Cerebral small vessel disease, including microvascular lesions, is considered to play an important role in the development of type 2 diabetes mellitus (T2DM)-associated cognitive deficits. With ultra-high field MRI, microvascular lesions (e.g., microinfarcts and microbleeds) can now be visualized in vivo. For the current study, 48 nondemented older individuals with T2DM (mean age 70.3 ± 4.1 years) and 49 age-, sex-, and education-matched control subjects underwent a 7-Tesla brain MRI scan and a detailed cognitive assessment. The occurrence of cortical microinfarcts and cerebral microbleeds was assessed on fluid-attenuated inversion recovery and T1-weighted and T2*-weighted images, respectively, compared between the groups, and related to cognitive performance. Microinfarcts were found in 38% of control subjects and 48% of patients with T2DM. Microbleeds were present in 41% of control subjects and 33% of patients (all P > 0.05). The presence and number of microinfarcts or microbleeds were unrelated to cognitive performance. This study showed that microvascular brain lesions on ultra-high field MRI are not significantly more common in well-controlled patients with T2DM than in control subjects.

Type 2 diabetes mellitus (T2DM) is associated with cognitive dysfunction and a twofold increased risk of dementia (1). The etiology is incompletely known, but vascular disease is likely to play a role (1). In the general population, vascular disease, in particular cerebral small vessel disease (SVD), is a major contributor to aging-related cognitive decline and dementia (2). On conventional MRI, SVD can be visualized as white matter hyperintensities (WMHs), lacunar infarcts, and microbleeds (3). However, these conventional markers of SVD do not capture the full burden of cerebral microvascular damage. Neuropathological studies have identified microinfarcts as another common microvascular pathology that is linked to antemortem cognitive decline and dementia (4).

T2DM is a known risk factor for vascular disease, affecting both large and small vessels. Microvascular complications of T2DM appear in the retina, peripheral nervous system, kidney, and probably also the brain. Ultra-high resolution MRI now, for the first time, permits visualization of cortical microinfarcts in vivo (5) and also greatly enhances the detection of cerebral microbleeds (6). We hypothesized that microinfarcts and microbleeds are more common in patients with T2DM than in control subjects and that these lesions are associated with cognitive dysfunction. The current study investigated the presence of cortical microinfarcts and cerebral microbleeds with 7-Tesla (T) MRI in patients with T2DM and in age-matched nondiabetic control subjects, and explored the relationship between these microvascular lesions and cognitive performance.

Study Population

Patients were recruited through six general practitioners as part of the second Utrecht Diabetic Encephalopathy Study (7). Eight hundred sixty-four randomly selected persons between 65 and 80 years of age (416 patients and 453 control subjects) received a letter to which they could respond if they were willing to participate. Two hundred sixty-three persons responded that they refused to participate; 168 responded that they were willing to participate, of whom 63 patients with T2DM and 61 age-, sex-, and education-matched control subjects met our inclusion criteria. For study inclusion, participants had to be 65–80 years of age, functionally independent, and Dutch speaking. The diagnosis of diabetes had to have been established at least 1 year prior to the study. Control subjects had to have a fasting blood glucose level of <7.0 mmol/L. Exclusion criteria were contraindications for 7-T MRI, a psychiatric or neurological disorder that could influence cognitive functioning (including dementia), recent nondisabling stroke (<2 years), or any disabling stroke, major depression, or alcohol abuse. All subjects underwent a standardized evaluation, including medical history, physical and neurological examination, neuropsychological assessment, laboratory testing, and both 3-T and 7-T MRI, all on the same day.

In 26 participants (15 patients with T2DM, 11 control subjects), no complete 7-T MRI could be obtained because of patient-related factors (e.g., contraindications for 7-T MRI or claustrophobia) or technical issues. One control participant proved to have a neurological disease that was not detected upon initial screening, leaving 97 subjects (48 patients with T2DM, 49 control subjects) for the current study.

The study was approved by the Medical Ethics Committee of the University Medical Center Utrecht, and all subjects gave written informed consent.

