Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma: an operational approach for clinical trials.

An operationalized workflow paradigm is presented and validated with pilot subject data. This approach is reproducible with a high concordance rate between individual readers (kappa 0.73 [confidence interval 0.59-0.87; P=<0.0001]) using a 5-point scale to assess [18F] labeled fluorodeoxyglucose metabolic activity in lymphomatous lesions. These results suggest an operationally practical 5-point scale workflow paradigm for potential use in larger clinical trials evaluating lymphoma therapeutics.

Companion diagnostics and molecular imaging-enhanced approaches for oncology clinical trials.

In the era of personalized medicine, diagnostic approaches are helping pharmaceutical and biotechnology sponsors streamline the clinical trial process. Molecular assays and diagnostic imaging are routinely being used to stratify patients for treatment, monitor disease, and provide reliable early clinical phase assessments. The importance of diagnostic approaches in drug development is highlighted by the rapidly expanding global cancer diagnostics market and the emergent attention of regulatory agencies worldwide, who are beginning to offer more structured platforms and guidance for this area. In this paper, we highlight the key benefits of using companion diagnostics and diagnostic imaging with a focus on oncology clinical trials. Nuclear imaging using widely available radiopharmaceuticals in conjunction with molecular imaging of oncology targets has opened the door to more accurate disease assessment and the modernization of standard criteria for the evaluation, staging, and treatment responses of cancer patients. Furthermore, the introduction and validation of quantitative molecular imaging continues to drive and optimize the field of oncology diagnostics. Given their pivotal role in disease assessment and treatment, the validation and commercialization of diagnostic tools will continue to advance oncology clinical trials, support new oncology drugs, and promote better patient outcomes.

Striatal dopamine in bulimia nervosa: a PET imaging study.

OBJECTIVE: Bulimia nervosa (BN) has been characterized as similar to an addiction, though the empirical support for this characterization is limited. This study utilized PET imaging to determine whether abnormalities in brain dopamine (DA) similar to those described in substance use disorders occur in BN. METHOD: PET imaging with [(11) C]raclopride, pre/post methylphenidate administration, to assess dopamine type 2 (D(2)) receptor binding (BP(ND)) and striatal DA release (ΔBP(ND)). RESULTS: There was a trend toward lower D(2) receptor BP(ND) in two striatal subregions in the patient group when compared with the control group. DA release in the putamen in the patient group was significantly reduced and, overall, there was a trend toward a difference in striatal DA release. Striatal DA release was significantly associated with the frequency of binge eating. DISCUSSION: These data suggest that BN is characterized by abnormalities in brain DA that resemble, in some ways, those described in addictive disorders.

Deficits in dopamine D(2) receptors and presynaptic dopamine in heroin dependence: commonalities and differences with other types of addiction.

BACKGROUND: Positron emission tomography (PET) imaging studies have shown that addiction to a number of substances of abuse is associated with a decrease in dopamine D(2/3) receptor binding and decreased presynaptic dopamine release in the striatum. Some studies have also shown that these reductions are associated with the severity of addiction. For example, in cocaine dependence, low dopamine release is associated with the choice to self-administer cocaine. The goal of the present study was to investigate these parameters of striatal dopamine transmission in heroin dependence and their association with drug seeking behavior. METHODS: Heroin-dependent and healthy control subjects were scanned with [(11)C]raclopride before and after stimulant administration (methylphenidate) to measure striatal D(2/3) receptor binding and presynaptic dopamine release. After the PET scans, the heroin-dependent subjects performed heroin self-administration sessions. RESULTS: Both striatal D(2/3) receptor binding and dopamine release were reduced in the heroin-dependent subjects compared with healthy control subjects. However, neither PET measure of dopamine transmission predicted the choice to self-administer heroin. CONCLUSIONS: These findings show that heroin addiction, like addiction to other drugs of abuse, is associated with low D(2/3) receptor binding and low presynaptic dopamine. However, neither of these outcome measures was associated with the choice to self-administer heroin.

Imaging dopamine transmission in cocaine dependence: link between neurochemistry and response to treatment.

