Diabetes Care 1 Clinical and MRI Features of Lena M. Thorn,1–3 Sara Shams,4 Daniel Gordin,1–3,5 Ron Liebkind,6 Cerebral Small-Vessel Disease in Carol Forsblom,1–3 Paula Summanen,1–3,7 Stefanie Hagg-Holmberg,¨ 1–3 Type 1 Diabetes Turgut Tatlisumak,6,8,9 Oili Salonen,10 Jukka Putaala,6 Juha Martola,4,10 and 1–3,11 https://doi.org/10.2337/dc18-1302 Per-Henrik Groop, on behalf of the FinnDiane Study Group OBJECTIVE To assess the prevalence of cerebral small-vessel disease (SVD) in subjects with type 1 diabetes compared with healthy control subjects and to characterize the diabetes-related factors associated with SVD. RESEARCH DESIGN AND METHODS This substudy was cross-sectional in design and included 191 participants with type 1 diabetes and median age 40.0 years (interquartile range 33.0–45.1) and 30 1Folkhalsan¨ Institute of Genetics, Folkhalsan¨ Re- healthy age- and sex-matched control subjects. All participants underwent search Center, Helsinki, Finland clinical investigation and brain MRIs, assessed for cerebral SVD. 2Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, RESULTS Helsinki, Finland 3 Cerebral SVD was more common in participants with type 1 diabetes than in Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland healthy control subjects: any marker 35 vs. 10% (P = 0.005), cerebral microbleeds 4Department of Radiology, Karolinska University (CMBs) 24 vs. 3.3% (P = 0.008), white matter hyperintensities 17 vs. 6.7% (P = Hospital, and Department of Clinical Neurosci- 0.182), and lacunes 2.1 vs. 0% (P = 1.000). Presence of CMBs was independently ence, Karolinska Institute, Stockholm, Sweden 5 associated with systolic blood pressure (odds ratio 1.03 [95% confidence interval Joslin Diabetes Center, Harvard Medical School, Boston, MA 1.00–1.05], P = 0.035). 6Department of Neurology, Helsinki University NOVEL COMMUNICATIONS IN DIABETES Hospital, Helsinki, Finland CONCLUSIONS 7Department of Ophthalmology, Helsinki Univer- Cerebral SVD, CMBs in particular, is more common in young people with type 1 sity Hospital, Helsinki, Finland 8 diabetes compared with healthy control subjects. Department of Clinical Neuroscience/Neurology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Type 1 diabetes is associated with a fivefold increased risk of stroke (1), with cerebral 9Department of Neurology, Sahlgrenska Univer- small-vessel disease (SVD) as the most common etiology (2). Cerebral SVD in type 1 sity Hospital, Gothenburg, Sweden 10 diabetes, however, remains scarcely investigated and is challenging to study in vivo Department of Radiology, Helsinki University per se owing to the size of affected vasculature (3); instead, MRI signs of SVD are Hospital, Helsinki, Finland 11Department of Diabetes, Central Clinical studied. In this study, we aimed to assess the prevalence of cerebral SVD in subjects School, Monash University, Melbourne, Australia with type 1 diabetes compared with healthy control subjects and to characterize Corresponding author: Per-Henrik Groop, per-henrik diabetes-related variables associated with SVD in stroke-free people with type 1 .groop@helsinki.fi diabetes. Received 16 June 2018 and accepted 29 October 2018 RESEARCH DESIGN AND METHODS L.M.T. and S.S. made equal contributions. J.M. All study participants are part of the Finnish Diabetic Nephropathy (FinnDiane) Study and P.-H.G. made equal contributions. (4). Participants attending the Helsinki University Hospital (HUH) study center were © 2018 by the American Diabetes Association. consecutively recruited and underwent brain MRI as part of their study visit. In 2011– Readers may use this article as long as the work 2017, we studied 191 participants with type 1 diabetes. Inclusion criteria were age 18– is properly cited, the use is educational and not for profit, and the work is not altered. More infor- 50 years and type 1 diabetes onset at age ,40 years. Exclusion criteria were presence mation is available at http://www.diabetesjournals of end-stage renal disease, clinical signs of cerebrovascular disease, or contraindications .org/content/license. Diabetes Care Publish Ahead of Print, published online December 14, 2018 2 Cerebral Small-Vessel Disease in Diabetes Diabetes Care for MRI. We studied 30 healthy age- and Gradient Echo), and magnetic resonance presented as medians (interquartile sex-matched control subjects with mean angiography time-of-flight. An experi- range). We analyzed categorical variables fasting glucose 4.4 6 0.4 mmol/L. enced neuroradiologist (J.M.) assessed with x2 test or Fisher exact test when The study protocol was approved by the the images, and repeated the assessment appropriate. We