Top
×
Neuroimmunol Neuroinflammation 2014;1:13-4.10.4103/2347-8659.135569
Open AccessResearch Highlight

Differences in stroke damage in aged mice may not be due to differential cerebral blood flow dynamics

1Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA.

2Department of Neurology, University of Connecticut Health Center, Farmington, CT 06030, USA.

3The Stroke Center at Hartford Hospital, Hartford, CT 06102, USA.

Correspondence Address: Dr. Louise D. McCullough, Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA. E-mail: lmccullough@uchc.edu

    ...

    This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License (http://creativecommons.org/licenses/by-nc-sa/3.0/), which allows others to remix, tweak and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

    Introduction

    Stroke is the leading cause of death and adult disability.[1-3] Aging is the most important nonmodifiable risk factor for stroke, and aged patients exhibit impaired stroke recovery.[4] Consistent with clinical data, findings from animal models have demonstrated that aged mice have higher mortality and worse outcomes when subjected to same duration of occlusion compared with young mice, yet paradoxically, the infarct damage is smaller in the aged mice.[5,6] Impaired recovery has been linked to several underlying mechanisms, including altered peripheral immune responses, enhanced neuroinflammation, and reductions in neurogenesis.[7-9] However, it was not known whether the discrepancy in histological outcome is associated with age-induced changes in the cerebral vasculature or cerebral blood flow.

    Consistent blockage of blood flow is essential to achieve a homogenous ischemic infarct. Previous animal studies use laser Doppler flowmetry (LDF) to confirm blood flow blockage after ischemic occlusion. However, this technique has often been criticized as it not quantitative and only examines blood flow changes in a small region of the brain. As aging leads to several morphological and pathological changes throughout the vasculature, leading to atherosclerosis and small vessel disease, these changes cannot be identified by LDF. These alterations might contribute to significant stroke damage variability in aged animals. Unlike LDF, laser speckle flowmetry (LSF) provides a broader spatial, and temporal pattern of blood flow changes in the brain, allowing investigators to better examine and control cerebral blood flow changes during and following occlusion.

    Comment

    To determine if the discrepancies in histological outcomes in aged mice were secondary to variability or differences in blood flow dynamics, we first assessed whether aged mice exhibited differential blood flow patterns after stroke compared to young mice using LSF. A structural immunohistochemical analysis of the vasculature was also performed by perfusing blood vessels with fluorescein isothiocyanate-dextran and co-labeling with the CD31 antibody. No significant difference in blood flow dynamics or microvascular density was observed between young (3-month-old) and aged (18-month-old) animals after middle cerebral artery occlusion (MCAO).

    Although these results refute the hypothesis that changes in cerebral blood flow or vascular density was responsible for the smaller infarcts in aged mice, the study has provided some very interesting findings. Based on the LSF data, focal ischemia during MCAO induced a dramatic blood flow drop to the ipsilateral hemisphere as expected, but it was also associated with reduced blood flow in the contralateral hemisphere. This is an interesting observation as it suggests that even a focal ischemic stroke induces changes throughout the brain.

    To further assess, the underlying mechanisms of smaller infarcts seen in aged mice, we investigated differences in blood-brain barrier breakdown after stroke. Somewhat surprisingly, IgG extravasation at both 24 h and 72 h after stroke was lower in aged mice compared with young mice, which likely correlated with the existence of smaller infarcts.

    Despite some limitations, this is a very interesting study as it is the first to utilize LSF to investigate blood flow changes in aged animals. The mechanism responsible for the higher mortality and poorer recovery seen in aged and elderly animals remain a mystery. Age-related changes in neuroinflammation and the immune response to stroke are areas under intense investigation by a number of researchers and will hopefully be answered in the future.

    Financial support and sponsorship

    This work was supported by the grants from American Heart Association and the National Institutes of Health/National Institute of Neurological Disorders and Stroke.

    Conflicts of interest

    There are no conflicts of interest.

    References

    • 1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER. Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation 2014;129:e28-292.

      DOIPubMedPMC
    • 2. Venna VR, McCullough LD. Role of social factors on cell death, cerebral plasticity and recovery after stroke. Metab Brain Dis 2014;22:301-22.

    • 3. Bushnell C, McCullough LD, Awad IA, Chireau MV, Fedder WN, Furie KL, Howard VJ, Lichtman JH, Lisabeth LD, Pi-a IL, Reeves MJ, Rexrode KM, Saposnik G, Singh V, Towfighi A, Vaccarino V, Walters MR, American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, Council. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:1545-88.

      DOIPubMed
    • 4. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y; American Heart Association Statistics Committee and Stroke Statistics. Heart disease and stroke statistics – 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117:e25-146.

      DOIPubMed
    • 5. Agarwal S, Scoffings DJ, Jones PS, Marrapu ST, Barry PJ, O'Brien EW, Baron JC, Warburton EA. Interaction of age with the ischaemic penumbra, leptomeningeal collateral circulation and haemodynamic variables in acute stroke: a pilot study. J Neurol Neurosurg Psychiatry 2013;84:271-6.

      DOIPubMed
    • 6. Liu F, Benashski SE, Persky R, Xu Y, Li J, McCullough LD. Age-related changes in AMP-activated protein kinase after stroke. Age (Dordr) 2012;34:157-68.

      DOIPubMedPMC
    • 7. Venna VR, Xu Y, Doran SJ, Patrizz A, McCullough LD. Social interaction plays a critical role in neurogenesis and recovery after stroke. Transl Psychiatry 2014;4:e351.

      DOIPubMedPMC
    • 8. Machado MC, Coelho AM, Carneiro D’Albuquerque LA, Jancar S. Effect of ageing on systemic inflammatory response in acute pancreatitis. Int J Inflam 2012;2012:270319.

      DOI
    • 9. Petcu EB, Smith RA, Miroiu RI, Opris MM. Angiogenesis in old aged subjects after ischemic stroke: a cautionary note for investigators. J Angiogenes Res 2010;2:26.

      DOIPubMedPMC

    Article Access Statistics

    • Viewed: 6758
    • Downloaded: 197
    • Cited: Crossref0

    Table of Contents