Clinical Research and Public HealthAgingEndocrinology Open Access | 10.1172/jci.insight.180226

Hetal S. Shah,1,2 Matthew N. DeSalvo,3 Anastasia Haidar,4 Surya Vishva Teja Jangolla,1,2 Marc Gregory Yu,1,2 Rebecca S. Roque,1 Amanda Hayes,1 John Gauthier,1 Nolan Ziemniak,1 Elizabeth Viebranz,1 I-Hsien Wu,1 Kyoungmin Park,1,2 Ward Fickweiler,1,5,6 Tanvi J. Chokshi,1,5 Tashrif Billah,4 Lipeng Ning,4 Atif Adam,1,2 Jennifer K. Sun,1,5,6 Lloyd Paul Aiello,1,5,6 Yogesh Rathi,3,4 Mel B. Feany,7 and George L. King1,2,6

1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

Find articles by Wu, I. in: JCI | PubMed | Google Scholar |

1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

Find articles by Park, K. in: JCI | PubMed | Google Scholar |

1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

Find articles by Fickweiler, W. in: JCI | PubMed | Google Scholar

1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

Find articles by Billah, T. in: JCI | PubMed | Google Scholar

1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

Find articles by Ning, L. in: JCI | PubMed | Google Scholar

1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

Find articles by Adam, A. in: JCI | PubMed | Google Scholar

1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

Find articles by Sun, J. in: JCI | PubMed | Google Scholar

1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

Find articles by Aiello, L. in: JCI | PubMed | Google Scholar

1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

Find articles by Rathi, Y. in: JCI | PubMed | Google Scholar

1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

Find articles by Feany, M. in: JCI | PubMed | Google Scholar

1Dianne Hoppes Nunnally Laboratory Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

3Department of Radiology, and

4Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

5Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Address correspondence to: Hetal S. Shah or George L. King, One Joslin Place, Boston, Massachusetts 02215, USA Phone: 617.309.4343; Email: Hetal.Shah@joslin.harvard.edu (HSS). Phone: 617.309.2622; Email: George.King@joslin.harvard.edu (GLK).

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Published January 30, 2025 - More info

Published in Volume 10, Issue 5 on March 10, 2025
JCI Insight. 2025;10(5):e180226. https://doi.org/10.1172/jci.insight.180226.
© 2025 Shah et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published January 30, 2025 - Version history
Received: April 26, 2024; Accepted: January 24, 2025 View PDF Abstract

BACKGROUND. We aimed to characterize factors associated with the under-studied complication of cognitive decline in aging people with long-duration type 1 diabetes (T1D).

METHODS. Joslin “Medalists” (n = 222; T1D ≥ 50 years) underwent cognitive testing. Medalists (n = 52) and age-matched nondiabetic controls (n = 20) underwent neuro- and retinal imaging. Brain pathology (n = 26) was examined. Relationships among clinical, cognitive, and neuroimaging parameters were evaluated.

RESULTS. Compared with controls, Medalists had worse psychomotor function and recall, which associated with female sex, lower visual acuity, reduced physical activity, longer diabetes duration, and higher inflammatory cytokines. On neuroimaging, compared with controls, Medalists had significantly lower total and regional brain volumes, equivalent to 9 years of accelerated aging, but small vessel disease markers did not differ. Reduced brain volumes associated with female sex, reduced psychomotor function, worse visual acuity, longer diabetes duration, and higher inflammation, but not with glycemic control. Worse cognitive function, lower brain volumes, and diabetic retinopathy correlated with thinning of the outer retinal nuclear layer. Worse baseline visual acuity associated with declining psychomotor function in longitudinal analysis. Brain volume mediated the association between visual acuity and psychomotor function by 57%. Brain pathologies showed decreased volumes, but predominantly mild vascular or Alzheimer’s-related pathology.

CONCLUSION. To our knowledge, this is the first comprehensive study of cognitive function, neuroimaging, and pathology in aging T1D individuals demonstrated that cognitive decline was related to parenchymal rather than neurovascular abnormalities, unlike type 2 diabetes, suggestive of accelerated aging in T1D. Improving visual acuity could perhaps be an important preventive measure against cognitive decline in people with T1D.

FUNDING. The Beatson Foundation, NIH/NIDDK grants 3P30DK036836-34S1 and P30DK036836-37, and Mary Iacocca fellowships.

