In vivo X-Nuclear MRS Imaging Methods for Quantitative Assessment of Neuroenergetic Biomarkers in Studying Brain Function and Aging

Brain relies on glucose and oxygen metabolisms to generate biochemical energy in the form of adenosine triphosphate (ATP) for supporting electrophysiological activities and neural signaling under resting or working state. Aging is associated with declined mitochondrial functionality and decreased cerebral energy metabolism, and thus, is a major risk factor in developing neurodegenerative diseases including Alzheimer’s disease (AD). However, there is an unmet need in the development of novel neuroimaging tools and sensitive biomarkers for detecting abnormal energy metabolism and impaired mitochondrial function, especially in an early stage of the neurodegenerative diseases. Recent advancements in developing multimodal high-field in vivo X-nuclear (e.g., 2H, 17O and 31P) MRS imaging techniques have shown promise for quantitative and noninvasive measurement of fundamental cerebral metabolic rates of glucose and oxygen consumption, ATP production as well as nicotinamide adenine dinucleotide (NAD) redox state in preclinical animal and human brains. These metabolic neuroimaging measurements could provide new insights and quantitative bioenergetic markers associated with aging processing and neurodegeneration and can therefore be employed to monitor disease progression and/or determine effectiveness of therapeutic intervention

Lokalisierte Quantifizierung des zerebralen Sauerstoffumsatzes (CMRO2) mit der 17O-Magnetresonanztomographie

Der zerebrale Sauerstoffumsatz (CMRO2) ist ein wichtiger Indikator für die Gesundheit und Lebensfähigkeit von Gewebe. In dieser Arbeit wird ein 17O-Inhalations- und Messverfahren präsentiert, mit dem der CMRO2 mit der 17O-MR-Bildgebung bei B0 =7T ortsaufgelöst quantifiziert werden kann. Auf Grund der geringen MR-Sensitivität des 17O-Kerns sind hierfür spezielle Bildgebungstechniken notwendig. Für die Optimierung der Bildgebung wurden zuerst die In-vivo-17O-Relaxationszeiten am Kopf gemessen; in globalen Messungen wurden Mittelwerte von T1 =(5,8±0,2) ms und T2 =(3,5±0,3) ms, in einer ortsaufgelösten Messung für Hirngewebe T2 =(2,0±0,2) ms gefunden. 17O-MRBildgebungstechniken wurden bei B0 =7T für dynamische Messungen optimiert. Es konnte gezeigt werden, dass ein 3D-Datensatz des Gehirns mit SNR>20 und einer nominellen räumlichen Auflösung von V =(5,0mm)3 in 10 min akquiriert werden kann. Zusätzlich wurde ein effizientes Atemsystem entwickelt und in einem Inhalationsexperiment zur Gabe von 70% angereichertem 17O-Gas (V =(2,2±0,34) l) an einem gesunden Probanden eingesetzt. Im Gehirn konnte während der Inhalation des 17O2 ein ortsabhängiger 17O-Signalanstieg von 10-30% detektiert werden, der in Arealen grauer Substanz 40% über dem für Bereiche weißer Substanz lag. Basierend auf einem mathematischen Modell zur Beschreibung der 17O2-Metabolisierung wurden Modellgleichungen für den 17O-Signalverlauf während des durchgeführten Inhalationsexperiments formuliert. Mit Hilfe dieses Modells konnte der CMRO2 in Regionen weißer / grauer Hirnsubstanz zu CMRO2 =((0,83±0,14) / (1,65±0,29)) μmol/g·min quantifiziert werden. Diese Werte zeigen eine gute Übereinstimmung mit Literaturwerten aus 15O-PET-Untersuchungen

Direct imaging of glymphatic flow using H217O MRI

The recently proposed glymphatic pathway for solute transport and waste clearance from the brain has been the focus of intense debate. By exploiting an isotopically enriched MRI tracer, H217O, we directly imaged glymphatic water transport in the rat brain in vivo for the first time. Our results reveal glymphatic transport that is dramatically faster and more extensive than previously thought and unlikely to be explained by diffusion alone. Moreover, we confirm the critical role of aquaporin-4 channels in glymphatic transport

Importance of CSF circulation following ischaemic stroke: A novel MRI investigation of CSF parenchymal flow

It has been proposed that intracranial pressure (ICP) elevation and collateral failure are responsible for unexplained early neurological deterioration (END) in stroke. Our aim was to investigate whether cerebrospinal fluid (CSF) dynamics, rather than oedema, are responsible for elevation of ICP after ischaemic stroke. Permanent middle cerebral artery occlusion (pMCAO) was induced with an intraluminal filament. At 24 hours after stroke, baseline ICP was measured, and CSF dynamics were probed via a steady-state infusion method. For the first time, we found a significant correlation between the baseline ICP at 24 hours post-stroke and the value of CSF outflow resistance. Results show that CSF outflow resistance, rather than oedema, was the mechanism responsible for ICP elevation following ischaemic stroke. This challenges current concepts and suggests the possibility that intracranial hypertension may be occurring undetected in a much wider range of stroke patients than is currently considered to be the case. Over the last decade, there has been significant renewed interest in the anatomical pathways and physiological mechanisms for the circulation of CSF. The glymphatic system is one such pathway that has been recently characterised. This network drives CSF into the brain along periarterial spaces and interstitial fluid (ISF) out along perivenous spaces. Aquaporin-4 (AQP4) water channels, densely expressed at the vascular endfeet of astrocytes, facilitate glymphatic transport. Glymphatic failure has been linked to a broad range of neurodegenerative diseases including ischaemic stroke. Accordingly, if the glymphatic circulation is a major outflow route for CSF, glymphatic dysfunction following ischaemic stroke could alter CSF dynamics and, therefore, ICP. Nevertheless, the glymphatic hypothesis is still controversial. All in vivo and biomechanical modelling studies that have investigated the glymphatic system have been based on utilizing a solute tracer to track the movement of CSF within the intracranial space. Since 99% of CSF is water, it is questionable whether nonwater tracer molecules can ever show the real dynamic flow of CSF. Hence, we sought the develop of a new MRI method to directly image CSF dynamics in-vivo, by exploiting an isotopically enriched MRI tracer, namely, H217O. Our results reveal glymphatic flow that is dramatically faster and more extensive than previously thought. Moreover, we confirm the critical role of aquaporin-4 (AQP4) channels in glymphatic flow by imaging CSF water dynamics in the brain using H217O alongside a potent blocker of AQP4. We hope in future that this new method can be used to investigate the responsible mechanism for the increased CSF resistance and ICP elevation following ischaemic stroke

45th Rocky Mountain Conference on Analytical Chemistry

Final program, abstracts, and information about the 45th annual meeting of the Rocky Mountain Conference on Analytical Chemistry, co-endorsed by the Colorado Section of the American Chemical Society and the Rocky Mountain Section of the Society for Applied Spectroscopy. Held in Denver, Colorado, July 27-31, 2003

43rd Rocky Mountain Conference on Analytical Chemistry

Final program, abstracts, and information about the 43rd annual meeting of the Rocky Mountain Conference on Analytical Chemistry, co-sponsored by the Colorado Section of the American Chemical Society and the Rocky Mountain Section of the Society for Applied Spectroscopy. Held in Denver, Colorado, July 29 - August 2, 2001