Faculty Bibliography

PURPOSE: To pool data across multiple institutions internationally and report on the cumulative experience of brainstem stereotactic radiosurgery (SRS). METHODS AND MATERIALS: Data on patients with brainstem metastases treated with SRS were collected through the International Gamma Knife Research Foundation. Clinical, radiographic, and dosimetric characteristics were compared for factors prognostic for local control (LC) and overall survival (OS) using univariate and multivariate analyses. RESULTS: Of 547 patients with 596 brainstem metastases treated with SRS, treatment of 7.4% of tumors resulted in severe SRS-induced toxicity (grade >/=3, increased odds with increasing tumor volume, margin dose, and whole-brain irradiation). Local control at 12 months after SRS was 81.8% and was improved with increasing margin dose and maximum dose. Overall survival at 12 months after SRS was 32.7% and impacted by age, gender, number of metastases, tumor histology, and performance score. CONCLUSIONS: Our study provides additional evidence that SRS has become an option for patients with brainstem metastases, with an excellent benefit-to-risk ratio in the hands of experienced clinicians. Prior whole-brain irradiation increases the risk of severe toxicity in brainstem metastasis patients undergoing SRS.

A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations. The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types. In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans. Here we describe a novel recombinant adeno-associated virus that restricts gene expression to GABAergic interneurons within the telencephalon. We demonstrate that the viral expression is specific and robust, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in both mice and non-genetically tractable species, thus opening the possibility to study GABAergic function in virtually any vertebrate species.

BACKGROUND: Among older adults receiving long-term services and supports (LTSS), debilitating hospitalizations is a pervasive clinical and research problem. Multiple chronic conditions (MCCs) are prevalent in LTSS recipients. However, the combination of MCCs and diseases associated with hospitalizations of LTSS recipients is unclear. OBJECTIVE: The purpose of this analysis was to determine the association between classes of MCCs in newly enrolled LTSS recipients and the number of hospitalizations over a 1-year period following enrollment. METHODS: This report is based on secondary analysis of extant data from a longitudinal cohort study of 470 new recipients of LTSS, 60 years and older, receiving services in assisted living facilities, nursing homes, or through home- and community-based services. Using baseline chronic conditions reported in medical records, latent class analysis was used to identify classes of MCCs and posterior probabilities of membership in each class. Poisson regressions were used to estimate the relative ratio between posterior probabilities of class membership and number of hospitalizations during the 3-month period prior to the start of LTSS (baseline) and then every 3 months forward through 12 months. RESULTS: Three latent MCC-based classes named Cardiopulmonary, Cerebrovascular/Paralysis, and All Other Conditions were identified. The Cardiopulmonary class was associated with elevated numbers of hospitalizations compared to the All Other Conditions class (relative ratio [RR] = 1.88, 95% CI [1.33, 2.65], p < .001). CONCLUSION: Older LTSS recipients with a combination of MCCs that includes cardiopulmonary conditions have increased risk for hospitalization.

OBJECTIVES/HYPOTHESIS: The primary objectives of this study were to determine the intrasubject reliability of repeated measures of maximum phonation time (MPT) duration during a single session and to examine the effects of age, sex, and total phonatory airflow on this reliability. STUDY DESIGN: This study used repeated measures. METHODS: Duration and total phonatory airflow during three consecutive MPT trials were collected from 20 participants evenly distributed between age (young/old) and sex (male/female) groups. Intraclass correlation coefficient and repeated-measures analysis of variance were used to examine the reliability of MPT across trials and to test for possible effects of age and sex. RESULTS: Intraclass correlation for MPT duration was strong across all participants (0.86), but MPT duration was not stable across trials (F2, 32 = 3.58, P = 0.04), with the second trial having the longest duration on average (P = 0.03). There was no effect of trial on total phonatory airflow (F2, 32 = 1.08, P = 0.35). The relationship between MPT duration and total phonatory airflow, however, did not remain consistent across trials (F2, 31 = 3.58, P = 0.04). There were no effects of age or sex on any variables. CONCLUSIONS: The variability in MPT duration across trials and the inconsistent relationship between MPT duration and total phonatory airflow indicate that there is variability in laryngeal efficiency across repeated MPT trials. Therefore, the results of this study corroborate previous research supporting the assertion that MPT is not a reliable measure of laryngeal aerodynamics.

