Faculty Bibliography

In the Alzheimer's disease (AD) continuum, the prodromal state of mild cognitive impairment (MCI) precedes AD dementia and identifying MCI individuals at risk of progression is important for clinical management. Our goal was to develop generalizable multivariate models that integrate high-dimensional data (multimodal neuroimaging and cerebrospinal fluid biomarkers, genetic factors, and measures of cognitive resilience) for identification of MCI individuals who progress to AD within 3 years. Our main findings were i) we were able to build generalizable models with clinically relevant accuracy (~93%) for identifying MCI individuals who progress to AD within 3 years; ii) markers of AD pathophysiology (amyloid, tau, neuronal injury) accounted for large shares of the variance in predicting progression; iii) our methodology allowed us to discover that expression of CR1 (complement receptor 1), an AD susceptibility gene involved in immune pathways, uniquely added independent predictive value. This work highlights the value of optimized machine learning approaches for analyzing multimodal patient information for making predictive assessments.

Making decisions when an objectively correct option is not obvious, involves different neurobiological mechanisms than "veridical" decision making. The dorsolateral prefrontal cortex (DLPFC) exhibits a distinct pattern of prefrontal activation in non-veridical cognition, but little is known about the role of underlying neurobiological endophenotypes. A functional polymorphism in the brain-derived neurotrophic factor (BDNF) gene, causing a valine (Val) to methionine (Met) amino acid substitution at codon 66, has been shown to be associated with structural and functional changes in DLPFC and affect veridical decision making. We hypothesized that the BDNF genotype may be related to non-veridical cognition. We explored whether the BDNF Val66Met polymorphism affected preferences in a cognitive task devoid of intrinsically correct or false choice, using the Cognitive Bias Task (CBT). We also studied if manipulating the right DLPFC with rTMS stimulation changes non-veridical preferences. Sixteen healthy adults, including 9 Val/Val and 7 Val/Met subjects, participated in the study. Participants with Val/Met genotype expressed a more context-independent, internally driven choice selection preference. Val/Val subjects' selection was more dependent on the context, driven by the properties of external stimuli. rTMS stimulation enhanced a preexisting bias in choice preferences. In Val/Val subjects, TMS stimulation shifted the non-veridical preference bias towards greater dependence on external context, while in Val/Met subjects the CBT score became more context-independent. Our study showed that BDNF genotype is associated with a bias in non-veridical preferences and that Val/Val and Val/Met subjects respond differently to right DLPFC rTMS stimulation, further enhancing their preexisting selection biases.

PURPOSE/OBJECTIVE:Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct glioma molecular subtype for which no effective molecularly-directed therapy exists. Low-grade gliomas, which are 80-90% IDH mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by immunohistochemistry in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in IDH mutant glioma. EXPERIMENTAL DESIGN/METHODS:We evaluated DLL3 expression by RNA using TCGA data and by immunohistochemistry in a discovery set of 63 gliomas and 20 non-tumor brain tissues and a validation set of 62 known IDH wildtype and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous IDH mutant glioma tumorspheres was determined by cell viability assay. RESULTS:Compared to IDH wildtype glioblastoma, IDH mutant gliomas have significantly higher DLL3 RNA (P<1x10-15) and protein by immunohistochemistry (P=0.0014 and P<4.3x10-6 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in IDH mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 non-tumor brains. Patient-derived IDH mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner. CONCLUSIONS:DLL3 is selectively and homogeneously expressed in IDH mutant gliomas and can be targeted with Rova-T in patient-derived IDH mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.

PURPOSE OF REVIEW/OBJECTIVE:To describe diverse neurologic and neuroradiologic presentations of two rare, immunologically mediated skin conditions: Sweet disease and localized scleroderma (morphea). RECENT FINDINGS/RESULTS:Core syndromes of neuro-Sweet disease (NSD) are steroid responsiveness, recurrent meningitis, and encephalitis. Focal neurologic, neuro-vascular, and neuro-ophthalmologic syndromes have been reported recently in NSD. A variety of steroid-sparing treatments and biologics have been used for relapsing NSD. Localized craniofacial scleroderma is associated with seizures, headaches, and, less commonly, focal deficits and cognitive decline. Immunosuppressive therapy may be required in patients with disease progression; some refractory cases have responded to IL-6 inhibition. Our review provides an up-to-date reference for neurologists faced with a patient with a history or skin findings consistent with Sweet disease or localized scleroderma. We hope that it will stimulate collaborative studies aimed at unraveling the pathogenesis of these disorders, better characterization of their neurologic manifestations, and discovery of optimal therapeutic solutions.

