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White matter hyperintensities in middle-aged adults with childhood-onset type 1 diabetes.

ABSTRACT: Although microvascular complications are common in type 1 diabetes mellitus (T1DM), few studies have quantified the severity, risk factors, and implications of cerebral microvascular damage in these patients. As life expectancy in patients with T1DM increases, patients are exposed to age- and disease-related factors that may contribute to cerebral microvascular disease.Severity and volume of white matter hyperintensities (WMH) and infarcts were quantified in 97 middle-aged patients with childhood-onset T1DM (mean age and duration: 50 and 41 years, respectively) and 81 non-T1DM adults (mean age: 48 years), concurrent with cognitive and health-related measures.Compared with non-T1DM participants, patients had more severe WMH (Fazekas scores 2 and 3 compared with Fazekas score 1, p < 0.0001) and slower information processing (digit symbol substitution, number correct: 65.7 ± 10.9 and 54.9 ± 13.6; pegboard, seconds: 66.0 ± 9.9 and 88.5 ± 34.2; both p < 0.0001) independent of age, education, or other factors. WMH were associated with slower information processing; adjusting for WMH attenuated the group differences in processing speed (13% for digit symbol, 11% for pegboard, both p ? 0.05). Among patients, prevalent neuropathies and smoking tripled the odds of high WMH burden, independent of age or disease duration. Associations between measures of blood pressure or hyperglycemia and WMH were not significant.Clinically relevant WMH are evident earlier among middle-aged patients with childhood-onset T1DM and are related to the slower information processing frequently observed in T1DM. Brain imaging in patients with T1DM who have cognitive difficulties, especially those with neuropathies, may help uncover cerebral microvascular damage. Longitudinal studies are warranted to fully characterize WMH development, risk factors, and long-term effects on cognition.

SUBMITTER: Nunley KA

PROVIDER: S-EPMC4442104 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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White matter hyperintensities in middle-aged adults with childhood-onset type 1 diabetes.

Nunley Karen A KA Ryan Christopher M CM Orchard Trevor J TJ Aizenstein Howard J HJ Jennings J Richard JR Ryan John J Zgibor Janice C JC Boudreau Robert M RM Costacou Tina T Maynard John D JD Miller Rachel G RG Rosano Caterina C Rosano Caterina C

Neurology 20150422 20

<h4>Objective</h4>Although microvascular complications are common in type 1 diabetes mellitus (T1DM), few studies have quantified the severity, risk factors, and implications of cerebral microvascular damage in these patients. As life expectancy in patients with T1DM increases, patients are exposed to age- and disease-related factors that may contribute to cerebral microvascular disease.<h4>Methods</h4>Severity and volume of white matter hyperintensities (WMH) and infarcts were quantified in 97 ...[more]

PMID: 25904692

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Project description:ObjectiveThe aim of this study was to investigate the presence and correlates of clinically relevant cognitive impairment in middle-aged adults with childhood-onset type 1 diabetes (T1D).Research design and methodsDuring 2010-2013, 97 adults diagnosed with T1D and aged <18 years (age and duration 49 ± 7 and 41 ± 6 years, respectively; 51% female) and 138 similarly aged adults without T1D (age 49 ± 7 years; 55% female) completed extensive neuropsychological testing. Biomedical data on participants with T1D were collected periodically since 1986-1988. Cognitive impairment status was based on the number of test scores ≥1.5 SD worse than demographically appropriate published norms: none, mild (only one test), or clinically relevant (two or more tests).ResultsThe prevalence of clinically relevant cognitive impairment was five times higher among participants with than without T1D (28% vs. 5%; P < 0.0001), independent of education, age, or blood pressure. Effect sizes were large (Cohen d 0.6-0.9; P < 0.0001) for psychomotor speed and visuoconstruction tasks and were modest (d 0.3-0.6; P < 0.05) for measures of executive function. Among participants with T1D, prevalent cognitive impairment was related to 14-year average A1c >7.5% (58 mmol/mol) (odds ratio [OR] 3.0; P = 0.009), proliferative retinopathy (OR 2.8; P = 0.01), and distal symmetric polyneuropathy (OR 2.6; P = 0.03) measured 5 years earlier; higher BMI (OR 1.1; P = 0.03); and ankle-brachial index ≥1.3 (OR 4.2; P = 0.01) measured 20 years earlier, independent of education.ConclusionsClinically relevant cognitive impairment is highly prevalent among these middle-aged adults with childhood-onset T1D. In this aging cohort, chronic hyperglycemia and prevalent microvascular disease were associated with cognitive impairment, relationships shown previously in younger populations with T1D. Two additional potentially modifiable risk factors for T1D-related cognitive impairment, vascular health and BMI, deserve further study.

