Peri-Operative Mortality and Survival After Repair of Abdominal Aortic Aneurysm in Advanced Age Patients: A National Study from the Norwegian Registry for Vascular Surgery Focused on Nonagenarians.

OBJECTIVE: Treatment of abdominal aortic aneurysm (AAA) in nonagenarians has become more frequent. This national observational cohort study aimed to investigate peri-operative mortality and survival after AAA surgery in nonagenarians in Norway. METHODS: All AAA repairs registered in the Norwegian Registry for Vascular Surgery from 2015 to 2021 were identified and stratified into nonagenarians > 90 years old (n = 77), octogenarians 80 - 89 years old (n = 1 362), and patients < 80 years old (n = 4 590). The patient characteristics and comorbidities were recorded, and the 30 and 90 day mortality rates were calculated. Kaplan-Meier analysis was performed to obtain the estimated median survival and survival curves. RESULTS: In the nonagenarians, the 30 day mortality rates were 2.5% in asymptomatic patients, 33.3% in symptomatic patients, and 59.1% in the patients with a ruptured AAA (rAAA). The estimated median survival (years) were 3.3 (95% confidence interval [CI] 1.95 - 4.59) for asymptomatic AAA, 2.9 (interquartile range [IQR] 2.82, 5.80) for symptomatic AAA, and 0.1 for rAAA (IQR 0.01, 3.04). For nonagenarians surviving the first 90 days, the estimated median survival (years) were 4.2 (95% CI 2.56 - 5.88) for asymptomatic AAA, 3.4 (IQR 2.86, 5.80) for symptomatic AAA, and 3.8 (IQR 1.49, 4.85) for rAAA. The 90 day mortality rates were 100.0%, 80.0%, and 62.5% for asymptomatic, symptomatic, and rAAA, respectively, after open surgical repair (OSR), and 5.1%, 10.0%, and 50.0%, respectively, after endovascular aortic repair (EVAR). CONCLUSION: Peri-operative mortality and survival results after AAA surgery in nonagenarians support treatment of selected asymptomatic patients. The 90 day survivors had an expected survival of more than three years, enabling balanced decision making regarding surgical vs. conservative treatment options in this challenging cohort. EVAR is the treatment method of choice for AAA in nonagenarians because most of them would probably live longer untreated than if treated by OSR.

Antithrombotic and Lipid Lowering Therapy is Associated With Improved Survival After Vascular Surgery: A Population Based Study From Norway.

OBJECTIVE: This population based retrospective cohort study aimed to investigate the association between combined treatment with lipid lowering drugs and antiplatelet or anticoagulation therapy and long term survival following vascular surgery in Norway. METHODS: The study included all patients who were registered for the treatment of carotid stenosis, abdominal aortic aneurysm (AAA), and atherosclerotic lower extremity arterial disease (LEAD) in the Norwegian Registry for Vascular Surgery between 2015 and 2019 and who were discharged alive. Clinical and medication details were retrieved from the register. Survival was assessed with Kaplan-Meier analysis and a multivariable Cox regression model. Stratification was according to treatment group, patient sex, and if patients received the recommended medications or not. Recommended medications were defined as lipid lowering drugs, usually statins, and antiplatelets, or sometimes anticoagulants, when comorbidity indicated anticoagulation therapy. RESULTS: In total, 15 810 patients had LEAD, 4 080 patients AAA, and 2 194 patients had carotid stenosis. In all treatment groups, survival was superior for patients who used the recommended medications upon discharge. The difference was greatest in patients with LEAD with mean survival periods of 4.33 (95% CI 4.29 - 4.36) and 3.7 (95% CI 3.64 - 3.77) years in patients discharged with and without the recommended medications, respectively (p < .001). The mean survival periods were 4.67 (95% CI 4.61 - 4.73) and 4.34 (95% CI 4.24 - 4.44) years in patients with AAA discharged with and without the recommended medications, respectively (p < .001). Cox regression analysis showed a statistically significantly lower mortality rate for patients discharged with the recommended medications for LEAD (HR 0.58; p < .001) and AAA (HR 0.57; p < .001). CONCLUSION: The recommended medications were associated with improved survival in all treatment groups and both sexes. The survival difference was statistically significant in patients with LEAD and AAA. Patients with LEAD had the greatest improvement; therefore, the recommended secondary prophylaxis is especially important in these patients.

Neuronal and astrocytic metabolism in a transgenic rat model of Alzheimer's disease.

