Increased incidence of neurodegenerative diseases in Finnish individuals with type 1 diabetes.

INTRODUCTION: Diabetes is linked to neurodegenerative diseases (NDs), but data in type 1 diabetes are scarce. Our aim was to assess the standardized incidence ratios (SIRs) of different NDs in type 1 diabetes, and to evaluate the impact of diabetic vascular complications and age at diabetes onset. RESEARCH DESIGN AND METHODS: In this observational cohort study, we included 4261 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy study, and 11 653 matched population-based controls without diabetes. NDs were identified from registers until the end of 2017. Diabetic complications were assessed at the baseline study visit. SIRs were calculated from diabetes onset, except for impact of complications that was calculated from baseline study visit. RESULTS: The SIRs for NDs were increased in type 1 diabetes: any dementia 2.24 (95% CI 1.79 to 2.77), Alzheimer's disease 2.13 (95% CI 1.55 to 2.87), vascular dementia 3.40 (95% CI 2.08 to 5.6), other dementias 1.70 (95% CI 1.22 to 2.31), and Parkinson's disease 1.61 (95% CI 1.04 to 2.37). SIR showed a twofold increased incidence already in those without albuminuria (1.99 (1.44-2.68)), but further increased in presence of diabetic complications: kidney disease increased SIR for Alzheimer's disease, while cardiovascular disease increased SIR for both Alzheimer's disease and other dementias. Diabetes onset <15 years, compared with ≥15 years, increased SIR of Alzheimer's disease, 3.89 (2.21-6.35) vs 1.73 (1.16-2.48), p<0.05, but not the other dementias. CONCLUSIONS: ND incidence is increased 1.7-3.4-fold in type 1 diabetes. The presence of diabetic kidney disease and cardiovascular disease further increased the incidence of dementia.

Whole-genome sequencing identifies variants in ANK1, LRRN1, HAS1, and other genes and regulatory regions for stroke in type 1 diabetes.

Individuals with type 1 diabetes (T1D) carry a markedly increased risk of stroke, with distinct clinical and neuroimaging characteristics as compared to those without diabetes. Using whole-exome or whole-genome sequencing of 1,051 individuals with T1D, we aimed to find rare and low-frequency genomic variants associated with stroke in T1D. We analysed the genome comprehensively with single-variant analyses, gene aggregate analyses, and aggregate analyses on genomic windows, enhancers and promoters. In addition, we attempted replication in T1D using a genome-wide association study (N = 3,945) and direct genotyping (N = 3,263), and in the general population from the large-scale population-wide FinnGen project and UK Biobank summary statistics. We identified a rare missense variant on SREBF1 exome-wide significantly associated with stroke (rs114001633, p.Pro227Leu, p-value = 7.30 × 10-8), which replicated for hemorrhagic stroke in T1D. Using gene aggregate analysis, we identified exome-wide significant genes: ANK1 and LRRN1 displayed replication evidence in T1D, and LRRN1, HAS1 and UACA in the general population (UK Biobank). Furthermore, we performed sliding-window analyses and identified 14 genome-wide significant windows for stroke on 4q33-34.1, of which two replicated in T1D, and a suggestive genomic window on LINC01500, which replicated in T1D. Finally, we identified a suggestively stroke-associated TRPM2-AS promoter (p-value = 5.78 × 10-6) with borderline significant replication in T1D, which we validated with an in vitro cell-based assay. Due to the rarity of the identified genetic variants, future replication of the genomic regions represented here is required with sequencing of individuals with T1D. Nevertheless, we here report the first genome-wide analysis on stroke in individuals with diabetes.

Stroke incidence increases with diabetic retinopathy severity and macular edema in type 1 diabetes.