Introduction

Both type 1 (T1D) and type 2 (T2D) diabetes are rapidly increasing in prevalence globally and affect more than 33 million people in the United States, including 25% of the aging population (people >65 years) (1). Along with other major complications, cognitive dysfunction is now recognized as a major morbidity associated with diabetes, and poses great socioeconomic burdens and reduced quality of life (2–5). Diabetes-associated cognitive decline may have multiple underlying mechanisms, including vascular abnormalities and changes in glucose, insulin sensitivity, and amyloid metabolism (2, 3). Studies examining diabetes-associated cognitive dysfunction have mostly focused on T2D, which itself, along with insulin resistance and obesity, are significant risk factors for dementia especially in Alzheimer’s disease and related disorders (6). Detailed clinical characterization of cognitive dysfunction in a large cohort with long T1D duration has been limited given that living longer than 55 years among those with T1D has only become possible recently (7, 8). Studies in younger T1D populations have suggested the important roles of poor glycemic control and hypoglycemia in cognitive decline, but their role in older T1D populations remains undefined (2, 3, 9, 10). Additionally, modifiable risk factors for T1D-associated cognitive decline may differ in older age groups compared with younger people (11). Brain imaging studies in T1D have been restricted to younger to mid-life adults, with reports of vascular and parenchymal changes (12). However, it is not clear whether these changes can be extrapolated to older individuals with long-standing T1D (12). No studies have comprehensively characterized both neuroimaging and pathological brain examinations and their relationships to cognitive changes in T1D. Furthermore, as retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy and could run in parallel with brain neurodegeneration (13–17), it is important to further tease out these relationships in the context of T1D.

The Joslin 50-year Medalist Study, a cohort of individuals (“Medalists”) with 50 or more years of T1D, is exceptionally well suited to characterize and identify potential novel markers of cognitive decline, especially since they do not exhibit clinical signs of insulin resistance and have relatively good glycemic and metabolic control (18–23). Yet, as reported, Medalists had similar levels of cognitive impairment to those of age-matched individuals with T2D and greater levels of impairment compared with age-matched individuals without diabetes (24). Thus, we aimed to characterize factors associated with cognitive decline in this elderly cohort with very long duration of T1D in a first comprehensive study of cognitive and clinical assessments, retinal and brain imaging, and gross and histopathological examination of postmortem brain specimens.

Results

Baseline characteristics of study groups. Supplemental Table 1 (supplemental material available online with this article; https://doi.org/10.1172/jci.insight.180226DS14) summarizes the baseline characteristics of Medalists in the overall cohort (n = 1034), and the following subsets: cognitive (n = 222), brain imaging (n = 52), longitudinal (n = 48), and brain donors (n = 26). At baseline, Medalists were 55% female, mean age 66 years, with 53 years of T1D, mean glycated hemoglobin (HbA1c) of 7.2%, and body mass index (BMI) of 26 kg/m2. While 77% of Medalists reported a history of hypertension, the average systolic and diastolic blood pressures were very well controlled, coupled with a cardiac-favorable lipid profile (mean LDL cholesterol [LDL-C] of 81 mg/dL and HDL-C of 65 mg/dL) and mean estimated glomerular filtration rate (eGFR) of 69.7 mL/min/1.73 m2, normal for the age group. Approximately 80% of Medalists reported that they do exercise. A third of Medalists had proliferative diabetic retinopathy (PDR), 40% had reported cardiovascular disease (CVD), but only 12% had diabetic nephropathy (DN). Participants of the various subsets were fairly representative of the overall study population, except for the brain imaging group which had a smaller proportion of individuals with CVD (19% vs. 40%) and DN (2% vs. 13%) at baseline. Only 17% had at least one APOE risk allele as compared with 26% in the overall study. The brain donor group had a higher proportion of individuals with CVD (46%) and DN (15%) at baseline than the overall Medalist cohort (Supplemental Table 1).

Cross-sectional characteristics of the study participants at time of cognitive or neuroimaging study visit, or last visit for brain donors, are shown in Table 1. Mean age at the time of the cognitive study was 71 years and duration of diabetes 61 years. Other characteristics are comparable to the baseline study visit. In the neuroimaging study group, there were approximately 50% females and an average age at study visit of 72 years, with higher HbA1c as expected, although still very good glycemic control, and a better lipid profile compared with age-matched nondiabetic controls (Table 1). At the time of brain MRI, the proportion of those with self-reported hypertension was 72% for Medalists and 47% for controls, while CVD was reported for 35% of the Medalists as compared with only 22% among control individuals (Table 1). There were no significant differences between Medalists and controls with respect to sex, age, BMI (both were in the non-overweight range), renal function, education, or lifestyle.

