Entwicklung von Therapieansätzen bei neurodegenerativen Erkrankungen

H. G. Niessen; J. Kaufmann; W. S. Kunz; S. Vielhaber

doi:10.1055/s-0038-1627125

Nervenheilkunde, Table of Contents

Nervenheilkunde 2008; 27(07): 652-658
DOI: 10.1055/s-0038-1627125

Original- und Übersichtsarbeiten - Original and Review Articles

Schattauer GmbH

Entwicklung von Therapieansätzen bei neurodegenerativen Erkrankungen

Die Bedeutung biologischer Marker am Beispiel der ALSDevelopment of therapeutic strategies in neurodegenerative diseasesthe significance of biological markers for ALS

H. G. Niessen

¹Otto-von-Guericke Universität Magdeburg, Medizinische Fakultät, Klinik für Neurologie II, (Direktor Prof. Dr. med. H.-J. Heinze)

,

J. Kaufmann

¹Otto-von-Guericke Universität Magdeburg, Medizinische Fakultät, Klinik für Neurologie II, (Direktor Prof. Dr. med. H.-J. Heinze)

,

W. S. Kunz

²Rheinische Friedrich-Wilhelms-Universität Bonn, Klinik für Epileptologie (Direktor: Prof. Dr. med. C. E. Elger)

,

S. Vielhaber

¹Otto-von-Guericke Universität Magdeburg, Medizinische Fakultät, Klinik für Neurologie II, (Direktor Prof. Dr. med. H.-J. Heinze)

› Author Affiliations

Abstract

Zusammenfassung

Magnetresonanzspektroskopie (1H-MRS) ermöglicht die In-vivo-Beobachtung von Stoffwechselvorgängen und neurozellulären Veränderungen im Gehirn. Am Beispiel der neurodegenerativen Modellerkrankung Amyotrophe Lateralsklerose (ALS) wird der Einfluss dieser innovativen Technik auf die Entwicklung neuer therapeutischer Ansätze besonders deutlich. Bei ALS-Patienten und einer Kontrollgruppe wurde die Wirkung einer prolongierten, oralen Anwendung von Kreatinmonohydrat auf den Hirnmetabolismus untersucht. Es konnte gezeigt werden, dass es nach mehrwöchiger oraler Kreatineinnahme zu einer Restitution des N-Azetylaspartat (NAA)-Gehalts im ALS-Motorkortex kommt und ein klarer Zusammenhang zur Mitochondrienfunktion besteht. Am transgenen Tiermodell der ALS (Überexpression der humanen SOD1 mit G93A-Mutation) konnten zusätzliche Einblicke in die präklinische Phase der Erkrankung gewonnen werden. Die Ergebnisse der tierexperimentellen Untersuchungen untermauern die Hypothese einer bereits präklinisch bestehenden Störung im mitochondrialen NAA-Metabolismus. Die Befunde unterstreichen am Beispiel der ALS das Potenzial der klinischen MR-Spektroskopie im Frühstadium neurodegenerativer Veränderungen und bei der Weiterentwicklung konservativer Therapiestrategien mithilfe biologischer Marker.

Summary

Modern imaging techniques such as magnetic resonance spectroscopy (1H-MRS) are suitable methods for the noninvasive visualisation of metabolic processes in the brain. Amyotrophic lateral sclerosis (ALS) represents an important neurodegenerative disease, where application of MRS will further influence treatment developments. In our study, we determined the effect of a prolongated oral substitution of creatine monohydrate on the brain metabolism. Upon creatine supplementation, we observed a recovery of NAA content in the ALS motor cortex, which was clearly linked to the mitochondrial function. In addition, the transgenic animal model of human ALS (mice overexpressing the mutated human G93A-superoxide dismutase 1) yielded insights especially into the preclinically pathology. The animal data suggest that a decline in NAA concentration is a very early effect which coincides with mitochondrial impairment. The findings support the important role of clinical MR-spectroscopy for the detection of neurodegenerative alterations and for the further development of therapeutic strategies by means of biological markers.