Medical History and Biometric Measurements

Medical history and medication use were assessed with standardized questionnaires. Blood pressure was measured at three different time points during the day and averaged. BMI was calculated as weight in kilograms divided by the square of height in meters. Levels of fasting glucose, HbA1c, and cholesterol were measured with standard laboratory testing. Impaired fasting glucose (IFG) was defined as fasting glucose levels of 5.6–6.9 mmol/L, according to the American Diabetes Association criteria.

Data on microvascular complications were recorded. Retinopathy was defined as self-report of a physician diagnosis. Neuropathy was rated using the Toronto Clinical Neuropathy Scoring System (8) but without a sensory test for temperature so that the maximum score is 18 points. A score of >6 was considered as indicative of neuropathy. A patient was considered to have macroalbuminuria in case of an albumin-to-creatinine ratio of >300 μg/mg (according to American Diabetes Association criteria), based on laboratory testing of a first midstream urine sample in the morning.

A macrovascular event was defined as a clinical history of myocardial infarction; stroke (not including transient ischemic attack); or endovascular or surgical treatment of carotid, coronal, or peripheral arterial disease.

MRI Scanning Protocol

Scans were acquired on a 7-T MRI system (Philips Healthcare, Cleveland, OH) with a volume transmit and 16- or 32-channel receive head coil (Nova Medical, Wilmington, MA). The standardized protocol included a dual-echo gradient echo sequence (repetition time [TR] 20 ms, echo time [TE]1 6.9 ms, TE2 15.8 ms, reconstructed voxel size 0.39 × 0.39 × 0.35 mm3), a volumetric (three-dimensional [3D]) T1-weighted sequence (TR 4.8 ms, TI 1,240 ms, TE 2.2 ms, reconstructed voxel size 0.66 × 0.66 × 0.50 mm3), and a 3D fluid-attenuated inversion recovery (FLAIR) sequence (TR 8,000 ms, TI 2,325 ms, TE 300 ms, reconstructed voxel size 0.49 × 0.49 × 0.40 mm3).

Scans on the 3-T MRI system (Philips Medical Systems, Best, the Netherlands) were acquired with a standardized protocol including, among others, a FLAIR sequence (TR 11,000 ms, TI 2,800 ms, TE 125 ms, reconstructed voxel size 0.96 × 0.95 × 3 mm3), a 3D T1-weighted sequence (TR 7.9 ms, TI 955 ms, TE 4.5 ms, voxel size 1.00 × 1.00 × 1.00 mm3), and a dual-echo T2-weighted sequence (TR 3,198 ms, TE1 19 ms, TE2 140 ms, reconstructed voxel size 0.96 × 0.95 × 3.00 mm3). The 3-T MRI data were used for the detection of brain infarcts and the determination of brain volumes and WMH volumes.

Detection of Microvascular Lesions

Microvascular lesions were rated visually on 7-T MRI scans by two independent raters, who were blinded to diabetes status and clinical information. In case of disagreement, consensus was obtained in a consensus meeting.

Cortical microinfarcts were defined as either small hyperintense (probably gliotic) lesions or hypointense with a hyperintense rim (probably cystic) lesions on the FLAIR image, corresponding with a hypointense lesion on the T1-weighted sequence (as previously described [9], but without use of a T2-weighted sequence) (Fig. 1). Each lesion had to be detectable on sagittal, coronal, and transversal views; ≤3 mm in length; and restricted to the cortex to be classified as a microinfarct. Because of the low signal-to-noise ratio on FLAIR images in the temporal lobes and cerebellum, these areas were not investigated.

Figure 1

An example of a cortical microinfarct (arrows; a more detailed view in the boxes), which appears hyperintense on FLAIR (A) and hypointense on T1-weighted (B) 7-T MRI.

Figure 1

An example of a cortical microinfarct (arrows; a more detailed view in the boxes), which appears hyperintense on FLAIR (A) and hypointense on T1-weighted (B) 7-T MRI.

Microbleeds were detected by the previously described semiautomatic method based on the radial symmetry transform (10). A slightly modified adaptation to the method was made by incorporating minimum intensity projection images. This improves the sensitivity and reduces the number of suspected microbleed locations. The radial symmetry transform result was then censored visually to select true microbleeds.

The interrater agreement was good for the number of microbleeds (intraclass correlation 0.83 [95% CI 0.75–0.88]) and moderate for number of microinfarcts (0.39 [0.21–0.55]).

