Arterial Stiffening Moderates the Relationship Between Type-2 Diabetes Mellitus and White Matter Hyperintensity Burden in Older Adults With Mild Cognitive Impairment.

Madeleine L Werhane,Alexandra J Weigand,Katherine J Bangen,Mark W Bondi,Kelsey R Thomas,Emily C Edmonds,Daniel A Nation,Lisa Delano-Wood,Erin E Sundermann

doi:10.3389/fnagi.2021.716638

Abstract

Background: Cerebrovascular dysfunction has been proposed as a possible mechanism underlying cognitive impairment in the context of type 2 diabetes mellitus (DM). Although magnetic resonance imaging (MRI) evidence of cerebrovascular disease, such as white matter hyperintensities (WMH), is often observed in DM, the vascular dynamics underlying this pathology remain unclear. Thus, we assessed the independent and combined effects of DM status and different vascular hemodynamic measures (i.e., systolic, diastolic, and mean arterial blood pressure and pulse pressure index [PPi]) on WMH burden in cognitively unimpaired (CU) older adults and those with mild cognitive impairment (MCI).Methods: 559 older adults (mean age: 72.4 years) from the Alzheimer’s Disease Neuroimaging Initiative were categorized into those with diabetes (DM+; CU = 43, MCI = 34) or without diabetes (DM-; CU = 279; MCI = 203). Participants underwent BP assessment, from which all vascular hemodynamic measures were derived. T2-FLAIR MRI was used to quantify WMH burden. Hierarchical linear regression, adjusting for age, sex, BMI, intracranial volume, CSF amyloid, and APOE ε4 status, examined the independent and interactive effects of DM status and each vascular hemodynamic measure on total WMH burden.Results: The presence of DM (p = 0.046), but not PPi values (p = 0.299), was independently associated with greater WMH burden overall after adjusting for covariates. Analyses stratified by cognitive status revealed a significant DM status x PPi interaction within the MCI group (p = 0.001) such that higher PPi values predicted greater WMH burden in the DM + but not DM- group. No significant interactions were observed in the CU group (all ps > 0.05).Discussion: Results indicate that higher PPi values are positively associated with WMH burden in diabetic older adults with MCI, but not their non-diabetic or CU counterparts. Our findings suggest that arterial stiffening and reduced vascular compliance may have a role in development of cerebrovascular pathology within the context of DM in individuals at risk for future cognitive decline. Given the specificity of these findings to MCI, future exploration of the sensitivity of earlier brain markers of vascular insufficiency (i.e., prior to macrostructural white matter changes) to the effects of DM and arterial stiffness/reduced vascular compliance in CU individuals is warranted.

Highlights

Type 2 diabetes has been repeatedly linked to an increased risk for developing dementia in late life (Arvanitakis et al, 2004; Crane et al, 2013)
Mean physiological (i.e., blood pressure (BP) [systolic, diastolic], arterial stiffness, mean arterial blood pressure (MABP)) and psychometric scores were in the non-clinical range2 both across the entire sample and within diabetes status groups, confirming that the sample was generally healthy with respect to vascular, psychiatric, cognitive, and functional symptomatology
The bivariate association between diabetes mellitus (DM) status and white matter hyperintensity (WMH) burden was not significant in the overall sample; a significant positive association was observed between diabetes status and WMH burden once covariates were included in an adjusted model (p = 0.045)

Summary

Introduction

Type 2 diabetes (hereby referred to as “diabetes” or DM) has been repeatedly linked to an increased risk for developing dementia in late life (Arvanitakis et al, 2004; Crane et al, 2013). Dementia in the context of diabetes has been linked to increased cerebrovascular pathology at autopsy, which stands in contrast to dementia without diabetes that on average has greater evidence of other neuropathological changes (e.g., amyloid beta and tau accumulation; Sonnen et al, 2009). Wellaligned with such findings is the observation that the most common neuroradiological finding associated with diabetes is the presence of increased white matter hyperintensity (WMH) burden in the brain (Van Harten et al, 2006). We assessed the independent and combined effects of DM status and different vascular hemodynamic measures (i.e., systolic, diastolic, and mean arterial blood pressure and pulse pressure index [PPi]) on WMH burden in cognitively unimpaired (CU) older adults and those with mild cognitive impairment (MCI)

Methods

Results

Discussion

Conclusion