BACKGROUND: As the retina is suggested to mirror the brain, we hypothesized that diabetic retinopathy and macular edema are indicative of stroke risk in type 1 diabetes and sought to assess this association in individuals with type 1 diabetes. METHODS: We included 1,268 adult FinnDiane Study participants with type 1 diabetes (age 38.7 ± 11.8 years, 51.7% men vs. 48.3% women, and 31.5% had diabetic kidney disease), data on baseline diabetic retinopathy severity, and first stroke during our observational follow-up. Retinopathy was graded by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and macular edema as clinically significant (CSME) or not. Strokes identified from registries were confirmed from medical files. Adjusted hazard ratios (HR) for stroke by retinopathy severity and CSME were calculated by Cox models adjusted for clinical confounders, including diabetic kidney disease. RESULTS: During median 18.0 (14.1-19.3) follow-up years, 130 strokes (96 ischemic, 34 hemorrhagic) occurred. With no-very mild (ETDRS 10-20) retinopathy as reference, the adjusted HR for stroke was 1.79 (95%CI 1.02-3.15) in non-proliferative (ETDRS 35-53), and 1.69 (1.02-2.82) in proliferative (ETDRS 61-85) retinopathy. Corresponding adjusted HR for ischemic stroke was 1.68 (0.91-3.10) in non-proliferative and 1.35 (0.77-2.36) in proliferative retinopathy. The adjusted HR for hemorrhagic stroke was 2.84 (0.66-12.28) in non-proliferative and 4.31 (1.16-16.10) in proliferative retinopathy. CSME did not increase HR for any stroke type after adjustment for clinical confounders (data not shown). CONCLUSIONS: Stroke incidence increases with the severity of diabetic retinopathy independently of comorbid conditions, including diabetic kidney disease.

Haptoglobin Genotype Does Not Confer a Risk of Stroke in Type 1 Diabetes.

The exon copy number variant in the haptoglobin gene is associated with cardiovascular and kidney disease. For stroke, previous research is inconclusive. We aimed to study the relationship between the haptoglobin Hp1/2 genotype and stroke in individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study. We included two partially overlapping cohorts: one with haptoglobin genotypes determined using genotyping for 179 individuals with stroke and 517 matched control subjects, and the other using haptoglobin genotype imputation for a larger cohort of 500 individuals with stroke and 3,806 individuals without stroke. We observed no difference in the Hp1-1, Hp2-1, and Hp2-2 genotype frequencies between individuals with or without stroke, neither in the genotyping nor the imputation cohorts. Haptoglobin genotypes were also not associated with the ischemic or hemorrhagic stroke subtypes. In our imputed haptoglobin cohort, 61% of individuals with stroke died during follow-up. However, the risk of death was not related to the haptoglobin genotype. Diabetic kidney disease and cardiovascular events were common in the cohort, but the haptoglobin genotypes were not associated with stroke when stratified by these complications. To conclude, the Hp1/2 genotypes did not affect the risk of stroke or survival after stroke in our cohort with type 1 diabetes.

The impact of parental risk factors on the risk of stroke in type 1 diabetes.

BACKGROUND: Individuals with type 1 diabetes have a markedly increased risk of stroke. In the general population, genetic predisposition has been linked to increased risk of stroke, but this has not been assessed in type 1 diabetes. Our aim was, therefore, to study how parental risk factors affect the risk of stroke in individuals with type 1 diabetes. METHODS: This study represents an observational follow-up of 4011 individuals from the Finnish Diabetic Nephropathy Study, mean age at baseline 37.6 ± 11.9 years. All strokes during follow-up were verified from medical records or death certificates. The strokes were classified as either ischemic or hemorrhagic. All individuals filled out questionnaires concerning their parents' medical history of hypertension, diabetes, stroke, and/or myocardial infarction. RESULTS: During a median follow-up of 12.4 (10.9-14.2) years, 188 individuals (4.6%) were diagnosed with their first ever stroke; 134 were ischemic and 54 hemorrhagic. In Cox regression analysis, a history of maternal stroke increased the risk of hemorrhagic stroke, hazard ratio 2.86 (95% confidence interval 1.27-6.44, p = 0.011) after adjustment for sex, age, BMI, retinal photocoagulation, and diabetic kidney disease. There was, however, no association between maternal stroke and ischemic stroke. No other associations between parental risk factors and ischemic or hemorrhagic stroke were observed. CONCLUSION: A history of maternal stroke increases the risk of hemorrhagic stroke in individuals with type 1 diabetes. Other parental risk factors seem to have limited impact on the risk of stroke.

The role of blood pressure in risk of ischemic and hemorrhagic stroke in type 1 diabetes.

