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Neuronal insulin signaling and brain structure in nondemented older adults: the Atherosclerosis Risk in Communities Study.

ABSTRACT: We used plasma neuronal extracellular vesicles to examine how neuronal insulin signaling proteins relate cross-sectionally to brain structure in nondemented older adults with varying levels of cortical amyloid. Extracellular vesicles enriched for neuronal origin by anti-L1CAM immunoabsorption were isolated from plasma of Atherosclerosis Risk in Communities-Positron Emission Tomography study participants (n = 88; mean age: 77 years [standard deviation: 6]). Neuronal extracellular vesicle levels of phosphorylated insulin signaling cascade proteins were quantified. Brain volume and white matter hyperintensity (WMH) volume were assessed using 3T magnetic resonance imaging. After adjusting for demographic variables and extracellular vesicle marker Alix, higher levels of a neuronal insulin signaling composite measure were associated with lower WMH and greater temporal lobe volume. Secondary analyses found the levels of downstream protein kinases involved in cell survival (p70S6K) and tau phosphorylation/neuroinflammation (GSK-3β) to be most strongly associated with WMH and temporal lobe volume, respectively. Associations between neuronal insulin signaling and lower WMH volume were attenuated in participants with elevated cortical amyloid. These results suggest that enhanced neuronal proximal insulin signaling is associated with preserved brain structure in nondemented older adults.

SUBMITTER: Walker KA

PROVIDER: S-EPMC7736127 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Prior studies have shown insulin resistance is associated with reduced cardiac autonomic function measured at rest, but few studies have determined whether insulin resistance is associated with reduced cardiac autonomic function measured during daily activities. METHODS:We examined older adults without diabetes with 48-h ambulatory electrocardiography (n?=?759) in an ancillary study of the Atherosclerosis Risk in Communities Study. Insulin resistance, the exposure, was defined by quartiles for three indexes: 1) the homeostatic model assessment of insulin resistance (HOMA-IR), 2) the triglyceride and glucose index (TyG), and 3) the triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C). Low heart rate variability, the outcome, was defined by <25th percentile for four measures: 1) standard deviation of normal-to-normal R-R intervals (SDNN), a measure of total variability; 2) root mean square of successive differences in normal-to-normal R-R intervals (RMSSD), a measure of vagal activity; 3) low frequency spectral component (LF), a measure of sympathetic and vagal activity; and 4) high frequency spectral component (HF), a measure of vagal activity. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals weighted for sampling/non-response, adjusted for age at ancillary visit, sex, and race/study-site. Insulin resistance quartiles 4, 3, and 2 were compared to quartile 1; high indexes refer to quartile 4 versus quartile 1. RESULTS:The average age was 78?years, 66% (n?=?497) were women, and 58% (n?=?438) were African American. Estimates of association were not robust at all levels of HOMA-IR, TyG, and TG/HDL-C, but suggest that high indexes were associated consistently with indicators of vagal activity. High HOMA-IR, high TyG, and high TG/HDL-C were consistently associated with low RMSSD (OR: 1.68 (1.00, 2.81), OR: 2.03 (1.21, 3.39), and OR: 1.73 (1.01, 2.91), respectively). High HOMA-IR, high TyG, and high TG/HDL-C were consistently associated with low HF (OR: 1.90 (1.14, 3.18), OR: 1.98 (1.21, 3.25), and OR: 1.76 (1.07, 2.90), respectively). CONCLUSIONS:In older adults without diabetes, insulin resistance was associated with reduced cardiac autonomic function - specifically and consistently for indicators of vagal activity - measured during daily activities. Primary prevention of insulin resistance may reduce the related risk of cardiac autonomic dysfunction.

Project description:Backgrounds: Abnormal retinal nerve fiber layer (RNFL) thickness has been observed in patients with Alzheimer's disease (AD) and therefore suggested to be a potential biomarker of AD. However, whether the changes in RNFL thickness are associated with the atrophy of brain structure volumes remains unknown. We, therefore, set out a prospective investigation to determine the association between longitudinal changes of RNFL thickness and brain atrophy in nondemented older participants over a period of 12 months. Materials and Methods: We measured the RNFL thickness using optical coherence tomography (OCT) and brain structure volumes by 3T magnetic resonance imaging (MRI) before and after 12 months. Cognitive function was assessed using the Chinese version of Mini-Mental State Examination (CMMSE) and Repeatable Battery for the Assessment of Neurological Status. Associations among the changes of RNFL, brain structures and cognitive function were analyzed with Spearman correlation and multiple linear regression models adjusting for the confounding factors. Results: Fifty old participants were screened and 40 participants (mean age 71.8 ± 3.9 years, 60% were male) were enrolled at baseline. Among them, 28 participants completed the follow-up assessments. The average reduction of RNFL thickness was inversely associated with the decrease of central cingulate cortex volume after the adjustment of age and total intracranial volume (β = -0.41, P = 0.039). Specifically, the reduction of RNFL thickness in the inferior, not other quadrants, was independently associated with the decline of central cingulate cortex volume after the adjustment (β = -0.52, P = 0.006). Moreover, RNFL thinning, central cingulate cortex atrophy and the aggregation of white matter hyperintensities (WMH) were found associated with episodic memory in these older adults with normal cognition. Conclusions: RNFL thinning was associated with cingulate cortex atrophy and episodic memory decline in old participants. The longitudinal changes of RNFL thickness are suggested to be a useful complementary index of neurocognitive aging or neurodegeneration.

Project description:AimsHigher levels of brain natriuretic peptide (BNP) have been associated with a decreased risk of diabetes in adults, but whether BNP is related to insulin resistance in older adults has not been established.MethodsN-terminal of the pro hormone brain natriuretic peptide (NT-pro BNP) was measured among Cardiovascular Health Study participants at the 1989-1990, 1992-1993 and 1996-1997 examinations. We calculated measures of insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Gutt index, Matsuda index] from fasting and 2-h concentrations of glucose and insulin among 3318 individuals with at least one measure of NT-proBNP and free of heart failure, coronary heart disease and chronic kidney disease, and not taking diabetes medication. We used generalized estimating equations to assess the cross-sectional association of NT-proBNP with measures of insulin resistance. Instrumental variable analysis with an allele score derived from nine genetic variants (single nucleotide polymorphisms) within or near the NPPA and NPPB loci was used to estimate an un-confounded association of NT-proBNP levels on insulin resistance.ResultsLower NT-proBNP levels were associated with higher insulin resistance even after adjustment for BMI, waist circumference and other risk factors (P < 0.001 for all four indices). Although the genetic score was strongly related to measured NT-proBNP levels amongst European Americans (F statistic = 71.08), we observed no association of genetically determined NT-proBNP with insulin resistance (P = 0.38; P = 0.01 for comparison with the association of measured levels of NT-proBNP).ConclusionsIn older adults, lower NT-proBNP is associated with higher insulin resistance, even after adjustment for traditional risk factors. Because related genetic variants were not associated with insulin resistance, the causal nature of this association will require future study.

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Neuronal insulin signaling and brain structure in nondemented older adults: the Atherosclerosis Risk in Communities Study.

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