Mitochondrial hypermetabolism precedes impaired autophagy and synaptic disorganization in App knock-in Alzheimer mouse models.

Accumulation of amyloid ß-peptide (Aß) is a driver of Alzheimer's disease (AD). Amyloid precursor protein (App) knock-in mouse models recapitulate AD-associated Aß pathology, allowing elucidation of downstream effects of Aß accumulation and their temporal appearance upon disease progression. Here we have investigated the sequential onset of AD-like pathologies in AppNL-F and AppNL-G-F knock-in mice by time-course transcriptome analysis of hippocampus, a region severely affected in AD. Strikingly, energy metabolism emerged as one of the most significantly altered pathways already at an early stage of pathology. Functional experiments in isolated mitochondria from hippocampus of both AppNL-F and AppNL-G-F mice confirmed an upregulation of oxidative phosphorylation driven by the activity of mitochondrial complexes I, IV and V, associated with higher susceptibility to oxidative damage and Ca2+-overload. Upon increasing pathologies, the brain shifts to a state of hypometabolism with reduced abundancy of mitochondria in presynaptic terminals. These late-stage mice also displayed enlarged presynaptic areas associated with abnormal accumulation of synaptic vesicles and autophagosomes, the latter ultimately leading to local autophagy impairment in the synapses. In summary, we report that Aß-induced pathways in App knock-in mouse models recapitulate key pathologies observed in AD brain, and our data herein adds a comprehensive understanding of the pathologies including dysregulated metabolism and synapses and their timewise appearance to find new therapeutic approaches for AD.

Clinical Value of 18F-FDOPA PET/CT With Contrast Enhancement and Without Carbidopa Premedication in Patients with Insulinoma.

AIM: We evaluated the clinical usefulness of 6-[18F]fluoro-3,4-dihydroxy-L-phenylalanine(18F-FDOPA)-positron-emission tomography (PET)/computed tomography (CT) in insulinoma detection with contrast enhancement, early acquisition time, and no carbidopa premedication. PATIENTS AND METHODS: Twenty-six patients diagnosed with hyperinsulinemic hypoglycemia underwent an 18F-FDOPA PET/CT examination. Patients without carbidopa premedication and contrast-enhanced CT were included. Imaging findings were compared to the overall final diagnosis (histological findings). RESULTS: In 10 of 26 patients (eight women, two men; mean age=53 years; age range=30-94 years), a detected lesion was confirmed histologically as an insulinoma. 18F-FDOPA PET detected the tumor in five out of ten patients. Contrast-enhanced CT also detected the tumor in five out of ten. Overall, 18F-FDOPA PET/CT, with contrast enhancement and without carbidopa premedication, was able to detect the insulinoma in seven out of ten patients (70%). CONCLUSION: Based on our data, 18F-DOPA PET/CT, with contrast enhancement and without carbidopa premedication, as a 'one-stop' diagnostic modality is a viable option for insulinoma detection.

Influence of a Pre-Exercise Glycerol Hydration Beverage on Performance and Physiologic Function During Mountain-Bike Races in the Heat.

OBJECTIVE: To determine if pre-exercise hydration with and without glycerol differentially affects physiologic and performance responses during mountain-bike races in the heat. DESIGN AND SETTING: Testing (random, crossover, double-blind design) included the following 3 treatments administered in conjunction with a 30-mile mountain-bike race consisting of three 10-mile (16-km) loops: (1) no water during exercise (NE): water consumed before the race and no water consumed during the race, (2) glycerol (G): mixture of water and glycerol consumed before the race and water via 2 water bottles consumed during the race, and (3) water (W): water consumed before the race and water via 2 water bottles consumed during the race. Subjects stopped for 8 minutes after each 10-mile loop for collection of data. SUBJECTS: Twelve heat-acclimated male mountain bikers with age = 24.5 +/- 1.1 years, percentage of body fat = 14.3 +/- 1.0%, mass = 76.9 +/- 1.9 kg, height = 179 +/- 2 cm. MEASUREMENTS: We measured body weight, percentage of body fat, rectal temperature, blood lactate, blood glucose, urine volume, urine color, urine specific gravity, thirst sensation, thermal sensation, rating of perceived exertion, fluid consumption, heart rate, and sweat rate. Each subject completed the Environmental Symptoms Questionnaire. RESULTS: The G trial was less dehydrated than the NE and W trials postexercise. Pre-exercise urine volume was less in the G trial than in the NE and W trials, and postexercise thirst was less in the G trial than the NE and W trials. Postexercise Environmental Symptoms Questionnaire scores were lower in the G trial than the NE or W trials. It is noteworthy that, although not significant, the G trial performed 5 minutes faster on loop 3 than the NE and W trials. CONCLUSIONS: Lower Environmental Symptoms Questionnaire scores and percentage of dehydration may indicate decreased signs and symptoms of heat strain in the G trial. Based on the NE trial performance, adequate pre-exercise hydration, even without glycerol, may limit the detrimental effects of dehydration.