Faculty Bibliography

The aim of this perspective article is to stimulate radical shifts in thinking and foster further discussion on the effective discovery, development, validation, and qualification process of biological markers derived from all available technical modalities that meet the complex conceptual and pathophysiological challenges across all stages of the complex, nonlinear, dynamic, and chronically progressive sporadic Alzheimer's disease (AD). This perspective evaluates the current state of the science regarding a broad spectrum of hypothesis-driven and exploratory technologies and "markers" as candidates for all required biomarker functions, in particular, surrogate indicators of adaptive to maladaptive and compensatory to decompensatory, reversible to irreversible brain "systems failure." We stress the future importance of the systems biology (SB) paradigm (next to the neural network paradigm) for substantial progress in AD research. SB represents an integrated and deeper investigation of interacting biomolecules within cells and organisms. This approach has only recently become feasible as high-throughput technologies and mass spectrometric analyses of proteins and lipids, together with rigorous bioinformatics, have evolved. Existing high-content data derived from clinically and experimentally derived neural tissues point to convergent pathophysiological pathways during the course of AD, transcending traditional descriptive studies to reach a more integrated and comprehensive understanding of AD pathophysiology, derived systems biomarkers, and "druggable" system nodes. The discussion is continued on the premise that the lack of integration of advanced biomarker technologies and transfertilization from more mature translational research fields (e.g., oncology, immunology, cardiovascular), which satisfy regulatory requirements for an accurate, sensitive, and well-validated surrogate marker of specific pathophysiological processes and/or clinical outcomes, is a major rate-limiting factor for the successful development and approval of effective treatments for AD prevention. We consider the conceptual, scientific, and technical challenges for the discovery-development-validation-qualification process of biomarker tools and analytical algorithms for detection of the earliest pathophysiological processes in asymptomatic individuals at elevated risk during preclinical stages of AD. The most critical need for rapid translation of putative markers into validated (performance) and standardized (harmonized standard operating procedures) biomarker tools that fulfill regulatory requirements (qualify for use in treatment trials: e.g., safety, target engagement, mechanism of action, enrichment, stratification, secondary and primary outcome, surrogate outcome) is the availability of a large-scale worldwide comprehensive longitudinal database that includes the following cohorts: (a) healthy aging, (b) people at elevated risks (genetic/epigenetic/lifestyle/comorbid conditions), and (c) asymptomatic-preclinical/prodromal-mild cognitive impairment/syndromal mild, moderate, or severe AD. Our proposal, as initial strategic steps for integrating markers into future development of diagnostic and therapy trial technologies, is to work toward: (a) creating the essential research and development infrastructure as an international shared resource, (b) building the organizational structure for managing such a multinational shared resource, and (c) establishing an integrated transsectoral multidisciplinary global network of collaborating investigators to help build and use the shared research resource.

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 x 10(-8)) and 11q and 17p (P<1 x 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.

Objectives.- Autism has been hypothesized to reflect neuronal disconnection. Several recent reports implicate the abnormalities of the white matter connectivity in autism. We aimed to focus on evaluating hemispheric asymmetry in autism spectrum disorders (ASD) using a Diffusion Tensor Imaging (DTI). Methods.- We examined the difference of white matter integrity between left and right hemispheres using the DTI in Korean boys with high functioning ASD and age and sex matched healthy controls. Results.- We found that the asymmetry of FA values between left and right hemispheres in inferior longitudinal fasciculus and inferior fronto-occipital fasciculus were significantly decreased in ASD group compared to controls. It mainly was due to reduced FA value of left hemisphere in ASD. Conclusions.- Our findings suggested that the ASD might have atypical hemispheric asymmetry of white matter integrity assessed with DTI. These findings will help on understanding of more advanced neurobiological basis underlying ASD