Facial recognition is widely thought to involve a holistic perceptual process, and optimal recognition performance can be rapidly achieved within two fixations. However, is facial identity encoding likewise holistic and rapid, and how do gaze dynamics during encoding relate to recognition? While having eye movements tracked, participants completed an encoding ("study") phase and subsequent recognition ("test") phase, each divided into blocks of one- or five-second stimulus presentation time conditions to distinguish the influences of experimental phase (encoding/recognition) and stimulus presentation time (short/long). Within the first two fixations, several differences between encoding and recognition were evident in the temporal and spatial dynamics of the eye-movements. Most importantly, in behavior, the long study phase presentation time alone caused improved recognition performance (i.e., longer time at recognition did not improve performance), revealing that encoding is not as rapid as recognition, since longer sequences of eye-movements are functionally required to achieve optimal encoding than to achieve optimal recognition. Together, these results are inconsistent with a scan path replay hypothesis. Rather, feature information seems to have been gradually integrated over many fixations during encoding, enabling recognition that could subsequently occur rapidly and holistically within a small number of fixations.

As a consequence of a growing population of immunocompromised individuals, including transplant recipients and cystic fibrosis patients, there has been a dramatic increase in chronic infections caused by Mycobacterium abscessus complex (MABC) strains that are usually recalcitrant to effective antibiotic therapy. The recent rise of macrolide resistance in MABC has further complicated this clinical dilemma, dramatizing the need for novel agents. The repurposing of current antibiotics is one rapid path from discovery to patient care. In this study, we have discovered that dual β-lactams, and specifically the combination of ceftazidime with either ceftaroline or imipenem, are synergistic and have clinically relevant activities, with MIC₅₀s of 0.25 (ceftaroline with 100 µg/ml ceftazidime) and 0.5 µg/ml (imipenem with 100 µg/ml ceftazidime) against clinical MABC isolates. Similar synergy was observed in time-kill studies against the M. abscessus ATCC 19977 strain using clinically achievable concentrations of either imipenem (4 µg/ml) or ceftaroline (2 µg/ml), as the addition of ceftazidime at concentrations of ≥50 µg/ml showed a persistent bactericidal effect over 5 days. Treatment of THP-1 human macrophages infected with three different M. abscessus clinical isolates supported the in vitro findings, as the combination of 100 µg/ml ceftazidime and 0.125 µg/ml ceftaroline or 100 µg/ml ceftazidime and 0.25 µg/ml imipenem dramatically reduced the CFU counts to near baseline levels of infection. This study's finding that there is synergy between certain β-lactam combinations against M. abscessus infection provides optimism toward identifying an optimum dual β-lactam treatment regimen.IMPORTANCE The emergence of chronic MABC infections among immunocompromised populations and their inherent and acquired resistance to effective antibiotic therapy have created clinical challenges in advancing patients for transplant surgery and treating those with disease. There is an urgent need for new treatment regimens, and the repurposing of existing antibiotics provides a rapid strategy to advance a laboratory finding to patient care. Our recent discoveries that dual β-lactams, specifically the combination of ceftazidime with ceftaroline or ceftazidime with imipenem, have significant in vitro MIC values and kill curve activities and are effective against infected THP-1 human macrophages provide optimism for a dual β-lactam treatment strategy against MABC infections. The unexpected synergistic activities reported in this study create a new path of discovery to repurpose the large family of β-lactam drugs.

