Faculty Bibliography

UNLABELLED:The PET tracer (11)C-(R)-PK11195 (PK) is an antagonist of the peripheral-type benzodiazepine binding site and allows the noninvasive imaging of microglial activation seen in several neurologic disorders affecting the mature and developing brain. The objective of this study was to derive the biodistribution and in vivo radiation dose estimates of PK in children studied for brain inflammatory conditions and in healthy adults. METHODS:Twenty-two children (mean age +/- SD, 9.5 +/- 4 y; range, 4-17 y; 10 girls) who underwent dynamic PK PET for conditions involving brain inflammation were studied. Seven healthy adults (age, 27.4 +/- 7.5 y; range, 22-41 y; 3 women) were evaluated using the same protocol. Normal-organ time-activity curves and residence times were derived and absorbed doses then calculated using the OLINDA software. Two other healthy young adults (1 man, 1 woman) also underwent sequential whole-body PET using a PET/CT scanner to obtain corresponding CT images and PK pharmacokinetics. RESULTS:PK uptake was highest in the gallbladder and urinary bladder, followed by the liver, kidney, bone marrow, salivary gland, and heart wall, with minimal localization in all other organs including normal brain and lungs. PK was excreted through the hepatobiliary and renal systems. The average effective dose equivalent was 11.6 +/- 0.6 microSv/MBq (mean +/- SD) for young children (age, 4-7 y), 7.7 +/- 1.0 microSv/MBq for older children (age, 8-12 y), 5.3 +/- 0.5 muSv/MBq for adolescents (age, 13-17 y), and 4.6 +/- 2.7 microSv/MBq for adults. The gallbladder wall received the highest radiation dose in children younger than 12 y, whereas the urinary bladder wall received the highest dose in older children and adults. For an administered activity of 17 MBq/kg (0.45 mCi/kg), the effective dose equivalent was about 5 mSv or below for all age groups. CONCLUSION/CONCLUSIONS:At clinically practical administered activities, the radiation dose from (11)C-PK11195 in both children and adults is comparable to that from other clinical PET tracers and diagnostic radiopharmaceuticals in routine clinical use.

Tourette syndrome is generally considered to be a genetic disorder, but symptoms mimicking Tourette syndrome can be secondary to an underlying lesion disrupting the basal ganglia circuitry. Described here is a case of secondary tics, or tourettism, in a child with a large oligodendroglioma of the right temporal lobe extending to the basal ganglia. He presented with attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and stimulant-induced tic disorder at the age of 11 years, and later also had also seizures. The family history was unremarkable. Cranial magnetic resonance imaging disclosed a right temporal lobe tumor extending to the basal ganglia. An alpha-[(11)C]methyl-l-tryptophan positron emission tomography scan showed asymmetric uptake in the basal ganglia and intense uptake in the tumor. He had a lesionectomy, and the histopathologic diagnosis was oligodendroglioma. Neuropsychologic testing after surgery revealed no attention-deficit hyperactivity disorder symptomatology, and only minimal features of obsessive-compulsive disorder. The present case provides additional evidence supporting the role of basal ganglia circuitry in the pathophysiology of tic disorder and its comorbid states. Children who present with attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and tic disorder of late onset in the absence of family history should be further investigated with neuroimaging to exclude the presence of a secondary cause.

