Abstract
Purpose
It is plausible that statins could improve cerebral blood flow through pleiotropic mechanisms. The purpose of this investigation was to assess the contribution of statins to cerebrovascular variables in older adults with dyslipidemia and familial history of dementia. Furthermore, we explored the interaction between statin use and sex due to prevalent bias in statin trials.
Methods
Middle cerebral artery blood flow velocity (MCAv) was measured using transcranial Doppler ultrasound. Continuous supine rest recordings lasted 8 min. Participants included in analyses were statin (n = 100) or non-statin users (n = 112).
Results
MCAv and cerebrovascular conductance were significantly higher in statin users (p = 0.047; p = 0.04), and pulsatility index (PI) was significantly lower in statin users (p < 0.01). An interaction effect between statin use and sex was present for PI (p = 0.02); female statin users had significantly lower cerebrovascular resistance than the other three groups.
Conclusion
In this cross-sectional analysis, statin use was positively associated with cerebrovascular variables in older adults at risk for dementia. Female statin users had significantly higher resting MCAv and cerebrovascular conductance than female non-statin users. The greatest contribution of statin use was the association with reduced cerebrovascular resistance. Given that cerebrovascular dysregulation is one of the earliest changes in Alzheimer’s disease and related dementia pathology, targeting the cerebrovasculature with statins may be a promising prevention strategy.
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Data availability
Data related to this manuscript will be available upon reasonable request to the corresponding author.
Abbreviations
- AIC:
-
Akaike information criterion
- ANOVA:
-
Analysis of variance
- AD:
-
Alzheimer’s disease
- AD8:
-
Eight-item informant interview to differentiate aging and dementia
- ADRD:
-
Alzheimer’s disease and related dementias
- CVCi:
-
Cerebrovascular conductance index
- dBP:
-
Diastolic blood pressure
- DSM-V:
-
Diagnostic and statistical manual of mental disorders fifth edition
- HDL-C:
-
High-density lipoprotein
- LDL- C:
-
Low-density lipoprotein
- MAP:
-
Mean arterial pressure
- MCAv:
-
Middle cerebral artery blood flow velocity
- MMSE:
-
Mini-mental state exam
- PI:
-
Pulsatility index
- sBP:
-
Systolic blood pressure
- TCD:
-
Transcranial Doppler ultrasound
References
Amin-Hanjani S, Stagliano NE, Yamada M, Huang PL, Liao JK, Moskowitz MA (2001) Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke 32(4):980–986. https://doi.org/10.1161/01.str.32.4.980
Arvanitakis Z, Capuano AW, Leurgans SE, Bennett DA, Schneider JA (2016) Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol 15(9):934–943. https://doi.org/10.1016/s1474-4422(16)30029-1
Bandyopadhyay S, Bayer AJ, O’Mahony MS (2001) Age and gender bias in statin trials. QJM 94(3):127–132. https://doi.org/10.1093/qjmed/94.3.127
Beach TG, Wilson JR, Sue LI, Newell A, Poston M, Cisneros R, Pandya Y, Esh C, Connor DJ, Sabbagh M, Walker DG, Roher AE (2007) Circle of Willis atherosclerosis: association with Alzheimer’s disease, neuritic plaques and neurofibrillary tangles. Acta Neuropathol 113(1):13–21. https://doi.org/10.1007/s00401-006-0136-y
Carlsson CM, Xu G, Wen Z, Barnet JH, Blazel HM, Chappell RJ, Stein JH, Asthana S, Sager MA, Alsop DC, Rowley HA, Fain SB, Johnson SC (2012) Effects of atorvastatin on cerebral blood flow in middle-aged adults at risk for Alzheimer’s disease: a pilot study. Curr Alzheimer Res 9(8):990–997. https://doi.org/10.2174/156720512803251075
Claassen JA (2015) New cardiovascular targets to prevent late onset Alzheimer disease. Eur J Pharmacol 763(Pt A):131–134. https://doi.org/10.1016/j.ejphar.2015.05.022
Cordonnier C, Sprigg N, Sandset EC, Pavlovic A, Sunnerhagen KS, Caso V, Christensen H (2017) Stroke in women - from evidence to inequalities. Nat Rev Neurol 13(9):521–532. https://doi.org/10.1038/nrneurol.2017.95
Crum RM, Anthony JC, Bassett SS, Folstein MF (1993) Population-based norms for the mini-mental state examination by age and educational level. JAMA 269(18):2386–2391
Cupples LA, Farrer LA, Sadovnick AD, Relkin N, Whitehouse P, Green RC (2004) Estimating risk curves for first-degree relatives of patients with Alzheimer’s disease: the REVEAL study. Genet Med 6(4):192–196. https://doi.org/10.1097/01.gim.0000132679.92238.58
Dietschy JM, Turley SD (2004) Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 45(8):1375–1397. https://doi.org/10.1194/jlr.R400004-JLR200
El Fakhri G, Kijewski MF, Johnson KA, Syrkin G, Killiany RJ, Becker JA, Zimmerman RE, Albert MS (2003) MRI-guided SPECT perfusion measures and volumetric MRI in prodromal Alzheimer disease. Arch Neurol 60(8):1066–1072. https://doi.org/10.1001/archneur.60.8.1066
Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK (1998) Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 95(15):8880–8885. https://doi.org/10.1073/pnas.95.15.8880
Ferretti MT, Iulita MF, Cavedo E, Chiesa PA, Schumacher Dimech A, Santuccione Chadha A, Baracchi F, Girouard H, Misoch S, Giacobini E, Depypere H, Hampel H (2018) Sex differences in Alzheimer disease - the gateway to precision medicine. Nat Rev Neurol 14(8):457–469. https://doi.org/10.1038/s41582-018-0032-9
Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB Sr, Gibbons R, Greenland P, Lackland DT, Levy D, O’Donnell CJ, Robinson J, Schwartz JS, Shero ST, Smith SC Jr, Sorlie P, Stone NJ, Wilson PW (2013) 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American college of cardiology/American heart association task force on practice guidelines. Circulation. https://doi.org/10.1161/01.cir.0000437741.48606.98
Gosling RG, King DH (1974) Arterial assessment by Doppler-shift ultrasound. Proc R Soc Med 67(6 Pt 1):447–449
Honea RA, Vidoni ED, Swerdlow RH, Burns JM (2012) Maternal family history is associated with Alzheimer’s disease biomarkers. J Alzheimers Dis 31(3):659–668. https://doi.org/10.3233/jad-2012-120676
Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5(5):347–360. https://doi.org/10.1038/nrn1387
Iadecola C (2010) The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol 120(3):287–296. https://doi.org/10.1007/s00401-010-0718-6
James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E (2014) 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth joint national committee (JNC 8). JAMA 311(5):507–520. https://doi.org/10.1001/jama.2013.284427
Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA (2000) Statins and the risk of dementia. Lancet 356(9242):1627–1631. https://doi.org/10.1016/s0140-6736(00)03155-x
Johnson NA, Jahng GH, Weiner MW, Miller BL, Chui HC, Jagust WJ, Gorno-Tempini ML, Schuff N (2005) Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology 234(3):851–859. https://doi.org/10.1148/radiol.2343040197
Kivipelto M, Solomon A (2006) Cholesterol as a risk factor for Alzheimer’s disease - epidemiological evidence. Acta Neurol Scand Suppl 185:50–57. https://doi.org/10.1111/j.1600-0404.2006.00685.x
Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A (2001) Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ 322(7300):1447–1451. https://doi.org/10.1136/bmj.322.7300.1447
Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J, Nissinen A, Soininen H (2002) Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med 137(3):149–155. https://doi.org/10.7326/0003-4819-137-3-200208060-00006
Kling MA, Trojanowski JQ, Wolk DA, Lee VM, Arnold SE (2013) Vascular disease and dementias: paradigm shifts to drive research in new directions. Alzheimers Dement 9(1):76–92. https://doi.org/10.1016/j.jalz.2012.02.007
Lahera V, Goicoechea M, de Vinuesa SG, Miana M, de las Heras N, Cachofeiro V, Luño J (2007) Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins. Curr Med Chem 14(2):243–248. https://doi.org/10.2174/092986707779313381
Laws KR, Irvine K, Gale TM (2016) Sex differences in cognitive impairment in Alzheimer’s disease. World J Psychiatry 6(1):54–65. https://doi.org/10.5498/wjp.v6.i1.54
Li J, Li JJ, He JG, Nan JL, Guo YL, Xiong CM (2010) Atorvastatin decreases C-reactive protein-induced inflammatory response in pulmonary artery smooth muscle cells by inhibiting nuclear factor-kappaB pathway. Cardiovasc Ther 28(1):8–14. https://doi.org/10.1111/j.1755-5922.2009.00103.x
Liao JK (2005) Clinical implications for statin pleiotropy. Curr Opin Lipidol 16(6):624–629. https://doi.org/10.1097/01.mol.0000191913.16321.60
Liao JK, Laufs U (2005) Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45:89–118. https://doi.org/10.1146/annurev.pharmtox.45.120403.095748
Mansi IA, Chansard M, Lingvay I, Zhang S, Halm EA, Alvarez CA (2021) Association of statin therapy initiation with diabetes progression: a retrospective matched-cohort study. JAMA Intern Med 181(12):1562–1574. https://doi.org/10.1001/jamainternmed.2021.5714
McConnachie A, Walker A, Robertson M, Marchbank L, Peacock J, Packard CJ, Cobbe SM, Ford I (2014) Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study. Eur Heart J 35(5):290–298. https://doi.org/10.1093/eurheartj/eht232
Miller BF, Thyfault JP (2020) Exercise-pharmacology interactions: metformin, statins, and healthspan. Physiology (Bethesda) 35(5):338–347. https://doi.org/10.1152/physiol.00013.2020
Mistry H, Morris S, Dyer M, Kotseva K, Wood D, Buxton M (2012) Cost-effectiveness of a European preventive cardiology programme in primary care: a Markov modelling approach. BMJ Open. https://doi.org/10.1136/bmjopen-2012-001029