Regional hypometabolism of glucose in the brain is a hallmark of Alzheimer's disease (AD). However, little is known about the specific alterations of neuronal and astrocytic metabolism involved in homeostasis of glutamate and GABA in AD. Here, we investigated the effects of amyloid ß (Aß) pathology on neuronal and astrocytic metabolism and glial-neuronal interactions in amino acid neurotransmitter homeostasis in the transgenic McGill-R-Thy1-APP rat model of AD compared with healthy controls at age 15 months. Rats were injected with [1-(13)C]glucose and [1,2-(13)C]acetate, and extracts of the hippocampal formation as well as several cortical regions were analyzed using (1)H- and (13)C nuclear magnetic resonance spectroscopy and high-performance liquid chromatography. Reduced tricarboxylic acid cycle turnover was evident for glutamatergic and GABAergic neurons in hippocampal formation and frontal cortex, and for astrocytes in frontal cortex. Pyruvate carboxylation, which is necessary for de novo synthesis of amino acids, was decreased and affected the level of glutamine in hippocampal formation and those of glutamate, glutamine, GABA, and aspartate in the retrosplenial/cingulate cortex. Metabolic alterations were also detected in the entorhinal cortex. Overall, perturbations in energy- and neurotransmitter homeostasis, mitochondrial astrocytic and neuronal metabolism, and aspects of the glutamate-glutamine cycle were found in McGill-R-Thy1-APP rats.

Glutamate metabolism is impaired in transgenic mice with tau hyperphosphorylation.

In neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia, the protein tau is hyperphosphorylated and eventually aggregates to develop neurofibrillary tangles. Here, the consequences of tau hyperphosphorylation on both neuronal and astrocytic metabolism and amino-acid neurotransmitter homeostasis were assessed in transgenic mice expressing the pathogenic mutation P301L in the human tau gene (pR5 mice) compared with nontransgenic littermate controls. Mice were injected with the neuronal and astrocytic substrate [1-(13)C]glucose and the astrocytic substrate [1,2-(13)C]acetate. Hippocampus and cerebral cortex extracts were analyzed using (1)H and (13)C nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry and high-performance liquid chromatography. The glutamate level was reduced in the hippocampus of pR5 mice, accompanied by reduced incorporation of (13)C label derived from [1-(13)C]glucose in glutamate. In the cerebral cortex, glucose utilization as well as turnover of glutamate, glutamine, and GABA, were increased. This was accompanied by a relative increase in production of glutamate via the pyruvate carboxylation pathway in cortex. Overall, we revealed that astrocytes as well as glutamatergic and GABAergic neurons in the cortex of pR5 mice were in a hypermetabolic state, whereas in the hippocampus, where expression levels of mutant human tau are the highest, glutamate homeostasis was impaired.

Brain [U-13 C]glucose metabolism in mice with decreased α-ketoglutarate dehydrogenase complex activity.

The activity of the α-ketoglutarate dehydrogenase complex (KGDHC), a mitochondrial enzyme complex that mediates the oxidative decarboxylation of α-ketoglutarate in the TCA cycle, is reduced in Alzheimer's disease. We investigated the metabolic effects of a partial KGDHC activity reduction on brain glucose metabolism using mice with disrupted expression of dihydrolipoyl succinyltransferase (DLST; gene encoding the E2k subunit of KGDHC). Brain tissue extracts from cortex and cerebellum of 6-week-old heterozygote DLST knockout mice (DLST+/-) and corresponding wild-type mice injected with [U-(13) C]glucose and decapitated 15 min later were analyzed. An increase in the concentration of glucose in cortex suggested a decrease in the cortical utilization of glucose in DLST+/- mice. Furthermore, the concentration and (13) C labelling of aspartate in cortex were reduced in DLST+/- mice. This decline was likely caused by a decrease in the pool of oxaloacetate. In contrast to results from cell culture studies, no indications of altered glycolysis or GABA shunt activity were found. Glucose metabolism in the cerebellum was unaffected by the decrease in KGDHC activity. Among metabolites not related to glucose metabolism, the concentration of taurine was decreased in the cortex, and that of tyrosine was increased in the cerebellum. These results imply that diminished KGDHC activity has the potential to induce the reduction in glucose utilization that is seen in several neurodegenerative diseases.

Altered 13C glucose metabolism in the cortico-striato-thalamo-cortical loop in the MK-801 rat model of schizophrenia.