Schlüsselwörter

Amyotrophe Lateralsklerose - Magnetresonanzspektroskopie - transgene Tiermodelle - Mitochondrien

Keywords

Amyotrophic lateral sclerosis - magnetic resonance spectroscopy - transgenic animal models - mitochondria

Full Text

References

Literatur
1 Angenstein F, Niessen HG, Goldschmidt J, Vielhaber S, Ludolph AC, Scheich H. Age-dependent changes in MRI of motor brain stem nuclei in a mouse model of ALS. Neuroreport 2004; 15: 2271-4.
2 Bates TE, Strangward M, Keelan J, Davey GP, Munro PM, Clark JB. Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo . Neuroreport 1996; 31: 1397-1400.
3 Beal MF. Mitochondria and the pathogenesis of ALS. Brain 2000; 123: 1291-2.
4 Block W. et al. Proton magnetic resonance spectroscopy of the primary motor cortex in patients with motor neuron disease: subgroup analysis and follow-up measurements. Arch Neurol 1998; 55: 931-6.
5 Boillée S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 2006; 52: 39-59.
6 Borthwick GM, Johnson MA, Ince PG, Shaw PJ, Turnbull DM. Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol 1999; 46: 787-90.
7 Brooks BR, Miller RG, Swash M, Munsat TL. World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1: 293-9.
8 Bucher S. et al. Vacuolization correlates with spinspin relaxation time in motor brainstem nuclei and behavioural tests in the transgenic G93A-SOD1 mouse model of ALS. Eur J Neurosci 2007; 26: 1895-901.
9 Chiu AY, Zhai P, Dal Canto MC, Peters TM, Kwon YW, Prattis SM, Gurney ME. Age-dependent penetrance of disease in a transgenic mouse model of familial amyotrophic lateral sclerosis. Mol Cell Neurosci 1995; 6: 349-362.
10 Clark JB. N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosc 1998; 20: 271-6.
11 Cooke FJ, Blamire AM, Manners DN, Styles P, Rajagopalan B. Quantitative proton magnetic resonance spectroscopy of the cervical spinal cord. Magn Reson Med 2004; 51: 1122-8.
12 Cosottini M. et al. Diffusion-tensor MR imaging of corticospinal tract in amyotrophic lateral sclerosis and progressive muscular atrophy. Radiology 2005; 237: 258-64.
13 Dal Canto MC, Gurney ME. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol 1994; 145: 1271-9.
14 Da Rocha AJ, Maia Junior AC, Nogueira RG, Lederman HM. Magnetic resonance findings in amyotrophic lateral sclerosis using a spin echo magnetization transfer sequence. Preliminary report. Arq Neuropsiquiatr 1999; 57: 912-5.
15 Davie CA. et al. Differentiation of multiple system atrophy from idiopathic Parkinson’s disease using proton magnetic resonance pectroscopy. Ann Neurol 1995; 37: 204-10.
16 Dechent P, Pouwels PJ, Wilken B, Hanefeld F, Frahm J. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol 1999; 277: 698-704.
17 Ellis AC, Rosenfeld J. The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders. CNS Drugs 2004; 18: 967-80.
18 Ferrante RJ. et al. Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci 2000; 20: 4389-97.
19 Gardner PR, Fridovich I. Inactivation-reactivation of aconitase in Escherichia coli. A sensitive measure of superoxide radical. J Biol Chem 1992; 267: 8757-63.
20 Groeneveld GJ. et al. A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Ann Neurol 2003; 53: 437-45.
21 Gurney ME. Transgenic-mouse model of amyotrophic lateral sclerosis. N Engl J Med 1994; 331: 1721-2.
22 Gurney ME. What transgenic mice tell us about neurodegenerative disease. Bioessays 2000; 22: 297-304.
23 Haenggeli C, Kato AC. Differential vulnerability of cranial motoneurons in mouse models with motor neuron degeneration. Neurosci Lett 2002; 335: 39-43.
24 Hemmer W, Wallimann T. Functional aspects of creatine kinase in brain. Dev Neurosci 1993; 15: 249-60.
25 Jenkins BG, Chen YCI, Rosen BR. Investigating the neurochemistry and etiology of neurodegenerative disorders using magnetic resonance spectroscopy. In: Mitochondria and Free Radicals in Neurodegenerative Diseases. Beal MF, Howell N, Bodis-Wollner I. (Hrsg) New York: Wiley-Liss; 1997
