persons with IGT are at a higher risk for cognitive decline than NGT, due to the fact that poor cognitive performance parallels the worsening of glucose tolerance status in such individuals (9). In addition, such fluctuations may cause cognitive impairment either by a direct neuronal damage mediated by the advanced glycosylated end-products or by an indirect neuronal damage, due to micro- and/or macrovascular atherosclerotic damage (2,10). Plasma glucose fluctuations are also responsible for a raise in reactive oxygen species (ROS) (23) and such pro-oxidative effect may actively contribute to an inappropriate regulation of vascular tone, permeability, coagulation, fibrinolysis, cell adhesion, and proliferation. It has also been suggested that ROS generation in endothelial cells exposed to plasma glucose spikes can lead to endothelial dysfunction (2), which in turn could also be responsible for decline in brain functioning due to arterial stiffness.

There is strong evidence indicating that neural activity is closely related to cerebral blood flow (CBF) (12,24). Due to the unique anatomical and complex characteristics of cerebral blood vessels and their close interaction with neurons and glia, cerebral vascular tone regulation may have an important role in cognitive decline (25). Indeed, it has been suggested that cognitive decline develops from a neuronal energy crisis triggered by vascular abnormalities that initiate the progressive neurodegenerative process (24). One important influence on the regulation of vascular tone is the release of endothelial nitric oxide (eNO) through the well-known vasodilation effect (26) as well as a role played by eNO on maintaining ideal endothelial cell shape (27). Therefore, peripheral endothelial dysfunction, which in turn may cause cerebral hypoperfusion, will result in microangioarchitectural distortions and consequent hemodynamic disturbances in the brain. Considering that there is a rigid vascular tone of peripheral arteries in older persons with IGT and microalbuminuria (9), our data further strengthen a possible role of peripheral endothelial function on CBF by suggesting the association between arterial stiffness and cognitive performance decline in a group of older persons at risk for endothelial dysfunction. Furthermore, a growing body of evidence on the vascular biology of the amyloid β peptide (Aβ) (28) strengthens the hypothesis that vascular factors play a pathogenic role in Alzheimer's disease due to the fact that the use of cholinesterase inhibitors also act by improving CBF (29). The accumulation of Aβ peptide causes the constriction of cerebral arteries due to reduced vascular endothelium dilatation, and could explain impaired neural activity due to altered CBF (30,31).

Endothelial function is commonly assessed by measuring the degree of brachial artery dilatation in response to increased flow after forearm occlusion with a blood pressure cuff (32). However, this method is not used in routine clinical practice. More recent and practical indicators of endothelial functions include PWV and the presence of microalbuminuria. Indeed, microalbuminuria is no longer considered a single marker of vascular dysfunction of the renal arterial bed alone, but reflects systemic dysfunction of the vascular endothelium with an increased risk of cardiovascular events (33). In a large epidemiological study (Insulin Resistance Atherosclerosis Study [IRAS]), microalbuminuric persons without type 2 diabetes (albumin-to-creatinine ratio 2 mg/mmol) had greater common carotid artery IMT than those with normal albuminuria (34). Moreover, another report demonstrated that essential hypertensive microalbuminuric patients had significantly higher values of aortic PWV than normoalbuminuric ones (35). Our data show that UAERs were significantly and positively associated with IMT and PWV in patients with microalbuminuria. Thus, our data also confirm that microalbuminuria should be considered a sign of generalized vascular disease. Indeed, our study demonstrated that endothelial dysfunction, as measured by PWV, was significantly higher in patients with microalbuminuria and negatively associated with cognitive performance. Our study is in agreement with previous research demonstrating a relationship between an invasive measure of peripheral endothelial function and global neuropsychological performance (12). It is also important to point out that the literature on vascular cognitive impairment suggests that the frontal cortex is implicated in executive functioning and such cerebral area is particularly susceptible to blood flow impairment (36). Indeed, our data show that CCS is correlated negatively with PWV and thus verifies a major role of vascular functioning on frontal lobe vulnerability.

PWV is considered a clinical indicator of arterial stiffness and is becoming widely used in clinical practice (15). PWV has also been associated with mild cognitive impairment, Alzheimer's disease, and vascular dementia in older persons with NGT (37). Furthermore, any vascular changes encompassing arterial stiffness, compromising the function of the blood–brain barrier would lead to increased vascular permeability as well as protein extravasation and thus β-amyloid accumulation and cognitive impairment (38). Recent reports have also demonstrated that β-amyloid interacts with endothelial cells in the production of free radicals (31).

A possible confounder of the relationship among cognitive performance, UAERs, and arterial stiffening may be linked to arterial blood pressure. Indeed, it is widely known that SBP and DBP are significantly associated with cognitive decline and arterial stiffening especially in older persons (39,40), and our data also report a negative correlation between cognitive performance and SBP in both normoalbuminuric and microalbuminuric patients at baseline. Nevertheless, a possible role of blood pressure, as a common underlying factor, between cognitive decline and increased UAERs can not be ruled out. In fact, the associations among UAERs, arterial blood pressure, and arterial stiffness have been investigated. In particular, the Prevention of Renal and Vascular End stage Disease (PREVEND) Study showed that the odds ratios for an increase in UAER during follow-up was almost twofold for each 10 mmHg increase in arterial blood pressure (41). Such a possibility was confirmed from our cross-sectional data, which showed that SBP was negatively associated with cognitive performance. Nevertheless, our longitudinal analyses evidenced that a relationship between cognitive decline and UAERs was independent of SBP.

Our study demonstrates that, in microalbuminuric older persons with IGT, there was a significant decline in cognitive functioning compared to that in those with normoalbuminuria. Our findings underline that UAE can be easily obtained compared to other vascular markers, like IMT and PWV, and therefore should also be considered an ideal marker in a geriatric population. Arterial stiffness, as demonstrated by PWV, seems to play a role on global cognitive performance as well as on executive and attention functioning.

	Footnotes

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Decision Editor: Luigi Ferrucci, MD, PhD

Received September 25, 2007

Accepted December 19, 2007

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