Utility For Early Detection Research Articles

Lactoferrin in Pediatric Chronic Kidney Disease and Its Relationship with Cardiovascular Risk.

Pediatric CKD is associated with a high risk of cardiovascular disease (CVD). Early detection of subclinical CVD in childhood CKD can be achieved through various cardiovascular (CV) assessments, including carotid intima-media thickness (cIMT), ambulatory blood pressure monitoring (ABPM), and arterial stiffness indices. Lactoferrin (LF), a key functional glycoprotein found in breast milk, has been linked to several diseases and has potential as a biomarker. In our study of 102 children with CKD stages G1-G4, we explored the relationship between LF and CV risk markers. We found that LF concentration was not related to the severity or underlying causes of childhood CKD, but was positively correlated with overweight/obesity. Lower LF levels were correlated with increased cIMT and elevated arterial stiffness indices. Notably, abnormalities in ABPM profiles were observed in up to 60% of the children with CKD, with low LF levels linked to nighttime hypertension, nocturnal non-dipping, and ABPM abnormalities. In conclusion, LF shows promise as a biomarker for detecting subclinical CVD in children with CKD. Its potential utility in early detection could be instrumental in guiding timely interventions and improving long-term CV outcomes, although further research is needed to clarify the underlying mechanisms.

Evaluating the diagnostic accuracy of microRNA-494 as a biomarker in cancers: A systematic review and meta-analysis

Abstract MicroRNA-494 (miR-494) has emerged as a potential diagnostic biomarker for cancer detection, but conflicting reports have led to uncertainty regarding its clinical utility. This study aims to address these discrepancies by conducting a comprehensive meta-analysis of miR-494 diagnostic performance across various cancer types. A comprehensive literature search was performed across multiple databases, including PubMed, Web of Science, Wanfang databases, and CNKI (China National Knowledge Infrastructure), with a cutoff date of April 23, 2024. Eligible studies were identified using predefined inclusion criteria and various search strategies to ensure a thorough coverage of the available evidence. To evaluate the diagnostic performance of miR-494 in cancer detection, relevant measures such as sensitivity, specificity, and other diagnostic accuracy indicators were extracted from the included studies. These data were synthesized using bivariate meta-analysis models to generate pooled estimates of miR-494 diagnostic performance. All statistical analyses were conducted using the STATA 16.0 software. This meta-analysis pooled data from 8 studies, comprising a total of 647 cancer cases and 407 healthy controls. The aggregated diagnostic performance of miR-494 was as follows: a sensitivity of 0.67 (95% confidence interval [CI], 0.52–0.80), a specificity of 0.85 (95% CI, 0.77–0.91), and an area under the curve of 0.86 (95% CI, 0.82–0.88), indicating good overall diagnostic accuracy. The diagnostic odds ratio (DOR) was 12.11 (95% CI, 7–21), suggesting that miR-494 has strong discriminatory power in distinguishing cancer patients from healthy individuals. The positive likelihood ratio of 4.62 (95% CI, 3.1–6.8) and negative likelihood ratio of 0.38 (95% CI, 0.26–0.56) further support the diagnostic utility of miR-494. Deeks’ funnel plot asymmetry test was employed to assess potential publication bias, yielding a P value of 0.50, which suggests the absence of significant bias in the included studies. The meta-analysis results suggest that miR-494 exhibits promising diagnostic performance in detecting cancer, with moderate accuracy. The pooled sensitivity, specificity, and high area under the receiver operating characteristic curve highlight its potential as a cancer biomarker, indicating its utility in early detection and accurate diagnosis.

Evaluating p-tau217 and p-tau231 as Biomarkers for Early Diagnosis and Differentiation of Alzheimer's Disease: A Narrative Review.

The escalating prevalence of Alzheimer's disease (AD) highlights the urgent need to develop reliable biomarkers for early diagnosis and intervention. AD is characterized by the pathological accumulation of amyloid-beta plaques and tau neurofibrillary tangles. Phosphorylated tau (p-tau) proteins, particularly p-tau217 and p-tau231, have been identified as promising biomarker candidates to differentiate the disease progression from preclinical stages. This narrative review is devoted to a critical evaluation of the diagnostic accuracy, sensitivity, and specificity of p-tau217 and p-tau231 levels in the detection of AD, measured in plasma, serum, and cerebrospinal fluid, compared to established biomarkers. Additionally, the efficacy of these markers in distinguishing AD from other neurodegenerative disorders is examined. The significant advances offered by p-tau217 and p-tau231 in AD diagnostics are highlighted, demonstrating their unique utility in early detection and differential diagnosis. This comprehensive analysis not only confirms the excellent diagnostic capabilities of these markers, but also deepens the understanding of the molecular dynamics of AD, contributing to the broader scientific discourse on neurodegenerative diseases. This review is aimed to provide key information for researchers and clinicians across disciplines, filling interdisciplinary gaps and highlighting the role of p-tau proteins in revolutionizing AD research and clinical practice.

