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Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.

During starvation, brain energy metabolism in humans changes toward oxidation of ketone bodies. To investigate if this shift is directly coupled to circulating blood concentrations of ketone bodies, we measured global cerebral blood flow (CBF) and global cerebral carbohydrate metabolism with the Kety-Schmidt technique before and during intravenous infusion with ketone bodies. During acute hyperketonemia (mean beta-hydroxybutyrate blood concentration 2.16 mM), cerebral uptake of ketones increased from 1.11 to 5.60 mumol.100 g-1.min-1, counterbalanced by an equivalent reduction of the cerebral glucose metabolism from 25.8 to 17.2 mumol.100 g-1.min-1, with the net result being an unchanged cerebral uptake of carbohydrates. In accordance with this, global cerebral oxygen metabolism was not significantly altered (144 vs. 135 mumol.100 g-1.min-1). The unchanged global cerebral metabolic activity was accompanied by a 39% increase in CBF from 51.0 to 70.9 ml.100 g-1.min-1. Regional analysis of the glucose metabolism by positron emission tomography-[18F]fluoro-2-deoxy-D-glucose indicated that mesencephalon does not oxidize ketone bodies to the same extent as the rest of the brain. It was concluded that the immediate oxidation of ketone bodies induced a decrease in cerebral glucose uptake in spite of an adequate glucose supply to the brain. Furthermore, acute hyperketonemia caused a resetting of the coupling between CBF and metabolism that could not be explained by alterations in arterial CO2 tension or pH.

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The effect of hyperinsulinemia on glucose blood-brain barrier (BBB) transport and cerebral metabolism (CMRglc) was studied using the intravenous double-indicator method and positron emission tomography using [18F]fluorodeoxyglucose as tracer (PET-FDG). Sixteen normal healthy control subjects (25 +/- 4 years old) were studied twice during a euglycemic and a euglycemic-hyperinsulinemic condition. Our hypothesis was that high physiologic levels of insulin did not affect the BBB transport or net metabolism of glucose. During insulin infusion, arterial plasma insulin levels increased from 48.5 to 499.4 pmol/l. The permeability-surface area products for glucose and FDG BBB transport obtained with the double-indicator method remained constant during hyperinsulinemia. Similarly using PET-FDG, no changes were observed in the unidirectional clearance of FDG from blood to brain. k2* (FDG transport from brain to blood) increased significantly by 15 and 18% (gray and white matter, respectively), and k4* (dephosphorylation of FDG) increased by 18%. The increase in k2* may be caused by insulin inducing a decrease in the available FDG brain pool. The increase in k4* may be related to an increased loss of labeled products during insulin fusion. Irrespective of these changes, CMRglc remained unchanged in all brain regions. We conclude that hyperinsulinemia within the normal physiologic range does not affect BBB glucose transport or net cerebral glucose metabolism.

The blood-brain barrier (BBB) permeability for glucose and beta-hydroxybutyrate (beta-OHB) was studied by the intravenous double-indicator method in nine healthy subjects before and after 3.5 days of starvation. In fasting, mean arterial plasma glucose decreased and arterial concentration of beta-OHB increased, whereas cerebral blood flow remained unchanged. The permeability-surface area product for BBB glucose transport from blood to brain (PS1) increased by 55 +/- 31%, whereas no significant change in the permeability from brain back to blood (PS2) was found. PS1 for beta-OHB remained constant during starvation. The expected increase in PS1 due to the lower plasma glucose concentration was calculated to be 22% using previous estimates of maximal transport velocity and Michaelis-Menten affinity constant for glucose transport. The determined increase was thus 33% higher than the expected increase and can only be partially explained by the decrease in plasma glucose. It is concluded that a modest upregulation of glucose transport across the BBB takes place after starvation. Brain transport of beta-OHB did not decrease as expected from the largely increased beta-OHB arterial level. This might be interpreted as an increase in brain transport of beta-OHB, which could be caused by induction mechanisms, but the large nonsaturable component of beta-OHB transport makes such a conclusion difficult. However, beta-OHB blood concentration and beta-OHB influx into the brain increased by > 10 times. This implies that the influx of ketone bodies into the brain is largely determined by the amount of ketones present in the blood, and any condition in which ketonemia occurs will lead to an increased ketone influx.

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Summary: During prolonged starvation, brain energy re quirements are covered in part by the metabolism of ke tone bodies. It is unknown whether short-term starvation of a few days' duration may lead to reduced brain glucose metabolism due to the change toward ketone body con sumption. In the present study we measured the cerebral metabolism of glucose and ketone bodies in nine healthy volunteers before and after 3.5 days of starvation. Re gional glucose metabolism was measured by dynamic positron emission tomography using [18F]2-fluoro-2-deoxy-n-glucose. The mean value of Kj in gray and white matter increased by 12% (p < 0.05), whereas kj, and kj were unchanged compared with control values. Regional glucose metabolism in cortical gray matter was reduced by 26% from 0.294 ± 0.054 to 0.217 ± 0.040 IJ.mol g-I min-I (p < 0.001). White matter glucose metabolism de creased by 27% (p < 0.02). The decrease was uniform in Under normal physiological conditions, glucose is the only significant energy source of the human brain (Kety, 1957). Owen et ai. (1967) showed that in obese subjects ketone bodies accounted for �60% of the energy supply to the brain after 5-6 weeks of starvation, thus replacing glucose as the predominant source of energy. Positron emission tomography (PET) studies of glucose metabolism using eSF]2-fluoro-2-deoxY-D-glucose (FDG) in hu mans exposed to 3 weeks of starvation have con firmed the reduction in glucose metabolism by 125gray and white matter with regional decreases ranging from 24 to 30%. A determination using Fick's principle confirmed the reduction in glucose metabolism yielding a decrease of 24% from 0.307 ± 0.050 to 0.233 ± 0.073 IJ.mol g -I min -I (p < 0.05), whereas CBF did not change (0.57 ± 0.07 vs. 0.57 ± 0.06 ml g-I min -I). The global net uptake of �-hydroxybutyrate increased 13-fold from 0.012 ± 0.024 to 0.155 ± 0.140 IJ.mol g-I min-I (p < 0.05). Net uptake of acetoacetate and net efflux of lactate and pyruvate did not change significantly during starva tion. The present study shows that the human brain adapts to the changes in energy supply as early as 3 days following initiation of starvation, at which time ketone bodies account for approximately one-fourth of the cere bral energy requirements. Key Words: Brain energy re quirements-Ketone bodies-Starvation.showing a 50% decrease in glucose tracer phosphor ylation and a 54% reduction of glucose utilization (Redies et aI., 1989). Thus, it seems established that during prolonged starvation in humans, glucose net uptake and utilization are reduced, as well as that ketone bodies supply a large fraction of the brain's energy demand. In contrast to human studies of long-term starvation, animal experiments have es sentially shown no reduction in glucose metabolism as a result of short-term starvation (few days) (Ru derman et aI., 1974;Gjedde and Crone, 1975; Cord dry et aI., 1982; Crane et aI., 1985; Cherel et aI., 1988). Furthermore, in the rat brain following 2 days of starvation, Hawkins et ai. (1986a) reported a ketone body util...