Plasma Matrix Metalloproteinases in Patients With Stroke During Intensive Rehabilitation Therapy


      • Matrix metalloproteinases are enzymes that participate in both injury and tissue repair after stroke.
      • The use of biomarkers could help to adjust individual rehabilitation programs.
      • Plasma matrix metalloproteinase-12 and matrix metalloproteinase-13 are associated with stroke severity and poor outcomes.
      • High levels of plasma matrix metalloproteinase-3 are found in patients with improved motor recovery.



      To study plasma levels of matrix metalloproteinases (MMPs) as potential markers of recovery during intensive rehabilitation therapy (IRT) after stroke.


      Prospective and descriptive 3-month follow-up study.


      Rehabilitation unit and research center.


      Patients with first-ever ischemic stroke (n=15) enrolled to IRT (≥3h/d and 5d/wk) and healthy volunteers (n=15) (N=30).


      Not applicable.

      Main Outcome Measures

      The primary outcome was to measure plasma MMP3, MMP12, and MMP13 levels and evaluate potential associations with motor/functional scales using a battery of tests (National Institutes of Health Stroke Scale, modified Rankin scale, Barthel Index, Fugl-Meyer Assessment, Functional Ambulation Categories, Medical Research Council scale, Chedoke Arm and Hand Activity Inventory, and the 10-m walk test) before IRT and at 1- and 3-month follow-ups. The secondary outcome was to evaluate the use of these MMPs as biomarkers as predictors of patient's outcome.


      MMP levels remained stable during the study period and were similar to those in the healthy volunteer group. However, baseline MMP12 and MMP13 levels were strongly associated with stroke severity and were found to be elevated in those patients with the poorest outcomes. Interestingly, plasma MMP3 was independent of baseline stroke characteristics but was found to be increased in patients with better motor/functional recovery and in patients with larger improvements during rehabilitation.


      MMPs might act as biologic markers of recovery during rehabilitation therapy related to their roles in both injury and tissue remodeling. Future confirmatory investigations in multicenter studies are warranted by our data.


      List of abbreviations:

