Entwicklung von Therapieansätzen bei neurodegenerativen Erkrankungen

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

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