Abstract 6084: Identification of plasma proteins for early detection of cancer, including lung, in the Atherosclerosis Risk in Communities (ARIC) study

Abstract Background: Plasma proteins, directly secreted from tumor cells or a result of the body’s response to a tumor, may have utility for early detection. We aimed to identify plasma protein combinations that predict prediagnostic cancers in a prospective study. Methods: We sampled from 8,186 ARIC study participants without a cancer diagnosis at blood draw and with 4,877 log2-transformed proteins measured by SomaScan. We selected as cases those diagnosed within 5 years after blood draw and were registry/medical record confirmed. We selected as controls those who never had a cancer history by 2015 and did not die of cancer. Participants with possible liver, kidney, or inflammatory conditions were excluded (eGFR-cr<30, top 1% of plasma AST, ALT, CRP). Highly correlated proteins (r>±0.75), abundant or known markers (albumin, CRP, PSA), and proteins with wide log2-transformed distributions (SD>1 and >10% outliers-1.5 IQR away from 25th or 75th percentile) among controls were excluded. Recursive feature elimination (RFE) with random forest (RF) was used to select the top 10 informative proteins based on accuracy. Non-protein features included demographic, lifestyle (e.g., smoking), and medical factors. We next divided participants into train and test sets in 7:3 ratio stratified by case status. RF including top 10 proteins from the RFE and non-protein features trained in the train set were used to predict near-term cancer status in the test set and to calculate prediction performance. Random Over-Sampling Examples were used to balance between rare cases (<3%) and controls in the dataset. Results: We included 210 cases (98 diagnosed within 2 years) and 7,042 controls with 3,476 proteins. 58% were female, 24% were Black, and median age was 57 years (IQR: 52-62). The most common cancer was lung (27%). In the test set, sensitivity and specificity of the model for total cases diagnosed within 2 years were 0.19 and 0.91. Results for cases diagnosed within 3 (0.24, 0.88) and 5 (0.29, 0.87) years were similar. Using the top 10 informative proteins for total cancer, sensitivity was 0.68 and specificity was 0.56 for lung cancers diagnosed within 2 years; for lung cancers diagnosed within 3 (0.55, 0.77) or 5 (0.53, 0.79) years, sensitivity decreased but specificity increased. Using the top 10 informative proteins specific for lung cancer, which did not overlap with the top 10 for total cancer, sensitivity and specificity were 0.69 and 0.67 for lung cancers diagnosed within 2 years. Conclusions: In this study, in which blood draw preceded diagnosis, top informative proteins did not provide sufficient sensitivity for all-cancer near-term prediction. For lung cancer, further optimization may improve the sensitivity and specificity to achieve the range required for population implementation for screening. Validation with more cases, and on other proteomic platforms are needed. Funding NHLBI, NCI, NPCR Citation Format: Meng Ru, Christopher Douville, Kenneth R. Butler, Corinne E. Joshu, Jiayun Lu, Anna Prizment, Josef Coresh, Elizabeth A. Platz. Identification of plasma proteins for early detection of cancer, including lung, in the Atherosclerosis Risk in Communities (ARIC) study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6084.

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications.