Many individuals with Parkinson disease (PD) have difficulty producing normal speech and voice, resulting in problems with interpersonal communication and reduced quality of life. Translational animal models of communicative dysfunction have been developed to assess disease pathology. However, it is unknown whether acoustic feature changes associated with vocal production deficits in these animal models lead to compromised communication. In rodents, male ultrasonic vocalizations (USVs) have a well-established role in functional inter-sexual communication. To test whether acoustic deficits in USVs observed in a PTEN-induced putative kinase 1 (PINK1) knockout (KO) PD rat model compromise communication, we presented recordings of male PINK1 KO USVs and normal wild-type (WT) USVs to female rat listeners. We measured approached behavior and immediate early gene expression (c-Fos) in brain regions implicated in auditory processing and sexual motivation. Our results suggest that females show reduced approach in response to PINK1 KO USVs compared with WT. Moreover, females exposed to PINK1 KO USVs had lower c-Fos immunolabeling in the nucleus accumbens, a region implicated in sexual motivation. These results are the first to demonstrate that vocalization deficits in a rat PD model result in compromised communication. Thus, the PINK1 KO PD model may be valuable for assessing treatments aimed at restoring vocal communicative function.

Fragile X Syndrome (FXS) is the leading form of inherited intellectual disability. It is caused by the transcriptional silencing of FMR1, the gene which codes for the Fragile X Mental Retardation Protein (FMRP). Patients who have FXS exhibit numerous behavioral and cognitive impairments, such as attention-deficit/hyperactivity disorder, obsessive compulsive disorder, and autistic-like behaviors. In addition to these behavioral abnormalities, FXS patients have also been shown to exhibit various deficits in communication such as abnormal sentence structures, increased utterances, repetition of sounds and words, and reduced articulation. These deficits can dramatically hinder communication for FXS patients, exacerbating learning and cognition impairments while decreasing their quality of life. To examine the biological underpinnings of these communication abnormalities, studies have used a mouse model of the Fragile X Syndrome; however, these vocalization studies have resulted in inconsistent findings that often do not correlate with abnormalities observed in FXS patients. Interestingly, a detailed examination of frequency modulated vocalizations that are believed to be a better assessment of rodent communication has never been conducted. The following study used courtship separation to conduct a detailed examination of frequency modulated ultrasonic vocalizations (USV) in FXS mice. Our analyses of frequency modulated USVs demonstrated that adult FXS mice exhibited longer phrases and more motifs. Phrases are vocalizations consisting of multiple frequency modulated ultrasonic vocalizations, while motifs are repeated frequency modulated USV patterns. Fragile X mice had a higher proportion of "u" syllables in all USVs and phrases while their wildtype counterparts preferred isolated "h" syllables. Although the specific importance of these syllables towards communication deficits still needs to be evaluated, these findings in production of USVs are consistent with the repetitive and perseverative speech patterns observed in FXS patients. This study demonstrates that FXS mice can be used to study the underlying biological mechanism(s) mediating FXS vocalization abnormalities.

OBJECTIVE: Optic gliomas are characterized as pilocytic astrocytoma (PA) or pilomyxoid astrocytoma (PMXA). Prominent chondroid myxoid matrix is typical of PMXA but not PA. We investigated the composition of myxoid matrix and its role in vasculariztion of optic gliomas. MATERIAL-METHODS: We reviewed clinicopathological data of 120 patients with optic glioma diagnosed at NYU Langone Medical Center from 1996 to 2014.We analyzed microvascular density (MVD), perfusion, hypoxia and proliferation by immunohistochemistry and ultrastructural features by electron microscopy. Liquid chromatography-mass spectrometry (LC-MS) was performed to identify components of the myxoid matrix in PMXA. RESULTS: PMXA showed significantly lowerMVD by CD34 (8.1 vs 14.5, pvalue < 0.002) and Erg (7 vs. 13.6, p-value 0.003) than PA, however GLUT-1 showed equal distribution. Electron microscopy showed that PMXA contains both regular blood vessels with endothelial lining and channels completely lacking endothelia and smooth muscle. LC-MS stratified optic gliomas into three distinct groups. We identified 5389 proteins of which 188 were differentially expressed in the three groups (p < 0.05, Benjamini-Hochberg adjustment). Between PAand PMXA,most of differentially expressed proteins (146/188) displayed a positive fold change (increasing in PMXA relative to PA), and a minority (42/188) showed a negative fold change. Abundant extracellular matrix proteins were a chondroitin sulfate proteoglycan versican (VCAN 3.7-fold increase Q=0.000463) and its paralog vertebrate Hyaluronan and Proteoglycan Link Protein 1 (HAPLN1, 22-fold increase from the PA to the PMXA group Q=4.60x10-7). CONCLUSIONS: Optic gliomas develop endothelium-independent channels evocative invertebrate blood supply. The myxoid matrix is composed of VCAN and linking paralog HAPLN1. Targeting the myxoid matrix may provide novel avenues for therapy of optic gliomas and PMA

Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1alpha (Hif1alpha)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.