Rationale: Endothelial cells (ECs) are highly glycolytic and generate the majority of their energy via the breakdown of glucose to lactate. At the same time, a main role of ECs is to allow the transport of glucose to the surrounding tissues. The facilitative glucose transporter isoform 1 (GLUT1/Slc2a1) is highly expressed in ECs of the central nervous system (CNS), and is often implicated in blood-brain barrier (BBB) dysfunction, but whether and how GLUT1 controls EC metabolism and function is poorly understood. Objective: We evaluated the role of GLUT1 in endothelial metabolism and function during postnatal CNS development as well as at the adult BBB. Methods and Results: Inhibition of GLUT1 decreases EC glucose uptake and glycolysis, leading to energy depletion and the activation of the cellular energy sensor AMPK, and decreases EC proliferation without affecting migration. Deletion of GLUT1 from the developing postnatal retinal endothelium reduces retinal EC proliferation and lowers vascular outgrowth, without affecting the number of tip cells. In contrast, in the brain, we observed a lower number of tip cells in addition to reduced brain EC proliferation, indicating that within the CNS, organotypic differences in EC metabolism exist. Interestingly, when ECs become quiescent, endothelial glycolysis is repressed and GLUT1 expression increases in a Notch-dependent fashion. GLUT1 deletion from quiescent adult ECs leads to severe seizures, accompanied by neuronal loss and CNS inflammation. Strikingly, this does not coincide with BBB leakiness, altered expression of genes crucial for BBB barrier functioning nor reduced vascular function. Instead, we found a selective activation of inflammatory and extracellular matrix (ECM) related gene sets. Conclusions: GLUT1 is the main glucose transporter in ECs and becomes uncoupled from glycolysis during quiescence in a Notch-dependent manner. It is crucial for developmental CNS angiogenesis and adult CNS homeostasis but does not affect BBB barrier function.

The purinergic P2X7 receptor is a key mediator in (neuro)inflammation, a process that is associated with neurodegeneration and excitotoxicity in Parkinson’s disease (PD). Recently, P2X7 imaging has become possible with [ 11 C]JNJ-(54173)717. We investigated P2X7 availability, in comparison with availability of the translocator protein (TSPO), in two well-characterized rat models of PD using in vitro autoradiography at multiple time points throughout the disease progression. Rats received either a unilateral injection with 6-hydroxydopamine (6-OHDA) in the striatum, or with recombinant adeno-associated viral vector overexpressing human A53T alpha-synuclein (α-SYN) in the substantia nigra. Transverse cryosections were incubated with [ 11 C]JNJ-717 for P2X7 or [ 18 F]DPA-714 for TSPO. [ 11 C]JNJ-717 binding ratios were transiently elevated in the striatum of 6-OHDA rats at day 14–28 post-injection, with peak P2X7 binding at day 14. This largely coincided with the time course of striatal [ 18 F]DPA-714 binding which was elevated at day 7–21, with peak TSPO binding at day 7. Increased P2X7 availability co-localized with microglial, but not astrocyte or neuronal markers. In the chronic α-SYN model, no significant differences were found in P2X7 binding, although in vitro TSPO overexpression was reported previously. This first study showed an increased P2X7 availability in the acute PD model in a time window corresponding with elevated TSPO binding and motor behavior changes. In contrast, the dynamics of TSPO and P2X7 were divergent in the chronic α-SYN model where no P2X7 changes were detectable. Overall, extended P2X7 phenotyping is warranted prior to implementation of P2X7 imaging for monitoring of neuroinflammation.

Purpose: The endocannabinoid system plays a regulatory role in a number of physiological functions, including motor control but also mood, emotion and cognition. A number of preclinical studies in Parkinson´s disease (PD) models demonstrated that modulating the type 1 cannabinoid receptor (CB1R) may improve motor symptoms and components of cognitive processing. However, the relation between CB1R, cognitive decline and behavioral symptoms has not been investigated in PD patients so far. The aim of this study was to examine whether CB1R availability is associated with measures of cognitive and behavioral function in PD patients.Methods: Thirty-eight PD patients and ten age-and gender-matched controls underwent a [ 18 F]MK-9470 PET scan to assess CB1R availability, as well as volumetric MR imaging. Neuropsychological symptoms were evaluated using an extensive cognitive and behavioral battery covering the five cognitive domains, depression, anxiety, apathy and psychiatric complications, and were correlated to CB1R availability using vowel-wise regression analysis (P<0.05, corrected for familywise error).Results: PD patients with poorer performance in episodic memory, executive functioning, speed and mental flexibility (range P: 0.003-0.03) showed lower CB1R availability in predominantly the midcingulate cortex and middle to superior frontal gyrus (Tpeak-level>4.0). Also, PD patients with more severe visuospatial dysfunction showed decreased CB1R availability in the precuneus, midcingulate, supplementary motor cortex, inferior orbitofrontal gyrus and thalamus (Tpeak-level=5.5). These correlations were not related to cortical grey matter atrophy. No relationship was found between CB1R availability and mood or behavioral symptom scores.Conclusions: Decreased CB1R availability in the prefrontal and midcingulate cortex in PD patients is strongly correlated with disturbances in executive functioning, episodic memory and visuospatial functioning. Further investigation of regional CB1R expression in groups of PD patients with mild cognitive impairment or dementia is warranted in order to further investigate the role of CB1R expression in different levels of cognitive impairment in PD.