      BI (Barthel Index), FAC (Functional Ambulation Categories), FMA (Fugl-Meyer Assessment), IRT (intensive rehabilitation therapy), MMP (matrix metalloproteinase), MRC (Medical Research Council), NIHSS (National Institutes of Health Stroke Scale)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Archives of Physical Medicine and Rehabilitation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Grossman A.W.
        • Broderick J.P.
        Advances and challenges in treatment and prevention of ischemic stroke.
        Ann Neurol. 2013; 74: 363-372
        • Bori I.
        • Martínez C.
        Conceptos fundamentales en rehabilitación en el ictus:¿dónde, cómo, quién, cuándo y cuánta? [Spanish.] Neuroreparación y Rehabilitación tras el ictus.
        Editorial Marge, Barcelona2010
        • Langhorne P.
        • Bernhardt J.
        • Kwakkel G.
        Stroke rehabilitation.
        Lancet. 2011; 377: 1693-1702
      1. Catalan Public Healthcare System. Clinical practice guideline for the management of stroke. Catalan Agency for Health Information, Assessment and Quality, Department of Health of Catalonia, 2007
      2. Canadian Heart and Stroke Foundation. Best practice guidelines for stroke rehabilitation management. Heart and Stroke Foundation of Ontario, 2003
        • Musicco M.
        • Emberti L.
        • Nappi G.
        • Caltagirone C.
        • Italian Multicenter Study on Outcomes of Rehabilitation of Neurological Patients
        Early and long-term outcome of rehabilitation in stroke patients: the role of patient characteristics, time of initiation, and duration of interventions.
        Arch Phys Med Rehabil. 2003; 84: 551-558
        • Kwakkel G.
        • van Peppen R.
        • Wagenaar R.C.
        • et al.
        Effects of augmented exercise therapy time after stroke: a meta-analysis.
        Stroke. 2004; 35: 2529-2539
        • Feys H.
        • De Weerdt W.
        • Verbeke G.
        • et al.
        Early and repetitive stimulation of the arm can substantially improve the long term outcome after stroke: a 5-year follow-up study of a randomized trial.
        Stroke. 2004; 35: 924-929
        • Langhorne P.
        • Pollock A.
        • Stroke Unit Trialists' Collaboration
        What are the components of effective stroke unit care?.
        Age Ageing. 2002; 31: 365-371
        • Teasell R.
        • Rice D.
        • Richardson M.
        • et al.
        The next revolution in stroke care.
        Expert Rev Neurother. 2014; 14: 1307-1314
        • Pekna M.
        • Pekny M.
        • Nilsson M.
        Modulation of neural plasticity as a basis for stroke rehabilitation.
        Stroke. 2012; 43: 2819-2828
        • Brewer L.
        • Horgan F.
        • Hickey A.
        • Williams D.
        Stroke rehabilitation: recent advances and future therapies.
        QJM. 2013; 106: 11-25
        • Rosell A.
        • Lo E.H.
        Multiphasic roles for matrix metalloproteinases after stroke.
        Curr Opin Pharmacol. 2008; 8: 82-89
        • Verslegers M.
        • Lemmens K.
        • Van Hove I.
        • Moons L.
        Matrix metalloproteinase-2 and -9 as promising benefactors in development, plasticity and repair of the nervous system.
        Prog Neurobiol. 2013; 105: 60-78
        • Cuadrado E.
        • Rosell A.
        • Borrell-Pagès M.
        • et al.
        Matrix metalloproteinase-13 is activated and is found in the nucleus of neural cells after cerebral ischemia.
        J Cereb Blood Flow Metab. 2009; 29: 398-410
        • Nagel S.
        • Sandy J.D.
        • Meyding-Lamade U.
        • Schwark C.
        • Bartsch J.W.
        • Wagner S.
        Focal cerebral ischemia induces changes in both MMP-13 and aggrecan around individual neurons.
        Brain Res. 2005; 1056: 43-50
        • Wells J.E.
        • Biernaskie J.
        • Szymanska A.
        • Larsen P.H.
        • Yong V.W.
        • Corbett D.
        Matrix metalloproteinase (MMP)-12 expression has a negative impact on sensorimotor function following intracerebral haemorrhage in mice.
        Eur J Neurosci. 2005; 21: 187-196
        • Solé S.
        • Petegnief V.
        • Gorina R.
        • Chamorro A.
        • Planas A.M.
        Activation of matrix metalloproteinase-3 and agrin cleavage in cerebral ischemia/reperfusion.
        J Neuropathol Exp Neurol. 2004; 63: 338-349
        • Riba-Llena I.
        • Jarca C.I.
        • Mundet X.
        • et al.
        Investigating silent strokes in hypertensives: a magnetic resonance imaging study (ISSYS): rationale and protocol design.
        BMC Neurol. 2013; 13: 130
        • Granger C.V.
        • Dewis L.S.
        • Peters N.C.
        • Sherwood C.C.
        • Barrett J.E.
        Stroke rehabilitation: analysis of repeated Barthel index measures.
        Arch Phys Med Rehabil. 1979; 60: 14-17
        • Barreca S.
        • Gowland C.K.
        • Stratford P.
        • et al.
        Development of the Chedoke Arm and Hand Activity Inventory: theoretical constructs, item generation, and selection.
        Top Stroke Rehabil. 2004; 11: 31-42
        • Arya K.N.
        • Verma R.
        • Garg R.K.
        Estimating the minimal clinically important difference of an upper extremity recovery measure in subacute stroke patients.
        Top Stroke Rehabil. 2011; 18: 599-610
        • Barreca S.R.
        • Stratford P.W.
        • Lambert C.L.
        • Masters L.M.
        • Streiner D.L.
        Test-retest reliability, validity, and sensitivity of the Chedoke arm and hand activity inventory: a new measure of upper-limb function for survivors of stroke.
        Arch Phys Med Rehabil. 2005; 86: 1616-1622