Other MRI Measures

WMHs, cerebral infarcts, and brain volumes were determined by 3-T MRI scans. WMHs were outlined manually on the FLAIR images, and their volumes were calculated. Brain infarcts were rated visually on FLAIR and T1-weighted images and were classified as large vessel infarcts (>1.5 cm) or lacunar infarcts. Gray and white matter volumes were computed automatically on the T1-weighted image using the FreeSurfer software (http://surfer.nmr.mgh.harvard.edu). Volumes were expressed as a percentage of intracranial volume, which was outlined manually on the T2-weighted images.

Cognitive Testing

All participants underwent a detailed standardized cognitive assessment, as described earlier (7), including tests for memory, information-processing speed and attention, and executive function. For each cognitive test, raw test scores were standardized into z scores and averaged to obtain one composite z score per cognitive domain.

The intelligence quotient (IQ) was estimated with the Dutch version of the National Adult Reading Test, which is generally accepted to reflect the premorbid level of intellectual functioning.

Statistical Analyses

Between-group differences in subject characteristics were analyzed with an independent samples t test for continuous variables, χ2 tests for proportions, and Mann-Whitney U tests for nonparametric data. Relationships between the presence of microvascular lesions and cognition were examined with linear regression analyses, which were adjusted for age, sex, estimated IQ, and group (i.e., control or T2DM group). Because the numbers of microbleeds and microinfarcts showed a skewed distribution, three groups with zero, one, or one or more lesions were distinguished.

Subject characteristics are summarized in Table 1. Control subjects and patients with T2DM did not differ in age, sex, and estimated IQ. Patients with T2DM used antihypertensive and cholesterol-lowering drugs significantly more often and had a higher BMI than control subjects. Patients with T2DM performed slightly worse than control subjects on all three cognitive domains (mean differences in standardized z scores between patients and control subjects were as follows: information-processing speed −0.24 [95% CI −0.58 to 0.11]); attention and executive functioning −0.21 [−0.50 to 0.09]; memory −0.14 [−0.44 to 0.17]; all P > 0.05), but the differences were not statistically significant.

Table 1

Group characteristics

CharacteristicsControl subjects (n = 49)Patients with T2DM (n = 48)P value
Age (years) 71.1 ± 4.5 70.3 ± 4.1 0.36 
Male sex 30 (61) 26 (54) 0.48 
Estimated IQ* 103 ± 13 101 ± 12 0.29 
Systolic blood pressure (mmHg) 146 ± 22 148 ± 13 0.69 
Diastolic blood pressure (mmHg) 81 ± 9 80 ± 10 0.78 
Antihypertensive medication 25 (51) 36 (75) 0.02 
Total cholesterol (mmol/L) 5.4 ± 1.0 4.7 ± 0.9 <0.01 
Cholesterol-lowering drugs 21 (43) 34 (71) <0.01 
Current smoking 8 (16) 5 (10) 0.62 
BMI (kg/m226.1 ± 3.2 29.5 ± 5.1 <0.01 
Antithrombotic use 12 (25) 18 (38) 0.17 
Fasting glucose (mmol/L) 5.6 ± 0.7 8.0 ± 2.0 <0.01 
HbA1c (%) 5.7 ± 0.4 6.8 ± 0.8 <0.01 
Diabetes duration (years) — 11.0 ± 9.3  
Insulin/oral medication or diet — 15/33 (31/69)  
Macrovascular event 3 (6) 7 (15) 0.17 
Retinopathy 0 (0) 5 (10) 0.02 
Peripheral neuropathy§ 5 (10) 10 (21) 0.15 
Macroalbuminuria 0 (0) 1 (2) 0.31 
Cognitive performance    
 Information-processing speed 0.13 ± 0.57 −0.11 ± 1.07 0.18 
 Attention and executive functioning 0.09 ± 0.56 −0.11 ± 0.84 0.16 
 Memory 0.07 ± 0.73 −0.07 ± 0.76 0.37 
CharacteristicsControl subjects (n = 49)Patients with T2DM (n = 48)P value
Age (years) 71.1 ± 4.5 70.3 ± 4.1 0.36 
Male sex 30 (61) 26 (54) 0.48 
Estimated IQ* 103 ± 13 101 ± 12 0.29 
Systolic blood pressure (mmHg) 146 ± 22 148 ± 13 0.69 
Diastolic blood pressure (mmHg) 81 ± 9 80 ± 10 0.78 
Antihypertensive medication 25 (51) 36 (75) 0.02 
Total cholesterol (mmol/L) 5.4 ± 1.0 4.7 ± 0.9 <0.01 
Cholesterol-lowering drugs 21 (43) 34 (71) <0.01 
Current smoking 8 (16) 5 (10) 0.62 
BMI (kg/m226.1 ± 3.2 29.5 ± 5.1 <0.01 
Antithrombotic use 12 (25) 18 (38) 0.17 
Fasting glucose (mmol/L) 5.6 ± 0.7 8.0 ± 2.0 <0.01 
HbA1c (%) 5.7 ± 0.4 6.8 ± 0.8 <0.01 
Diabetes duration (years) — 11.0 ± 9.3  
Insulin/oral medication or diet — 15/33 (31/69)  
Macrovascular event 3 (6) 7 (15) 0.17 
Retinopathy 0 (0) 5 (10) 0.02 
Peripheral neuropathy§ 5 (10) 10 (21) 0.15 
Macroalbuminuria 0 (0) 1 (2) 0.31 
Cognitive performance    
 Information-processing speed 0.13 ± 0.57 −0.11 ± 1.07 0.18 
 Attention and executive functioning 0.09 ± 0.56 −0.11 ± 0.84 0.16 
 Memory 0.07 ± 0.73 −0.07 ± 0.76 0.37 