Information exchange is essential for the brain, where it communicates the physiological and pathological signals to the periphery and vice versa. Extracellular vesicles (EVs) are a heterogeneous group of membrane-bound cellular informants actively transferring informative calls to and from the brain via lipids, proteins, and nucleic acid cargos. In recent years, EVs have also been widely used to understand brain function, given their "cell-like" properties. On the one hand, the presence of neuron and astrocyte-derived EVs in biological fluids have been exploited as biomarkers to understand the mechanisms and progression of multiple neurological disorders; on the other, EVs have been used in designing targeted therapies due to their potential to cross the blood-brain-barrier (BBB). Despite the expanding literature on EVs in the context of central nervous system (CNS) physiology and related disorders, a comprehensive compilation of the existing knowledge still needs to be made available. In the current review, we provide a detailed insight into the multifaceted role of brain-derived extracellular vesicles (BDEVs) in the intricate regulation of brain physiology. Our focus extends to the significance of these EVs in a spectrum of disorders, including brain tumors, neurodegenerative conditions, neuropsychiatric diseases, autoimmune disorders, and others. Throughout the review, parallels are drawn for using EVs as biomarkers for various disorders, evaluating their utility in early detection and monitoring. Additionally, we discuss the promising prospects of utilizing EVs in targeted therapy while acknowledging the existing limitations and challenges associated with their applications in clinical scenarios. A foundational comprehension of the current state-of-the-art in EV research is essential for informing the design of future studies.

Abstract SY30-02: Oncosomes in the early stages of breast cancer

Abstract Comprehensive analysis of cellular, acellular and plasma components of the Liquid Biopsy provides the opportunity to investigate cancer evolution and the interactions with the immune system at the systemic level in the individual patient. This presentation will discuss early findings supporting the relevance of oncosomes, large extracellular vesicles, in early-stage breast cancer and its potential utility in early detection and cell-level staging of the disease when combined with the cellular profiles. Breast cancer (BC) affects 1 in every 8 women in the United States and is currently the most prevalent cancer worldwide. Precise staging at diagnosis and prognosis are essential components for the clinical management of BC patients. We set out to evaluate the feasibility of a next generation liquid biopsy platform to stratify late-stage BC, early-stage BC, and age- and gender matched controls using peripheral blood samples. Utilizing 5 biomarkers, we can identify rare circulating events with epithelial, mesenchymal, endothelial and hematological origin. We detected a higher level of CTCs in late-stage patients, compared to the early-stage and normal donors. We observed more tumor-associated oncosomes in the early-stage, compared to late-stage and the normal donor groups. Overall, we were able to detect reproducible patterns in the enumeration of rare cells and oncosomes of cancer vs. normal donors with an AUC of 99%. An initial concept for cell-level staging with the liquid biopsy was applied to early-stage vs. late-stage BC samples and reached an AUC of 91% allowing for robust stratification. Citation Format: Peter Kuhn. Oncosomes in the early stages of breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY30-02.

Early Detection of Mild Cognitive Impairment, Dementia and Alzheimer’s Using qEEG

Abstract This article reports the biomarkers of the Mild Cognitive Impairment (MCI) among the elderly group aged around 60-75 years old by analyzing the EEG signals recorded by using the quantitative electroencephalograph (qEEG). There is growing evidence that EEG analysis in resting state condition are useful in early detection of neural signatures of Alzheimer’s and dementia. EEG findings and analysis shows potential of discriminating MCI, Alzheimer’s and dementia. In this research, the purpose is to 1) develop the indexes for each of the EEG bands and sub-bands such as delta (1.5 – 3.5 Hz), theta (3.3 – 7.5 Hz), alpha ( 8 – 12 Hz), beta 1 (15 – 18 Hz) and beta 2 (22 – 30 Hz); 2) provide reference for early diagnosis; 3) extract and analyze the brainwave pattern of MCI and cognitively healthy group. This study involved 19 channel resting state EEG from a total of 30 subjects, 18 diagnosed as having MCI and 12 cognitively healthy elderly with criteria for inclusion if the mini mental state examination (MMSE) score is more than or equal to 28, based on the age and educational level. Development of qEEG index started by decomposition of EEG by performing Fourier analysis, averaging and normalizing the value from the 19 channels to obtain the z-score. Findings showed promise of utility in early detection of Alzheimer’s. Notably, 1) Increases in delta/ theta posterior temporal and prefrontal area i.e., H(6.64) vs. MCI(26.29); beta temporal region, 2) Decreases in alpha at sensory motor region i.e., H(0.27) vs. MCI(0.23).

