The new FDG brain revolution: the neurovascular unit and the default network

Abstract

"Our aim is, more than see new things, to see with new eyes what has already been seen" Baruch SpinozaThe first FDG brain revolutionThe first revolution was explosive. Using 18 F-fluorodeoxyglucose (FDG), it was possible to see and study the living brain in humans! Pioneers were top experts who provided different specialized expertise, but strictly cooperating between themselves [1]. Physicists, engineers and mathematicians were actively involved in producing the best hardware and software. The research on crystals, in identifying the most effective electronics, in defining accurate methods for attenuation and scatter correction and so on, was nevertheless limited by the relatively poor technology, with the main consideration being limited computer power. These developments stimulated a major interest in the brain. Satisfactory sensitivity and resolution, together with reliable solutions to the technical problems, were only achieved with dedicated cerebral PET scanners which had a field of view that permitted exclusive analysis of the brain.Basic scientists had the possibility of realizing a scientific dream: the transfer of data on cerebral glucose metabolism acquired in animals by quantitative autoradiography to humans. Another issue in the original FDG PET research was to consider mandatory absolute quantification. Thus arterial (or arterialized) sampling, to obtain data to be included in mathematical models, was routinely performed. However, because the equations included nonmeasurable parameters, the presence of a lumped constant affected absolute measurement in an individual [2][3][4]. PET teams included (and were directed by) clinical experts including not only nuclear physicians, but also other professionals such as neuroradiologists, neurologists and psychiatrists, who frequently cooperated with psychologists, anatomists and physiologists.Because of the unsatisfactory spatial resolution and the negative influence of the partial volume effect, in presence of glucose uptake in the normal brain, only a low lesion/background ratio was achievable, except for hot spots, i.e. the presence of focal areas of increased uptake determined by physiological and/or pathological causes. Therefore, the use of FDG as a positive indicator was restricted in the first studies and in the search for hot spots, many studies involved physiological stimulation tests (closed/open eyes, auditory system, etc.) in normal subjects [5,6]. Similarly, major interest in pathological analysis was directed to the evaluation of brain tumours, starting from Warburg's hypothesis of higher FDG uptake in malignant lesions with respect to benign ones [7]. With further clinical experience, in the analysis of patients with epilepsy, a higher sensitivity was clearly demonstrated during the ictal phase, the focus being seen as a hot spot, with respect to the interictal period when the lesion was not easily detectable, being an area with a slightly reduced overall FDG uptake [8,9]. Discrepant results in epilepsy clearly demonstrate how, in the absenc...

Brain imaging of neurovascular dysfunction in Alzheimer’s disease

“…Metabolic patterns of FDG-PET uptake have also been shown to discriminate between individuals with normal cognition, MCI, and clinical AD [100, 102]. Measurements derived from FDG-PET do not simply reflect neuronal activity but are impacted by principles of neurovascular coupling involving vascular, astroglial, and neuronal cells, and dynamic CBF [96, 149]. For instance, vasodilation is believed to be a response to neural activity but is impacted by the control of astrocytes on cerebral microcirculation [84, 132].…”

From Homo sapiens to Homo in nexu (connected man): could functional imaging redefine the brain of a “new human species”?

“…In this issue Tian et al [1] report that PET can be used to reveal brain functional changes in subjects with internet gaming disorder (IGD), using either N-methylspiperone ( 11 C-NMSP), to assess the availability of D2/5-HT2A receptors, or 18 Ffluoro-D-glucose ( 18 F-FDG). Twelve drug-naive men who met the criteria for IGD and 14 matched controls were studied under both resting and internet gaming task states, playing World of Warcraft, one of the most widely recognized "massively multiplayer online role-playing games" (MMORPG), which showed a compulsive behaviour in many people worldwide.…”

“…A significant improvement in FDG PET could be achieved from a more rigorous and reliable methodological approach, including quantitative analysis [17] and a better understanding of glucose metabolic rate resulting from the activity of astrocytes/neuroglia, more than of neurons [18]. Further developments could be achieved from a deeper knowledge of mirror neurons, that fire both when an animal acts and when an animal observes the same action performed by another [19].…”

Resting metabolic connectivity in Alzheimer’s disease

“…In the field of degenerative dementias, specifically that of AD, FDG PET plays a major clinical role by showing (or not) a disease-specific pattern of hypometabolism thought to correspond broadly to the brain regions damaged in the earliest stages of the disease [28], which are, interestingly, part of the DMN. However, 18 F-FDG studies both in patients with neurodegenerative diseases [29] and in patients with brain tumors [27,30] also revealed hypometabolism in brain areas neurally connected to the structurally damaged site. This phenomenon, called diaschisis, is well evident also in the clinical single-patient setting and implies that 18 F-FDG PET is capable of identifying functional alterations determined by the loss of neuronal connections.…”

“…Indeed, the high energy demands of neuronal synaptic activity are met by the provision of lactate through glia cells, leading to increased glucose consumption in these cells [26]. In particular, when 18 F-FDG PET is performed at rest, glucose uptake distribution is driven mainly by basal neuronal glutamatergic activity and, therefore, provides an index of general neural integrity [27]. Thus, glucose metabolism has been shown to be closely coupled to neuronal function both at rest and during functional activation [26].…”