Pfrieger FW (2003) Cholesterol homeostasis and function in neurons of the central nervous system. Cell Mol Life Sci 60(6):1158–1171. https://doi.org/10.1007/s00018-003-3018-7
Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJ, de Lemos JA, Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N, Ray KK (2011) Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 305(24):2556–2564. https://doi.org/10.1001/jama.2011.860
Ruigrok AN, Salimi-Khorshidi G, Lai MC, Baron-Cohen S, Lombardo MV, Tait RJ, Suckling J (2014) A meta-analysis of sex differences in human brain structure. Neurosci Biobehav Rev 39(100):34–50. https://doi.org/10.1016/j.neubiorev.2013.12.004
Ruitenberg A, den Heijer T, Bakker SL, van Swieten JC, Koudstaal PJ, Hofman A, Breteler MM (2005) Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam study. Ann Neurol 57(6):789–794. https://doi.org/10.1002/ana.20493
Scarmeas N, Habeck CG, Stern Y, Anderson KE (2003) APOE genotype and cerebral blood flow in healthy young individuals. JAMA 290(12):1581–1582. https://doi.org/10.1001/jama.290.12.1581
Serrador JM, Picot PA, Rutt BK, Shoemaker JK, Bondar RL (2000) MRI measures of middle cerebral artery diameter in conscious humans during simulated orthostasis. Stroke 31(7):1672–1678. https://doi.org/10.1161/01.str.31.7.1672
Szabo-Reed AN, Vidoni E, Binder EF, Burns J, Cullum CM, Gahan WP, Gupta A, Hynan LS, Kerwin DR, Rossetti H, Stowe AM, Vongpatanasin W, Zhu DC, Zhang R, Keller JN (2019) Rationale and methods for a multicenter clinical trial assessing exercise and intensive vascular risk reduction in preventing dementia (rrAD Study). Contemp Clin Trials 79:44–54. https://doi.org/10.1016/j.cct.2019.02.007
Verbree J, Bronzwaer A, van Buchem MA, Daemen M, van Lieshout JJ, van Osch M (2017) Middle cerebral artery diameter changes during rhythmic handgrip exercise in humans. J Cereb Blood Flow Metab 37(8):2921–2927. https://doi.org/10.1177/0271678x16679419
Wang CY, Liu PY, Liao JK (2008) Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol Med 14(1):37–44. https://doi.org/10.1016/j.molmed.2007.11.004
Wang L, Roe CM, Snyder AZ, Brier MR, Thomas JB, Xiong C, Benzinger TL, Morris JC, Ances BM (2012) Alzheimer disease family history impacts resting state functional connectivity. Ann Neurol 72(4):571–577. https://doi.org/10.1002/ana.23643
Wiesmann M, Kiliaan AJ, Claassen JA (2013) Vascular aspects of cognitive impairment and dementia. J Cereb Blood Flow Metab 33(11):1696–1706. https://doi.org/10.1038/jcbfm.2013.159
Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 57(10):1439–1443. https://doi.org/10.1001/archneur.57.10.1439
Yamada M, Huang Z, Dalkara T, Endres M, Laufs U, Waeber C, Huang PL, Liao JK, Moskowitz MA (2000) Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by L-arginine after chronic statin treatment. J Cereb Blood Flow Metab 20(4):709–717. https://doi.org/10.1097/00004647-200004000-00008
Yarchoan M, Xie SX, Kling MA, Toledo JB, Wolk DA, Lee EB, Van Deerlin V, Lee VM, Trojanowski JQ, Arnold SE (2012) Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias. Brain 135(Pt 12):3749–3756. https://doi.org/10.1093/brain/aws271
Zhang R, Vongpatanasin W, Levine BD (2015) Faster brain shrinkage in the ACCORD MIND study: an unexpected result? JAMA Intern Med 175(1):144. https://doi.org/10.1001/jamainternmed.2014.6971
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The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this work has been supported under the Clinical and Translational Science Award (CTSA) grant from the National Center for Advancing Translational Sciences (NCATS) awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# TL1TR002368) and National Institute of Health (NIH) grants R01AG049749, R01AR071263, and P30AG072973. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCATS.
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SEA and TT: conducted experiments. RZ, EDV, JMB, and SAB: oversaw experiments. SEA and RNM: analyzed the data. SEA and SAB: conceived of the manuscript. SEA: wrote the manuscript. All authors read and approved the final draft of the manuscript.
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The protocol was reviewed and approved by the individual site’s respective institutional review boards (IRB number STUDY00004510 at the KU Medical Center and STU052016-076 at the UT Southwestern Medical Center).
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Communicated by I. Mark Olfert.
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Aaron, S.E., Tomoto, T., Zhang, R. et al. Statin contribution to middle cerebral artery blood flow velocity in older adults at risk for dementia. Eur J Appl Physiol 122, 2417–2426 (2022). https://doi.org/10.1007/s00421-022-05022-1
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DOI: https://doi.org/10.1007/s00421-022-05022-1