OBJECTIVE: Previous research has shown that dopamine signaling in the limbic striatum is crucial for selecting adaptive, motivated behavior and that disrupted dopamine transmission is associated with impulsive and maladaptive behavior. In humans, positron emission tomography (PET) imaging studies have shown that cocaine dependence is associated with the dysregulation of striatal dopamine signaling, which is linked to cocaine-seeking behavior. The goal of the present study was to investigate whether this association applies to the treatment setting. The authors hypothesized that dopamine signaling in the limbic striatum would be associated with response to a behavioral treatment that uses positive reinforcement to replace impulsive cocaine use with constructive personal goals. METHOD: Prior to treatment, cocaine-dependent subjects underwent two PET scans using [(11)C]raclopride, before and after the administration of a stimulant (methylphenidate), for measurement of striatal dopamine D(2/3) receptor binding and presynaptic dopamine release. RESULTS: Both of the outcome measures were lower in the volunteers who did not respond to treatment than in those who experienced a positive treatment response. CONCLUSIONS: These findings provide insight into the neurochemistry of treatment response and show that low dopamine transmission is associated with treatment failure. In addition, these data suggest that the combination of behavioral treatment with methods that increase striatal dopamine signaling might serve as a therapeutic strategy for cocaine dependence.

(99m)Tc hexamethyl-propylene-aminoxime single-photon emission computed tomography prediction of conversion from mild cognitive impairment to Alzheimer disease.

OBJECTIVE: To examine the utility of single-photon emission computed tomography (SPECT) to predict conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). DESIGN: Longitudinal, prospective study. SETTING: University-based memory disorders clinic. PARTICIPANTS: One hundred twenty seven patients with MCI and 59 healthy comparison subjects followed up for 1-9 years. MEASUREMENTS: Diagnostic evaluation, neuropsychological tests, social/cognitive function, olfactory identification, apolipoprotein E genotype, magnetic resonance imaging, and brain Tc hexamethyl-propylene-aminoxime SPECT scan with visual ratings, and region of interest (ROI) analyses were done. RESULTS: Visual ratings of SPECT temporal and parietal blood flow did not distinguish eventual MCI converters to AD (N = 31) from nonconverters (N = 96), but the global rating predicted conversion (41.9% sensitivity and 82.3% specificity, Fisher's exact test p = 0.013). Blood flow in each ROI was not predictive, but when dichotomized at the median value of the patients with MCI, low flow increased the hazard of conversion to AD for parietal (hazard ratio: 2.96, 95% confidence interval: 1.16-7.53, p = 0.023) and medial temporal regions (hazard ratio: 3.12, 95% confidence interval: 1.14-8.56, p = 0.027). In the 3-year follow-up sample, low parietal (p <0.05) and medial temporal (p <0.01) flow predicted conversion to AD, with or without controlling for age, Mini-Mental State Examination, and apolipoprotein E ε4 genotype. These measures lost significance when other strong predictors were included in logistic regression analyses: verbal memory, social/cognitive functioning, olfactory identification deficits, hippocampal, and entorhinal cortex volumes. CONCLUSIONS: SPECT visual ratings showed limited utility in predicting MCI conversion to AD. The modest predictive utility of quantified low parietal and medial temporal flow using SPECT may decrease when other stronger predictors are available.

F-18 FDG PET imaging of chronic traumatic brain injury in boxers: a statistical parametric analysis.

PURPOSE: The participation in concussive susceptible sports such as boxing may cause chronic traumatic brain injury. The objective of this study was to determine whether there are unique patterns of reduced brain glucose metabolism in professional and amateur boxers. METHOD: We compared the fluorine-18 fluorodeoxyglucose (F-18 FDG) PET brain scans of boxers (group) (N=19) with those of controls (group) (N=7) using both statistical parametric mapping and region of interest analysis. RESULTS: Boxers showed decreased F-18 FDG uptake by 8-15% in the following brain areas: posterior cingulate cortex, parieto-occipito, frontal lobes (Broca's area) bilaterally, and the cerebellum (P<0.005) as compared with controls. CONCLUSION: Our results suggest that F-18 FDG PET scans of boxers suspected of chronic traumatic brain injury show unique patterns of hypometabolism, and that these patterns may reflect the mechanisms of repeated traumatic brain injury unique to boxers.

Pittsburgh compound B (11C-PIB) and fluorodeoxyglucose (18 F-FDG) PET in patients with Alzheimer disease, mild cognitive impairment, and healthy controls.

