As adults with Type 1 Diabetes (T1D) live longer, they are increasingly more likely to develop brain abnormalities in addition to multiple micro- and macro-vascular complications. These brain features are strikingly similar to those observed in older adults and should not be considered benign. Similar to what is known for age-related brain changes, the potential mechanisms of brain abnormalities in T1D include vascular damage secondary to hyperglycemia and insulin dysfunction. We propose to quantify the nature, severity and risk factors re brain abnormalities in a large group of middle-aged adults with T1D. We will use cutting-edge imaging technology to measure neural activation, blood flow and micro-structural abnormalities that are not visible on conventional brain magnetization resonance imaging (MRI). Our preliminary results indicate that brain atrophy and lower cerebral blood flow in T1D are localized within fronto-parietal and subcortical regions. Therefore, we hypothesize that middle-aged adults with T1D have accelerated brain aging within the fronto-parietal and subcortical regions and connecting tracts and that cumulative exposure and severity of T1D-specific factors and complications can explain the burden of focal accelerated brain aging. We propose to obtain 190 brain magnetization resonance imaging (MRI) from participants of the ongoing longitudinal Epidemiology of Diabetes Complications (EDC) cohort study (mean age [SD]: 48 [7.6], 50% women, 95% white) who have been followed from 1989 to date. Brain MRI data will be a) compared with existing data of two groups of non diabetic adults of similar age (n=96) and of older age (N=167);b) related to diabetes-risk factors and complications that have been directly ascertained for 22 years in the EDC;c) examined in relationship with measures of processing speed. Results from this project will be the stepping stone for future studies in the EDC cohort to examine progression of brain damage and rate of cognitive decline. Results of this study also have the potential to clarify mechanisms underlying brain degeneration in Type 2 diabetes. This proposal is uniquely timed to capture important information during the funded data collection phase of the EDC cohort beginning in 2009. Our project has been strategically designed to complete the scope of work within four years. This project will use an existing recruitment infrastructure, a brain MRI center with scanners dedicated to research to collect new data, a team of research staff and investigators with track record of multidisciplinary previous collaborations in neuroepidemiology and imaging, and existing longitudinal data on diabetes complications collected over 22 years.

Public Health Relevance

Brain changes are common in persons with Type 1 Diabetes (T1D) and they are strikingly similar to abnormalities observed in older adults. We propose to characterize the nature of accelerated brain aging in T1D (cerebral perfusion, neural activation and micro-structure level) and identify their determinants.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Neurological, Aging and Musculoskeletal Epidemiology (NAME)
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Jones, Teresa L Z
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University of Pittsburgh
Public Health & Prev Medicine
Schools of Public Health
United States
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Nunley, Karen A; Metti, Andrea L; Klein, Ronald et al. (2018) Long-term changes in retinal vascular diameter and cognitive impairment in type 1 diabetes. Diab Vasc Dis Res 15:223-232
Nunley, Karen A; Orchard, Trevor J; Ryan, Christopher M et al. (2017) Statin use and cognitive function in middle-aged adults with type 1 diabetes. World J Diabetes 8:286-296
Nunley, Karen A; Ryan, Christopher M; Aizenstein, Howard J et al. (2017) Regional Gray Matter Volumes as Related to Psychomotor Slowing in Adults with Type 1 Diabetes. Psychosom Med 79:533-540
Hwang, Misun; Tudorascu, Dana L; Nunley, Karen et al. (2016) Brain Activation and Psychomotor Speed in Middle-Aged Patients with Type 1 Diabetes: Relationships with Hyperglycemia and Brain Small Vessel Disease. J Diabetes Res 2016:9571464
Nunley, Karen A; Ryan, Christopher M; Orchard, Trevor J et al. (2015) White matter hyperintensities in middle-aged adults with childhood-onset type 1 diabetes. Neurology 84:2062-9
Nunley, Karen A; Rosano, Caterina; Ryan, Christopher M et al. (2015) Clinically Relevant Cognitive Impairment in Middle-Aged Adults With Childhood-Onset Type 1 Diabetes. Diabetes Care 38:1768-76
Ryan, John P; Aizenstein, Howard J; Orchard, Trevor J et al. (2015) Age of Childhood Onset in Type 1 Diabetes and Functional Brain Connectivity in Midlife. Psychosom Med 77:622-30
Costacou, Tina; Rosano, Caterina; Aizenstein, Howard et al. (2015) The haptoglobin 1 allele correlates with white matter hyperintensities in middle-aged adults with type 1 diabetes. Diabetes 64:654-9
Ryan, John P; Fine, David F; Rosano, Caterina (2014) Type 2 diabetes and cognitive impairment: contributions from neuroimaging. J Geriatr Psychiatry Neurol 27:47-55
Hughes, Timothy M; Ryan, Christopher M; Aizenstein, Howard J et al. (2013) Frontal gray matter atrophy in middle aged adults with type 1 diabetes is independent of cardiovascular risk factors and diabetes complications. J Diabetes Complications 27:558-64

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