Data are presented as mean ± SD or n (%), unless otherwise specified.

*Estimated by the Dutch version of the National Adult Reading Test.

†Mean values for three measurements; blood pressure was not examined for one control subject.

‡Defined as a clinical history of myocardial infarction, stroke (not including transient ischemic attack), or endovascular or surgical treatment of carotid, coronal, or peripheral arterial disease.

§Rated with the Toronto Clinical Neuropathy Scoring System (8).

‖Defined as an albumin-to-creatinine ratio of >300 μg/mg.

¶Data are presented as mean standardized z scores ± SD.

MRI findings are described in Table 2. Cortical microinfarcts were found in 19 control subjects (38%) (5 subjects showed more than one microinfarct) and in 23 patients with T2DM (48%) (7 subjects showed more than one microinfarct; P > 0.05) (Fig. 2). Microbleeds were present in 20 control subjects (41%) (10 subjects showed more than one microbleed) and in 16 patients with T2DM (33%) (10 patients showed more than one microbleed; P > 0.05) (Fig. 2). Microbleed distribution (i.e., the presence and number of lobar and deep/infratentorial microbleeds) was also similar between the groups.

Table 2

MRI findings

FindingsControl subjects (n = 49)Patients with T2DM (n = 48)P value
Microvascular lesions*    
 Cortical microinfarct presence 19 (38) 23 (48) 0.36 
 Cortical microinfarcts 0 (0–11) 0 (0–5) 0.35 
 Microbleed presence 20 (41) 16 (33) 0.33 
 Microbleeds 0 (0–5) 0 (0–13) 0.55 
 Strictly deep/infratentorial microbleeds 3 (7) 1 (2) 0.32 
 Strictly lobar microbleeds 11 (24) 12 (27) 0.76 
Other MRI markers    
 WMH volume (mL) 6.9 ± 10.2 5.4 ± 5.5 0.36 
 Lacunar infarction 13 (27) 10 (21) 0.51 
 Large vessel infarction 2 (4) 3 (6) 0.63 
 Gray matter volume (% ICV) 39.1 ± 2.0 38.0 ± 2.2 0.02 
 White matter volume (% ICV) 30.5 ± 3.1 29.9 ± 2.4 0.30 
 Lateral ventricle volume (% ICV) 2.0 ± 1.0 2.7 ± 1.5 0.02 
FindingsControl subjects (n = 49)Patients with T2DM (n = 48)P value
Microvascular lesions*    
 Cortical microinfarct presence 19 (38) 23 (48) 0.36 
 Cortical microinfarcts 0 (0–11) 0 (0–5) 0.35 
 Microbleed presence 20 (41) 16 (33) 0.33 
 Microbleeds 0 (0–5) 0 (0–13) 0.55 
 Strictly deep/infratentorial microbleeds 3 (7) 1 (2) 0.32 
 Strictly lobar microbleeds 11 (24) 12 (27) 0.76 
Other MRI markers    
 WMH volume (mL) 6.9 ± 10.2 5.4 ± 5.5 0.36 
 Lacunar infarction 13 (27) 10 (21) 0.51 
 Large vessel infarction 2 (4) 3 (6) 0.63 
 Gray matter volume (% ICV) 39.1 ± 2.0 38.0 ± 2.2 0.02 
 White matter volume (% ICV) 30.5 ± 3.1 29.9 ± 2.4 0.30 
 Lateral ventricle volume (% ICV) 2.0 ± 1.0 2.7 ± 1.5 0.02 

