Guallar, Eliseo

BACKGROUND: Studies of the neurovascular contribution to dementia have largely focused on cerebral small vessel disease (CSVD), but the role of intracranial atherosclerotic disease (ICAD) remains unknown in the general population. The objective of this study was to determine the risk of incident dementia from ICAD after adjusting for CSVD and cardiovascular risk factors in a US community-based cohort. METHODS: We acquired brain magnetic resonance imaging examinations from 2011 through 2013 in 1980 Black and White participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective cohort conducted in 4 US communities. Magnetic resonance imaging examinations included high-resolution vessel wall magnetic resonance imaging and magnetic resonance angiography to identify ICAD. Of these participants, 1590 without dementia, without missing covariates, and with adequate magnetic resonance image quality were followed through 2019 for incident dementia. Associations between ICAD and incident dementia were assessed using Cox proportional hazard ratios adjusted for CSVD (characterized by white matter hyperintensities, lacunar infarctions, and microhemorrhages), APOE4 genotype (apolipoprotein E gene ε4), and cardiovascular risk factors. RESULTS: The mean age (SD) of study participants was 77.4 (5.2) years. ICAD was detected in 34.6% of participants. After a median follow-up of 5.6 years, 286 participants developed dementia. Compared with participants without ICAD, the fully adjusted hazard ratios (95% CIs) for incident dementia in participants with any ICAD, with ICAD only causing stenosis ≤50%, and with ICAD causing stenosis >50% in ≥1 vessel were 1.57 (1.17–2.11), 1.41 (1.02–1.95), and 1.94 (1.32–2.84), respectively. ICAD was associated with dementia even among participants with low white matter hyperintensities burden, a marker of CSVD. CONCLUSIONS: ICAD was associated with an increased risk of incident dementia, independent of CSVD, APOE4 genotype, and cardiovascular risk factors. The increased risk of dementia was evident even among participants with low CSVD burden, a group less likely to be affected by vascular dementia, and in participants with ICAD causing only low-grade stenosis. Our results suggest that ICAD may partially mediate the effect that cardiovascular risk factors have on the brain leading to dementia. Both ICAD and CSVD must be considered to understand the vascular contributions to cognitive decline.

Background Accurate measurement of the cholesterol within lipoprotein(a) (Lp[a]‐C) and its contribution to low‐density lipoprotein cholesterol (LDL‐C) has important implications for risk assessment, diagnosis, and treatment of atherosclerotic cardiovascular disease, as well as in familial hypercholesterolemia. A method for estimating Lp(a)‐C from particle number using fixed conversion factors has been proposed (Lp[a]‐C from particle number divided by 2.4 for Lp(a) mass, multiplied by 30% for Lp[a]‐C). The accuracy of this method, which theoretically can isolate “Lp(a)‐free LDL‐C,” has not been validated. Methods and Results In 177 875 patients from the VLDbL (Very Large Database of Lipids), we compared estimated Lp(a)‐C and Lp(a)‐free LDL‐C with measured values and quantified absolute and percent error. We compared findings with an analogous data set from the Mayo Clinic Laboratory. Error in estimated Lp(a)‐C and Lp(a)‐free LDL‐C increased with higher Lp(a)‐C values. Median error for estimated Lp(a)‐C <10 mg/dL was −1.9 mg/dL (interquartile range, −4.0 to 0.2); this error increased linearly, overestimating by +30.8 mg/dL (interquartile range, 26.1–36.5) for estimated Lp(a)‐C ≥50 mg/dL. This error relationship persisted after stratification by overall high‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol subtypes. Similar findings were observed in the Mayo cohort. Absolute error for Lp(a)‐free LDL‐C was +2.4 (interquartile range, −0.6 to 5.3) for Lp(a)‐C<10 mg/dL and −31.8 (interquartile range, −37.8 to −26.5) mg/dL for Lp(a)‐C≥50 mg/dL. Conclusions Lp(a)‐C estimations using fixed conversion factors overestimated Lp(a)‐C and subsequently underestimated Lp(a)‐free LDL‐C, especially at clinically relevant Lp(a) values. Application of inaccurate Lp(a)‐C estimations to correct LDL‐C may lead to undertreatment of high‐risk patients.