performed logistic re- ethics committee of the HUH, and the study three times per participant, for markers gression to determine independent asso- was carried out in accordance with the of SVD (5,6): presence of cerebral micro- ciations with cerebral SVD and present Declaration of Helsinki. Each participant bleeds (CMBs), cortical superficial side- results as odds ratio (OR) with 95% CIs. signed a written informed consent form. rosis, white matter hyperintensities Statistical significance was P , 0.05. All All participants underwent a clinical (WMHs) (Fazekas scale used, with cate- analyses were performed with IBM SPSS study visit (4). Brain MRI was performed gory $1 considered to be significant Statistics, version 22.0, software (IBM, with a 3.0 Tesla scanner (Achieva; Philips, burden), or lacunes. The neuroradiolo- Armonk, NY). Best, the Netherlands) at the Helsinki gist was blinded to clinical data but not Medical Imaging Center, HUH, and in- to whether the participant had diabetes. RESULTS cluded T1, T2, fluid-attenuated inversion We analyzed parametric variables with Clinical characteristics and MRI findings recovery, susceptibility-weighted imaging, t tests with results presented as means 6 of the 191 participants with type 1 di- T2*, diffusion-weighted imaging, T1 SD and nonparametric variables with abetes and the 30 age- and sex-matched MPRAGE (Magnetization-Prepared RApid Mann-Whitney U tests with results control subjects appear in Table 1. Of Table 1—Clinical characteristics and MRI findings in participants with type 1 diabetes and control subjects matched for age and sex Subjects with type 1 diabetes Control subjects P N 191 30 Clinical characteristics Female sex 101 (53) 17 (57) 0.699 Age, years 40.0 (33.0–45.1) 38.4 (31.4–43.2) 0.443 Diabetes duration, years 21.7 (18.3–30.9) dd BMI, kg/m2 26.7 6 4.2 24.5 6 3.2 0.002 Systolic blood pressure, mmHg 130 6 14 121 6 11 0.001 Diastolic blood pressure, mmHg 77 (71–82) 76 (74–85) 0.387 HbA1c, % (mmol/mol) 8.2 6 1.1 (66 6 12) 5.1 6 0.2 (33 6 2) ,0.001 Creatinine, mmol/L 68 (61–79) 74 (68–81) 0.067 Total cholesterol, mmol/L 4.4 (4.0–4.9) 4.6 (4.2–5.4) 0.178 LDL cholesterol, mmol/L 2.4 (2.0–2.9) 2.6 (2.3–3.3) 0.017 HDL cholesterol, mmol/L 1.50 (1.25–1.80) 1.46 (1.26–1.68) 0.362 Triglycerides, mmol/L 0.90 (0.68–1.38) 0.84 (0.69–1.26) 0.398 Antihypertensive medication 68 (36) 0 ,0.001 Statin therapy 42 (22) 0 0.002 Aspirin therapy 15 (7.9) 0 0.232 Albuminuria 30 (16) 0 0.018 Retinal photocoagulation 42 (22) 0 0.002 Coronary heart disease 1 (0.5) 0 1.000 Current smoking 15 (7.9) 5 (17) 0.118 Other autoimmune disease 63 (33) 6 (20) 0.149 MRI findings Cerebral SVD 67 (35) 3 (10) 0.005 CMBs 45 (24) 1 (3.3) 0.008 Number of CMBs 1.000 1, N (% of those with CMBs) 27 (60) 1 (100) 2, N (% of those with CMBs) 6 (13) 0 $3, N (% of those with CMBs) 12 (27) 0 Topography of CMBs Strictly lobar, N (% of those with CMBs) 38 (84) 1 (50) 0.315 Strictly deep or infratentorial, N (% of those with CMBs) 3 (6.7) 1 (50) 0.165 Mixed, N (% of those with CMBs) 4 (8.9) 0 1.000 Cortical superficial siderosis 0 0 d Any WMH 44 (23) 2 (6.7) 0.051 Fazekas category 1 33 (17) 2 (6.7) 0.182 Lacunes 4 (2.1) 0 1.000 Stenosis of carotid arteries 2 (1.0) 0 1.000 Incidental findings 20 (10) 4 (13) 0.751 Unremarkable MRI scan 107 (56) 24 (80) 0.013 Data are n (%), median (interquartile range), or mean 6 SD unless otherwise indicated. care.diabetesjournals.org Thorn and Associates 3 the 67 participants with type 1 diabetes including 67 participants with type 1 di- results, with some reporting more WMHs and SVD, 32 (48%) had only CMBs, abetes and 33 control subjects, there was in type 1 diabetes (14) and others not 20 (30%) only WMHs, 11 (16%) both no difference in WMH prevalence but a (9,15). Most WMHs in our study were CMBs and WMHs, 2 (3%) both CMBs higher prevalence of CMBs in partici- classified as Fazekas category 1, and and lacunes, and 2 (3%) both WMHs and pants with type 1 diabetes and retinop- only four participants had lacunesdall lacunes (Supplementary Fig. 1). athy compared with control subjects (9). of them with type 1 diabetes. Participants with type 1 diabetes and In the current study, CMBs were not The strengths of our study include CMBs more often had presence of albu- associated with retinopathy but were, standardized enrollment of participants, minuria (27 vs. 12%, P = 0.021), were on on the other hand, associated with al- age- and sex-matched healthy con- antihypertensive medication (49 vs. 32%, buminuria, a strong marker of general- trol subjects, and standardized imaging P = 0.033), and had higher systolic blood ized microvascular disease.