BACKGROUND: Hypertension is one of the strongest risk factors for stroke in the general population, while systolic blood pressure has been shown to independently increase the risk of stroke in type 1 diabetes. The aim of this study was to elucidate the association between different blood pressure variables and risk of stroke in type 1 diabetes, and to explore potential nonlinearity of this relationship. METHODS: We included 4105 individuals with type 1 diabetes without stroke at baseline, participating in the nationwide Finnish Diabetic Nephropathy Study. Mean age at baseline was 37.4 ± 11.9 years, median duration of diabetes 20.9 (interquartile range 11.5-30.4) years, and 52% were men. Office systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Based on these pulse pressure (PP) and mean arterial pressure (MAP) were calculated. Strokes were classified based on medical and autopsy records, as well as neuroimaging. Cox proportional hazard models were performed to study how the different blood pressure variables affected the risk of stroke and its subtypes. RESULTS: During median follow-up time of 11.9 (9.21-13.9) years, 202 (5%) individuals suffered an incident stroke; 145 (72%) were ischemic and 57 (28%) hemorrhagic. SBP, DBP, PP, and MAP all independently increased the risk of any stroke. SBP, PP, and MAP increased the risk of ischemic stroke, while SBP, DBP, and MAP increased the risk of hemorrhagic stroke. SBP was strongly associated with stroke with a hazard ratio of 1.20 (1.11-1.29)/10 mmHg. When variables were modeled using restricted cubic splines, the risk of stroke increased linearly for SBP, MAP, and PP, and non-linearly for DBP. CONCLUSIONS: The different blood pressure variables are all independently associated with increased risk of stroke in individuals with type 1 diabetes. The risk of stroke, ischemic stroke, and hemorrhagic stroke increases linearly at blood pressure levels less than the current recommended treatment guidelines.

Clinical and MRI Features of Cerebral Small-Vessel Disease in Type 1 Diabetes.

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 healthy age- and sex-matched control subjects. All participants underwent clinical investigation and brain MRIs, assessed for cerebral SVD. RESULTS: Cerebral SVD was more common in participants with type 1 diabetes than in healthy control subjects: any marker 35% vs. 10% (P = 0.005), cerebral microbleeds (CMBs) 24% vs. 3.3% (P = 0.008), white matter hyperintensities 17% vs. 6.7% (P = 0.182), and lacunes 2.1% vs. 0% (P = 1.000). Presence of CMBs was independently associated with systolic blood pressure (odds ratio 1.03 [95% CI 1.00-1.05], P = 0.035). CONCLUSIONS: Cerebral SVD, CMBs in particular, is more common in young people with type 1 diabetes compared with healthy control subjects.

Prognosis and Its Predictors After Incident Stroke in Patients With Type 1 Diabetes.

OBJECTIVE: Although patients with type 1 diabetes have a poor prognosis after a stroke, predictors of survival after an incident stroke in these patients are poorly studied. RESEARCH DESIGN AND METHODS: In this observational study, a total of 144 patients of 4,083 with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study suffered an incident stroke in 1997-2010, and were followed for a mean 3.4 ± 3.1 years after the stroke. Information was recorded on hard cardiovascular events and death as a result of cardiovascular or diabetes-related cause, collectively referred to as vascular composite end point. Information was collected from medical records, death certificates, and the National Care Register of Health Care. Predictors at the time of the incident stroke were studied for the end points. RESULTS: During follow-up, 104 (72%) patients suffered a vascular composite end point. Of these, 33 (32%) had a recurrent stroke, 33 (32%) a hard cardiovascular event, and 76 (53%) died of cardiovascular or diabetes-related causes, with an overall 1-year survival of 76% and 5-year survival of 58%. The predictors of a vascular composite end point were hemorrhagic stroke subtype (hazard ratio 2.03 [95% CI 1.29-3.19]), as well as chronic kidney disease stage 2 (2.48 [1.17-5.24]), stage 3 (3.04 [1.54-6.04]), stage 4 (3.95 [1.72-9.04]), and stage 5 (6.71 [3.14-14.34]). All-cause mortality increased with deteriorating kidney function. CONCLUSIONS: Patients with type 1 diabetes with an incident stroke have a poor cardiovascular prognosis and a high risk of all-cause mortality. In particular, hemorrhagic stroke subtype and progression of diabetic kidney disease conveys worse outcome.