26 Kalra S, Hanstock CC, Martin WR, Allen PS, Johnston WS. Detection of cerebral degeneration in amyotrophic lateral sclerosis using high-field magnetic resonance spectroscopy. Arch Neurol 2006; 63: 1144-8.
27 Karitzky J, Ludolph AC. Imaging and neurochemical markers for diagnosis and disease progression in ALS. J Neurol Sci 2001; 191: 35-41.
28 Kirmani BF, Jacobowitz DM, Namboodiri MA. Developmental increase of aspartoacylase in oligodendrocytes parallels CNS myelination. Brain Res Dev Brain Res 2003; 140: 105-15.
29 Klivenyi P. et al. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med 1999; 5: 347-50.
30 Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosi 1998; 18: 3241-50.
31 Kudin AP, Bimpong-Buta NY, Vielhaber S, Elger CE, Kunz WS. Characterization of superoxideproducing sites in isolated brain mitochondria. J Biol Chem 2004; 279: 4127-35.
32 Leichsenring A. et al. Ascending neuropathology in the CNS of a mutant SOD1 mouse model of amyotrophic lateral sclerosis. Brain Res 2006; 1096: 180-195.
33 Mattiazzi M, D’Aurelio M, Gajewski CD, Martushova K, Kiaei M, Beal MF, Manfredi G. Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J Biol Chem 2002; 277: 29626-33.
34 Meyerhoff DJ. et al. Axonal injury and membrane alterations in Alzheimer’s disease suggested by in vivo proton magnetic resonance spectroscopic imaging. Ann Neurol 1994; 36: 40-7.
35 Mierisova S. et al. New approach for quantitation of short echo time in vivo 1H MR spectra of brain using AMARES. NMR Biomed 1998; 11: 32-9.
36 Niessen HG. et al. In vivo quantification of spinal and bulbar motor neuron degeneration in the G93A-SOD1 transgenic mouse model of ALS by T2 relaxation time and apparent diffusion coefficient. Exp Neurol 2006; 201: 293-300.
37 Niessen HG. et al. Metabolic progression markers of neurodegeneration in the transgenic G93ASOD1 mouse model of amyotrophic lateral sclerosis. Eur J Neurosci 2007; 25: 1669-77.
38 Petroff OA, Errante LD, Rothman DL, Kim JH, Spencer DD. Neuronal and glial metabolite content of the epileptogenic human hippocampus. Ann Neurol 2002; 52: 635-42.
39 Pfeuffer J, Tkac I, Provencher SW, Gruetter R. Toward an in vivo neurochemical profile: quantification of 18 metabolites in short-echo-time (1)H NMR spectra of the rat brain. J Magn Reson 1999; 141: 104-20.
40 Pioro EP. et al. 1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla. Neurology 1999; 53: 71-9.
41 Rosen DR. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993; 362: 59-62.
42 Sanchez-Pernaute R. et al. Clinical correlation of striatal 1H MRS changes in Huntington’s disease. Neurology 1999; 53: 806-12.
43 Shefner JM. et al; NEALS Consortium. A clinical trial of creatine in ALS. Neurology 2004; 63: 1656-61.
44 Urenjak J, Williams SR, Gadian DG, Noble M. Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 1993; 13: 981-9.
45 Vielhaber S. et al. Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain 2000; 123: 1339-48.
46 Vielhaber S. et al. Effect of creatine supplementation on metabolite levels in ALS motor cortices. Exp Neurol 2001; 172: 377-82.
47 Vielhaber S. et al. Hippocampal N-acetyl aspartate levels do not mirror neuronal cell densities in creatine-supplemented epileptic rats. Eur J Neurosci 2003; 18: 2292-300.
48 Vielhaber S. et al. Brain 1H magnetic resonance spectroscopic differences in myotonic dystrophy type 2 and type 1. Muscle Nerve 2006; 34: 145-52.
49 Vielhaber S. et al. Subfield-specific Loss of Hippocampal N-acetyl Aspartate in Temporal Lobe Epilepsy. Epilepsia 2008; 49: 40-50.
50 Wang S. et al. Amyotrophic lateral sclerosis: diffusion- tensor and chemical shift MR imaging at 3.0 T. Radiology 2006; 239: 831-8.
51 Wiedemann FR. et al. Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis. J Neurol Sci 1998; 156: 65-72.