Knowledge of the long-term course of childhood Attention Deficit Hyperactivity Disorder (ADHD) is limited by the lack of longitudinal studies that extend beyond the third decade. Information about the later adult status of children with ADHD, one of the most common disorders of childhood, is important since the disorder is widely reported to persist through adulthood. Findings from a prospective 30 year longitudinal study addresses the extended course of ADHD. We report on the functional and psychiatric outcome of 135 males at mean age 41, diagnosed with ADHD at mean age of 8 (range, 6-12 years), and 136 non-ADHD males matched for age and SES, interviewed blindly by trained clinicians. As expected, ADHD at follow-up was significantly elevated in probands (P < 0.001). When the number of ADHD criteria is reduced, as recommended for ADHD in adults, rates rise in both groups. Other disorders significantly more prevalent in probands were:antisocial personality disorder (APD), drug (non-alcohol) disorders, and nicotine dependence. Childhood ADHD was not associated with elevated rates of mood or anxiety disorders in adulthood. Findings pertaining to other functional domains also will be presented. The extended clinical course of ADHD appears diagnostically specific, consisting of ADHD, APD and drug (non-alcohol) use disorders, supporting the validity of the ADHD diagnosis

Tubulocystic renal cell carcinoma (TC-RCC) is a rare, typically unilateral renal tumor. We report the first case of bilateral multifocal TC-RCC associated with end-stage renal disease with cytogenetic, immunohistochemical, and ultrastructural studies. A 62-year-old man with type 2 diabetes, hypertension, and end-stage renal disease on hemodialysis had bilateral complex renal masses smaller than 3.0 cm in greatest dimension found incidentally. Follow-up imaging studies demonstrated slowly enlarging masses. The patient underwent bilateral laparoscopic radical nephrectomy. Grossly, both kidneys had multifocal, unencapsulated, sharply demarcated, gray, spongy cystic lesions (0.3-2.5 cm) in cortex and medulla. The lesions contained clear serous fluid. Microscopically, the background kidneys showed end-stage changes with glomerulosclerosis and atrophic tubules. The well-delineated cystic lesions are composed of tightly packed tubules and cysts, separated by bland fibrous stroma. The lining cells are single-layer, flattened, cuboidal to columnar, with abundant eosinophilic cytoplasm, large round to oval nuclei, and prominent nucleoli. Hobnail cells are common. No desmoplastic reaction or cellular ovarian-like stroma is present. No solid growth or papilla is seen in either kidney. Immunohistochemically, the tumor cells showed diffuse and strong positivity for AMACR, AE1/AE3, CK8/18, CD10, and PAX2; focally strong positivity for CK7, EMA, vimentin, and 34BE12; and negativity for p63 and CK20. TC-RCC was diagnosed. Fuhrman nuclear grade was 2 to 3. Pathologic stage was pT1 on both kidneys. Fluorescence in situ hybridization shows gain of chromosome 7 and chromosome 17. Transmission electronic microscopy showed 2 types of epithelial cells: type I cells reminiscent of proximal tubular cells and lining the tubules and type II cells reminiscent of distal tubular cells lining the cysts. The patient was disease-free 3 years after radiologic detection and 12 months after bilateral nephrectomy. Our studies suggest TC-RCC is closely related to papillary RCC. This tumor appears to be low-grade with no metastasis

Studies of spike timing-dependent plasticity (STDP) have revealed that long-term changes in the strength of a synapse may be modulated substantially by temporal relationships between multiple presynaptic and postsynaptic spikes. Whereas long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength have been modeled as distinct or separate functional mechanisms, here, we propose a new shared resource model. A functional consequence of our model is fast, stable, and diverse unsupervised learning of temporal multispike patterns with a biologically consistent spiking neural network. Due to interdependencies between LTP and LTD, dendritic delays, and proactive homeostatic aspects of the model, neurons are equipped to learn to decode temporally coded information within spike bursts. Moreover, neurons learn spike timing with few exposures in substantial noise and jitter. Surprisingly, despite having only one parameter, the model also accurately predicts in vitro observations of STDP in more complex multispike trains, as well as rate-dependent effects. We discuss candidate commonalities in natural long-term plasticity mechanisms.

The sentinel lymph node is the initial site of metastasis. Downregulation of antitumor immunity has a role in nodal progression. Our objective was to investigate the relationship between immune modulation and sentinel lymph node positivity, correlating it with outcome in melanoma patients. Lymph node/primary tissues from melanoma patients prospectively accrued and followed at New York University Medical Center were evaluated for the presence of regulatory T cells (Foxp3(+)) and dendritic cells (conventional: CD11c(+), mature: CD86(+)) using immunohistochemistry. Primary melanoma immune cell profiles from sentinel lymph node-positive/-negative patients were compared. Logistic regression models inclusive of standard-of-care/immunological primary tumor characteristics were constructed to predict the risk of sentinel lymph node positivity. Immunological responses in the positive sentinel lymph node were also compared with those in the negative non-sentinel node from the same nodal basin and matched negative sentinel lymph node. Decreased immune response was defined as increased regulatory T cells or decreased dendritic cells. Associations between the expression of these immune modulators, clinicopathological variables, and clinical outcome were evaluated using univariate/multivariate analyses. Primary tumor conventional dendritic cells and regression were protective against sentinel lymph node metastasis (odds ratio=0.714, 0.067; P=0.0099, 0.0816, respectively). Antitumor immunity was downregulated in the positive sentinel lymph node with an increase in regulatory T cells compared with the negative non-sentinel node from the same nodal basin (P=0.0005) and matched negative sentinel lymph node (P=0.0002). The positive sentinel lymph node also had decreased numbers of conventional dendritic cells compared with the negative sentinel lymph node (P<0.0001). Adding sentinel lymph node regulatory T cell expression improved the discriminative power of a recurrence risk assessment model using clinical stage. Primary tumor regression was associated with prolonged disease-free (P=0.025) and melanoma-specific (P=0.014) survival. Our results support an assessment of local immune profiles in both the primary tumor and sentinel lymph node to help guide therapeutic decisions.

BACKGROUND: While 20% of schizophrenia patients worldwide speak tonal languages (e.g. Mandarin), studies are limited to Western-language patients. Western-language patients show tonal deficits that are related to impaired emotional processing of speech. However, language processing is minimally affected. In contrast, in Mandarin, syllables are voiced in one of four tones, with word meaning varying accordingly. We hypothesized that Mandarin-speaking schizophrenia patients would show impairments in underlying basic auditory processing that, unlike in Western groups, would relate to deficits in word recognition and social outcomes.MethodAltogether, 22 Mandarin-speaking schizophrenia patients and 44 matched healthy participants were recruited from New York City. The auditory tasks were: (1) tone matching; (2) distorted tunes; (3) Chinese word discrimination; (4) Chinese word identification. Social outcomes were measured by marital status, employment and most recent employment status. RESULTS: Patients showed deficits in tone-matching, distorted tunes, word discrimination and word identification versus controls (all p<0.0001). Impairments in tone-matching across groups correlated with both word identification (p<0.0001) and discrimination (p<0.0001). On social outcomes, tonally impaired patients had 'lower-status' jobs overall when compared with tonally intact patients (p<0.005) and controls (p<0.0001). CONCLUSIONS: Our study is the first to investigate an interaction between neuropsychology and language among Mandarin-speaking schizophrenia patients. As predicted, patients were highly impaired in both tone and auditory word processing, with these two measures significantly correlated. Tonally impaired patients showed significantly worse employment-status function than tonally intact patients, suggesting a link between sensory impairment and employment status outcome. While neuropsychological deficits appear similar cross-culturally, their consequences may be language- and culture-dependent

Rats were trained in a 2-alternative odor choice task to discriminate between a 10-component odor mixture and the same mixture with one component removed and replaced with 1 of 3 concentrations of a different monomolecular odor (contaminant). All stimuli were presented within a training session, thus the rat essentially had to learn to discriminate the 10-component mixture from "not" the 10-component mixture. Rats performed most poorly discriminating the complete mixture from the mixture with one component removed and no contaminant added. As the concentration of the contaminant increased from 10 ppm to a concentration equal to the other components (100 ppm), discrimination improved linearly. In analyses of individual differences, rats that spent more time in the sampling port (sampling and making a decision) were more accurate than rats that spent less time. Together, these results emphasize the balance between perceptual stability and perceptual discrimination expressed by the olfactory system dealing with dynamic mixtures and the robust effects of contamination on those processes. In addition, they provide further support that modification of sampling/decision time is a strategy used by rats to deal with difficult discriminations of complex odors.