Amyloid load in the brain using Pittsburgh compound B ((11)C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using fluorodeoxyglucose ((18)F-FDG) PET were evaluated in patients with mild Alzheimer disease (AD, n = 18), mild cognitive impairment (MCI, n = 24), and controls (CTR, n = 18). ( 11)C-PIB binding potential (BP(ND)) was higher in prefrontal cortex, cingulate, parietal cortex, and precuneus in AD compared to CTR or MCI and in prefrontal cortex for MCI compared to CTR. For (18)F-FDG, regional cerebral metabolic rate for glucose (rCMRGlu) was decreased in precuneus and parietal cortex in AD compared to CTR and MCI, with no MCI-CTR differences. For the AD-CTR comparison, precuneus BP(ND) area under the receiver operating characteristic (ROC) curve (AUC) was 0.938 and parietal cortex rCMRGlu AUC was 0.915; for the combination, AUC was 0.989. ( 11)C-PIB PET BP(ND) clearly distinguished diagnostic groups and combined with (18)F-FDG PET rCMRGlu, this effect was stronger. These PET techniques provide complementary information in strongly distinguishing diagnostic groups in cross-sectional comparisons that need testing in longitudinal studies.

Epilepsy duration impacts on brain glucose metabolism in temporal lobe epilepsy: results of voxel-based mapping.

OBJECTIVE: [(18)F]Fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) is a valuable method for detecting focal brain dysfunction associated with epilepsy. Evidence suggests that a progressive decrease in [(18)F]FDG uptake occurs in the epileptogenic cortex with an increase in the duration of epilepsy. In this study, our aim was to use statistical parametric mapping (SPM) to test the validity of this relationship in a retrospective study of patients with temporal lobe epilepsy (TLE). METHODS: [(18)F]FDG-PET scans of 46 adult patients with pharmacoresistant unilateral TLE (25 RTLE and 21 LTLE) were subjected to SPM analysis. RESULTS: Forty-six patients were diagnosed with nonlesional TLE, 16 of whom had hippocampal sclerosis (HS). The average duration of epilepsy was 17.4 +/- 12.3 years (3-46 years), <5 years in 10 patients and >or=10 years in 30 patients. Visual analysis of [(18)F]FDG-PET scans revealed hypometabolism in the epileptogenic temporal cortex in 31 (67%) patients. After SPM analysis of all [(18)F]FDG-PET images, hypometabolism was unilateral and reported in lateral and mesial structures of the epileptogenic temporal cortex in addition to the ipsilateral fusiform and middle occipital gyrus. Subsequent analysis revealed that temporal lobe hypometabolism was present only in patients with longer epilepsy duration (>or=10 years) in parahippocampal gyrus, uncus, and middle and superior temporal gyrus (P < 0.05 corrected). Epilepsy duration was inversely correlated with decreased glucose uptake in the inferior temporal gyrus, hippocampus, and parahippocampal gyrus of the epileptogenic temporal cortex (P < 0.05). Age at seizure onset did not affect the correlation between epilepsy duration and glucose uptake except in the inferior temporal gyrus (P < 0.05). CONCLUSION: Voxel-based mapping supports the assertion that glucose hypometabolism of the epileptogenic temporal lobe cortex and other neighboring cortical regions increases with longer epilepsy duration in TLE.

Dopamine type 2/3 receptor availability in the striatum and social status in human volunteers.

BACKGROUND: Previous positron emission tomography (PET) imaging studies in nonhuman primates have shown that striatal dopamine type 2/3 (D(2/3)) receptors correlate with social hierarchy in monkeys and that dominant animals exhibit higher levels of D(2/3) receptor binding. The goal of the present study was to examine this phenomena in human subjects using PET and the radiotracer [(11)C]raclopride. METHODS: Fourteen healthy volunteers were scanned with [(11)C]raclopride to measure D(2/3) receptor binding potential (BP). Social status was assessed using the Barratt Simplified Measure of Social Status. In addition, participants were asked to assess their level of social support using the Multidimensional Scale of Perceived Social Support (MSPSS). RESULTS: A correlation was seen between social status and dopamine D(2/3) receptors, where volunteers with the higher status had higher values for [(11)C]raclopride BP. A similar correlation was seen with the perceived social support, where higher [(11)C]raclopride BP correlated with higher scores on the MSPSS. CONCLUSIONS: The results of this study support the hypothesis that social status and social support is correlated with D(2/3) receptor binding.

Lower level of endogenous dopamine in patients with cocaine dependence: findings from PET imaging of D(2)/D(3) receptors following acute dopamine depletion.

