Anatomic & metabolic brain markers of the m.3243A>G mutation: A multi-parametric 7T MRI study

One of the most common mitochondrial DNA (mtDNA) mutations, the A to G transition at base pair 3243, has been linked to changes in the brain, in addition to commonly observed hearing problems, diabetes and myopathy. However, a detailed quantitative description of m.3243A>G patients' brains has not been provided so far. In this study, ultra-high field MRI at 7T and volume- and surface-based data analyses approaches were used to highlight morphology (i.e. atrophy)-, microstructure (i.e. myelin and iron concentration)- and metabolism (i.e. cerebral blood flow)-related differences between patients (N = 22) and healthy controls (N = 15). The use of quantitative MRI at 7T allowed us to detect subtle changes of biophysical processes in the brain with high accuracy and sensitivity, in addition to typically assessed lesions and atrophy. Furthermore, the effect of m.3243A>G mutation load in blood and urine epithelial cells on these MRI measures was assessed within the patient population and revealed that blood levels were most indicative of the brain's state and disease severity, based on MRI as well as on neuropsychological data. Morphometry MRI data showed a wide-spread reduction of cortical, subcortical and cerebellar gray matter volume, in addition to significantly enlarged ventricles. Moreover, surface-based analyses revealed brain area-specific changes in cortical thickness (e.g. of the auditory cortex), and in T1, T2* and cerebral blood flow as a function of mutation load, which can be linked to typically m.3243A>G-related clinical symptoms (e.g. hearing impairment). In addition, several regions linked to attentional control (e.g. middle frontal gyrus), the sensorimotor network (e.g. banks of central sulcus) and the default mode network (e.g. precuneus) were characterized by alterations in cortical thickness, T1, T2* and/or cerebral blood flow, which has not been described in previous MRI studies. Finally, several hypotheses, based either on vascular, metabolic or astroglial implications of the m.3243A>G mutation, are discussed that potentially explain the underlying pathobiology. To conclude, this is the first 7T and also the largest MRI study on this patient population that provides macroscopic brain correlates of the m.3243A>G mutation indicating potential MRI biomarkers of mitochondrial diseases and might guide future (longitudinal) studies to extensively track neuropathological and clinical changes

Acute inorganic nitrate intake increases regional insulin action in the brain:Results of a double-blind, randomized, controlled cross-over trial with abdominally obese men

Aims: Improving brain insulin sensitivity may be a promising approach in the prevention and treatment of metabolic and cognitive diseases. Our aim was to investigate acute effects of inorganic nitrate on regional cerebral blood flow (CBF) responses to intranasal insulin in abdominally obese men. Methods: Eighteen apparently healthy men, aged 18–60 years and with a waist circumference ≥ 102 cm, participated in a randomized, double-blind, placebo-controlled cross-over trial. The study consisted of two test days separated by at least one week. Men received in random order a drink providing 10 mmol (i.e., 625 mg nitrate) potassium nitrate or an isomolar placebo drink with potassium chloride. Brain insulin action was assessed 120–150 min after the drinks by quantifying acute effects of nasal insulin on regional CBF using arterial spin labeling Magnetic Resonance Imaging. Glucose and insulin concentrations were measured at regular intervals, while blood pressure was determined fasted and at 240 min. Results: Inorganic nitrate intake increased regional insulin action in five brain clusters. The two largest clusters were located in the right temporal lobe (ΔCBF: 7.0 ± 3.8 mL/100 g/min, volume: 5296 mm3, P < 0.001; and ΔCBF: 6.5 ± 4.3 mL/100 g/min, volume: 3592 mm3, P < 0.001), while two other cortical clusters were part of the right frontal (ΔCBF: 9.0 ± 6.0 mL/100 g/min, volume: 1096 mm3, P = 0.007) and the left parietal lobe (ΔCBF: 6.1 ± 4.3 mL/100 g/min, volume: 1024 mm3, P = 0.012). One subcortical cluster was located in the striatum (ΔCBF: 5.9 ± 3.2 mL/100 g/min, volume: 1792 mm3, P < 0.001). No effects of nitrate were observed on CBF before administration. Following nitrate intake, circulating nitrate plus nitrite concentrations increased over time (P = 0.003), but insulin and glucose concentrations and blood pressure did not change. Conclusion: Acute inorganic nitrate intake may improve regional brain insulin action in abdominally obese men. These regions are involved in the regulation of different metabolic and cognitive processes.The trial was registered on January 6th, 2021 at ClinicalTrials.gov as NCT04700241