BACKGROUND:Tryptophan catabolism via the kynurenine pathway, mediated by indoleamine 2,3-dioxygenase (IDO), is a mechanism involved in tumor immunoresistance. Positron emission tomography (PET) with alpha-[(11)C]methyl-L-tryptophan (AMT) can quantify transport and metabolism of tryptophan in infiltrating gliomas and glioneuronal tumors. In the present study, we investigated whether increased tryptophan metabolism in brain tumors measured by PET is related to expression of IDO in resected brain tumor specimens. METHODS:IDO expression was assessed by immunohistochemistry in tumor specimens from 15 patients (median age, 34 years) with primary brain tumors who underwent AMT PET scanning before tumor resection. Patterns of IDO expression were compared between low- and high-grade tumors and also to AMT transport and metabolism measured on PET. RESULTS:IDO immunoreactivity was seen in tumor cells in six of seven low-grade tumors but only in one of eight high-grade tumors (p = 0.01); three of these latter tumors showed endothelial staining only. Low-grade neoplasms showed lower transport rate (p < 0.01) but higher metabolic rate (p = 0.003) for AMT as compared to high-grade tumors. AMT metabolic rates were lower in tumor samples with no or minimal IDO expression as compared to those with widespread IDO staining (p = 0.017). CONCLUSION/CONCLUSIONS:Low-grade tumors show widespread IDO expression, while IDO expression in high-grade brain tumors can be absent or largely confined to endothelial cells. AMT PET can be useful to identify brain tumors with different profiles of IDO expression, thus providing a useful imaging marker for emerging treatments targeting tumor IDO activity.

BACKGROUND AND PURPOSE/OBJECTIVE:Several studies have questioned the traditional belief that the corticospinal tract (CST) arises exclusively from the precentral gyrus and passes through the anterior half of the posterior limb of the internal capsule (PLIC) in humans; however, no direct evidence existed from structural imaging, and developmental aspects of CST origin have not been clarified. We used diffusion tensor imaging (DTI) tractography to test the hypotheses that CST can originate from both pre- and postcentral gyri and is located posteriorly in the PLIC, and we also determined how age, sex, or handedness affected these locations. MATERIALS AND METHODS/METHODS:Forty-two healthy children (2.6-17.5 years of age; 20 girls) underwent DTI. Subsequently, tractography was performed on the basis of fiber assignment by continuous tracking (FACT) algorithm and brute force approach, with a fractional anisotropy (FA) threshold of <0.2 and an angle threshold of >50 degrees . The CST was isolated by using a knowledge-based region-of-interest approach, and its cortical origin and location on the PLIC was determined. RESULTS:DTI revealed that the CST originated from both pre- and postcentral gyri in 71.4% of hemispheres, from the precentral gyrus only in 19%, and from the postcentral gyrus only in 7.1%. The overall distribution was similar in both hemispheres. However, children with CST originating from both pre- and postcentral gyri were older (mean, 11.1 years of age) than those with precentral origin (mean, 5.8 years of age) or postcentral origin (mean, 7.8 years of age) only (P = .00003). The center of the CST was localized at 65% of the length (from its anterior margin) of the PLIC, and the CST occupied 26.5% of its anteroposterior length. There was a significant positive correlation between age and FA of the CST (r = 0.49; P = .002). The volume of the precentral portion of the left CST was significantly higher than that of its postcentral portion (P = .01) and that of the right CST (P = .0002). The pattern of cortical origin of CST, its location at the level of PLIC, and its volume and FA were unaffected by sex or handedness. CONCLUSIONS:The CST most frequently originates from both pre- and postcentral gyri, especially in older children, and is typically centered approximately two thirds of the distance from the anterior margin of the PLIC and occupies about a quarter of its anteroposterior length. In young children, the CST can often be seen originating exclusively from the precentral gyrus by DTI.

Maturational studies of the auditory-evoked brain response at the 50 ms latency provide an insight into why this response is aberrant in a number of psychiatric disorders that have developmental origin. Here, using intracranial recordings we found that neuronal activity of the primary contributors to this response can be localised at the lateral part of Heschl's gyrus already at the age of 3.5 years. This study provides results to support the notion that deviations in cognitive function(s) attributed to the auditory P50 in adults might involve abnormalities in neuronal activity of the frontal lobe or in the interaction between the frontal and temporal lobes. Validation and localisation of progenitors of the adults' P50 in young children is a much-needed step in the understanding of the biological significance of different subcomponents that comprise the auditory P50 in the adult brain. In combination with other approaches investigating neuronal mechanisms of auditory P50, the present results contribute to the greater understanding of what and why neuronal activity underlying this response is aberrant in a number of brain dysfunctions. Moreover, the present source localisation results of auditory response at the 50 ms latency might be useful in paediatric neurosurgery practice.

