White matter hyperintensities effect on cognition in type 2 diabetes is moderated by education level

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Abstract Submission 

Mohamed Salah Khlif¹, Carolina Restrepo², Sheila Patel³, Leonid Churilov⁴, Louise Burrell³, Amy Brodtmann¹

¹Cognitive Health Initiative, Central Clinical School, Monash University, Melbourne, VIC, ²Cabrini Health, Melbourne, VIC, ³Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, ⁴Melbourne Medical School, University of Melbourne, Melbourne, VIC

Mohamed Salah Khlif  
Cognitive Health Initiative, Central Clinical School, Monash University
Melbourne, VIC

Carolina Restrepo  
Cabrini Health
Melbourne, VIC

Sheila Patel  
Department of Medicine, University of Melbourne, Austin Health
Heidelberg, VIC

Leonid Churilov  
Melbourne Medical School, University of Melbourne
Melbourne, VIC

Louise Burrell  
Department of Medicine, University of Melbourne, Austin Health
Heidelberg, VIC

Amy Brodtmann, MBBS FRACP PhD  
Cognitive Health Initiative, Central Clinical School, Monash University
Melbourne, VIC

White matter hyperintensities (WMH) are a cerebral small vessel disease (cSVD) marker (Li et al., 2022). Factors that lead to WMH accumulation and to cSVD include increasing age, obesity, hypertension, and type 2 diabetes mellitus (T2DM). WMH burden has been linked to neurodegeneration and cognitive decline (Rizvi et al., 2018). Conversely, there is a positive association between education attainment level and cognitive ability across an adult life span (Lövdén et al., 2020). We conducted a moderation analysis in a group of people with T2DM to determine if education level attenuates the causal relationship between WMH volume and cognitive performance (see Fig. 1).

Baseline multimodal MRI was completed as part of the Diabetes and Dementia (D2) (Patel et al., 2017), an observational longitudinal case control study that followed 150 adults with T2DM. Age, obesity (BMI > 30 kg/m2), hypertension (24-hour blood pressure mean > 140/90 mmHg), and education level (0/1 based on a threshold of 12 years of education, YOE) were included as covariates. WMH volumes (predictor, mm3) were estimated using manual delineations on FLAIR images and cognitive screening (response) was done using the Montreal Cognitive Assessment (MoCA) test (Nasreddine et al., 2005). The causal effects of WMH on cognitive ability were estimated and stratified by the level of education attainment. The "WeightIt" R package was used for generating the balancing weights based on the "optweight" method (https://cran.r-project.org/web/packages/WeightIt/index.html). We used the g-computation algorithm and set 'vcov' to 'HC3' for robust estimations of causal effects and confidence intervals.

We included 129 participants (age: 65.1 ± 7.2 years, men: 72): 93 participants had YOE > 12 years; 45 had current/untreated hypertension based on ambulatory BP testing, and 68 were classified as obese. The distributions of unadjusted covariates at baseline stratified by education level are shown in Fig. 1. Covariate balancing after weighting is provided in Fig. 2/A showing WMH-covariate correlations below 5%. We found a causal effect of WMH accumulation on cognitive ability (p = 0.00154, Fig. 2/C) only in the group of T2DM patients with lower level of education. This was also reflected in the plot of the average dose-response function (ADRF) in Fig. 2/B. Testing also showed that the education moderation effect was significant (p = 0.00585, Fig. 2/C).

In this sample of participants with T2DM, we report a significant effect of higher education attainment in attenuating the causal effects of cSVD, reflected by WMH accumulation, on cognitive abilities. These results are consistent with the concept of cognitive resilience imparted by prior educational attainment, even in the setting of increasingly cSVD.

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) ¹

Other Methods ²

Cerebrovascular Disease

Cognition

Degenerative Disease

STRUCTURAL MRI

Other - WMH, Hypertension, Causal inference, moderation