Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study

Abstract

Background: Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals.

Methods: The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG)-PET, and annual percentage change in [¹⁸F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach.

Findings: This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [¹⁸F]FDG uptake compared with low risk (β=-0·008 [95% CI -0·013 to -0·002]; p_FDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; p_FDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [¹⁸F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (β=-0·269 [95% CI -0·509 to -0·027]; p=0·029).

Interpretation: Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life.

Funding: Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation.

Figure 1

Study flow PESA participants with documented subclinical atherosclerosis at baseline underwent two [¹⁸F]FDG-PET scans over a 4·7-year period. Of the 547 participants with a valid brain [¹⁸F]FDG-PET scan at baseline, 404 underwent a second scan and, of those, 370 participants were included in the longitudinal analysis. [¹⁸F]FDG=[¹⁸F]fluorodeoxyglucose.

Figure 2

Association between persistent high cardiovascular risk over time and decline in brain glucose metabolism, and its mediation by NfL (A, B) Scatter plots showing the association between annual change in SCORE2 and the percentage annual change in [¹⁸F]FDG-PET SUVR in the cortex (A) and in the Alzheimer's disease meta-ROI (B) with a linear regression model. The line shows the regression fitting and the shading shows 95% CI. (C, D) Mean plots showing the trajectory of [¹⁸F]FDG-PET SUVR over time in each SCORE2 progression group in the cortex (C) and in the Alzheimer's disease meta-ROI (D). (E) Mean plot showing the trajectory of plasma NfL over time in each of the SCORE2 progression groups. SUVR and NfL in mean plots were normalised to that of the stable low-risk group at baseline. Group and slope effects were tested with a linear mixed effects model and bars show the 95% CI. (F) Schematic of the mediation analysis output showing that brain metabolism decline was 19·8% (indirect effect) mediated by NfL in the stable high-risk group. β corresponds to the regression coefficients of each model in the direction of the arrow and describe average direct effects. β′ corresponds to the average causal mediation effects. The β coefficients of the indirect effects correspond to the proportion of the SUVR variance mediated by the mediator, NfL. Bold font refers to statistically significant results. (G, H) Statistical voxelwise maps showing the spatial distribution of the main effect (G) and the interaction effect between time and SCORE2 progression groups on [¹⁸F]FDG uptake (H), including stable high and stable low. Coloured bars represent the magnitude of the voxel significance corrected for multiple comparisons (p_FDR<0·05). All models were adjusted for age, sex, education, and APOE genotype; in the case of SUVR models, by basal glucose concentrations as well; and in the case of NfL models, by BMI and creatinine as well. [¹⁸F]FDG=[¹⁸F]fluorodeoxyglucose. FDR=false discovery rate. NfL=neurofilament light chain. ROI=region of interest. SUVR=standard uptake value ratio. *p_FDR<0·05 (interaction effect). †p_FDR<0·05 (main effect).

Figure 3

Association between continuous presence of hypertension and decline in brain glucose metabolism (A, B) Boxplots showing the association between the progression of hypertension and the annual percentage change in [¹⁸F]FDG-PET SUVR in the cortex (A) and in the Alzheimer's disease meta-ROI (B). Group differences were tested with ANOVA. The horizontal line within the boxes shows the median and the upper and lower edges of the boxes show the 75th and 25th percentiles. (C, D) Mean plots showing the trajectory of [¹⁸F]FDG-PET SUVR over time in each hypertension progression group in the cortex (C) and in the Alzheimer's disease meta-ROI (D). SUVR was normalised to that of the stable normotensive group at baseline. Group and slope effects were tested with a linear mixed effects model and bars show the 95% CI. The stable hypertensive, change to hypertensive, and stable normotensive groups had a mean cortical SUVR decrease of 2·85% (95% CI 1·79–3·90), 3·28% (2·08–4·48), and 2·78% (2·25–3·31), respectively. (E) Summary table with regression coefficients (β) and p_FDR values derived from linear regression and LME models testing the effect of hypertension progression on brain glucose metabolism progression in the cortex and in the Alzheimer's disease meta-ROI. Bold font refers to statistically significant results. All models were adjusted for age, sex, education, APOE genotype, and basal glucose concentrations. [¹⁸F]FDG=[¹⁸F]fluorodeoxyglucose. FDR=false discovery rate. LME=linear mixed effects. ROI=region of interest. SUVR=standard uptake value ratio. *p_FDR<0·05 (main effect). †This p value was not FDR-corrected (only secondary analyses were FDR-corrected).

Figure 4

Association between progression of subclinical carotid plaque volume and decline in brain glucose metabolism (A–D) Scatter plots showing the association of annual percentage change in [¹⁸F]FDG-PET SUVR in the cortex (A, C) and in the Alzheimer's disease meta-ROI (B, D) with annual change in carotid plaque volume (n=261) and with annual change in femoral plaque volume (n=261), respectively. The line shows the regression fittings and the shading shows the 95% CI. (E) Summary table with regression coefficients (β) and p_FDR values derived from linear regression models testing the effect of carotid and femoral plaque volume progression on brain glucose metabolism progression in both ROIs. Bold font refers to statistically significant results. (F) Statistical voxelwise maps showing the brain regions where there is a negative correlation between annual in carotid plaque volume and annual percentage change in [¹⁸F]FDG-PET SUVR for the different models. Coloured bars show the magnitude of the voxel significance corrected for multiple comparisons (p_FDR<0·05). Plots and statistics represent part of the dataset, excluding those participants without atherosclerotic burden. All models were adjusted for age, sex, education, APOE genotype and basal glucose levels (base model). [¹⁸F]FDG=[¹⁸F]fluorodeoxyglucose. FDR=false discovery rate. ROI=region of interest. SUVR=standard uptake value ratio. *This p value was not FDR-corrected (only secondary analyses were FDR-corrected).