The spatial relationship between an intracranial EEG-defined epileptic focus and cortical hypometabolism on glucose PET has not been precisely described. In order to quantitatively evaluate the hypothesis that ictal seizure onset and/or rapid seizure propagation, detected by subdural EEG monitoring, commonly involves normometabolic cortex adjacent to hypometabolic cortical regions, we applied a novel, landmark-constrained conformal mapping approach in 14 children with refractory neocortical epilepsy. The 3D brain surface was parcellated into finite cortical elements (FCEs), and hypometabolism was defined using lobe- and side-specific asymmetry indices derived from normal adult controls. The severity and location of hypometabolic areas vs. ictal intracranial EEG abnormalities were compared on the 3D brain surface. Hypometabolism was more severe in the seizure onset zone than in cortical areas covered by non-onset electrodes. However, similar proportions of the onset electrodes were located over and adjacent to (within 2 cm) hypometabolic regions (46% vs. 41%, respectively), whereas rapid seizure spread electrodes preferred these "adjacent areas" rather than the hypometabolic area itself (51% vs. 22%). On average, 58% of the hypometabolic regions had no early seizure involvement. These findings strongly support that the seizure onset zone often extends from hypometabolic to adjacent normometabolic cortex, while large portions of hypometabolic cortex are not involved in seizure onset or early propagation. The clinical utility of FDG PET in guiding subdural electrode placement in neocortical epilepsy could be greatly enhanced by extending grid coverage to at least 2 cm beyond hypometabolic cortex, when feasible.

An Inattentive/Overactive (I/O) behavioral phenotype has been reported in a significant percentage of children raised from birth in orphanages. While a number of studies have identified both functional and structural brain abnormalities in children raised from birth in orphanages, no published studies have evaluated potential neural correlates of the I/O phenotype. We applied diffusion tensor imaging (DTI) to 15 pre-teen children raised in orphanages in Eastern Europe or Asia and later adopted to the US. Fiber tracts were constructed from DTI data using probabilistic fiber tracking and the cortical fiber distribution of fibers originating from the head of the caudate was compared between the early deprivation (ED) group and 12 age-matched controls. The ED group showed a more diffuse connectivity pattern, especially in the right hemisphere, potentially related to incomplete neuronal pruning during development. These structural abnormalities may be associated with inattention and overactivity encountered in children with ED.

PURPOSE/OBJECTIVE:To determine whether previously undetected symptoms of depression and psychiatric help-seeking behaviors are associated with demographic or epilepsy-related variables in a predominantly African American sample of pediatric epilepsy patients. METHODS:Ninety-six serially recruited parent-child dyads (55% African American, 39% Caucasian) completed the Short Mood and Feelings Questionnaire (SMFQ). Regression analyses determined whether depressive symptoms measured by the SMFQ were associated with demographic (age, gender, and ethnic background) or epilepsy-related variables (age of seizure onset, duration of epilepsy, seizure type, time since last seizure, and number of antiepileptic drugs). Dyads with positive SMFQ screens (score > or = 12) received information about depression and were advised to seek mental health services. Six months later, parents completed follow-up interviews to ascertain mental health service utilization. RESULTS:Thirty-five participants (36.5%) screened positive for probable depression. Greater number of antiepileptic drugs was the only predictor variable independently associated with greater (worse) depression scores (p = 0.005). At 6-month follow-up, 12 patients (36.4%) had received mental health care, whereas 21 guardians (63.6%) denied depressive symptoms in their child and never sought mental health services (two dyads lost to follow-up). Logistic regression analyses found no associations between demographic, epilepsy-related, or depressive variables and psychiatric help-seeking. DISCUSSION/CONCLUSIONS:This study indicates the necessity and feasibility of screening for previously undetected symptoms of depression in pediatric epilepsy clinics serving diverse populations, particularly among patients receiving antiepileptic polytherapy. Additional research on the correlates of depressive symptoms and determinants of psychiatric help-seeking is needed to develop evidence-based interventions for youths with epilepsy and symptoms of depression.