Biomarkers and perfusion--training-induced changes after stroke (BAPTISe): protocol of an observational study accompanying a randomized controlled trial

Alexander H Nave, Jan M Kröber, Peter Brunecker, Jochen B Fiebach, Jonathan List, Ulrike Grittner, Matthias Endres, Andreas Meisel, Agnes Flöel, Martin Ebinger, Alexander H Nave, Jan M Kröber, Peter Brunecker, Jochen B Fiebach, Jonathan List, Ulrike Grittner, Matthias Endres, Andreas Meisel, Agnes Flöel, Martin Ebinger

Abstract

Background: Physical activity is believed to exert a beneficial effect on functional and cognitive rehabilitation of patients with stroke. Although studies have addressed the impact of physical exercise in cerebrovascular prevention and rehabilitation, the underlying mechanisms leading to improvement are poorly understood. Training-induced increase of cerebral perfusion is a possible mediating mechanism. Our exploratory study aims to investigate training-induced changes in blood biomarker levels and magnetic resonance imaging in patients with subacute ischemic stroke.

Methods/design: This biomarker-driven study uses an observational design to examine a subgroup of patients in the randomized, controlled PHYS-STROKE trial. In PHYS-STROKE, 215 patients with subacute stroke (hemorrhagic and ischemic) receive either 4 weeks of physical training (aerobic training, 5 times a week, for 50 minutes) or 4 weeks of relaxation sessions (5 times a week, for 50 minutes). A convenience sample of 100 of these patients with ischemic stroke will be included in BAPTISe and will receive magnetic resonance imaging (MRI) scans and an additional blood draw before and after the PHYS-STROKE intervention. Imaging scans will address parameters of cerebral perfusion, vessel size imaging, and microvessel density (the Q factor) to estimate the degree of neovascularization in the brain. Blood tests will determine several parameters of immunity, inflammation, endothelial function, and lipometabolism. Primary objective of this study is to evaluate differential changes in MRI and blood-derived biomarkers between groups. Other endpoints are next cerebrovascular events and functional status of the patient after the intervention and after 3 months assessed by functional scores, in particular walking speed and Barthel index (co-primary endpoints of PHYS-STROKE). Additionally, we will assess the association between functional outcomes and biomarkers including imaging results. For all endpoints we will compare changes between patients who received physical fitness training and patients who had relaxation sessions.

Discussion: This exploratory study will be the first to investigate the effects of physical fitness training in patients with ischemic stroke on MRI-based cerebral perfusion, pertinent blood biomarker levels, and functional outcome. The study may have an impact on current patient rehabilitation strategies and reveal important information about the roles of MRI and blood-derived biomarkers in ischemic stroke.

Trial registration: NCT01954797.

Figures

Figure 1
Figure 1
Flow chart of the BAPTISe trial.