OBJECTIVE: Previous positron emission tomography (PET) imaging studies have demonstrated that cocaine dependence is associated with a decrease in dopamine type 2 and 3 (D(2)/D(3)) receptor binding in cocaine-dependent individuals relative to healthy comparison subjects. However, given the nature of PET imaging, it is possible that the measured decrease in radiotracer binding results from an increase in baseline dopamine levels. The purpose of this study was to measure D(2)/D(3) receptors following acute dopamine depletion in cocaine-dependent volunteers relative to healthy comparison subjects. METHOD: Cocaine-dependent volunteers (N=15) and healthy matched comparison subjects (N=15) were scanned using PET, with the dopamine receptor radiotracer [(11)C]raclopride, at baseline and again following acute depletion of endogenous dopamine via alpha-methyl-para-tyrosine (AMPT) administration. Changes in radiotracer binding were measured in the subdivisions of the striatum (caudate, putamen, and ventral striatum) in addition to the striatum as a whole. RESULTS: Findings revealed that cocaine-dependent volunteers exhibited lower levels of endogenous dopamine relative to comparison subjects, which was measured as an increase in [(11)C]raclopride binding following AMPT administration. The increase in [(11)C]raclopride binding in the striatum was 11.1% (SD=4.4%) in healthy comparison subjects and 5.7% (SD=5.9%) in cocaine-dependent volunteers. Similar differences were seen in the subdivisions of the striatum. CONCLUSIONS: The decrease in striatal D(2)/D(3 )receptors associated with cocaine dependence cannot be attributed to higher levels of endogenous dopamine.

Regional cerebral blood flow and metabolic rate in persistent Lyme encephalopathy.

CONTEXT: There is controversy regarding whether objective neurobiological abnormalities exist after intensive antibiotic treatment for Lyme disease. OBJECTIVES: To determine whether patients with a history of well-characterized Lyme disease and persistent cognitive deficit show abnormalities in global or topographic distributions of regional cerebral blood flow (rCBF) or cerebral metabolic rate (rCMR). DESIGN: Case-controlled study. SETTING: A university medical center. PARTICIPANTS: A total of 35 patients and 17 healthy volunteers (controls). Patients had well-documented prior Lyme disease, a currently reactive IgG Western blot, prior treatment with at least 3 weeks of intravenous cephalosporin, and objective memory impairment. MAIN OUTCOME MEASURES: Patients with persistent Lyme encephalopathy were compared with age-, sex-, and education-matched controls. Fully quantified assessments of rCBF and rCMR for glucose were obtained while subjects were medication-free using positron emission tomography. The CBF was assessed in 2 resting room air conditions (without snorkel and with snorkel) and 1 challenge condition (room air enhanced with carbon dioxide, ie, hypercapnia). RESULTS: Statistical parametric mapping analyses revealed regional abnormalities in all rCBF and rCMR measurements that were consistent in location across imaging methods and primarily reflected hypoactivity. Deficits were noted in bilateral gray and white matter regions, primarily in the temporal, parietal, and limbic areas. Although diminished global hypercapnic CBF reactivity (P < .02) was suggestive of a component of vascular compromise, the close coupling between CBF and CMR suggests that the regional abnormalities are primarily metabolically driven. Patients did not differ from controls on global resting CBF and CMR measurements. CONCLUSIONS: Patients with persistent Lyme encephalopathy have objectively quantifiable topographic abnormalities in functional brain activity. These CBF and CMR reductions were observed in all measurement conditions. Future research should address whether this pattern is also seen in acute neurologic Lyme disease.

Interventional nuclear brain imaging.

Interventional nuclear brain imaging incorporates a variety of radiopharmaceutical techniques to enhance the functional assessment of the central nervous system. Many interventional nuclear brain imaging techniques initially were used in research protocols. In recent years, however, these same challenge paradigms are being increasingly applied with clinical imaging studies. At present, clinical interventional brain imaging techniques include pharmaceutical manipulations with drug administration or withdrawal, physical provocation, electrical stimulation, cognitive activation, and targeting of neurocircuitries with specific molecular receptor-ligand interactions. This review highlights how these approaches have resulted in more accurate measurement of regional cerebral metabolism, delineation of neurocircuitries, presurgical patient selection, and treatment management.

11C-dihydrotetrabenazine PET of the pancreas in subjects with long-standing type 1 diabetes and in healthy controls.

