Enzyme replacement reverses abnormal cerebrovascular responses in Fabry disease

David F Moore, Gheona Altarescu, Peter Herscovitch, Raphael Schiffmann, David F Moore, Gheona Altarescu, Peter Herscovitch, Raphael Schiffmann

Abstract

Background: Fabry disease is a lysosomal X-linked enzyme deficiency of alpha-galactosidase A associated with an increased mortality and morbidity due to renal failure, cardiac disease and early onset stroke.

Methods: We examined the functional blood flow response of the brain after visual stimulation (reversing checkerboard pattern), and cerebral vasoreactivity following acetazolamide (15 mg/kg) with [15O]H2O and positron emission tomography (PET) in Fabry disease. Twenty-six hemizygous patients (age range 19-47 years) were enrolled in a randomized double-blind placebo-controlled 6-month trial of enzyme replacement therapy administered by intravenous infusion every two weeks. Regional cerebral blood flow (rCBF) was measured with PET at the beginning and end of the trial.

Results: Fabry patients had a significantly greater increase in rCBF following visual stimulation and acetazolamide challenge compared to controls. Visual reactivity was normal. The time for recovery of the cerebral vasculature following acetazolamide was prolonged in Fabry patients compared to controls. The abnormal rCBF response induced by visual stimulation and acetazolamide decreased significantly following enzyme replacement therapy, as did the prolonged recovery of the cerebral vasculature.

Conclusions: Enzyme replacement therapy reverses the exaggerated cerebrovascular response in Fabry disease.

Figures

Figure 1
Figure 1
rCBF SPM{t} map of significantly increased blood flow in the Fabry group (n = 26) compared to the control group (n = 10) during visual stimulation. No significant rCBF elevation was found in the control group compared to Fabry patients at the same set-level of inference (results not shown).
Figure 2
Figure 2
Acetazolamide challenge rCBF SPM{t} map of significantly increased blood flow in the Fabry group (n = 26) compared to normal controls (n = 10). The rCBF at thirty minutes post-infusion of acetazolamide was significantly greater in Fabry patients in many brain regions, with a posterior predominance. No significant rCBF elevation at the same set-level of inference was found in the control group compared to Fabry patients (results not shown).
Figure 3
Figure 3
SPM{t} map of significantly lower rCBF in the ERT treatment group (n = 14) during visual stimulation compared to the placebo group (n = 11) in many regions throughout the brain.
Figure 4
Figure 4
SPM{t} map of significantly lower rCBF 30-minute following acetazolamide challenge in the ERT group (n = 13) compared to the placebo group (n = 9).

