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Plasma Biomarkers of Brain Injury and Their Association With Brain MRI and Cognition in Type 1 Diabetes

Karger, Amy B; Nasrallah, Ilya M; Braffett, Barbara H; Luchsinger, José A; Ryan, Christopher M; Bebu, Ionut; Arends, Valerie; Habes, Mohamad; Gubitosi-Klug, Rose A; Chaytor, Naomi; Biessels, Geert J; Jacobson, Alan M; ,
OBJECTIVE:To evaluate associations between plasma biomarkers of brain injury and MRI and cognitive measures in participants with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. RESEARCH DESIGN AND METHODS/METHODS:Plasma amyloid-β-40, amyloid-β-42, neurofilament light chain (NfL), phosphorylated Tau-181 (pTau-181), and glial fibrillary acidic protein (GFAP) were measured in 373 adults who participated in the DCCT/EDIC study. MRI assessments included total brain and white matter hyperintensity volumes, white matter mean fractional anisotropy, and indices of Alzheimer disease (AD)-like atrophy and predicted brain age. Cognitive measures included memory and psychomotor and mental efficiency tests and assessments of cognitive impairment. RESULTS:Participants were 60 (range 44-74) years old with 38 (30-51) years' T1D duration. Higher NfL was associated with an increase in predicted brain age (0.51 years per 20% increase in NfL; P < 0.001) and a 19.5% increase in the odds of impaired cognition (P < 0.01). Higher NfL and pTau-181 were associated with lower psychomotor and mental efficiency (P < 0.001) but not poorer memory. Amyloid-β measures were not associated with study measures. A 1% increase in mean HbA1c was associated with a 14.6% higher NfL and 12.8% higher pTau-181 (P < 0.0001). CONCLUSIONS:In this aging T1D cohort, biomarkers of brain injury did not demonstrate an AD-like profile. NfL emerged as a biomarker of interest in T1D because of its association with higher HbA1c, accelerated brain aging on MRI, and cognitive dysfunction. Our study suggests that early neurodegeneration in adults with T1D is likely due to non-AD/nonamyloid mechanisms.
PMID: 38861647
ISSN: 1935-5548
CID: 5668972

Urinary symptoms and female sexual dysfunction in women with type 1 diabetes: the role of depression

Fernandez Moncaleano, Golena; Gibbons, Cody M; Holt, Sarah; Braffett, Barbara; Pop-Busui, Rodica; Jacobson, Alan; Wessells, Hunter; Sarma, Aruna
BACKGROUND:Some reports suggest that women with type 1 diabetes (T1D) have a greater burden of female sexual dysfunction (FSD) than women without T1D, but the etiology of this elevated risk is poorly understood. AIM/OBJECTIVE:To examine the associations between FSD and urinary incontinence/lower urinary tract symptoms (UI/LUTS) in women with T1D and to evaluate how depression may mediate these relationships. METHODS:LUTS and UI symptoms were assessed in women with T1D who participated in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study. Multivariable logistic regression models estimated associations between FSD and UI/LUTS (overall and specific domains) and the impact of depression on these associations. OUTCOMES/RESULTS:FSD was measured with the Female Sexual Function Index-Reduced. RESULTS:In total, 499 self-reported sexually active women completed validated assessments of sexual and urinary function (mean ± SD age, 47.7 ± 7.6 years; T1D duration, 23.4 ± 5.15 years). FSD was reported in 232 (46%) responders. The frequency of UI and LUTS was 125 (25.1%) and 96 (19.2%), respectively. Neither UI nor its subcategories (urge, stress) were associated with FSD. Although LUTS (odds ratio [OR], 1.75; 95% CI, 1.09-2.77) and its symptoms of urgency (OR, 1.99; 95% CI, 1.09-3.61) and incomplete emptying (OR, 2.44; 95% CI, 1.23-4.85) were associated with FSD, these associations were attenuated following adjustment for depression and antidepressant medication use. Depression indicators were independently associated with FSD overall and across domains. CLINICAL IMPLICATIONS/CONCLUSIONS:The complex interplay of voiding dysfunction, mental health, and sexual function warrants further investigation to understand the potential implications for patient assessment, goal setting, treatment, and care planning. STRENGTHS AND LIMITATIONS/UNASSIGNED:Data are from a prospective study of individuals with T1D. These results are unable to explore cause-and-effect relationships among LUTS, UI, depression, and FSD. The sample may not be representative of the general population of women with T1D. Because participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study are mostly White, generalizing the findings to other races and to type 2 diabetes may not be appropriate. While exclusion of sexually inactive women likely biases our findings toward the null, this design element permitted study of LUTS and UI in relation to aspects of FSD, the primary objective of this study. CONCLUSIONS:The significant associations between LUTS/UI and FSD among middle-aged women with T1D were greatly attenuated when depression was considered a mediating factor.
PMID: 37933193
ISSN: 1743-6109
CID: 5603022

