Faculty Bibliography

Rationale: While the ionotropic glutamate receptors (iGluRs) have been extensively studied, little is known about the role of metabotropic glutamate receptors (mGluRs) in seizure generation and epileptogenesis associated with altered brain development, including Tuberous Sclerosis Complex (TSC) and focal cortical dysplasia (FCD). Animal model studies show that Group I mGluRs, including mGluR1 and mGluR5, are pro-convulsive, while specific mGluR antagonists are effective in suppressing seizure activity. Furthermore, experimental deletion of Tsc1 impairs mGluR-dependent long-term depression. We hypothesized that Group I mGluRs are expressed at higher levels in TSC and FCD compared to controls, which may significantly contribute to altered synaptic function, network excitability and information processing in these patients. Methods: Cortical samples from TSC (n= 5; ages 0.9-5 years) and non-TSC epilepsy patients (n=5; ages 21.5-37 years) were obtained during brain surgery for treatment of pharmaco-resistant epilepsy at NYU Langone Medical Center. The cases were further diagnosed as either TSC or FCD Type Ia by standard neuropathological examination. Age-matched and region-matched control specimens from cases with normal neurological history (n=6; ages 2-24 years) were obtained from University of Maryland Brain and Tissue Bank. The study was approved by the local Institutional Review Board. Frozen cortical samples were used to separate the membrane fraction and blots were probed for mGluR1 (1:1000) and mGluR5 (1:1000). Mean expression levels were compared among groups and statistical significance (p<0.05) was established using two-tailed t-tests. Results: mGluR1 expression was significantly upregulated relative to controls in both TSC (270+40% of control; p<0.05) and FCD cortex (136+10% of control; p<0.05), with higher levels in TSC relative to FCD (p<0.05). mGluR5 was also significantly elevated in TSC (370+34% of control; p<0.01) and FCD (321+25% of control; p<0.001), with no significant differen!

Integrated PET/MR with simultaneous acquisition may improve the identification of pathologic findings in patients. This pilot study evaluated metabolic activity differences between epilepsy patients and healthy controls and directly correlated FDG uptake with MR regional abnormality. Epilepsy patients (n=11) and controls (n=6) were imaged on a whole-body simultaneous PET/MR scanner. After FDG injection, simultaneous images were acquired for 60 minutes. Statistical analyses on SUV values (over 117 brain regions, including left and right, for 96 cortical and 21 subcortical regions) derived from three normalization methods, by individual subject's mean cortical, white matter or global brain, were compared between groups. The asymmetry was compared. T2, T1 and PET co-registered images were also used for lesion detection and correlation of PET and MR regional abnormality. Left and right postcentral gyri were found to be consistently hypermetabolic regions, while right temporal pole and planum polare were consistently hypometabolic regions by all three normalization methods. Using the asymmetry index (AI > 10% or SUV ratios > 1.2), more metabolic asymmetry regions were detected in patients than in controls, with 96.2% agreement. The presence of hippocampal abnormalities or cortical tubers detected via T2 FLAIR in patients correlated well with the hypometabolism detected via FDG-PET. Our results showed specific patterns of metabolic abnormality and asymmetry over 117 brain regions in epilepsy patients, as compared to controls, suggest that simultaneous PET/MR imaging provides a useful tool to help understand etiopathogenesis and localize seizure foci.

IMPORTANCE: Animal data suggest that chronic stress is associated with a reduction in norepinephrine transporter (NET) availability in the locus coeruleus. However, it is unclear whether such models are relevant to posttraumatic stress disorder (PTSD), which has been linked to noradrenergic dysfunction in humans. OBJECTIVES: To use positron emission tomography and the radioligand [11C]methylreboxetine to examine in vivo NET availability in the locus coeruleus in the following 3 groups of individuals: healthy adults (HC group), adults exposed to trauma who did not develop PTSD (TC group), and adults exposed to trauma who developed PTSD (PTSD group) and to evaluate the relationship between NET availability in the locus coeruleus and a contemporary phenotypic model of PTSD symptoms. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional positron emission tomography study under resting conditions at academic and Veterans Affairs medical centers among 56 individuals in the following 3 study groups: HC (n = 18), TC (n = 16), and PTSD (n = 22). MAIN OUTCOMES AND MEASURES: The [11C]methylreboxetine-binding potential of NET availability in the locus coeruleus and the severity of PTSD symptoms assessed using the Clinician-Administered PTSD Scale. RESULTS: The PTSD group had significantly lower NET availability than the HC group (41% lower, Cohen d = 1.07). NET availability did not differ significantly between the TC and HC groups (31% difference, Cohen d = 0.79) or between the TC and PTSD groups (15% difference, Cohen d = 0.28). In the PTSD group, NET availability in the locus coeruleus was independently positively associated with the severity of anxious arousal (ie, hypervigilance) symptoms (r = 0.52) but not with any of the other PTSD symptom clusters. CONCLUSIONS AND RELEVANCE: These results suggest that PTSD is associated with significantly reduced NET availability in the locus coeruleus and that greater NET availability in this brain region is associated with increased severity of anxious arousal symptoms in individuals with PTSD.