Abstract 5135: Characterization of a data independent acquisition mass spectrometry-based workflow in the plasma of NSCLC subjects reveals host immune response mechanisms

Abstract Background: Measurement of circulating biomarkers in cancer has proven utility for early detection, differential diagnosis, and predicting pre-treatment response to therapy. More recently, circulating proteomic biomarkers for pre-treatment prediction of therapeutic response have received additional attention due to the heterogeneous responses to immunotherapies. To develop a greater understanding of the circulating plasma proteome in subjects with cancer we have optimized a depleted plasma proteomic workflow, based on label-free data independent acquisition (DIA) mass spectrometry, and applied it to plasma from subjects with late stage NSCLC. This approach provides a deep and unbiased description of the plasma proteome and the dysregulated biological pathways associated with lung cancer. Methods: Plasma samples from subjects with Stage III-IV non-small cell lung cancer (NSCLC, n = 15) and age matched healthy donors (n = 15) were depleted of 14 high abundance proteins using MARS Hu-14 spin columns (Agilent). The resulting flow through was prepared for mass spectrometry using a filter aided sample preparation method (FASP). All samples were analyzed using 2h gradients on a C18 column coupled to a Thermo Scientific Q Exactive mass spectrometer operated in DIA mode. Data was extracted using Spectronaut (Biognosys) with combined sample specific and resource spectral libraries and statistical analysis was conducted to identify disease associated biomarker candidates. Pathway analysis highlights dysregulated biological functions. Results: An overview of assay optimization will be presented which resulted in the final workflow. In summary, a comprehensive protein spectral library was created containing 1,827 unique proteins and in DIA acquisition, 1,304 proteins were quantified across all samples. Univariate statistical testing identified 162 dysregulated proteins (125 up-regulated and 37 down-regulated; q-value > 0.05 and log2 fold change > 0.58). In addition to the acute phase proteins (e.g. CRP and SAA1) which were previously verified to be elevated in subjects with NSCLC, multivariate analysis identified additional proteins that are differentially expressed between the sample groups. Most relevant to immune function was CLC (Galectin-10), which has been identified as key component supporting the suppressive function of Tregs1 and S100A9 which is a known therapeutic target associated myeloid-derived suppressor cells2. Furthermore, F13A1 was suppressed in the NSCLC samples which is known to be associated with macrophage activation. Conclusions: Multiple plasma proteins were found to be dysregulated and associated with NSCLC reflecting the host immune response via acute phase response signaling and immunosuppressive mechanisms. Several of these markers have been linked to patient outcomes and represent known therapeutic targets.1. Kubach, J., et. al. Blood 2007 110:1550-1558 2. Shen, L., et. al. Cancer Immunol Res. 2015 3(2): 136-148. Citation Format: Nicholas Dupuis, Linda Sensbach, Sebastian Muller, Lukas Reiter. Characterization of a data independent acquisition mass spectrometry-based workflow in the plasma of NSCLC subjects reveals host immune response mechanisms [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5135.

Extracellular vesicle microRNA cargo is correlated with HPV status in oropharyngeal carcinoma.

The incidence of human papilloma virus positive (HPV+ ) oropharyngeal squamous cell carcinoma (OPSCC) has increased rapidly in recent decades. These tumours have a favourable outcome compared to HPV-negative (HPV- ) OPSCC. However, HPV+ tumours are more likely to metastasise to distant sites, suggesting a difference in how these tumour subtypes interact with the metastatic niche. Extracellular vesicles (EVs) have emerged as important players in cell-to-cell communication and are a potential source of biomarkers for cancer diagnosis. This study aims to characterise the microRNA cargo of small EVs released by HPV+ and HPV- OPSCC cell lines. Extracellular vesicles produced by HPV+ (SCC2 and SCC90) and HPV- (SCC72 an SCC89) OPSCC cells were characterised by tunable resistive pulse sensing (TRPS) and western blotting. RNA was extracted from EVs and analysed by small RNA sequencing. A bioinformatics approach was used to identify EV miRNA signatures associated with HPV status. HPV- OPSCC cells produced more EVs than HPV+ OPSCC cells. EVs were positive for the common EV markers CD63, CD9 and TSG101. Unbiased hierarchical clustering analysis of EV miRNA cargo revealed that samples clustered based on HPV status. 14 miRNA were enriched in HPV+ cell-derived EVs, whereas 19 miRNA were enriched in EVs derived from HPV- cell lines. Here, we identify EV miRNA signatures indicative of the HPV status of the parent cell. This may provide a platform from which to validate salivary or blood-based biomarkers with utility for early detection and stratifying risk in OPSCC patients.