Aerobic Exercise Training Improves Cerebral Blood Flow and Executive Function:A Randomized, Controlled Cross-Over Trial in Sedentary Older Men

Background Physical activity may attenuate age-related cognitive decline by improving cerebrovascular function. The aim of this study was therefore to investigate effects of aerobic exercise training on cerebral blood flow (CBF), which is a sensitive physiological marker of cerebrovascular function, in sedentary older men. Methods Seventeen apparently healthy men, aged 60-70 years and with a BMI between 25 and 35 kg/m(2), were included in a randomized, controlled cross-over trial. Study participants were randomly allocated to a fully-supervised, progressive, aerobic exercise training or no-exercise control period for 8 weeks, separated by a 12-week wash-out period. Measurements at the end of each period included aerobic fitness evaluated using peak oxygen consumption during incremental exercise (VO2peak), CBF measured with pseudo-continuous arterial spin labeling magnetic resonance imaging, and post-load glucose responses determined using an oral glucose tolerance test (OGTT). Furthermore, cognitive performance was assessed in the domains of executive function, memory, and psychomotor speed. Results VO2peak significantly increased following aerobic exercise training compared to no-exercise control by 262 +/- 236 mL (P <0.001). CBF was increased by 27% bilaterally in the frontal lobe, particularly the subcallosal and anterior cingulate gyrus (cluster volume: 1008 mm(3); P <0.05), while CBF was reduced by 19% in the right medial temporal lobe, mainly temporal fusiform gyrus (cluster volume: 408 mm(3); P <0.05). Mean post-load glucose concentrations determined using an OGTT decreased by 0.33 +/- 0.63 mmol/L (P = 0.049). Furthermore, executive function improved as the latency of response was reduced by 5% (P = 0.034), but no changes were observed in memory or psychomotor speed. Conclusion Aerobic exercise training improves regional CBF in sedentary older men. These changes in CBF may underlie exercise-induced beneficial effects on executive function, which could be partly mediated by improvements in glucose metabolism. This clinical trial is registered on as NCT03272061

Novel insights into hippocampal perfusion using high-resolution, multi-modal 7T MRI

We present a comprehensive study on the non-invasive measurement of hippocampal perfusion. Using high-resolution 7 Tesla arterial spin labelling data, we generated robust perfusion maps and observed significant variations in perfusion among hippocampal subfields, with CA1 exhibiting the lowest perfusion levels. Notably, these perfusion differences were robust and detectable even within five minutes and just fifty perfusion-weighted images per subject. To understand the underlying factors, we examined the influence of image quality metrics, various tissue microstructure and morphometry properties, macrovasculature and cytoarchitecture. We observed higher perfusion in regions located closer to arteries, demonstrating the influence of vascular proximity on hippocampal perfusion. Moreover, cytoarchitectonic features based on neuronal density differences appeared to correlate stronger with hippocampal perfusion than morphometric measures like gray matter thickness. These findings emphasize the interplay between microvasculature, macrovasculature, and metabolic demand in shaping hippocampal perfusion. Our study expands the current understanding of hippocampal physiology and its relevance to neurological disorders. By providing evidence of perfusion differences between hippocampal subfields, our findings have implications for diagnosis and potential therapeutic interventions. In conclusion, our study provides a valuable resource for extensively characterising hippocampal perfusion