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that modify extracellular matrix components and play crucial roles in development and numerous diseases. ADAMTS18 is a member of the ADAMTS family, and genome-wide association studies made an initial association of ADAMTS18 with white matter integrity in healthy people of 72-74 years old. However, the potential roles of ADAMTS18 in central nervous system remain unclear. In this study, we showed that Adamts18 mRNA is highly abundant in developing brains, especially in the cerebellum granular cell layer and the hippocampus dentate gyrus (DG) granular cell layer. Adamts18 knockout (KO) mice displayed higher dendritic branching complexity and spine density on hippocampal DG granular cells. Behavioral tests showed that Adamts18 KO mice had reduced levels of depression-like behaviors compared to their wild-type (WT) littermates. The increased neurite formation could be attributed in part to reduced phosphorylation levels of the collapsin response mediator protein-2 (CRMP2) due to activation of the laminin/PI3K/AKT/GSK-3β signaling pathway. Our findings revealed a critical role of ADAMTS18 in neuronal morphogenesis and emotional control in mice.

OBJECTIVEA systematic analysis on the utility of prophylactic antibiotics for neuroendovascular procedures has not been performed. At the authors' institution there is a unique setup to address this question, with some attending physicians using prophylactic antibiotics (cefazolin or vancomycin) for all of their neurointerventions while others generally do not.METHODSThe authors performed a retrospective review of the last 549 neurointerventional procedures in 484 patients at Tisch Hospital, NYU Langone Medical Center. Clinical and radiological data were collected for analysis, including presence of prophylactic antibiotic use, local or systemic infection, infection laboratory values, and treatment. Overall, 306 aneurysms, 117 arteriovenous malformations/arteriovenous fistulas, 86 tumors, and 40 vessel stenosis/dissections were treated with coiling (n = 109), Pipeline embolization device (n = 197), embolization (n = 203), or stenting (n = 40).RESULTSAntibiotic prophylaxis was used in 265 of 549 cases (48%). There was no significant difference between patients with or without antibiotic prophylaxis in sex (p = 0.48), presence of multiple interventions (p = 0.67), diseases treated (p = 0.11), or intervention device placed (p = 0.55). The mean age of patients in the antibiotic prophylaxis group (53.4 years) was significantly lower than that of the patients without prophylaxis (57.1 years; p = 0.014). Two mild local groin infections (0.36%) and no systemic infections (0%) were identified in this cohort, with one case in each group (1/265 [0.38%] vs 1/284 [0.35%]). Both patients recovered completely with local drainage (n = 1) and oral antibiotic treatment (n = 1).CONCLUSIONSThe risk of infection associated with endovascular neurointerventions with or without prophylactic antibiotic use was very low in this cohort. The data suggest that the routine use of antibiotic prophylaxis seems unnecessary and that to prevent antibiotic resistance and reduce costs antibiotic prophylaxis should be reserved for selected patients deemed to be at increased infection risk.

Hypusine is formed post-translationally from lysine and is found in a single cellular protein, eukaryotic translation initiation factor-5A (eIF5A), and its homolog eIF5A2. Biosynthesis of hypusine is a two-step reaction involving the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). eIF5A is highly conserved throughout eukaryotic evolution and plays a role in mRNA translation, cellular proliferation, cellular differentiation, and inflammation. DHPS is also highly conserved and is essential for life, as Dhps-null mice are embryonic lethal. Using exome sequencing, we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families. These individuals have similar neurodevelopmental features that include global developmental delay and seizures. Two of four affected females have short stature. All five affected individuals share a recurrent missense variant (c.518A>G [p.Asn173Ser]) in trans with a likely gene disrupting variant (c.1014+1G>A, c.912_917delTTACAT [p.Tyr305_Ile306del], or c.1A>G [p.Met1?]). cDNA studies demonstrated that the c.1014+1G>A variant causes aberrant splicing. Recombinant DHPS enzyme harboring either the p.Asn173Ser or p.Tyr305_Ile306del variant showed reduced (20%) or absent in vitro activity, respectively. We co-transfected constructs overexpressing HA-tagged DHPS (wild-type or mutant) and GFP-tagged eIF5A into HEK293T cells to determine the effect of these variants on hypusine biosynthesis and observed that the p.Tyr305_Ile306del and p.Asn173Ser variants resulted in reduced hypusination of eIF5A compared to wild-type DHPS enzyme. Our data suggest that rare biallelic variants in DHPS result in reduced enzyme activity that limits the hypusination of eIF5A and are associated with a neurodevelopmental disorder.