Sudoscan in the evaluation and follow-up of patients and carriers with TTR mutations: experience from an Italian Centre

Objective: To evaluate the utility of Sudoscan as possible marker of disease progression and disease onset in a cohort of hereditary ATTR amyloidosis (hATTR amyloidosis) polyneuropathy patients and carriers.Patients and methods: We regularly performed different clinical scales, nerve conductions studies (NCS), and Sudoscan on a cohort of hATTR amyloidosis patients and carriers from a single centre of central Italy, a non-endemic area, in the last 2 years.Results: About 18 hATTR amyloidosis patients and 8 asymptomatic carriers were enrolled. All patients had a neuropathy affecting large fibres, small fibres or both. Two subjects developed symptoms and neurophysiological alterations during follow-up. Sudoscan data from hand and feet inversely correlated with neuropathy severity and with disease duration. Moreover, global disease status, expressed by Kumamoto scale also inversely correlated with Sudoscan values.Conclusions: We confirmed that Sudoscan is a reliable marker of disease progression in late-onset hATTR amyloidosis patients and we suggest its possible utility in early detection of disease in this population.

Differences in upper gastrointestinal neoplasm detection rates based on inspection time and esophagogastroduodenoscopy training.

Background and study aims Esophagogastroduodenoscopy (EGD) has utility in early detection of upper gastrointestinal (UGI) neoplasms. However, previous studies report shorter inspection times and inexperienced endoscopists contribute to overlooking gastric neoplasms. We investigated neoplasm detection rates according to inspection time and extent of EGD training. Patients and methods In this retrospective observational study, we reviewed routine EGDs for 3,925 consecutive cases between October 2014 and March 2015. We divided the endoscopists into three groups based on median inspection time during EGD without undergoing biopsy. Using cut-off median inspection times of 7 and 10 minutes, three, five, and eight endoscopists were classified into the fast, moderate, and slow groups, respectively. We compared detection rates according to inspection time and the extent of EGD training. Results The median inspection time among all endoscopists was 9.3 minutes (range, 6.6 – 12.0 min). The detection rate for UGI neoplasms was as follows: fast group, 3.6%; moderate group, 3.3 %; and slow group, 3.1 % ( P = 0.807). The median inspection time was significantly shorter among the intensive training ≥ 1-year group than among the < 1-year group (< 1-year: median 6.3 min; range 8.2 – 13.9 min, ≥ 1-year: median 8.9 min; range 6.4 – 11.4 min, P < 0.001). The detection rate for UGI neoplasms was significantly higher among the intensive training ≥ 1-year group than among the < 1-year group (< 1-year: 2.2 %; ≥ 1-year: 3.7 %, OR = 1.65, 95 % CI: 1.02 – 2.68, P = 0.041). Conclusions There was no association between inspection times and neoplasm detection rates. The quality of EGD, as measured by neoplasm detection rates, may be improved by ≥ 1-year of intensive training.

Abstract 5571: Changes in plasma genomic abnormalities at chromosome 8 and 20 predict treatment response and monitor disease progression in advanced gastric cancer

Abstract Gastric cancer (GC) is the fifth most common cancer diagnosis with roughly 60% of patients with metastatic disease. Tumor heterogeneity represents a major challenge to personalized cancer therapy. Intratumor heterogeneity can result in missing critical DNA genomic alterations using conventional tumor biopsies. Circulating cell-free DNA (cfDNA) in the peripheral blood has the potential to capture DNA alterations in a more dynamic manner in particular types of advanced tumors where feasibility of repeat tissue biopsies is limited. Using low-pass whole-genome sequencing (LP-WGS) data from 329 blood plasma samples collected from 63 1L metastatic (mGC) patients enrolled in phase II trial NCT01590719, receiving either onartuzumab or placebo in combination with mFOLFOX6, we evaluated the global percent genome change (%GC) and copy number (CN) gain at baseline and throughout the course of treatment. cfDNA samples were isolated with the automated QIAsymphony system and analyzed on the Illumina NextSeq 500 system with a novel LP-WGS protocol at 0.5x coverage. Seven chromosomes (chr1, 7, 8, 14, 15, 20, and 21) showed the most frequent CN gains of evaluated patients (≥15%). Of these seven chromosomes, chr8 and 20 featured the largest number of genes at baseline with CN gains with 30.2% (19/63) at chr8 and 25.4% (16/63) at chr20. 81% of patients (13/16) with chr20 CN gain also showed an increase in CN at chr8. Patients with gains at chr8 and/or 20 have higher %GC compared to patients with normal copy status. Recurrent CN gains at chr8 and 20 in tumor tissues were previously reported in GC patients and correlated with tumor progression. Copy number gains at chr8 and 20 in cfDNA from mGC patients, reported here for the first time, suggests a potential utility for early detection of disease progression. Moreover, patients with CN gains at chr8 and/or 20 had higher circulating tumor cells detected at baseline (p=0.003) and also showed the most decrease in %GC post-treatment. 75% (9/12) of the patients with CN gains at chr8 and/or 20 were responders and showed a mean 3-fold decrease (range of 1.6-4.7 fold change) in tumor size post-treatment. This suggests CN gain at chr8 or 20 in cfDNA could be used as a noninvasive measure to identify a novel subset of mGC patients sensitive to chemo-based treatment. When comparing %GC pre- and post-treatment, the %GC decreased significantly at C2D1 (p=0.006). This decrease in %GC correlates with a decrease in tumor burden in patients with response, while %GC and tumor burden remain unchanged or increased in nonresponders. Monitoring %GC pre- and post-treatment demonstrates the ability to assess the depth of the treatment and early detection of disease progression. Findings from this study suggest that plasma genomic abnormality monitoring may be used for treatment decision-making in mGC and should be evaluated further in clinical trials. Citation Format: An D. Do, Charles D. Baudo, Samir Seshadri, Xiaoji Chen, Rebecca Suttmann, David S. Shames, Mark R. Lackner, Shih-Min A. Huang, Teiko Sumiyoshi. Changes in plasma genomic abnormalities at chromosome 8 and 20 predict treatment response and monitor disease progression in advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5571.