To quantify the thickness of the inner retinal layers in the foveal pit where the nerve fiber layer (NFL) is absent, and quantify changes in the ganglion cells and inner plexiform layer. Pixel-by-pixel volumetric measurements were obtained via Spectral-Domain optical coherence tomography (SD-OCT) from 50 eyes of Parkinson disease (PD) (n = 30) and 50 eyes of healthy control subjects (n = 27). Receiver operating characteristics (ROC) were used to classify individual subjects with respect to sensitivity and specificity calculations at each perifoveolar distance. Three-dimensional topographic maps of the healthy and PD foveal pit were created. The foveal pit is thinner and broader in PD. The difference becomes evident in an annular zone between 0.5 and 2 mm from the foveola and the optimal (ROC-defined) zone is from 0.75 to 1.5 mm. This zone is nearly devoid of NFL and partially overlaps the foveal avascular zone. About 78 % of PD eyes can be discriminated from HC eyes based on this zone. ROC applied to OCT pixel-by-pixel analysis helps to discriminate PD from HC retinae. Remodeling of the foveal architecture is significant because it may provide a visible and quantifiable signature of PD. The specific location of remodeling in the fovea raises a novel concept for exploring the mechanism of oxidative stress on retinal neurons in PD. OCT is a promising quantitative tool in PD research. However, larger scale studies are needed before the method can be applied to clinical follow-ups.

The highly diverse serotonergic system with at least 16 different receptor subtypes is implicated in the pathophysiology of most neuropsychiatric disorders including affective and anxiety disorders, obsessive compulsive disorder, post-traumatic stress disorder, eating disorders, sleep disturbance, attention deficit/hyperactivity disorder, drug addiction, suicidal behavior, schizophrenia, Alzheimer, etc. Alterations of the interplay between various pre- and postsynaptic receptor subtypes might be involved in the pathogenesis of these disorders. However, there is a lack of comprehensive in vivo values using standardized procedures. In the current PET study we quantified 3 receptor subtypes, including the major inhibitory (5-HT(1A) and 5-HT(1B)) and excitatory (5-HT(2A)) receptors, and the transporter (5-HTT) in the brain of healthy human subjects to provide a database of standard values. PET scans were performed on 95 healthy subjects (age=28.0+/-6.9years; 59% males) using the selective radioligands [carbonyl-(11)C]WAY-100635, [(11)C]P943, [(18)F]altanserin and [(11)C]DASB, respectively. A standard template in MNI stereotactic space served for region of interest delineation. This template follows two anatomical parcellation schemes: 1) Brodmann areas including 41 regions and 2) AAL (automated anatomical labeling) including 52 regions. Standard values (mean, SD, and range) for each receptor and region are presented. Mean cortical and subcortical binding potential (BP) values were in good agreement with previously published human in vivo and post-mortem data. By means of linear equations, PET binding potentials were translated to post-mortem binding (provided in pmol/g), yielding 5.89pmol/g (5-HT(1A)), 23.5pmol/g (5-HT(1B)), 31.44pmol/g (5-HT(2A)), and 11.33pmol/g (5-HTT) being equivalent to the BP of 1, respectively. Furthermore, we computed individual voxel-wise maps with BP values and generated average tracer-specific whole-brain binding maps. This knowledge might improve our interpretation of the alterations taking place in the serotonergic system during neuropsychiatric disorders.

INTRODUCTION: It has been suggested that brown adipose tissue (BAT) in humans may play a role in energy balance and obesity. We conducted ex vivo and in vivo evaluation using [(11)C]MRB, a highly selective NET (norepinephrine transporter) ligand for BAT imaging at room temperature, which is not achievable with [(18)F]FDG. METHODS: PET images of male Sprague-Dawley rats with [(18)F]FDG and [(11)C]MRB were compared. Relative [(18)F]FDG or [(11)C]MRB retention at 20, 40 and 60 min post-injection was quantified on awake rats after exposing to cold (4 degrees C for 4h) or remaining at room temperature. Rats pretreated with unlabeled MRB or nisoxetine 30 min before [(11)C]MRB injection were also assessed. The [(11)C]MRB metabolite profile in BAT was evaluated. RESULTS: PET imaging demonstrated intense [(11)C]MRB uptake (SUV of 2.9 to 3.3) in the interscapular BAT of both room temperature and cold-exposed rats and this uptake was significantly diminished by pretreatment with unlabeled MRB; in contrast, [(18)F]FDG in BAT was only detected in rats treated with cold. Ex vivo results were concordant with the imaging findings; i.e. the uptake of [(11)C]MRB in BAT was 3 times higher than that of [(18)F]FDG at room temperature (P=0.009), and the significant cold-stimulated uptake in BAT with [(18)F]FDG (10-fold, P=0.001) was not observed with [(11)C]MRB (P=0.082). HPLC analysis revealed 94%-99% of total radioactivity in BAT represented unchanged [(11)C]MRB. CONCLUSIONS: Our study demonstrates that BAT could be specifically labeled with [(11)C]MRB at room temperature and under cold conditions, supporting a NET-PET strategy for imaging BAT in humans under basal conditions.