Utility of the NIH Toolbox Cognition Battery in middle to older aged adults with longstanding type 1 diabetes: The DCCT/EDIC study

Chaytor, Naomi S; Trapani, Victoria R; Braffett, Barbara H; Fonseca, Luciana M; Lorenzi, Gayle M; Gubitosi-Klug, Rose A; Hitt, Susan; Farrell, Kaleigh; Jacobson, Alan M; Ryan, Christopher M
PMID: 37814481
ISSN: 1744-4144
CID: 5604852

CKD Associates with Cognitive Decline in Middle-Aged and Older Adults with Long-Standing Type 1 Diabetes

Khatri, Minesh; Ryan, Christopher M; Gao, Xiaoyu; de Boer, Ian H; Braffett, Barbara H; Molitch, Mark; Karger, Amy B; Lorenzi, Gayle M; Lee, Pearl; Trapani, Victoria R; Lachin, John M; Jacobson, Alan M
KEY POINTS:We found that development of both albuminuria and reduced eGFR was associated with clinically significant cognitive decline, particularly in the psychomotor and mental efficiency domain. There was also a significant interaction between worsened albuminuria and eGFR, the combination of which augmented cognitive deficits. A more comprehensive longitudinal phenotype of albuminuria showed that regressed albuminuria did not associate with worsened cognitive decline, as opposed to persistent albuminuria. BACKGROUND:Individuals with CKD or type 1 diabetes (T1D) are at risk for cognitive decline, but it is unclear whether these associations are with albuminuria, eGFR, or both. METHODS:) in models using eGFR and albuminuria measurements over the first 15–20 years with subsequent change in cognitive function over the ensuing 14 years (when decline in cognition was greatest). RESULTS:−0.915; 95% CI, −1.613 to −0.217). CONCLUSIONS:In T1D, development of CKD was associated with a subsequent reduction on cognitive tasks requiring psychomotor and mental efficiency. These data highlight the need for increased recognition of risk factors for neurologic sequelae in patients with T1D, as well as preventive and treatment strategies to ameliorate cognitive decline.
PMID: 37291722
ISSN: 2641-7650
CID: 5589972

Patterns of Regional Brain Atrophy and Brain Aging in Middle- and Older-Aged Adults With Type 1 Diabetes