Using a modified MK-801 (dizocilpine) N-methyl-D-aspartic acid (NMDA) receptor hypofunction model for schizophrenia, we analyzed glycolysis, as well as glutamatergic, GABAergic, and monoaminergic neurotransmitter synthesis and degradation. Rats received an injection of MK-801 daily for 6 days and on day 6, they also received an injection of [1-(13)C]glucose. Extracts of frontal cortex (FCX), parietal and temporal cortex (PTCX), thalamus, striatum, nucleus accumbens (NAc), and hippocampus were analyzed using (13)C nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, and gas chromatography-mass spectrometry. A pronounced reduction in glycolysis was found only in PTCX, in which (13)C labeling of glucose, lactate, and alanine was decreased. (13)C enrichment in lactate, however, was reduced in all areas investigated. The largest reductions in glutamate labeling were detected in FCX and PTCX, whereas in hippocampus, striatum, and Nac, (13)C labeling of glutamate was only slightly but significantly reduced. The thalamus was the only region with unaffected glutamate labeling. γ-Aminobutyric acid (GABA) labeling was reduced in all areas, but most significantly in FCX. Glutamine and aspartate labeling was unchanged. Mitochondrial metabolites were also affected. Fumarate labeling was reduced in FCX and thalamus, whereas malate labeling was reduced in FCX, PTCX, striatum, and NAc. Dopamine turnover was decreased in FCX and thalamus, whereas that of serotonin was unchanged in all regions. In conclusion, neurotransmitter metabolism in the cortico-striato-thalamo-cortical loop is severely impaired in the MK-801 (dizocilpine) NMDA receptor hypofunction animal model for schizophrenia.

Knockout of GAD65 has major impact on synaptic GABA synthesized from astrocyte-derived glutamine.

γ-Aminobutyric acid (GABA) synthesis from glutamate is catalyzed by glutamate decarboxylase (GAD) of which two isoforms, GAD65 and GAD67, have been identified. The GAD65 has repeatedly been shown to be important during intensified synaptic activity. To specifically elucidate the significance of GAD65 for maintenance of the highly compartmentalized intracellular and intercellular GABA homeostasis, GAD65 knockout and corresponding wild-type mice were injected with [1-(13)C]glucose and the astrocyte-specific substrate [1,2-(13)C]acetate. Synthesis of GABA from glutamine in the GABAergic synapses was further investigated in GAD65 knockout and wild-type mice using [1,2-(13)C]acetate and in some cases γ-vinylGABA (GVG, Vigabatrin), an inhibitor of GABA degradation. A detailed metabolic mapping was obtained by nuclear magnetic resonance (NMR) spectroscopic analysis of tissue extracts of cerebral cortex and hippocampus. The GABA content in both brain regions was reduced by ∼20%. Moreover, it was revealed that GAD65 is crucial for maintenance of biosynthesis of synaptic GABA particularly by direct synthesis from astrocytic glutamine via glutamate. The GAD67 was found to be important for synthesis of GABA from glutamine both via direct synthesis and via a pathway involving mitochondrial metabolism. Furthermore, a severe neuronal hypometabolism, involving glycolysis and tricarboxylic acid (TCA) cycle activity, was observed in cerebral cortex of GAD65 knockout mice.

GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity.

GABA is synthesized from glutamate by glutamate decarboxylase (GAD), which exists in two isoforms, that is, GAD65 and GAD67. In line with GAD65 being located in the GABAergic synapse, several studies have demonstrated that this isoform is important during sustained synaptic transmission. In contrast, the functional significance of GAD65 in the maintenance of GABA destined for extrasynaptic tonic inhibition is less well studied. Using GAD65-/- and wild type GAD65+/+ mice, this was examined employing the cortical wedge preparation, a model suitable for investigating extrasynaptic GABA(A) receptor activity. An impaired tonic inhibition in GAD65-/- mice was revealed demonstrating a significant role of GAD65 in the synthesis of GABA acting extrasynaptically. The correlation between an altered tonic inhibition and metabolic events as well as the functional and metabolic role of GABA synthesized by GAD65 was further investigated in vivo. Tonic inhibition and the demand for biosynthesis of GABA were augmented by injection of kainate into GAD65-/- and GAD65+/+ mice. Moreover, [1-(13) C]glucose and [1,2-(13) C]acetate were administered to study neuronal and astrocytic metabolism concomitantly. Subsequently, cortical and hippocampal extracts were analyzed by NMR spectroscopy and mass spectrometry, respectively. Although seizure activity was induced by kainate, neuronal hypometabolism was observed in GAD65+/+ mice. In contrast, kainate evoked hypermetabolism in GAD65-/- mice exhibiting deficiencies in tonic inhibition. These findings underline the importance of GAD65 for synthesis of GABA destined for extrasynaptic tonic inhibition, regulating epileptiform activity.