Faculty Bibliography

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

beta-Amyloid (A beta) plaques in the blood vessels of the brain are associated with cerebral amyloid angiopathy (CAA), which is a common cause of stroke and vascular diseases. Imaging agents that can differentiate between A beta plaques in the brain and those on the walls of cerebrovascular vessels will provide non-invasive biomarkers to interrogate the pathogenesis of CAA and give insights into the mechanisms, significance and impact of A beta-CAA for developing effective therapies for CAA and stroke. A new series of Tc-99m-labeled benzothiazole and stilbene derivatives with positive charge were developed and evaluated for selectively targeting A beta plaques in the blood vessels of the brain. The rhenium complexes 6, 7, 13 and 14 displayed medium binding affinity to A beta(1-42) aggregates with K-i values of 162, 37, 366 and 78 nM, respectively. In vitro fluorescence staining of 7 and 14 demonstrated an intense labeling of A beta plaques associated with blood vessel walls on brain sections of a patient with Alzheimer's diseases. A relatively low initial brain uptake for [Tc-99m]7 and [Tc-99m]14, 0.18 and 0.24 ID% per gram, respectively, suggests that they may be useful SPECT imaging agents for selectively detecting A beta plaques associated with cerebral vessels in the living human brain. C1 [Jia, Jianhua; Cui, Mengchao; Wang, Xuedan; Jia, Hongmei; Liu, Boli] Beijing Normal Univ, Coll Chem, Minist Educ, Key Lab Radiopharmaceut, Beijing 100875, Peoples R China. [Dai, Jiapei] South Cent Univ Nationalities, Wuhan Inst Neurosci & Neuroengn, Wuhan, Peoples R China. [Ding, Yu-Shin] NYU, Sch Med, Dept Chem, Dept Radiol, New York, NY USA. [Ding, Yu-Shin] NYU, Sch Med, Dept Psychiat, Dept Chem, New York, NY USA

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.