References

    1. Lakka TA, Venäläinen JM, Rauramaa R, Salonen R, Tuomilehto J, Salonen JT. Relation of leisure-time physical activity and cardiorespiratory fitness to the risk of acute myocardial infarction. N Engl J Med. 1994;330:1549–1554. doi: 10.1056/NEJM199406023302201.
    1. Blair SN, Kohl HW, Barlow CE, Paffenbarger RS, Gibbons LW, Macera C. Changes in physical fitness and all-cause mortality. A prospective study of healthy and unhealthy men. JAMA. 1995;273:1093–1098. doi: 10.1001/jama.1995.03520380029031.
    1. Physical Activity and Cardiovascular Health. NIH Consensus Development Panel on Physical Activity and Cardiovascular Health. JAMA. 1996;276:241.
    1. Schmidt W, Endres M, Dimeo F, Jungehulsing GJ. Train the vessel, gain the brain: physical activity and vessel function and the impact on stroke prevention and outcome in cerebrovascular disease. Cerebrovasc Dis. 2013;35:303–312. doi: 10.1159/000347061.
    1. Defina LF, Willis BL, Radford NB, Gao A, Leonard D, Haskell WL, Weiner MF, Berry JD. The association between midlife cardiorespiratory fitness levels and later-life dementia: a cohort study. Ann Intern Med. 2013;158:162–168. doi: 10.7326/0003-4819-158-3-201302050-00005.
    1. Flöel A, Ruscheweyh R, Krüger K, Willemer C, Winter B, Völker K, Lohmann H, Zitzmann M, Mooren F, Breitenstein C, Knecht S. Physical activity and memory functions: are neurotrophins and cerebral gray matter volume the missing link? Neuroimage. 2010;49:2756–2763. doi: 10.1016/j.neuroimage.2009.10.043.
    1. Ruscheweyh R, Willemer C, Krüger K, Duning T, Warnecke T, Sommer J, Völker K, Ho HV, Mooren F, Knecht S, Flöel A. Physical activity and memory functions: an interventional study. Neurobiol Aging. 2011;32:1304–1319. doi: 10.1016/j.neurobiolaging.2009.08.001.
    1. Pinter MM, Brainin M. Rehabilitation after stroke in older people. Maturitas. 2012;71:104–108. doi: 10.1016/j.maturitas.2011.11.011.
    1. Gordon CD, Wilks R, McCaw-Binns A. Effect of Aerobic Exercise (Walking) Training on Functional Status and Health-related Quality of Life in Chronic Stroke Survivors: A Randomized Controlled Trial. Stroke. 2013;4:1179–1181.
    1. Rogers RL, Meyer JS, Mortel KF, Mahurin RK, Thornby J. Age-related reductions in cerebral vasomotor reactivity and the law of initial value: a 4-year prospective longitudinal study. J Cereb Blood Flow Metab. 1985;5:79–85. doi: 10.1038/jcbfm.1985.11.
    1. Bakker SL, De Leeuw FE, De Groot JC, Hofman A, Koudstaal PJ, Breteler MM. Cerebral vasomotor reactivity and cerebral white matter lesions in the elderly. Neurology. 1999;52:578–583. doi: 10.1212/WNL.52.3.578.
    1. Silvestrini M, Vernieri F, Pasqualetti P, Matteis M, Passarelli F, Troisi E, Caltagirone C. Impaired cerebral vasoreactivity and risk of stroke in patients with asymptomatic carotid artery stenosis. JAMA. 2000;283:2122–2127. doi: 10.1001/jama.283.16.2122.
    1. Matteis M, Troisi E, Monaldo BC, Caltagirone C, Silvestrini M. Age and Sex Differences in Cerebral Hemodynamics : A Transcranial Doppler Study. Stroke. 1998;29:963–967. doi: 10.1161/01.STR.29.5.963.
    1. Ainslie PN, Cotter JD, George KP, Lucas S, Murrell C, Shave R, Thomas KN, Williams MJA, Atkinson G. Elevation in cerebral blood flow velocity with aerobic fitness throughout healthy human ageing. J Physiol. 2008;586:4005–4010. doi: 10.1113/jphysiol.2008.158279.
    1. Bailey DM, Marley CJ, Brugniaux JV, Hodson D, New KJ, Ogoh S, Ainslie PN. Elevated Aerobic Fitness Sustained Throughout the Adult Lifespan Is Associated With Improved Cerebral Hemodynamics. Stroke. 2013;11:3235–3238.
    1. Davenport MH, Hogan DB, Eskes GA, Longman RS, Poulin MJ. Cerebrovascular reserve: the link between fitness and cognitive function? Exerc Sport Sci Rev. 2012;40:153–158.
    1. Ivey FM, Ryan AS, Hafer-Macko CE, Macko RF. Improved cerebral vasomotor reactivity after exercise training in hemiparetic stroke survivors. Stroke. 2011;42:1994–2000. doi: 10.1161/STROKEAHA.110.607879.