        • Fulk G.D.
        • Echternach J.L.
        Test-retest reliability and minimal detectable change of gait speed in individuals undergoing rehabilitation after stroke.
        J Neurol Phys Ther. 2008; 32: 8-13
        • Mehrholz J.
        • Wagner K.
        • Rutte K.
        • Meißner D.
        • Pohl M.
        Predictive validity and responsiveness of the functional ambulation category in hemiparetic patients after stroke.
        Arch Phys Med Rehabil. 2007; 88: 1314-1319
        • Hochberg Y.
        • Benjamini Y.
        More powerful procedures for multiple significance testing.
        Stat Med. 1990; 9: 811-818
        • Stroke Unit Trialists’ Collaboration
        Organised inpatient (stroke unit) care for stroke.
        Cochrane Database Syst Rev. 2007; : CD000197
        • Berkhemer O.A.
        • Fransen P.S.
        • Beumer D.
        • et al.
        A randomized trial of intraarterial treatment for acute ischemic stroke.
        N Engl J Med. 2015; 372: 11-20
        • Jovin T.G.
        • Chamorro A.
        • Cobo E.
        • et al.
        Thrombectomy within 8 hours after symptom onset in ischemic stroke.
        N Engl J Med. 2015; 372: 2296-2306
        • Teasell R.W.
        • Foley N.C.
        • Salter K.L.
        • Jutai J.W.
        A blueprint for transforming stroke rehabilitation care in Canada: the case for change.
        Arch Phys Med Rehabil. 2008; 89: 575-578
        • Lee K.B.
        • Lim S.H.
        • Kim K.H.
        • et al.
        Six-month functional recovery of stroke patients: a multi-time-point study.
        Int J Rehabil Res. 2015; 38: 173-180
        • Lohse K.R.
        • Lang C.E.
        • Boyd L.A.
        Is more better? Using metadata to explore dose-response relationships in stroke rehabilitation.
        Stroke. 2014; 45: 2053-2058
        • Veerbeek J.M.
        • van Wegen E.
        • van Peppen R.
        • et al.
        What is the evidence for physical therapy poststroke? A systematic review and meta-analysis.
        PLoS One. 2014; 9: e87987
        • Nagase H.
        • Visse R.
        • Murphy G.
        Structure and function of matrix metalloproteinases and TIMPs.
        Cardiovasc Res. 2006; 69: 562-573
        • Van Hove I.
        • Lemmens K.
        • Van de Velde S.
        • Verslegers M.
        • Moons L.
        Matrix metalloproteinase-3 in the central nervous system: a look on the bright side.
        J Neurochem. 2012; 123: 203-216
        • Rosenberg G.A.
        Matrix metalloproteinases and their multiple roles in neurodegenerative diseases.
        Lancet Neurol. 2009; 8: 205-216
        • Cuadrado E.
        • Rosell A.
        • Penalba A.
        • et al.
        Vascular MMP-9/TIMP-2 and neuronal MMP-10 up-regulation in human brain after stroke: a combined laser microdissection and protein array study.
        J Proteome Res. 2009; 8: 3191-3197
        • Rosell A.
        • Alvarez-Sabín J.
        • Arenillas J.F.
        • et al.
        A matrix metalloproteinase protein array reveals a strong relation between MMP-9 and MMP-13 with diffusion-weighted image lesion increase in human stroke.
        Stroke. 2005; 36: 1415-1420
        • Ueno M.
        • Wu B.
        • Nishiyama A.
        • et al.
        The expression of matrix metalloproteinase-13 is increased in vessels with blood-brain barrier impairment in a stroke-prone hypertensive model.
        Hypertens Res. 2009; 32: 332-338
        • Chelluboina B.
        • Warhekar A.
        • Dillard M.
        • et al.
        Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage.
        Sci Rep. 2015; 5: 9504
        • Nakayama H.
        • Jørgensen H.S.
        • Raaschou H.O.
        • Olsen T.S.
        The influence of age on stroke outcome. The Copenhagen Stroke Study.
        Stroke. 1994; 25: 808-813
        • Bagg S.
        • Pombo A.P.
        • Hopman W.
        Effect of age on functional outcomes after stroke rehabilitation.
        Stroke. 2002; 33: 179-185
        • Van Hove I.
        • Verslegers M.
        • Buyens T.
        • et al.
        An aberrant cerebellar development in mice lacking matrix metalloproteinase-3.
        Mol Neurobiol. 2012; 45: 17-29
        • Suzuki Y.
        • Nagai N.
        • Umemura K.
        • Collen D.
        • Lijnen H.R.
        Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice.
        J Thromb Haemost. 2007; 5: 1732-1739
        • Yang Y.
        • Thompson J.F.
        • Taheri S.
        • et al.
        Early inhibition of MMP activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery.
        J Cereb Blood Flow Metab. 2013; 33: 1104-1114
        • Cucchiara B.
        • Montaner J.
        Blood biomarkers for predicting outcome after stroke: reading the tea leaves.
        Neurology. 2013; 80: 1270-1271
        • Hasan N.
        • McColgan P.
        • Bentley P.
        • Edwards R.J.
        • Sharma P.
        Towards the identification of blood biomarkers for acute stroke in humans: a comprehensive systematic review.
        Br J Clin Pharmacol. 2012; 74: 230-240
        • Blicher J.U.
        • Near J.
        • Næss-Schmidt E.
        • et al.
        GABA levels are decreased after stroke and GABA changes during rehabilitation correlate with motor improvement.
        Neurorehabil Neural Repair. 2015; 29: 278-286
        • Hsieh Y.W.
        • Lin K.C.
        • Korivi M.
        • Lee T.H.
        • Wu C.Y.
        • Wu K.Y.
        The reliability and predictive ability of a biomarker of oxidative DNA damage on functional outcomes after stroke rehabilitation.
        Int J Mol Sci. 2014; 15: 6504-6516