Habes, Mohamad; Jacobson, Alan M; Braffett, Barbara H; Rashid, Tanweer; Ryan, Christopher M; Shou, Haochang; Cui, Yuhan; Davatzikos, Christos; Luchsinger, Jose A; Biessels, Geert J; Bebu, Ionut; Gubitosi-Klug, Rose A; Bryan, R Nick; Nasrallah, Ilya M
IMPORTANCE:Little is known about structural brain changes in type 1 diabetes (T1D) and whether there are early manifestations of a neurodegenerative condition like Alzheimer disease (AD) or evidence of premature brain aging. OBJECTIVE:To evaluate neuroimaging markers of brain age and AD-like atrophy in participants with T1D in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, identify which brain regions are associated with the greatest changes in patients with T1D, and assess the association between cognition and brain aging indices. DESIGN, SETTING, AND PARTICIPANTS:This cohort study leveraged data collected during the combined DCCT (randomized clinical trial, 1983-1993) and EDIC (observational study, 1994 to present) studies at 27 clinical centers in the US and Canada. A total of 416 eligible EDIC participants and 99 demographically similar adults without diabetes were enrolled in the magnetic resonance imaging (MRI) ancillary study, which reports cross-sectional data collected in 2018 to 2019 and relates it to factors measured longitudinally in DCCT/EDIC. Data analyses were performed between July 2020 and April 2022. EXPOSURE:T1D diagnosis. MAIN OUTCOMES AND MEASURES:Psychomotor and mental efficiency were evaluated using verbal fluency, digit symbol substitution test, trail making part B, and the grooved pegboard. Immediate memory scores were derived from the logical memory subtest of the Wechsler memory scale and the Wechsler digit symbol substitution test. MRI and machine learning indices were calculated to predict brain age and quantify AD-like atrophy. RESULTS:This study included 416 EDIC participants with a median (range) age of 60 (44-74) years (87 of 416 [21%] were older than 65 years) and a median (range) diabetes duration of 37 (30-51) years. EDIC participants had consistently higher brain age values compared with controls without diabetes, indicative of approximately 6 additional years of brain aging (EDIC participants: β, 6.16; SE, 0.71; control participants: β, 1.04; SE, 0.04; P < .001). In contrast, AD regional atrophy was comparable between the 2 groups. Regions with atrophy in EDIC participants vs controls were observed mainly in the bilateral thalamus and putamen. Greater brain age was associated with lower psychomotor and mental efficiency among EDIC participants (β, -0.04; SE, 0.01; P < .001), but not among controls. CONCLUSIONS AND RELEVANCE:The findings of this study suggest an increase in brain aging among individuals with T1D without any early signs of AD-related neurodegeneration. These increases were associated with reduced cognitive performance, but overall, the abnormal patterns seen in this sample were modest, even after a mean of 38 years with T1D.
PMID: 37261829
ISSN: 2574-3805
CID: 5541242

Improving quality of life and self-care for patients on hemodialysis using cognitive behavioral strategies: A randomized controlled pilot trial

Shirazian, Shayan; Smaldone, Arlene M; Jacobson, Alan M; Fazzari, Melissa J; Weinger, Katie
INTRODUCTION:Behavioral-education interventions have the potential to improve quality of life and self-care for patients on hemodialysis (HD) but have not been incorporated into routine clinical practice. The purpose of this pilot study was to determine the feasibility of delivering a simple behavioral-education intervention using cognitive behavioral strategies in patients receiving HD with poor quality of life. METHODS:In this mixed methods study, HD patients were randomly assigned to the study intervention (8 behavioral-education sessions delivered over 12 weeks) or a control group of dialysis education alone. Kidney disease quality of life (KDQOL)-36 scores, depressive symptoms and self-care behaviors were measured at weeks 0, 8, and 16. Following study completion, participants, social workers, and physicians provided their perspectives about the intervention via qualitative interviews. FINDINGS:Forty-five participants were randomized. Due, in part, to social worker attrition from the intervention arm, 34 participants (76%) completed at least 1 study session and were included in the analysis. The intervention led to modest, but non-significant, increase in KDQOL-physical component summary scores (+3.1±1.2 points) from week 0 to week 16. There were small, non-significant decreases in interdialytic weight gain and pre-dialysis phosphorus levels in the intervention group. Participants felt that chair-side delivery was practical and efficient, and that content related to the impact of dialysis on daily life was unique and important. Suggestions for adapting the intervention included narrowing its content and its delivery by additional providers that are not necessarily therapy trained. DISCUSSION:In this pilot study, we were able to deliver a simple behavioral-education intervention to improve both quality of life and self-care. Participants had a positive impression of the intervention, but we did not find significant improvements in quality of life or self-care. We will now adapt our intervention by narrowing its content and by using other providers that are focused solely on delivering the intervention.
PMID: 37141225
ISSN: 1932-6203
CID: 5503102

Physical Function in Middle-aged and Older Adults With Type 1 Diabetes: Long-term Follow-up of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