References

    1. Brady R, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L. Enzymatic defect in Fabry disease: ceramide trihexosidase deficiency. N Engl J Med. 1967;276:1163–1167.
    1. Kint J. Alpha-galactosidase deficiency. Science. 1970;167:1268.
    1. Kanda A, Nakao S, Tsuyama S, Murata F, Kanzaki T. Fabry disease: ultrastructural lectin histochemical analyses of lysosomal deposits. Virchows Arch. 2000;436:36–42.
    1. Desnick R, Ioannou YA, Eng CM. α-Galactosidase A Deficiency: Fabry Disease. In: R Charles, Scriver, Arthur L, Beaudet William, S Sly David, editor. Valle. New York, McGraw-Hill; 2001. pp. 3733–3774.
    1. Moore DF, Scott LJC, Gladwin MT, Altarescu G, Kaneski C, Suzuki K, Pease-Fye M, Ferri R, Brady RO, Herscovitch P, Schiffmann R. Regional Cerebral Hyper-Perfusion and Nitric Oxide Pathway Dysregulation in Fabry Disease: Reversal by Enzyme Replacement Therapy. Circulation. 2001;104:1506–1512.
    1. Schiffmann R, Kopp J, Austin H, Sabnis S, Moore DF, Weibel T, Balow J, Brady RO. A randomized double-blind, placebo-controlled trial of enzyme replacement therapy in Fabry disease. JAMA. 2001;285:2743–2749. doi: 10.1001/jama.285.21.2743.
    1. Mitsias P, Levine SR. Cerebrovascular complications of Fabry's disease. Ann Neurol. 1996;40:8–17.
    1. Evans O, Parker CC, Haas RH, Naidu S, Moser H, Bock HGO. " Inborn errors of metabolism of the nervous system. Chapter 68, Neurology in Clinical Practice.,". Butterworth-Heinemann, Woburn, MA, ed Third Edition, 2000.
    1. Altarescu G, Moore DF, Pursley R, Campia U, Goldstein S, Bryant M, Panza JA, Schiffmann R. Enhanced endothelium-dependent vasodilation in Fabry disease. Stroke. 2001;32:1559–1562.
    1. Moore DF, Herscovitch P, Schiffmann R. Selective arterial distribution of cerebral hyper-perfusion in Fabry disease. J Neuroimaging. 2001;11:303–307.
    1. Crutchfield K, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, Barton NW, Schiffmann R. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology. 1998;50:1746–1749.
    1. Fox P, Raichle ME. Stimulus rate determines regional brain blood flow in the striate cortex. Ann Neurol. 1985;17:303–305.
    1. Herscovitch P, Markham J, Raichle ME. Brain blood flow measured with intravenous O-15 water. Theory and error analysis. J Nucl Med. 1983;24:782–789.
    1. Koeppe R, Holden JE, Polcyn RE, Nickles RJ, Hutchins GD, Weese JL. Performance comparison of parameter estimation techniques for the quantitation of local cerebral blood flow by dynamic positron computed tomography. J Cereb Blood Flow Metab. 1985;5:214–223.
    1. Collins D, Zijdenbos AP, Kollokian JG, Kabani NJ, Holmes CJ, Evans AC. Design and construction of a realistic digital brain phantom. IEEE Transactions on Medical Imaging. 1998;17:463–469. doi: 10.1109/42.712135.
    1. Friston K, Ashburner J, Frith CD, Poline JB, Heather JD, Frackowiak RSJ. Spatial registration and normalization of images. Human Brain Mapping. 1995;2:165–189.
    1. Nowinski W, Bryan RN, Raghavan R. The Electronic Clinical Brain Atlas. New YorK, Thieme. 1999.
    1. Faraci F, Heistad DD. Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels. Physiological Reviews. 1998;78:53–97.
    1. Szabo C. Physiological and pathophysiological roles of nitric oxide in the central nervous system. Brain Research Bulletin. 1996;41:131–141. doi: 10.1016/S0361-9230(96)00159-1.
    1. Inao S, Tadokoro M, Nishino M, Mizutani N, Terada K, Bundo M, Kuchiwaki H, Yoshida J. Neural Activation of the Brain with Hemodynamic Insufficiency. J Cereb Blood Flow Metab. 1998;18:960–967. doi: 10.1097/00004647-199809000-00005.
    1. Dahl A, Russell D, Rootwell K, Nyber-Hansen R, Kerty E. Cerebral vasoreactivity assessed with transcranial Doppler and regional cerebral blood flow measurements. Dose, serum concentration, and time course of the response to acetazolamide. Stroke. 1995;26:2302–2306.
    1. Hayashida K, Tanaka Y, Hirose Y, Kume N, Iwama T, Mikyake Y, Ishida Y, Matsuura H, Miyake Y, Nishimura T. Vasoreactive effect of acetazolamide as a function of time with sequential PET 15O-water measurements. Nuclear Medicine Communications. 1996;17:1047–1051.
    1. Kiss B, Dallinger S, Findl O, Rainer G, Eichler HG, Schmetterer L. Acetazolamide-induced cerebral and ocular vasodilation in humans is independent of nitric oxide. Am J Physiol. 1999;276:R1661–R1667.
    1. White R, Deane C, Vallance P, Markus HS. Nitric Oxide Synthase Inhibition in Humans Reduces Cerebral Blood Flow but Not the Hyperemic Response to Hypercapnia. Stroke. 1998;29:467–472.
    1. Razani B, Engelman JA, Wang XB, Schubert W, Zhang XL, Marks CB, Macaluso F, Russell RG, Li M, Pestell RG, Di Vizio D, Hou H, Kneitz B, Lagaud G, Christ GJ, Edelmann W, Lisanti MP. Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. Journal of Biological Chemistry. 2001;276:38121–38138. doi: 10.1074/jbc.M008340200.
    1. Razani B, Lisanti MP. Caveolin-deficient mice: insights into caveolar function and human disease. Journal of Clinical Investigation. 2001;108:1553–1561. doi: 10.1172/JCI200114611.
    1. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000;87:840–844.
    1. Wei E, Christman CW, Kontos HA, Povlishock JT. Effects of oxygen radicals on cerebral arterioles. Am J Physiol. 1985;248:H157–H162.
    1. Etchevers H, Vincent C, Le Dourarin NM, Couly GF. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development. 2001;128:1059–1068.

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