Table 1

Cross-sectional characteristics of study participants

Cognitive function. Compared with controls, Medalists had significantly worse recall, psychomotor function, and global cognition (Table 1). In bivariate analysis among Medalists, worse psychomotor function in both dominant and nondominant domains was (P < 0.05) associated with increased age, longer duration of diabetes, increased interleukin 6 (IL-6), worse renal function (higher albumin/creatinine ratio [ACR] and lower eGFR), and lower visual acuity. Better function was associated with higher education (Figure 1). Worse motor function in the dominant hand also associated significantly with higher C-reactive protein (CRP) and PDR. In the nondominant hand it was associated with higher systolic blood pressure, IL-1β, and coronary artery calcification (CAC) (Figure 1). In multivariable models incorporating all these significant covariates, only education, duration, and visual acuity remained significant (P < 0.05) for both dominant and nondominant hands, while IL-6 remained significant for the dominant hand (Supplemental Table 2).

Figure 1

Associations of clinical characteristics with cognitive function in T1D (n = 222). Heatmaps showing bivariate standardized estimates of associations between clinical characters as independent variables and cognitive function domains as dependent variables in linear regression models. The estimates represent changes in cognitive function per 1 SD change in the clinical predictor. Color and intensity represent the strength and direction (positive, zero or no, and negative) of association. Better cognitive function is represented by more blue estimates, and worse by red. MIS, memory index score. Blank squares not significant. *P < 0.05, **P < 0.01, ***P < 0.0001. (A) Markers of sociodemographics and lifestyle. (B) Glycemic markers. Life.Hypog, lifetime hypoglycemia severity; CV, coefficient of variation of glucose on CGM; TAR>250, time above range of glucose > 250 mg/dL; TIR 70–180, time-in-range 70–180 mg/dL; TBR<70, time below range of glucose < 70 mg/dL; CEL, CML, and MGH1 are advanced glycation end products. (C) Cardiometabolic markers. DBP and SBP, diastolic and systolic blood pressure; CRP, C-reactive protein; IL, interleukin; IFN-γ, interferon γ; TNF-α, tumor necrosis factor α. (D) Insulin resistance markers. BMI, body mass index; eGDR, estimated glucose disposal rate; eIS, estimated insulin sensitivity; VAI, visceral adiposity index; TG:HDL, triglyceride/HDL ratio; WHR, waist/hip ratio. (E) Complications. ACR, urine albumin/creatinine ratio; eGFR, estimated glomerular filtration rate; D and ND, dominant and nondominant hands; DN, diabetic nephropathy; RHA, reduced hypoglycemia awareness; DPN, diabetic peripheral neuropathy; AN, autonomic neuropathy; CVD, cardiovascular disease; CAC, coronary artery calcification; VA, visual acuity; PDR, proliferative diabetic retinopathy.

Worse immediate recall was associated (P < 0.05) with higher triglyceride/HDL ratio, CVD, and CAC. Better immediate recall was associated with female sex, higher HDL, and total cholesterol, and better insulin sensitivity (Figure 1). Better delayed recall (P < 0.05) was associated with female sex, CRP, and interferon γ (IFN-γ) levels, while worse delayed recall was associated with IL-1β (Figure 1). In multivariable models, female sex remained significant for both types of recall, while IL-1β and IFN-γ also remained significant for delayed recall (Supplemental Table 2). Worse executive function associated significantly with higher age, duration, LDL, ACR, triglycerides, total cholesterol, IL-1β, CAC, and with lower visual acuity (Figure 1). In multivariable models, total cholesterol and IL-1β remained significant for associations with executive function (Supplemental Table 2). Better working memory was associated significantly with higher education and estimated insulin sensitivity index (eIS), while worse working memory was associated with higher triglycerides, triglyceride/HDL ratio, visceral adiposity index (VAI), and CVD (Figure 1). However, none of these remained significant in multivariable analysis (Supplemental Table 2). None of the cognitive domains were associated with HbA1c, lifetime hypoglycemia severity, continuous glucose monitoring (CGM) indices, or advanced glycation end products (AGEs), including carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL), and methylglyoxal-hydroimidazolone-1 (MGH1) (Figure 1B).

Better global cognition delayed recall (captured by memory index score [MIS]) was associated with female sex and CML, while worse outcome was associated with age at diagnosis, SBP, and eGFR. Worse total global cognition was associated with increasing age, SBP, and CAC, and with reduced visual acuity. However, in multivariable models, female sex, SBP, and eGFR remained significant for the global cognition recall, while visual acuity remained significant for the total global cognition (Supplemental Table 2).

For physical activity reported in the Paffenbarger surveys, in age-, sex-, and education-adjusted models, increased numbers of daily stairs climbed and blocks walked were associated with better executive function and psychomotor speed, respectively (P < 0.05) (Supplemental Table 3). Increased weekly duration of, and caloric expenditure from, swimming associated with better delayed recall (Supplemental Table 3).

From the lifestyle activity questionnaire (LAQ), driving was associated with better executive function (Supplemental Table 3). Sewing and talking about politics reduced psychomotor function, while going to the movies was associated with poorer executive function (Supplemental Table 3).

Higher adherence to Mediterranean, Dietary Ap