T67. Electroencephalogram utility in early detection of dementia

The brain and its neurons are continuously active, this activity occurs spontaneously as well as in response to external stimulation, the computerized electroencephalogram collects the information of brain activity and its importance is that provides sufficiently reliable information about if there a normal or pathological brain function, in addition through this method it is possible to follow closely the dynamics of these processes making possible the characterization and control of the disease process. Regarding the usefulness of the EEG in dementia according to the findings of a study, it is as accurate as the clinical examination in the diagnosis of Alzheimer’s dementia (about 90% according to Cummings et al., 1998) and others affirm that the diagnostic relevance is comparable with other more complex and less accessible exams such as PET positron emission tomography (Szelies and Grond, 1992; Dierks and Jelic, 2000). According to the characterization, Stigsby et al. (1981) found greater diffuse activity of theta and delta, and lower alpha and beta, as well as the frontal deceleration, more prominent to Silvio’s fissure. Another study about prediction revealed the value of the EEG as a predictor with the 95% of accuracy in identifying those, in the study participants, who would suffer from neurocognitive decline, and those who not (Prichep et al., 2005). A qualitative cross - sectional descriptive methodology was proposed with the objective of knowing the brain activity, prior to treatment, in five patients with Dementia. The study was performed in awake state and activation using two methods: opening/closing the eyes and hyperventilation. Exclusion criteria were: presence of comorbidity psychiatric, history of brain damage and consumption of psychoactive substances, considering that these conditions may influence the results of the CEEG. I was detected some heterogeneous data such as presences of theta waves in the left frontal lobe (in 1 of 5 patients), linked to diffuse corticosubcortical dysfunction and generalized low voltage (1 of 5 patients), related to cortical hypofunction suggestive of loss of nerve cells and therefore of functionality, nevertheless, it is important to emphasize the absence of alpha waves in all of them (5 of 5 patients) which is related to alterations in the synchronicity of the corticocortical connections. In conclusion, the findings show characteristics in the EEG in the presented patients, this characterization could be related to an alteration in the cerebral functioning, which provides favorable data about the value of the EEG as a tool for early detection of dementia, in conjunction with other assessment tools, even in the early stages of cognitive impairment, coinciding this with the revised literature. The study also presents limitation, the small number of patients studied and the absence of a control group.

UTILITY OF DISEASE-LINKED DEPLETION OF AUTOANTIBODIES AS BIOMARKERS FOR EARLY, BLOOD-BASED DETECTION AND MONITORING OF ALZHEIMER’S AND OTHER NEURODEGENERATIVE DISEASES