Data are presented as n (%), median (range), or mean ± SD, unless otherwise specified.

ICV, intracranial volume.

*Determined at 7-T field strength.

†Determined at 3-T field strength.

Figure 2

Number of microinfarcts (A) and microbleeds (B) in control subjects (closed circles) and patients with T2DM (open circles). The number of microvascular lesions did not differ between the groups (Mann-Whitney U test: for number of microinfarcts P = 0.35; for number of microbleeds P = 0.55).

Figure 2

Number of microinfarcts (A) and microbleeds (B) in control subjects (closed circles) and patients with T2DM (open circles). The number of microvascular lesions did not differ between the groups (Mann-Whitney U test: for number of microinfarcts P = 0.35; for number of microbleeds P = 0.55).

Cerebral gray matter volumes were smaller and lateral ventricle volumes larger in the patients with T2DM than in the control subjects, but WMH and white matter volumes and the occurrence of brain infarcts did not differ between the groups (Table 2).

Across the two groups, cognitive performance on the three cognitive domains was not related to microvascular lesion load (regression coefficient B for information-processing speed: microinfarcts 0.06 [95% CI −0.17 to 0.29], microbleeds 0.11 [−0.08 to 0.31]; for attention and executive functioning: microinfarcts 0.04 [−0.16 to 0.23], microbleeds 0.02 [−0.14 to 0.19]; and for memory: microinfarcts 0.10 [−0.11 to 0.31], microbleeds 0.06 [−0.12 to 0.24]; all P > 0.05).

When control participants with IFG (n = 25; 51%) were excluded, microbleeds were present in 11 of the remaining 24 control subjects (46%), and microinfarcts in 10 of the remaining 24 control subjects (42%). Between-group comparisons on MRI markers and cognition for control subjects without IFG and patients with T2DM did not show results that were different from the main analyses (data not shown).

In this study on microvascular brain lesions in people with T2DM on ultra-high field MRI, we did not observe an increased occurrence of microinfarcts or microbleeds compared with control subjects. The presence and number of microinfarcts or microbleeds were unrelated to cognitive performance.

Previous estimates on the occurrence of cerebral microinfarcts are solely based on autopsy studies, which identified them in ∼24% of nondemented older individuals, with no significant differences between patients with T2DM and control subjects (11). However, in autopsy studies that specifically addressed people with dementia (12,13), microinfarcts were more common in patients with T2DM than in those without. In autopsy studies not specifically focusing on patients with T2DM (14,15), microinfarcts have been related to cognitive impairment and dementia diagnosis before death. These results suggest that the relationship between microinfarcts and cognition becomes evident only in cognitively symptomatic individuals. This may explain why we did not find a relation between microinfarcts and cognition in the current study.

Specific studies on the prevalence of microbleeds in patients with T2DM are scarce. A few population-based studies showed diabetes to be associated with microbleeds (odds ratio 2.2 [95% CI 1.2–4.2]) (16). Two recent studies, including the AGES Reykjavik study, specifically addressed patients with T2DM. Those studies (17,18) showed no difference in overall microbleed occurrence between patients with T2DM and control subjects, although an increased likelihood of two or more microbleeds in diabetic patients (7%) compared with control subjects (4%) was reported (18). Both studies used 1.5-T MRI and found much lower prevalences compared with our study. Microbleeds did not mediate the association of diabetes and worse cognitive performance (18). In previous large population-based cohorts, not specifically addressing T2DM, only weak associations between microbleeds and cognitive deficits have been reported (19,20), e.g., 0.4 Mini-Mental State Examination points for people with five or more microbleeds relative to those without (20). These studies are in line with our results showing modest or no relationships with cognition, despite the high sensitivity of high-field strength MRI to detect microbleeds.

