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Journal article
PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment Reasons for Geographic and Racial Differences in Stroke Study (REGARDS)
Circulation (New York, N.Y.), v 137(12), pp 1260-1269
20 Mar 2018
PMID: 29146683
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Abstract
BACKGROUND: Despite concerns about adverse neurocognitive events raised by prior trials, pharmacological PCSK9 (proprotein convertase subtilisin/kexin type-9) inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in lifelong exposure to lower levels of low-density lipoprotein cholesterol can provide information on the potential long-term effects of lower low-density lipoprotein cholesterol on neurocognitive impairment and decline.
METHODS: We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among black REGARDS study (Reasons for Geographic and Racial Differences in Stroke) participants with (n=241) and without (n=10454) C697X or Y142X LOF variants. Neurocognitive tests included the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery (Word List Learning, World List Delayed Recall, Semantic Animal Fluency) and Six-Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score >= 1.5 SD below age, sex, and education-based stratum-specific means on 2 or 3 CERAD assessments or, separately, a score <5 on any SIS assessment at baseline or during follow-up. Neurocognitive decline was assessed using standardized continuous scores on individual neurocognitive tests.
RESULTS: The mean sample age was 64 years (SD, 9), 62% were women, and the prevalence of neurocognitive impairment at any assessment was 6.3% by CERAD and 15.4% by SIS definitions. Adjusted odds ratios for neurocognitive impairment for participants with versus without PCSK9 LOF variants were 1.11 (95% confidence interval [CI], 0.58-2.13) using the CERAD battery and 0.89 (95% CI, 0.61-1.30) using the SIS assessment. Standardized average differences in individual neurocognitive assessment scores over the 5.6-year (range, 0.1-9.1) study period ranged between 0.07 (95% CI, -0.06 to 0.20) and -0.07 (95% CI, -0.18 to 0.05) among participants with versus without PCSK9 LOF variants. Patterns of neurocognitive decline were similar between participants with and without PCSK9 LOF variants (all P>0.10). Odds ratios for neurocognitive impairment per 20 mg/dL low-density lipoprotein cholesterol decrements were 1.02 (95% CI, 0.96-1.08) and 0.99 (95% CI, 0.95-1.02) for the CERAD and SIS definitions of impairment, respectively.
CONCLUSIONS: These results suggest that lifelong exposure to low PCSK9 levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks.
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Details
- Title
- PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment Reasons for Geographic and Racial Differences in Stroke Study (REGARDS)
- Creators
- Matthew T. Mefford - University of Alabama at BirminghamRobert S. Rosenson - Icahn School of Medicine at Mount SinaiMary Cushman - University of VermontMichael E. Farkouh - Peter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre, University of Toronto, Ontario, Canada (M.E.F.).Leslie A. McClure - Drexel UniversityVirginia G. Wadley - Department of Medicine (V.G.W., V.B.)Marguerite R. Irvin - University of Alabama at BirminghamVera Bittner - Department of Medicine (V.G.W., V.B.)Monika M. Safford - Cornell CollegeRansi Somaratne - AmgenKeri L. Monda - AmgenPaul Muntner - University of Alabama at BirminghamEmily B. Levitan - University of Alabama at Birmingham
- Publication Details
- Circulation (New York, N.Y.), v 137(12), pp 1260-1269
- Publisher
- Lippincott Williams & Wilkins
- Number of pages
- 10
- Grant note
- R01HL080477 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R01 HL80477 / National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) University of Alabama at Birmingham U01NS041588 / National Institute of Neurological Disorders and Stroke; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Amgen Inc.; Amgen National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA US Department of Health and Human Services T32HS013852 / AGENCY FOR HEALTHCARE RESEARCH AND QUALITY; United States Department of Health & Human Services; Agency for Healthcare Research & Quality
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Epidemiology and Biostatistics
- Web of Science ID
- WOS:000428027400011
- Scopus ID
- 2-s2.0-85049324428
- Other Identifier
- 991019168275004721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cardiac & Cardiovascular Systems
- Peripheral Vascular Disease