Project description:Vascular dysfunction may occur prior to declines in cognitive function and accumulation of neuropathology. White matter hyperintensities (WMH) develop due to cerebral ischemia and elevated blood pressure in midlife. The purpose of this study was to evaluate associations between cardiovascular and cerebrovascular responses to sympathoexcitatory stimuli and WMH burden in cognitively unimpaired middle-aged and older adults. Sixty-eight adults (age = 63 ± 4y, men = 20, women = 48) participated in this study. Participants completed isometric handgrip exercise (IHG) exercise at 40% of maximal voluntary contraction until fatigue followed by a 90s period of post-exercise ischemia. Heart rate (HR), mean arterial pressure (MAP), middle cerebral artery blood velocity (MCAv), and end-tidal CO2 were continuously measured throughout the protocol. Cerebrovascular resistance index (CVRi) was calculated as MAP/MCAv. WMH lesion volume and intracranial volume (ICV) were measured using a FLAIR and T1 scan on a 3T MRI scanner, respectively. WMH fraction was calculated as (WMH lesion volume/ICV)*100 and cubic root transformed. Multiple linear regressions were used to determine the association between cardiovascular and cerebrovascular responses to IHG exercise and post-exercise ischemia and WMH fraction. Multiple linear regression models were adjusted for age, sex, apolipoprotein ε4 status, and total work performed during IHG exercise. During IHG exercise, there were significant increases from baseline in HR (25 ± 12%), MAP (27 ± 11%), MCAv (5 ± 10%), and CVRi (22 ± 17%; P < 0.001 for all). During post-exercise ischemia, HR (8 ± 7%), MAP (22 ± 9%), and CVRi (23 ± 16%) remained elevated (P < 0.001) while MCAv (0 ± 10%) was not different compared to baseline. There was an inverse association between the percent change in HR (r = -0.42, P = 0.002), MAP (r = -0.41, P = 0.002), and CVRi (r = -0.31, P = 0.045), but not MCAv (r = 0.19, P = 0.971) in response to IHG exercise and WMH fraction. There were no associations between responses to post-exercise ischemia and WMH fraction. Lower sympathoexcitatory responses to IHG exercise are associated with greater WMH burden in middle-aged to older adults. These findings suggest that individuals who demonstrate smaller increases in HR, MAP, and CVRi in response to sympathoexcitatory stress have greater WMH burden.

Project description:BACKGROUND:White matter hyperintensities (WMH) of presumed vascular origin have been associated with an increased risk of Alzheimer's disease (AD). This study aims to describe the patterns of WMH associated with dementia risk estimates and individual risk factors in a cohort of middle-aged/late middle-aged individuals (mean 58 (interquartile range 51-64) years old). METHODS:Magnetic resonance imaging and AD risk factors were collected from 575 cognitively unimpaired participants. WMH load was automatically calculated in each brain lobe and in four equidistant layers from the ventricular surface to the cortical interface. Global volumes and regional patterns of WMH load were analyzed as a function of the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) dementia risk score, as well as family history of AD and Apolipoprotein E (APOE) genotype. Additional analyses were performed after correcting for the effect of age and hypertension. RESULTS:The studied cohort showed very low WMH burden (median 1.94 cm3) and 20-year dementia risk estimates (median 1.47 %). Even so, higher CAIDE scores were significantly associated with increased global WMH load. The main drivers of this association were age and hypertension, with hypercholesterolemia and body mass index also displaying a minor, albeit significant, influence. Regionally, CAIDE scores were positively associated with WMH in anterior areas, mostly in the frontal lobe. Age and hypertension showed significant association with WMH in almost all regions analyzed. The APOE-?2 allele showed a protective effect over global WMH with a pattern that comprised juxtacortical temporo-occipital and fronto-parietal deep white matter regions. Participants with maternal family history of AD had higher WMH load than those without, especially in temporal and occipital lobes. CONCLUSIONS:WMH load is associated with AD risk factors even in cognitively unimpaired subjects with very low WMH burden and dementia risk estimates. Our results suggest that tight control of modifiable risk factors in middle-age/late middle-age could have a significant impact on late-life dementia.

Project description:Frontal lobe structures decline faster than most other brain regions in older adults. Age-related change in the frontal lobe is associated with poorer executive function (e.g., working memory, switching/set-shifting, and inhibitory control). The effects and presence of frontal lobe white matter hyperintensities (WMH) on executive function in normal aging is relatively unknown. The current study assessed relationships between region-specific frontal WMH load and cognitive performance in healthy older adults using three executive function tasks from the NIH Toolbox (NIHTB) Cognition Battery. A cohort of 279 healthy older adults ages 65-88 completed NIHTB and 3T T1-weighted and FLAIR MRI. Lesion Segmentation Toolbox quantified WMH volume and generated lesion probability maps. Individual lesion maps were registered to the Desikan-Killiany atlas in FreeSurfer 6.0 to define regions of interest (ROI). Independent linear regressions assessed relationships between executive function performance and region-specific WMH in frontal lobe ROIs. All models included age, sex, education, estimated total intracranial volume, multi-site scanner differences, and cardiovascular disease risk using Framingham criteria as covariates. Poorer set-shifting performance was associated with greater WMH load in three frontal ROIs including bilateral superior frontal (left β = -0.18, FDR-p = 0.02; right β = -0.20, FDR-p = 0.01) and right medial orbitofrontal (β = -0.17, FDR-p = 0.02). Poorer inhibitory performance associated with higher WMH load in one frontal ROI, the right superior frontal (right β = -0.21, FDR-p = 0.01). There were no significant associations between working memory and WMH in frontal ROIs. Our study demonstrates that location and pattern of frontal WMH may be important to assess when examining age-related differences in cognitive functions involving switching/set-shifting and inhibition. On the other hand, working memory performance was not related to presence of frontal WMH in this sample. These data suggest that WMH may contribute selectively to age-related declines in executive function. Findings emerged beyond predictors known to be associated with WMH presence, including age and cardiovascular disease risk. The spread of WMH within the frontal lobes may play a key role in the neuropsychological profile of cognitive aging. Further research should explore whether early intervention on modifiable vascular factors or cognitive interventions targeted for executive abilities may help mitigate the effect of frontal WMH on executive function.

Dataset Information

White matter hyperintensities in middle-aged adults with childhood-onset type 1 diabetes.

Publications

White matter hyperintensities in middle-aged adults with childhood-onset type 1 diabetes.

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