The strengths of our study include the advanced technique for the detection of microvascular lesions, with a substantial sample size for an ultra-high field MRI study. We also used a comprehensive cognitive examination in a well-defined population-based cohort. Importantly, our scan protocol has the advantage over neuropathology that almost the complete supratentorial part of the brain can be assessed (except for the temporal lobes), whereas autopsy studies only sample a small portion of the brain microscopically. Moreover, in previous neuropathological studies, the temporal lobe has not been reported as a location of preference (11).

There are also limitations to this study. Our MRI protocol can detect only the largest microinfarcts (9). It is uncertain whether the detected lesions are a good representation of the complete lesion load in the brain. Moreover, the assessment of microinfarcts is particularly rater dependent. Nevertheless, because the raters were blinded we do not expect systematic errors in lesion counts for the groups. Finally, in the patient group glycemia and vascular risk factors were relatively well controlled. Although this does reflect the current clinical practice guidelines (21), it may have attenuated the contrast between the groups and may limit the generalizability of our findings. Moreover, control subjects with IFG were not excluded from the study, which might add to this effect. Our findings may therefore underestimate the occurrence of microvascular lesions in less well-controlled patient populations. Nevertheless, the patients in our cohort did have other brain MRI abnormalities that are typical for T2DM. They had a modest degree of brain atrophy, which is in line with the literature (22), and we previously reported that these patients had disturbed white matter connectivity relative to control subjects (7,23), despite the observation that WMH volumes and the occurrence of brain infarcts did not differ between the groups, which has also been reported before (24,25). Finally, the effect size of the difference in cognitive performance compared with control subjects of ∼0.2, although not statistically significant, is in line with a recent meta-analysis of the literature (26), which reports effect sizes of 0.2–0.4.

To conclude, this study showed no increased burden of cerebral microvascular damage in this well-controlled group of patients with T2DM compared with control subjects. Further studies should assess whether cerebral microvascular lesions occur in patients whose conditions are less well controlled or who have a high burden of microvascular complications elsewhere in the body.

Appendix

Members of the Utrecht Vascular Cognitive Impairment (VCI) Study Group involved in the Utrecht Diabetic Encephalopathy Study (in alphabetical order by department): Department of Neurology: G.J. Biessels, W. Bouvy, M. Brundel, S. Heringa, L.J. Kappelle, and E. van den Berg; Department of Radiology/Image Sciences Institute: J. de Bresser, H.J. Kuijf, A. Leemans, P.R. Luijten, W.P.Th.M. Mali, M.A. Viergever, K.L. Vincken, and J. Zwanenburg; and Julius Center for Health Sciences and Primary Care: A. Algra and G.E.H.M. Rutten.

Acknowledgments. The authors thank the primary care practices Ametisthof, Glennhof, De Poort, ‘t Steyn, and De Weegbree of Huisartsenzorg IJsselstein, IJsselstein, the Netherlands (mentor Ph.L. Salomé), and G. Visser, Nieuwegein, the Netherlands, for their supportive role in the recruitment process.

Funding. The research of G.J.B. is supported by Vidi grant 91711384 from ZonMw, the Netherlands Organisation for Health Research and Development, and by grant 2010T073 from the Netherlands Heart Foundation.

Duality of Interest. G.J.B. consults for and receives research support from Boehringer Ingelheim. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. M.B. acquired the data, performed the analyses, wrote the manuscript, gave final approval of the version to be published, and agreed to be listed as an author. Y.D.R. acquired the data, made critical revisions to the manuscript, gave final approval of the version to be published, and agreed to be listed as an author. S.J.v.V. and H.J.K. researched the data, critically revised the manuscript, gave final approval of the version to be published, and agreed to be listed as authors. P.R.L. critically revised the manuscript, gave final approval of the version to be published, and agreed to be listed as an author. L.J.K. and G.J.B. made substantial contributions to the conception and design of the study, critically revised the manuscript for important intellectual content, gave final approval of the version to be published, and agreed to be listed as authors. M.B. and G.J.B. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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