UNLABELLED: Type 2 vesicular monoamine transporter (VMAT2), found in the brain, is also expressed by beta-cells of the pancreas in association with insulin. Preclinical experiments suggested that (11)C-dihydrotetrabenazine PET-measured VMAT2 binding might serve as a biomarker of beta-cell mass. We evaluated the feasibility of (11)C-dihydrotetrabenazine PET quantification of pancreatic VMAT2 binding in healthy subjects and patients with long-standing type 1 diabetes. METHODS: (11)C-Dihydrotetrabenazine PET was performed on 6 patients and 9 controls. VMAT2 binding potential (BP(ND)) was estimated voxelwise by using the renal cortex as reference tissue. As an index of total pancreatic VMAT2, the functional binding capacity (the sum of voxel BP(ND) x voxel volume) was calculated. Pancreatic BP(ND), functional binding capacity, and stimulated insulin secretion measurements were compared between groups. RESULTS: The pancreatic mean BP(ND) was decreased in patients (1.86 +/- 0.05) to 86% of control values (2.14 +/- 0.08) (P = 0.01). In controls, but not in patients, BP(ND) correlated with stimulated insulin secretion (r(2) = 0.50, P = 0.03). The average functional binding capacity was decreased by at least 40% in patients (P = 0.001). The changes in functional binding capacity and BP(ND) were less than the near-complete loss of stimulated insulin secretion observed in patients (P = 0.001). CONCLUSION: These results suggest that (11)C-dihydrotetrabenazine PET allows quantification of VMAT2 binding in the human pancreas. However, BP(ND) and functional binding capacity appear to overestimate beta-cell mass given the near-complete depletion of beta-cell mass in long-standing type 1 diabetes, which may be due to higher nonspecific binding in the pancreas than in the renal cortex.

Whole body [11C]-dihydrotetrabenazine imaging of baboons: biodistribution and human radiation dosimetry estimates.

PURPOSE: Vesicular monoamine transporter type 2 abundance quantified using the radiotracer [(11)C]-dihydrotetrabenazine (DTBZ) has been used to study diagnosis and pathogenesis of dementia and psychiatric disorders in humans. In addition, it may be a surrogate marker for insulin-producing pancreatic beta cell mass, useful for longitudinal measurements using positron emission tomography to track progression of autoimmune diabetes. To support the feasibility of long-term repeated administrations, we estimate the biodistribution and dosimetry of [(11)C]-DTBZ in humans. METHODS: Five baboon studies were acquired using a Siemens ECAT camera. After transmission scanning, 165-210 MBq of [(11)C]-DTBZ were injected, and dynamic whole body emission scans were conducted. Time-activity data were used to obtain residence times and estimate absorbed radiation dose according to the MIRD model. RESULTS: Most of the injected tracer localized to the liver and the lungs, followed by the intestines, brain, and kidneys. The highest estimated absorbed radiation dose was in the stomach wall. CONCLUSIONS: The largest radiation dose from [(11)C]-DTBZ is to the stomach wall. This dose estimate, as well as the radiation dose to other radiosensitive organs, must be considered in evaluating the risks of multiple administrations.

Biodistribution and radiation dosimetry of 11C-harmine in baboons.

OBJECTIVE: Monoamine oxidase A is a mitochondrial enzyme which is responsible for the metabolism of catecholamines such as dopamine, norepinephrine, as well as serotonin. This study describes the biodistribution and dosimetry of 11C-harmine, a tracer designed to specifically bind to monoamine oxidase A for positron emission tomography imaging. METHODS: Three baboon studies were acquired using a Seimens ECAT camera. Dynamic whole-body emission scans were collected in two-dimensional mode over a 2 h period after 223-255 MBq of 11C-harmine was injected. Regions of interest were drawn on transmission corrected images to encompass the entire activity in visible organs at each time point. Time-activity data were used to obtain residence times and absorbed radiation dose to various organs and to the entire body. RESULTS: Tracer uptake was greatest in the lungs, followed by kidney, small intestine, liver and brain. The largest absorbed dose based on averaged residence times was found in the lungs (reference adult/female 3.99x10(-2)/5.03x10(-2) mSv x MBq(-1)). CONCLUSION: The lungs are the critical organs for administration of 11C-harmine. For example, in the United States, the absorbed dose to the lungs would limit a single 11C-harmine administration for a research subject with the approval of a Radioactive Drug Research Committee to 1258/999 MBq (34/27 mCi) in the adult male/female. Quantitative measurement of monoamine oxidase A activity in the brain and elsewhere may aid in understanding the pathophysiology of several disease processes including neuroendocrine neoplasms and depression.

PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density?

AIM: Overstimulation of the CRF type 1 receptor (CRF1) is implicated in anxiety and depressive disorders. The aim of this study was to investigate the in vivo binding characteristics of [11C]R121920 and [11C]DMP696 in the nonhuman primate for application in positron emission tomography (PET) studies of CRF1. METHODS: PET imaging with the two novel CRF1 radioligands was performed in baboon. In vitro binding studies for CRF1 were performed in postmortem brain tissue of baboon and human to assess sufficiency of receptor density for PET. RESULTS: Both [11C]R121920 and [11C]DMP696 distributed rapidly and uniformly throughout the brain. Washout was comparable across brain regions, without differences in volume of distribution between regions reported to have high and low in vitro CRF1 binding. Membrane-enriched tissue homogenate assay using [(125)I]Tyr(0)-sauvagine and specific CRF1 antagonists CP154,526 and SN003 in human occipital cortex yielded maximal binding (Bmax) of 63.3 and 147.3 fmol/mg protein, respectively, and in human cerebellar cortex yielded Bmax of 103.6 and 64.6 fmol/mg protein, respectively. Dissociation constants (K(D)) were subnanomolar. In baboon, specific binding was not detectable in the same regions; therefore, Bmax and K(D) were not measurable. Autoradiographic results were consistent except there was also detectable CRF1-specific binding in baboon cerebellum. CONCLUSION: Neither [11C]R121920 nor [11C]DMP696 demonstrated quantifiable regional binding in vivo in baboon. In vitro results suggest CRF1 density in baboon may be insufficient for PET. Studies in man may generate more promising results due to the higher CRF1 density compared with baboon in cerebral cortex and cerebellum.

Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography.

CONTEXT: Depression in bipolar disorder is clinically indistinguishable from that observed in major depressive disorder. As in major depression, selective serotonin reuptake inhibitors targeting brain serotonin transporters are first-line treatments for bipolar depression. Associations of serotonin transporter promoter polymorphisms and bipolarity have been reported; however, research on alterations in serotonergic neurotransmission in bipolar depression remains scant. OBJECTIVES: To assess in vivo brain serotonin transporter binding potential (BP(1), proportional to serotonin transporter number) in patients with bipolar depression and controls and to examine the relationship between serotonin transporter binding and genotype. DESIGN: Case-control study. SETTING: University hospital. PARTICIPANTS: A sample of 18 medication-free patients with bipolar depression and 41 controls. MAIN OUTCOME MEASURES: In vivo brain serotonin transporter binding was measured using positron emission tomography and radiolabeled trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline ([(11)C](+)-McNeil 5652). Participants were genotyped assessing biallelic and triallelic 5-HTTLPR polymorphisms. RESULTS: Patients with bipolar disorder had 16% to 26% lower serotonin transporter BP(1) in the midbrain, amygdala, hippocampus, thalamus, putamen, and anterior cingulate cortex. Triallelic 5-HTTLPR genotypes were unrelated to serotonin transporter BP(1). CONCLUSIONS: Lower serotonin transporter BP(1) in bipolar depression overlaps with that observed in major depression and suggests that serotonergic dysfunction is common to depressive conditions.

Brain glucose supply and the syndrome of infantile neuroglycopenia.

OBJECTIVE: To describe neuroglycopenia as a specific syndrome caused by insufficient glucose availability during brain development. DESIGN: Neurologic examinations, neuropsychologic tests, biochemical methods, and functional imaging. PARTICIPANTS: Patients afflicted by genetic mutation of the cerebral glucose transporter type 1 and a patient afflicted by persistent infantile hypoglycemia (hyperinsulinism) matched to her healthy twin. RESULTS: The hallmark of the phenotype is the combination of infantile epilepsy and cerebellar and pyramidal tract dysfunction, together with permanent neuropsychologic abnormalities and reduced thalamocortical glucose uptake despite subsequent supply of energetic substrate. CONCLUSIONS: When neuroglycopenia-the lack of adequate glucose supply to the nervous system-occurs in the developing brain, thalamic and cortical metabolism mature aberrantly, causing epilepsy associated with other characteristic neurologic and behavioral disturbances, a pattern also reflected in functional images, as if there were a temporal window during which glucose were crucial for brain development. When maturation is complete, glucose merely serves as a fuel, and then, when deficient, it only causes unrelated disturbances.