Introduction 1 2 3 4 5 6 2 3 4 7 8 5 9 10 9 11 12 13 15 16 19 The aim of the present study was to identify possible metabolic and vascular determinants of cognitive dysfunction and changes on brain MRI in patients with type 2 diabetes. Given the uncertainty about these determinants, an exploratory design was chosen. A detailed neuropsychological examination and brain MRI were obtained from a large cross-sectional sample of type 2 diabetes patients and related to different measures of glucose metabolism, vascular risk factors, microvascular complications and macrovascular disease. Methods Participants 6 20 Neuropsychological examination 6 z z 21 Brain MRI 22 6 23 23 z z z z z z z Diabetes characteristics and glucose metabolism 1c 24 24 Vascular risk factors Microvascular disease 25 26 Macrovascular disease 27 28 Statistical analysis t U 2 z z z p p Results Participant characteristics 1 Table 1 Participant characteristics Characteristic Type 2 diabetes group Control group n 122 56 Sex (male/female) 62/60 25/31 Age (years) 66.0 ± 5.8 65.1 ± 5.2 a 4 (3–5) 4 (3–5) Estimated premorbid IQ 99 ± 15 101 ± 14 b 8.7 ± 6.1  Diabetes treatment (%)    Diet 10   Oral medication alone 61  b 29  1c b , d 5.5 ± 0.3 b 8.6 ± 2.9** 5.5 ± 0.6 b,c , e n n b,c , f 2.6 ± 1.8 2 b 28.1 ± 4.4 27.3 ± 5.3 Data are given as number or percentage (as indicated), mean ± SD or ranges p a 49 b c z d p e p f p 6 z p p p z p p 18 p 4 10 3 12 p p Glucose metabolism 1c p 1 1c z 1c p 1c p p p p Vascular risk factors 2 p p p p p 2 Table 2 Vascular risk factors Characteristic n n a b 98 ± 10 a 65 ± 15* 59 ± 16 a 73** 34 Antihypertensive drugs (%) 70** 32 a 22 14 a 5.0 ± 0.9** 5.8 ± 1.1 a 4.3 ± 1.2 4.4 ± 1.5 a 1.9 ± 1.0 1.6 ± 1.1 a c 21 Data are given as percentage or mean ± SD p p a b p c p z p p p p z p p p 2 Microvascular disease p 3 Table 3 Microvascular disease Characteristic n n n n a ,b 1 (2)  Background  33  1  Severe non-proliferative 4   a 47 (39)** 7 (13)  Mild neuropathy 25  7   Moderate neuropathy 18  0  Severe neuropathy 4  0 n n a 16 (16) 3 (7)  Microalbuminuria 9 3  Macroalbuminuria 7  0 c 72 (59)** 11 (20) Data are given as values (percentage) p a b p c z p 3 Macrovascular disease p p 4 Table 4 Macrovascular disease Characteristic n n a 18 (15)**  0  Claudicatio intermittens 14 (11)** 0  Vascular surgery femoral artery 4 (3) 0  Vascular surgery (AAA) 3 (3) 0 a ,b 2 (4)  Myocardial infarction 15 (12)* 1 (2)  CABG 13 (11)* 1 (2) a ,b,c 4 (8) a 7 (6) 2 (4) a 2 (2) 1 (2) a ,b,c 4 (7) a 0.093 ± 0.018 0.092 ± 0.023 Data are given as value (percentage) or mean ± SD AAA, abdominal aortic aneurysm; CABG, coronary artery bypass grafting p p a b p c P z z p p p z p p p p p p p 4 z Multivariate analysis 5 Table 5 Multivariate risk factor analyses within the type 2 diabetes group   Single factors β (95% CI) Full model β (95% CI) Final model β (95% CI) Cognition  Age  −0.30 (−0.44, −0.16)*** −0.29 (−0.43, −0.14)***  Sex  −0.12 (−0.24, 0.02)   Estimated IQ  0.65 (0.50, 0.79)*** 0.65 (0.50, 0.80)*** 1c −0.14 (−0.28, −0.002)* −0.11 (−0.25, 0.02)   Hypertension −0.14 (−0.26, 0.002) −0.12 (−0.26, 0.01) −0.14 (−0.27, −0.001)*  Current smoking −0.14 (−0.29, 0.001) −0.15 (−0.29, −0.02)* −0.14 (−0.27, 0.001)  Lipid-lowering drugs 0.12 (−0.02, 0.26) 0.17 (0.03, 0.31)* 0.17 (0.03, 0.31)*  Any vascular event −0.18 (−0.32, −0.03)* −0.18 (−0.32, −0.03)* −0.19 (−0.34, −0.05)** a −0.18 (−0.32, −0.04)*   Cortical atrophy  Sex  −0.005 (−0.23, 0.22)   Age  0.35 (0.18, 0.52)*** 0.34 (0.18, 0.51)***  Estimated IQ  −0.07 (−0.24, 0.10)   Lipid-lowering drugs −0.20 (−0.37, −0.02)* −0.19 (−0.36, −0.03)* −0.18 (−0.35, −0.02)*  Retinopathy 0.24 (0.05, 0.43)* 0.21 (0.04, 0.39)* 0.22 (0.06, 0.39)**  Brain infarct on MRI 0.22 (0.04, 0.39)* 0.23 (0.06, 0.40)** 0.23 (0.06, 0.40)** DWML  Sex  0.13 (−0.05, 0.30)   Age  0.20 (0.02, 0.35)* 0.22 (0.04, 0.39)*  Estimated IQ  −0.14 (−0.31, 0.04)   Insulin level 0.29 (0.08, 0.51)** 0.26 (0.04, 0.47)* 0.24 (0.03, 0.45)*  Any vascular event 0.19 (−0.002, 0.37) 0.15 (−0.03, 0.34)  PWML  Sex  0.16 (−0.02, 0.34) 0.16 (−0.02, 0.34)  Age  0.25 (0.07, 0.43)** 0.24 (0.07, 0.42)**  Estimated IQ  −0.12 (−0.30, 0.06)   Mean arterial pressure 0.20 (0.02, 0.38)* 0.15 (−0.03, 0.33) 0.17 (−0.004, 0.35)  Lipid-lowering drugs −0.22 (−0.35, −0.001)* −0.20 (−0.38, −0.02)* −0.18 (−0.35, 0.001)*  Brain infarct on MRI 0.17 (−0.006, 0.35) 0.18 (0.01, 0.36)* 0.18 (0.009, 0.36)* β B β p β β p p p a 5 Discussion Patients with type 2 diabetes had more cortical and subcortical atrophy and more DWML than control participants and their overall performance in the five cognitive domains was worse. As expected, patients with type 2 diabetes had more microvascular complications, more macrovascular (atherosclerotic) disease and more hypertension than the control group. In multivariate regression analyses within the type 2 diabetes group, hypertension and a history of vascular events were associated with worse cognitive performance, while statin use was associated with better performance. Retinopathy and brain infarcts on MRI were associated with more severe cortical atrophy and statin use with less atrophy. Insulin level and brain infarcts were associated with more severe WML and statin use with less severe WML. 2 3 4 5 29 30 30 1c z 11 1c 2 9 31 31 32 33 34 35 36 37 38 41 7 9 42 43 44 17 18 19 16 45 46 48 5 Type 2 diabetes is associated with modest impairments in cognition, as well as with atrophy and vascular lesions on MRI. This ‘diabetic encephalopathy’ is a multifactorial condition, for which atherosclerotic (macroangiopathic) vascular disease is an important determinant. Chronic hyperglycaemia, hypertension and hyperinsulinaemia may play additional roles. Electronic supplementary material Below is the link to the electronic supplementary material.
 ESM The Utrecht Diabetic Encephalopathy Study Group (PDF 12.8 kb)