title: Metabolic progression markers of neurodegeneration in the transgenic G93A-SOD1 mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. Visualizing corresponding metabolic changes in the brain of patients with ALS with proton magnetic resonance spectroscopy ((1)H-MRS) may provide surrogate markers for an early disease detection, for monitoring the progression and for evaluating a treatment response. The primary objective of our study was to evaluate whether modifications in MR metabolite levels occur before clinical disease onset, and whether these changes are directly linked to a distinct spatial progression pattern in the CNS. Therefore, age-dependent alterations in the cerebral and spinal metabolic profile in the mouse model of ALS overexpressing the mutated human G93A-superoxide dismutase 1 (G93A-SOD1) were determined by high-resolution MRS of tissue extracts at 14.1 Tesla. Both non-transgenic mice (control mice) and transgenic mice overexpressing the non-mutated human SOD1 (tg-SOD1) served as controls. In the spinal cord of G93A-SOD1 mice significantly decreased levels of N-acetyl aspartate were already detected 34 days postpartum, i.e. about 60 days before the average disease onset caused by motor neuron decline. In addition, glutamine and gamma-aminobutyric acid concentrations were significantly diminished at Day 75, which is still in the presymptomatic phase of the disease. These metabolic changes were further progressive in the course of the disease and started to involve the brainstem at Day 75. Overall, high-resolution (1)H-MRS allows a sensitive spatial and temporal metabolite profiling in the presymptomatic phase of ALS even before significant neuronal cell loss occurs.
authors: Department of Neurology II, Otto-von-Guericke University Magdeburg, Leipziger Str 44, Magdeburg, Germany.
authors: Heiko G
authors: HG
authors: Niessen
authors: Grazyna
authors: G
authors: Debska-Vielhaber
authors: Kerstin
authors: K
authors: Sander
authors: Frank
authors: F
authors: Angenstein
authors: Albert C
authors: AC
authors: Ludolph
authors: Liane
authors: L
authors: Hilfert
authors: Wieland
authors: W
authors: Willker
authors: Dieter
authors: D
authors: Leibfritz
authors: Hans-Jochen
authors: HJ
authors: Heinze
authors: Wolfram S
authors: WS
authors: Kunz
authors: Stefan
authors: S
authors: Vielhaber
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009410:Nerve Degeneration / Q000175:diagnosis* / Q000209:etiology*; D013482:Superoxide Dismutase / Q000235:genetics*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005973:Glutamine; D001224:Aspartic Acid; D005680:gamma-Aminobutyric Acid; C000179:N-acetylaspartate; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase