Improving the Accuracy of DaT Scan Interpretation: a retrospective study to identify variables that standardize the review of DaT scans for idiopathic Parkinson’s disease

Introduction: Until recently, the diagnosis of Parkinson’s disease (PD) has been based solely on clinical observation. The DaT scan is a tool that allows clinicians to visualize areas of neurodegeneration in PD and can help guide diagnosis. However, there is a discordance between clinical judgement and interpretation of DaT scans. In this study, we aim to improve the utility of DaT scans in the diagnosis of PD by identifying factors that can lead to a misdiagnosis and determine which image findings predict a clinical syndrome of parkinsonism. Methods: We will conduct a retrospective chart review to analyze DaT scans of 100 patients clinically diagnosed with PD. We will calculate the initial SN/SP/PPV/NPV for diagnoses based clinically compared to scan. We will then blindly review and reclassify all scans as definitely abnormal, definitely normal, or indeterminate. We will then recalculate a revised SN/SP/PPV/NPV to see if these values changed following reanalysis. From the discordant scans, we will attempt to identify factors that can further assist in interpreting DaT scans. Results: Patients have been identified and we are in the process of extracting data. We anticipate that after systematic, careful re-review, the specificity of DaT scans will be higher, due to improvement in identifying positive scans. Discussion: Imaging can be costly and cumbersome for patients and clinicians alike. Currently, DaT scans do not offer an improved accuracy in diagnosis over clinical judgement. If the interpretation of DaT scans can be optimized, they will be of greater utility to both patients and physicians

MODERATE ACCUMULATION OF TDP-43 IN NEURONS IS SUFFICIENT TO CAUSE ADULT-ONSET MOTOR NEURON DISEASE

Cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), accompanied by its nuclear clearance, is a key common pathological hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Mutations in TARDBP (the gene encoding TDP-43) linked to familial and sporadic ALS established this essential RNA binding protein to play a central role in the pathogenesis of ALS and FTLD. While most mutations cluster within the C-terminal, prion-like domain of TDP-43, a few are found within the 3’ untranslated region (3’ UTR) where TDP-43 binds and regulates the level of its own mRNA. ALS cases harboring the 3’ UTR mutation exhibited modest elevation of TDP-43, possibly because the mutation compromised the ability of TDP-43 to downregulate its own transcript. To determine whether modest increase of TDP-43 is sufficient to cause motor neuron disease, two lines of transgenic mice that accumulate modest levels of TDP-43 in the nervous system are generated and characterized. One of these lines, S97, expressed TARDBP carrying the ALS associated missense mutation (corresponding to the mutant G298S protein), whereas the other line, W2, expressed wild-type human TARDBP. S97 and W2 transgenic mice survive to adulthood, gain weight appropriately before plateauing, exhibit a progressive loss of strength, and lose large motor axons in their adult life. Also, S97 and W2 transgenic mice display adult-onset muscle degeneration and neuromuscular junction and motor end-plate abnormalities. Significantly, a percentage of S97 and W2 transgenic mice progress to paralysis late in life. The S97 and W2 lines represent the first transgenic TDP-43 lines with mice that exhibit motor neuron degeneration leading to paralysis in late adulthood. As such, these mouse lines will be useful to further clarify disease mechanisms and for testing therapeutic strategies to attenuate neurodegeneration in ALS. Advisor: Dr. Philip C. Wong Readers: Dr. Philip C. Wong and Dr. Joseph L. Mankowsk

Endemic melioidosis in central Taiwan—A longitudinal case cohort study

BackgroundMelioidosis is a systemic and suppurative disease endemic in the Southeast Asia. In Taiwan, most cases are reported in the southern region and no relevant profiles have been reported in central region. In this study, we performed the epidemiologic and clinical analyses from the melioidosis cases in central Taiwan.MethodsThe demographic, clinical, laboratory, radiologic, and outcome profiles were collected retrospectively and analyzed from patients whom Burkhoderia pseudomallei was isolated from clinical specimens during the 12-year study period (2011–2022).ResultsTotally 11 melioidosis cases (10 males and 1 female) were diagnosed, among them only 2 (18.2%) cases lived in suburban areas. Seven (63.6%) cases were diagnosed during 2019–2020, and diabetes mellitus was the most relevant comorbidity (5, 45.4%). All cases presented with fever at arrival, but only 4 (36.4%) and 2 (18.2%) cases presented with dyspnea and shock, respectively. Pneumonitis and extrapulmonary involvement were found in 5 cases (45.4%) each. Appropriate empiric and targeted antibiotic treatments were found in 4 (36.4%) and 10 (91.0%) case, respectively. Two cases (18.2%) succumbed to infection despite appropriate treatment including targeted antibiotics.ConclusionMelioidosis has become endemic in central Taiwan. Septic patients who present with suppurative or undetermined foci and have unsatisfied responses to standard treatment should arouse clinicians to take melioidosis into consideration

Converging evidence for the processing costs associated with ambiguous quantifier comprehension.

Traditional neuroanatomic models of language comprehension have emphasized a core language network situated in peri-Sylvian cortex. More recent evidence appears to extend the neuroanatomic network beyond peri-Sylvian cortex to encompass other aspects of sentence processing. In this study, we evaluate the neuroanatomic basis for processing the ambiguity in doubly-quantified sentences. For example, a sentence like All the dogs jumped in a lake can be interpreted with a collective interpretation (e.g., several dogs jumping into a single lake) or a distributive interpretation (e.g., several dogs each jumping into a different lake). In Experiment 1, we used BOLD fMRI to investigate neuroanatomic recruitment by young adults during the interpretation of ambiguous doubly-quantified sentences in a sentence-picture verification task. We observed that young adults exhibited a processing cost associated with interpreting ambiguous sentences and this was related to frontal and parietal cortex recruitment. In Experiment 2, we investigate ambiguous sentence processing with the identical materials in non-aphasic patients with behavioral variant frontotemporal dementia (bvFTD) who have frontal cortex disease and executive and decision-making limitations. bvFTD patients are insensitive to ambiguity associated with doubly-quantified sentences, and this is related to the magnitude of their frontal cortex disease. These studies provide converging evidence that cortical regions that extend beyond peri-Sylvian cortex help support the processing costs associated with the interpretation of ambiguous doubly-quantified sentences

Capturing Initial Understanding and Impressions of Surgical Therapy for Parkinson’s Disease to Enhance Patient Education

Purpose: Deep Brain Stimulation (DBS) is an underutilized surgical therapy for Parkinson’s Disease (PD). Both physician and patient hesitancies have been described as barriers to DBS, but specific perceptions of DBS have not been well characterized. To better understand DBS hesitancy, our objective is to pinpoint what specific concerns and fears our patient population have and use this information to enhance education for those contemplating DBS. Methods: A 30-question survey assessing impressions of surgical therapy for PD was administered to PD patients seen at an urban movement-disorders clinic. Patients had not yet undergone DBS implantation or neurosurgeon consultation. Questions were developed by an interdisciplinary team based on prior studies and common patient impressions previously noticed by clinicians. The survey assessed three domains: reported surgical history, openness to hypothetical surgery, and perceptions of DBS. Results and Conclusions: 102 patients completed the survey. The majority of patients thought that DBS is invasive (77%) and should be used only as a last resort (62%). Cost and insurance coverage were common concerns (53%). Eighty-two (80%) patients reported familiarity with DBS, with the majority having first heard about it from the internet. Sources of DBS information were not associated with willingness to undergo DBS, nor were they associated with impressions of DBS effectiveness or other DBS concerns (all p\u3e0.05). These findings provide us with insight regarding patient hesitancy, helping inform clinicians patient’s direct concerns. Further, we can bridge gaps in patient education and improve educational materials moving forward

Advertisement-Click Prediction Based on Mobile Big Data from HyXen AdLocus

The popularity of Internet has made advertisement marketing gone virtualized and location-based mobile advertising successful in recent years. Adlocus, an APP developed by HyXen Technology, is one good example to achieve this. This advertising software can tailor to the campaign needs and target users within a diameter of 1 km. However, the question is that is it possible to predict whether the user is willing to click on the advertisement. This paper adopts many ways to analyze how these relations influence in different kinds of mobile advertisement. A comprehensive performance comparison of different models is provided, and the analysis of different factors is also discussed, including click time, advertisement category, language, and mobile phone manufacturers

Network Influence of the Cerebellum for Predicting DBS Response in Patients with Advanced Parkinson’s Disease

Introduction: Deep brain stimulation (DBS) is a treatment option for reducing motor symptoms in patients with Parkinson’s Disease (PD) when first-line medication becomes ineffective. Existing literature has hypothesized that the clinical outcome of DBS may depend on brain connectivity profiles of the stimulation site to distant brain regions. However, the potential of brain connectivity profiles to predict response to DBS in PD remains unclear. Objective: This study aimed to investigate how changes in structural and functional connectivity may relate to patient response to DBS, through the examination of brain network changes using graph theory. Methods: Ten patients with advanced PD were included in this study. Diffusion tensor imaging (DTI) and resting-state fMRI scans were acquired prior to DBS implantation. Pre-DBS and post-DBS UPDRS-III scores were obtained. Network analysis of the DTI and fMRI scans was performed using GRETNA to compute structural and functional graph theory metrics, respectively. Metrics were correlated with UPDRS-III improvement to identify significant correlations to UPDRS improvement due to DBS. Results: Combined structural and functional graph theory metrics highlighted 32 structures to be significantly correlated with UPDRS-III improvement. Mainly, connections to the cerebellum were found to be significantly correlated with UPDRS-III improvement across several metrics for both structural and functional connectivity. Discussion: This work combined DTI, fMRI, and graph theory analysis to evaluate improvement with DBS. Several imaging biomarkers were identified that are robust predictors for UPDRS-III improvement. This work warrants investigation into the compensatory effect of the cerebellum and other potential biomarkers for identifying DBS candidates

Tumor suppressive microRNA-137 negatively regulates Musashi-1 and colorectal cancer progression

Stem cell marker, Musashi-1 (MSI1) is over-expressed in many cancer types; however the molecular mechanisms involved in MSI1 over-expression are not well understood. We investigated the microRNA (miRNA) regulation of MSI1 and the implications this regulation plays in colorectal cancer. MicroRNA miR-137 was identified as a MSI1-targeting microRNA by immunoblotting and luciferase reporter assays. MSI1 protein was found to be highly expressed in 79% of primary rectal tumors (n=146), while miR-137 expression was decreased in 84% of the rectal tumor tissues (n=68) compared to paired normal mucosal samples. In addition to reduced MSI1 protein, exogenous expression of miR-137 inhibited cell growth, colony formation, and tumorsphere growth of colon cancer cells. Finally, in vivo studies demonstrated that induction of miR-137 can decrease growth of human colon cancer xenografts. Our results demonstrate that miR-137 acts as a tumor-suppressive miRNA in colorectal cancers and negatively regulates oncogenic MSI1

Genetic copy number variants in myocardial infarction patients with hyperlipidemia

<p>Abstract</p> <p>Background</p> <p>Cardiovascular disease is the chief cause of death in Taiwan and many countries, of which myocardial infarction (MI) is the most serious condition. Hyperlipidemia appears to be a significant cause of myocardial infarction, because it causes atherosclerosis directly. In recent years, copy number variation (CNV) has been analyzed in genomewide association studies of complex diseases. In this study, CNV was analyzed in blood samples and SNP arrays from 31 myocardial infarction patients with hyperlipidemia.</p> <p>Results</p> <p>We identified seven CNV regions that were associated significantly with hyperlipidemia and myocardial infarction in our patients through multistage analysis (P<0.001), at 1p21.3, 1q31.2 (<it>CDC73</it>), 1q42.2 (<it>DISC1</it>), 3p21.31 (<it>CDCP1</it>), 10q11.21 (<it>RET</it>) 12p12.3 (<it>PIK3C2G</it>) and 16q23.3 (<it>CDH13</it>), respectively. In particular, the CNV region at 10q11.21 was examined by quantitative real-time PCR, the results of which were consistent with microarray findings.</p> <p>Conclusions</p> <p>Our preliminary results constitute an alternative method of evaluating the relationship between CNV regions and cardiovascular disease. These susceptibility CNV regions may be used as biomarkers for early-stage diagnosis of hyperlipidemia and myocardial infarction, rendering them valuable for further research and discussion.</p

Identification and Validation of Novel Small Molecule Disruptors of HuR-mRNA Interaction

HuR, an RNA binding protein, binds to adenine- and uridine-rich elements (ARE) in the 3′-untranslated region (UTR) of target mRNAs, regulating their stability and translation. HuR is highly abundant in many types of cancer, and it promotes tumorigenesis by interacting with cancer-associated mRNAs, which encode proteins that are implicated in different tumor processes including cell proliferation, cell survival, angiogenesis, invasion, and metastasis. Drugs that disrupt the stabilizing effect of HuR upon mRNA targets could have dramatic effects on inhibiting cancer growth and persistence. In order to identify small molecules that directly disrupt the HuR–ARE interaction, we established a fluorescence polarization (FP) assay optimized for high throughput screening (HTS) using HuR protein and an ARE oligo from Musashi RNA-binding protein 1 (Msi1) mRNA, a HuR target. Following the performance of an HTS of ~6000 compounds, we discovered a cluster of potential disruptors, which were then validated by AlphaLISA (Amplified Luminescent Proximity Homogeneous Assay), surface plasmon resonance (SPR), ribonucleoprotein immunoprecipitation (RNP IP) assay, and luciferase reporter functional studies. These compounds disrupted HuR–ARE interactions at the nanomolar level and blocked HuR function by competitive binding to HuR. These results support future studies toward chemical probes for a HuR function study and possibly a novel therapy for HuR-overexpressing cancers. NA-binding proteins (RBPs) are critical trans factors that associate with specific cis elements present in mRNAs, thereby regulating the fate of target mRNAs.1 The RBP Hu antigen R (HuR, also known as HuA; Hu references the patient's initials from whom an anti-HuR, autoinflammatory antibody was first isolated2) is a member of the embryonic lethal abnormal vision-like (ELAVL) protein family that binds to adenine- and uridine-rich elements (ARE) mainly located in the mRNA 3′-untranslated region (UTR).1,3,4 HuR is elevated in a broad range of cancer tissues compared with the corresponding normal tissues.5 In early reports, upregulated HuR in brain and colon cancers was linked to the enhanced expression of COX-2, VEGF, TGF-β, IL-8, and other cancer-associated proteins,6,7 Subsequent studies revealed that HuR was broadly overexpressed in virtually all malignancies tested, including cancers of the colon,5,8,9 prostate,10,11 breast,12 brain,6 ovaries,13 pancreas,14 and lung.15 Elevated cytoplasmic accumulation of HuR correlates with high-grade malignancy and serves as a prognostic factor of poor clinical outcome in those cancers.3,4,16 HuR is proposed to play a causal role in tumor development. Cultured carcinoma cells with elevated HuR produced significantly larger tumors than those arising from control populations in a mouse xenograft model,5 while reducing HuR by siRNA or microRNA led to decreased tumor size.5,17 HuR contains three RNA recognition motifs (RRM), of which RRM1 and RRM2 are involved in RNA binding, whereas RRM3 does not contribute to RNA binding but is needed for cooperative assembly of HuR oligomers on RNA.18 Many cytokine and proto-oncogene mRNAs have been identified as containing AREs within their 3′-UTRs, which confer a short mRNA half-life.19 Cytoplasmic binding of HuR to these ARE-containing mRNAs is generally accepted as leading to mRNA stabilization and increased translation.20,21 HuR promotes tumorigenesis by interacting with cancer-associated mRNAs which encode proteins implicated in different tumor processes including cell proliferation, cell survival, angiogenesis, invasion, and metastasis.3,4,16 HuR also promotes the translation of several target mRNAs encoding proteins that are involved in cancer treatment resistance.16,22–24 Taken together, these findings suggest that HuR is an attractive target for developing novel cancer therapies. RBPs have been considered “undruggable targets” due to the lack of a well-defined binding pocket for target mRNA. Indeed, there has globally been limited success in finding small molecules that directly disrupt the HuR interaction with AREs of target mRNAs, with limited reports indicating several active hits arising from screening for HuR inhibitors.25–27 Those reported hits are structurally independent, so they cannot provide information for later structure–activity relationship (SAR) analysis to design more potent and specific HuR inhibitors. Currently, the most potent hit reported (MS-444) acts via inhibition of HuR homodimerization, leading to disruption of the HuR–ARE interaction.25 Here, we try to identify HuR inhibitors, which competitively bind to HuR and directly disrupt the HuR–ARE interaction. In this study, we optimized a fluorescent polarization-based (FP-based) binding assay using human full-length HuR protein and an ARE region of Musashi1 (Msi1) 3′-UTR mRNA. HuR binds to and stabilizes the mRNA of Msi128 allowing for oncogenic overexpression of Msi1 and negative regulation of Numb and adenomatous polyposis coli (APC), which are involved in controlling Notch and Wnt signaling pathways.29 Using this FP-based HTS, we screened a library of ~6000 compounds and identified a set of HuR–ARE disruptors, which were validated by AlphaLISA assay, SPR, RNP IP, and luciferase reporter functional studies. The discovery of these inhibitors and related inactive compounds provides the impetus for rational design of more potent and specific HuR–ARE disruptors