Several lines of evidence point to alterations in glutamatergic signaling in Parkinson's disease (PD) and levodopa-induced dyskinesia (LID), involving the metabotropic glutamate receptor type 5 (mGluR5). Using small-animal positron emission tomography (PET) with [F]FPEB and proton magnetic resonance spectroscopy, we investigated cerebral changes in the mGluR5 and glutamate/glutamine availability in vivo in PD rats and following onset of LIDs. In parallel, behavioral tests were performed. Comparing PD to control rats, mGluR5 binding potential was decreased in a cluster comprising the bilateral caudate-putamen (CP), ipsilateral motor cortex and somatosensory cortex, and the contralateral somatosensory cortex and parietal association cortex, with the most pronounced reduction in the ipsilateral CP. mGluR5 binding potentials were not significantly altered upon levodopa (L-DOPA) treatment. However, following L-DOPA, an increase in relative mGluR5 uptake was present in the contralateral motor cortex and somatosensory cortex. Glutamate and glutamine concentrations did not differ between control and untreated PD rats or between hemispheres. Though, glutamine levels were higher in the contralateral CP of saline- and L-DOPA-treated rats as compared to the ipsilateral side. Relative mGluR5 uptake in the CP of levodopa-treated rats was also found positively correlated with abnormal involuntary movement scores. Conclusively, mGluR5 availability and glutamine concentrations in the CP are involved in PD, whereas mGluR5 availability in cortical regions may be involved in LID pathology.

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The exposure of the fingers is one of the major radiation protection concerns in nuclear medicine (NM). The purpose of this paper is to provide an overview of the exposure, dosimetry and protection of the extremities in NM. A wide range of reported finger doses were found in the literature. Historically, the highest finger doses are found at the fingertip in the preparation and dispensing of 18F for diagnostic procedures and 90Y for therapeutic procedures. Doses can be significantly reduced by following recommendations on source shielding, increasing distance and training. Additionally, important trends contributing to a lower dose to the fingers are the use of automated procedures (especially for positron emission tomography (PET)) and the use of prefilled syringes. On the other hand, the workload of PET procedures has substantially increased during the last ten years. In many cases, the accuracy of dose assessment is limited by the location of the dosimeter at the base of the finger and the maximum dose at the fingertip is underestimated (typical dose ratios between 1.4 and 7). It should also be noted that not all dosimeters are sensitive to low-energy beta particles and there is a risk for underestimation of the finger dose when the detector or its filter is too thick. While substantial information has been published on the most common procedures (using 99mTc, 18F and 90Y), less information is available for more recent applications, such as the use of 68Ga for PET imaging. Also, there is a need for continuous awareness with respect to contamination of the fingers, as this factor can contribute substantially to the finger dose.

Currently TAR DNA binding protein 43 (TDP-43) pathology, underlying Amyotrophic Lateral Sclerosis (ALS), remains poorly understood which hinders both clinical diagnosis and drug discovery efforts. To better comprehend the disease pathophysiology, positron emission tomography (PET) and multi-parametric magnetic resonance imaging (mp-MRI) provide a non-invasive mode to investigate molecular, structural, and neurochemical abnormalities in vivo . For the first time, we report the findings of a longitudinal PET-MR study in the TDP-43 A315T ALS mouse model, investigating disease-related changes in the mouse brain. 2-deoxy-2-[ 18 F]fluoro-D-glucose [ 18 F]FDG PET showed significantly lowered glucose metabolism in the motor and somatosensory cortices of TDP-43 A315T mice whereas metabolism was elevated in the region covering the bilateral substantia nigra, reticular and amygdaloid nucleus between 3 and 7 months of age, as compared to non-transgenic controls. MR spectroscopy data showed significant changes in glutamate + glutamine (Glx) and choline levels in the motor cortex and hindbrain of TDP-43 A315T mice compared to controls. Cerebral blood flow (CBF) measurements, using an arterial spin labelling approach, showed no significant age- or group-dependent changes in brain perfusion. Diffusion MRI indices demonstrated transient changes in different motor areas of the brain in TDP-43 A315T mice around 14 months of age. Cytoplasmic TDP-43 proteinaceous inclusions were observed in the brains of symptomatic, 18-month-old mice, but not in non-symptomatic transgenic or wild-type mice. Our results reveal that disease- and age-related functional and neurochemical alterations, together with limited structural changes, occur in specific brain regions of transgenic TDP-43 A315T mice, as compared to their healthy counterparts. Altogether these findings shed new light on TDP-43 A315T disease pathogenesis and may prove useful for clinical management of ALS.

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