    1. Seevinck PR, Deddens LH, Dijkhuizen RM. Magnetic resonance imaging of brain angiogenesis after stroke. Angiogenesis. 2010;13:101–111. doi: 10.1007/s10456-010-9174-0.
    1. Jensen JH, Chandra R. MR imaging of microvasculature. Magn Reson Med. 2000;44:224–230. doi: 10.1002/1522-2594(200008)44:2<224::AID-MRM9>;2-M.
    1. Gertz K, Priller J, Kronenberg G, Fink KB, Winter B, Schröck H, Ji S, Milosevic M, Harms C, Böhm M, Dirnagl U, Laufs U, Endres M. Physical activity improves long-term stroke outcome via endothelial nitric oxide synthase-dependent augmentation of neovascularization and cerebral blood flow. Circ Res. 2006;99:1132–1140. doi: 10.1161/01.RES.0000250175.14861.77.
    1. Endres M, Gertz K, Lindauer U, Katchanov J, Schultze J, Schröck H, Nickenig G, Kuschinsky W, Dirnagl U, Laufs U. Mechanisms of stroke protection by physical activity. Ann Neurol. 2003;54:582–590. doi: 10.1002/ana.10722.
    1. Swain RA, Harris AB, Wiener EC, Dutka MV, Morris HD, Theien BE, Konda S, Engberg K, Lauterbur PC, Greenough WT. Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience. 2003;117:1037–1046. doi: 10.1016/S0306-4522(02)00664-4.
    1. Endres M, Piriz J, Gertz K, Harms C, Meisel A, Kronenberg G, Torres-Aleman I. Serum insulin-like growth factor I and ischemic brain injury. Brain Res. 2007;1185:328–335.
    1. Gertz K, Kronenberg G, Kälin RE, Baldinger T, Werner C, Balkaya M, Eom GD, Hellmann-Regen J, Kröber J, Miller KR, Lindauer U, Laufs U, Dirnagl U, Heppner FL, Endres M. Essential role of interleukin-6 in post-stroke angiogenesis. Brain. 2012;135(Pt 6):1964–1980.
    1. Whiteley W, Wardlaw J, Dennis M, Lowe G, Rumley A, Sattar N, Welsh P, Green A, Andrews M, Sandercock P. The use of blood biomarkers to predict poor outcome after acute transient ischemic attack or ischemic stroke. Stroke. 2012;43:86–91. doi: 10.1161/STROKEAHA.111.634089.
    1. De Smedt A, Brouns R, Uyttenboogaart M, De Raedt S, Moens M, Wilczak N, Luijckx G-J, De Keyser J. Insulin-like growth factor I serum levels influence ischemic stroke outcome. Stroke. 2011;42:2180–2185. doi: 10.1161/STROKEAHA.110.600783.
    1. Meisel A, Meisel C, Harms H, Hartmann O, Ulm L. Predicting post-stroke infections and outcome with blood-based immune and stress markers. Cerebrovasc Dis. 2012;33:580–588. doi: 10.1159/000338080.
    1. Xu C, Schmidt WUH, Villringer K, Brunecker P, Kiselev V, Gall P, Fiebach JB. Vessel size imaging reveals pathological changes of microvessel density and size in acute ischemia. J Cereb Blood Flow Metab. 2011;31:1687–1695. doi: 10.1038/jcbfm.2011.38.
    1. Kaplan RC, McGinn AP, Pollak MN, Kuller LH, Strickler HD, Rohan TE, Cappola AR, Xue X, Psaty BM. Association of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke. J Clin Endocrinol Metab. 2007;92:1319–1325. doi: 10.1210/jc.2006-1631.
    1. Di Napoli M, Papa F, Bocola V. Prognostic Influence of Increased C-Reactive Protein and Fibrinogen Levels in Ischemic Stroke. Stroke. 2001;32:133–138. doi: 10.1161/01.STR.32.1.133.
    1. Kernagis DN, Laskowitz DT. Evolving role of biomarkers in acute cerebrovascular disease. Ann Neurol. 2012;71:289–303. doi: 10.1002/ana.22553.
    1. Whiteley W, Tian Y, Jickling GC. Blood biomarkers in stroke: research and clinical practice. Int J Stroke. 2012;7:435–439. doi: 10.1111/j.1747-4949.2012.00784.x.
    1. Xu C, Schmidt WUH, Galinovic I, Villringer K, Hotter B, Ostwaldt A-C, Denisova N, Kellner E, Kiselev V, Fiebach JB. The potential of microvessel density in prediction of infarct growth: a two-month experimental study in vessel size imaging. Cerebrovasc Dis. 2012;33:303–309. doi: 10.1159/000335302.
    1. Bosomtwi A, Jiang Q, Ding GL, Zhang L, Zhang ZG, Lu M, Ewing JR, Chopp M. Quantitative evaluation of microvascular density after stroke in rats using MRI. J Cereb Blood Flow Metab. 2008;28:1978–1987. doi: 10.1038/jcbfm.2008.85.

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