ABSTRACT
Biochemical alterations underlying the symptoms and pathomechanisms of Alzheimer's disease (AD) are not fully understood. However, alterations of glucose metabolism and mitochondrial dysfunction certainly play an important role. (1)H- and (13)C-NMR spectroscopy exhibits promising results in providing information about those alterations in vivo in patients and animals, especially regarding the mitochondrial tricarboxylic acid (TCA) cycle. Accordingly, transgenic mice expressing mutant human amyloid precursor protein (APP(SL))-serving as a model of neuropathological changes in AD-were examined with in vitro 1D (1)H- and 2D (1)H-(13)C-HSQC-NMR spectroscopy after oral administration of 1-(13)C-glucose and acquisition of brain material after 30 min. Perchloric acid extracts were measured using a 500 MHz spectrometer, providing more detailed information compared to in vivo spectra achievable nowadays. Area under curve (AUC) data of metabolite peaks were obtained and normalized in relation to the creatine signal, serving as internal reference. Besides confirming well-known metabolic alterations in AD like decreased N-acetylaspartate (NAA)/Creatine (Cr) ratio, new findings such as a decrease in phosphorylcholine (PC) are presented. Glutamate (Glu) and glutamine (Gln) concentrations were decreased while γ-aminobutyric acid (GABA) was elevated in Thy1-APP(SL) mice. (13)C-NMR spectroscopy revealed a shift in the Glx-2/Glx-4-ratio-where Glx represents a combined Glu/Gln-signal-towards Glx-2 in AD. These findings correlated well with the NAA/Cr-ratio. The Gln-4/Glu-4-ratio is altered in favor of Glu. Our findings suggest that glutamine synthetase (GS), which is predominantly present in glial cells may be impaired in the brain of Thy1-APP(SL) transgenic mice. Since GS is an ATP-dependent enzyme, mitochondrial dysfunction might contribute to reduced activity, which might also account for the increased metabolism of glutamate via the GABA shunt, a metabolic pathway to bypass intra-mitochondrial α-ketoglutarate-dehydrogenase, resulting in elevated GABA levels.
Subject(s)
Alzheimer Disease/metabolism , Brain/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Carbon-13 Magnetic Resonance Spectroscopy , Creatine/metabolism , Disease Models, Animal , Female , Glucose/metabolism , Glutamic Acid/metabolism , Glutamine/metabolism , Humans , Inositol/metabolism , Male , Mice, Transgenic , Mutation , Peptide Fragments/metabolism , Phosphorylcholine/metabolism , Proton Magnetic Resonance Spectroscopy , gamma-Aminobutyric Acid/metabolismABSTRACT
OBJECTIVES: To compare functional pelvic cine-MRI in patients with post-prostatectomy incontinence before and after implantation of a bulbourethral composite suspension. PATIENTS AND METHODS: Functional pelvic 1.5 T cine-MRI was performed at rest, under standardized Valsalva pressure and during micturition in six patients with post-prostatectomy incontinence before and 3 months after a bulbourethral composite suspension. Visibility and positioning of the implant as well as membranous urethral length (MUL) and positioning of the bladder neck (BN) in comparison with the pubococcygeal line (PCL) were evaluated. Clinical outcome was measured by patient-reported pad use and standardized questionnaires (ICIQ-UI SF and I-QOL). Paired data were tested with a Wilcoxon signed-ranks test. RESULTS: Surgery was successfully performed in all patients. All patients returned to complete voiding. The ICIQ-UI SF score decreased significantly from median 16.5 to 5 (p = 0.016). I-QOL increased significantly from 70.5 to 93.5 (p = 0.047). Pad use improved from median 2 pads to 0 pads postoperatively (p = 0.031). Four of six patients were completely pad-free, and 2 were failures with persisting urinary incontinence. MRI revealed significant differences of the MUL at rest with median of 8 mm pre- and 13 mm postoperatively (p = 0.016). BN showed a significant elevation with respect to PCL under Valsalva with in median 0.5 to 5 mm postoperatively (p = 0.016). No significant MRI differences were found between patients showing clinical success or failure. CONCLUSIONS: The bulbourethral composite suspension was associated with an increase in urethral length, urethral coaptation zone and bladder neck elevation, implying a non-compressive mode of action.