Martin, Catherine L; Trapani, Victoria R; Backlund, Jye-Yu C; Lee, Pearl; Braffett, Barbara H; Bebu, Ionut; Lachin, John M; Jacobson, Alan M; Gubitosi-Klug, Rose; Herman, William H
OBJECTIVE:To describe the prevalence and clinical correlates of functional limitations in middle-aged and older adults with long-standing type 1 diabetes. RESEARCH DESIGN AND METHODS/METHODS:Functional limitations were assessed for 1,094 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, a multicenter, longitudinal, observational follow-up of participants with type 1 diabetes randomly assigned to intensive or conventional diabetes therapy during the Diabetes Control and Complications Trial (DCCT). The primary outcome measure was a score <10 on the Short Physical Performance Battery (SPPB). The secondary outcome, self-reported functional limitation, was assessed by written questionnaire. Logistic regression models were used to assess associations of both outcomes with demographic and clinical factors (glycemic and nonglycemic factors, micro- and macrovascular complications, DCCT cohort, and treatment assignment). RESULTS:Participants were 53% male, with mean ± SD age 59.5 ± 6.8 years and diabetes duration 37.9 ± 4.9 years. The prevalence of SPPB score <10 was 21%. The prevalence of self-reported functional limitations was 48%. While DCCT treatment assignment was not associated with physical function outcomes measured ∼25 years after the end of the DCCT, the time-weighted mean DCCT/EDIC HbA1c was associated with both outcomes. Other clinical factors associated with both outcomes in multivariable analyses were BMI, general psychological distress, and cardiac autonomic neuropathy. CONCLUSIONS:Almost half of the middle-aged and older adults with long-standing type 1 diabetes reported functional limitations, which were associated with higher HbA1c and BMI, general psychological distress, and cardiac autonomic neuropathy. Future research is needed to determine whether these findings are generalizable.
PMID: 35880807
ISSN: 1935-5548
CID: 5276322

Brain Structure Among Middle-aged and Older Adults With Long-standing Type 1 Diabetes in the DCCT/EDIC Study

Jacobson, Alan M; Braffett, Barbara H; Erus, Guray; Ryan, Christopher M; Biessels, Geert J; Luchsinger, José A; Bebu, Ionut; Gubitosi-Klug, Rose A; Desiderio, Lisa; Lorenzi, Gayle M; Trapani, Victoria R; Lachin, John M; Bryan, R Nick; Habes, Mohamad; Nasrallah, Ilya M
OBJECTIVE:Individuals with type 1 diabetes mellitus (T1DM) are living to ages when neuropathological changes are increasingly evident. We hypothesized that middle-aged and older adults with long-standing T1DM will show abnormal brain structure in comparison with control subjects without diabetes. RESEARCH DESIGN AND METHODS/METHODS:MRI was used to compare brain structure among 416 T1DM participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study with that of 99 demographically similar control subjects without diabetes at 26 U.S. and Canadian sites. Assessments included total brain (TBV) (primary outcome), gray matter (GMV), white matter (WMV), ventricle, and white matter hyperintensity (WMH) volumes and total white matter mean fractional anisotropy (FA). Biomedical assessments included HbA1c and lipid levels, blood pressure, and cognitive assessments of memory and psychomotor and mental efficiency (PME). Among EDIC participants, HbA1c, severe hypoglycemia history, and vascular complications were measured longitudinally. RESULTS:Mean age of EDIC participants and control subjects was 60 years. T1DM participants showed significantly smaller TBV (least squares mean ± SE 1,206 ± 1.7 vs. 1,229 ± 3.5 cm3, P < 0.0001), GMV, and WMV and greater ventricle and WMH volumes but no differences in total white matter mean FA versus control subjects. Structural MRI measures in T1DM were equivalent to those of control subjects who were 4-9 years older. Lower PME scores were associated with altered brain structure on all MRI measures in T1DM participants. CONCLUSIONS:Middle-aged and older adults with T1DM showed brain volume loss and increased vascular injury in comparison with control subjects without diabetes, equivalent to 4-9 years of brain aging.
PMID: 35699949
ISSN: 1935-5548
CID: 5282592

Hyperglycemia and hyperinsulinemia effects on anterior cingulate cortex myoinositol-relation to brain network functional connectivity in healthy adults

Bolo, Nicolas R; Jacobson, Alan M; Musen, Gail; Simonson, Donald C
Brain mechanisms underlying the association of diabetes metabolic disorders-hyperglycemia and insulin resistance-with cognitive impairment are unknown. Myoinositol is a brain metabolite involved in cell osmotic balance, membrane phospholipid turnover, and second messenger neurotransmission, which affect brain function. Increased brain myoinositol and altered functional connectivity have been found in diabetes, mild cognitive impairment, and Alzheimer's disease, but the independent effects of plasma glucose and insulin on brain myoinositol and function are not characterized. We measured myoinositol concentrations in the pregenual anterior cingulate cortex (ACC), a region involved in self-reflective awareness and decision making, using proton magnetic resonance spectroscopy, and whole brain resting-state functional connectivity using fMRI, during acute hyperglycemia (with attendant hyperinsulinemia) and euglycemic-hyperinsulinemia compared with basal fasting-euglycemia (EU) in 11 healthy nondiabetic participants (5 women/6 men, means ± SD, age: 27 ± 7 yr, fasting-glucose: 5.2 ± 0.4 mmol/L, fasting-insulin: 4.9 ± 4.4 μU/mL). Brain MR data were acquired during two separate visits: 1) EU followed by a 60-min hyperglycemic-clamp (glucose: 10.7 ± 0.2 mmol/L, insulin: 33 ± 6 μU/mL); 2) EU followed by a hyperinsulinemic-euglycemic-clamp (glucose: 5.3 ± 0.1 mmol/L, insulin: 27 ± 5 μU/mL) designed to match individual insulin levels achieved during the visit 1 hyperglycemic-clamp. Myoinositol decreased by 14% during the hyperglycemic-clamp (from 7.7 ± 1.5 mmol/kg to 6.6 ± 0.8 mmol/kg, P = 0.031), and by 9% during the hyperinsulinemic-euglycemic-clamp (from 7.1 ± 0.7 mmol/kg to 6.5 ± 0.7 mmol/kg, P = 0.014), with no significant difference between the two clamps. Lower myoinositol was associated with higher functional connectivity of the thalamus and precentral cortex with insula-ACC-related networks, suggesting myoinositol is involved in insulin modulation of cognitive/emotional network function in healthy adults. Regional brain myoinositol levels may be useful biomarkers for monitoring cognitive and mood-enhancing treatment responses.NEW & NOTEWORTHY Hyperinsulinemia-related decreases of brain anterior cingulate cortex (ACC) myoinositol independent of plasma glucose levels and the association of low ACC myoinositol with increased functional connectivity between sensorimotor regions and ACC/insula-related networks suggest involvement of myoinositol in insulin-modulated brain network function in healthy adults. In diabetes, elevated brain myoinositol may be due to reduced brain insulin levels or action, rather than hyperglycemia, and may be involved in brain network dysfunctions leading to cognitive or mood disorders.
PMID: 35417272
ISSN: 1522-1598
CID: 5213882

Diabetic Peripheral Neuropathy and Urological Complications in Type 1 Diabetes: Findings From the Epidemiology of Diabetes Interventions and Complications Study

Pop-Busui, Rodica; Braffett, Barbara H; Wessells, Hunter; Herman, William H; Martin, Catherine L; Jacobson, Alan M; Sarma, Aruna V
OBJECTIVE:To evaluate associations between diabetic peripheral neuropathy (DPN) and urological complications in men and women with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS:Measurements of DPN at Epidemiology of Diabetes Intervention and Complications (EDIC) years 1, 14, and 17 and urological complications at EDIC year 17 were examined in 635 men (mean age 51.6 years, diabetes duration 29.5 years) and 371 women (mean age 50.6 years, diabetes duration 29.8 years) enrolled in the Diabetes Control and Complications Trial (DCCT)/EDIC study. DPN was defined by symptoms, signs, and abnormal electrophysiology or by abnormal Michigan Neuropathy Screening Instrument (MNSI) examination or questionnaire scores. RESULTS:Erectile dysfunction (ED) in combination with lower urinary tract symptoms (LUTS) was reported in 15% of men and female sexual dysfunction (FSD), LUTS, and urinary incontinence (UI) in 16% of women. Adjusted for age, drinking status, BMI, depression, DCCT/EDIC time-weighted mean HbA1c, microalbuminuria, hypertension, triglycerides, and statin medication use, the odds of reporting ED and LUTS versus no ED or LUTS at EDIC year 17 were 3.52 (95% CI 1.69, 7.31) times greater in men with confirmed DPN at EDIC year 13/14 compared to men without confirmed DPN. Compared to men without DPN, men with DPN based on abnormal MNSI examination or questionnaire scores had significantly higher odds of reporting ED and LUTS versus no ED or LUTS at EDIC year 17. There were no significant differences in DPN between women reporting both FSD and LUTS/UI compared with those without FSD or LUTS/UI at EDIC year 17. CONCLUSIONS:In long-standing T1D, DPN is associated with the later development of urological complications in men.
PMID: 34728530
ISSN: 1935-5548
CID: 5220832