We have shown that autoantibodies are ubiquitous in human blood and that specific changes in autoantibody profiles occur that reflect the presence of disease. Autoantibody production is presumably increased in response to the appearance of disease-specific tissue debris in the blood. For AD, our previous studies have exploited this phenomenon and developed panels of autoantibodies that can be used to distinguish healthy control subjects from those with early-stage AD pathology at mild cognitive impairment (MCI), and at more advanced mild-moderate AD with high overall accuracy. Here, we show that early AD pathology can also be linked to the selective depletion of specific brain-reactive autoantibodies, which also has utility for AD detection at both the MCI and mild-moderate AD stages, potentially opening the door to preclinical detection. Sera from over 300 subjects, including 50 MCI (with low CSF Aβ42) and 50 mild-moderate AD subjects, as well as those with Parkinson's disease, and multiple sclerosis were screened with human protein microarrays containing 9,486 potential antigen targets to identify autoantibodies that are selectively depleted due to the presence of disease. For each disease, 50 autoantibodies with depleted titers relative to controls were identified and evaluated using Random Forest and Receiver Operating Characteristic (ROC) curves for their ability to distinguish disease subjects from age- and sex-matched controls, and from individuals with other neurodegenerative diseases. Results demonstrate that detection of depleted autoantibodies in serum can readily differentiate disease subjects from age- and sex-matched controls with high overall accuracy, sensitivity, and specificity. Depletion biomarkers were able to distinguish subjects with early AD pathology at MCI from controls with 90.0% overall accuracy in the Testing Set (sensitivity=88.0%; specificity=92.0%). Comparable accuracies were obtained for identification of subjects with mild-moderate AD, early-stage Parkinson's disease and multiple sclerosis. Results demonstrate that monitoring the disease-linked depletion of brain-reactive autoantibodies in blood has utility for early detection and staging of AD and other neurodegenerative diseases. Since autoantibody depletion may reflect neuropathological events prior to significant neurodegeneration, we hypothesize that depleted autoantibody biomarkers may be particularly useful for preclinical disease detection, perhaps years before the onset of symptoms.

Unique Associations between Childhood Temperament Characteristics and Subsequent Psychopathology Symptom Trajectories from Childhood to Early Adolescence.

Existing research suggests that temperamental traits that emerge early in childhood may have utility for early detection and intervention for common mental disorders. The present study examined the unique relationships between the temperament characteristics of reactivity, approach-sociability, and persistence in early childhood and subsequent symptom trajectories of psychopathology (depression, anxiety, conduct disorder, and attention-deficit hyperactivity disorder; ADHD) from childhood to early adolescence. Data were from the first five waves of the older cohort from the Longitudinal Study of Australian Children (n=4983; 51.2% male), which spanned ages 4-5 to 12-13. Multivariate ordinal and logistic regressions examined whether parent-reported child temperament characteristics at age 4-5 predicted the study child's subsequent symptom trajectories for each domain of psychopathology (derived using latent class growth analyses), after controlling for other presenting symptoms. Temperament characteristics differentially predicted the symptom trajectories for depression, anxiety, conduct disorder, and ADHD: Higher levels of reactivity uniquely predicted higher symptom trajectories for all 4 domains; higher levels of approach-sociability predicted higher trajectories of conduct disorder and ADHD, but lower trajectories of anxiety; and higher levels of persistence were related to lower trajectories of conduct disorder and ADHD. These findings suggest that temperament is an early identifiable risk factor for the development of psychopathology, and that identification and timely interventions for children with highly reactive temperaments in particular could prevent later mental health problems.

Abstract 3137: NGS-based detection of KRAS hotspot mutations in plasma cell-free DNA of pancreatic cancer cases

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by hotspot mutations in the KRAS gene (codons 12, 13 or 61) in 85-90% of cases. Codon 12 KRAS mutations have been detected in pancreatic juice, blood and stool samples from pancreatic cancer cases and represent promising biomarkers for early detection. However, the proportion of tumor-derived KRAS mutations in cell-free DNA fragments (cfDNA) has shown large variations, probably because of the heterogeneity in biosamples and assays tested. Deep sequencing technologies (NGS) allow the identification of low-abundance somatic variants, but have not previously been applied to the detection of KRAS hotspot mutations in cfDNA of PDAC cases. Moreover, variant calling methods have rarely been tested against cancer-free individuals so the proportion of false positives is unknown. We investigated whether deep sequencing of KRAS mutations at codons 12, 13 and 61 in plasma samples could represent a robust assay to distinguish pancreatic cancer from chronic pancreatitis and healthy controls. Methods: We developed an Ion Torrent-based NGS KRAS assay (partial exons 2 and 3, totalling 208bp) to screen cfDNA from plasma samples of 461 PDAC cases, 154 individuals with chronic pancreatitis and 421 healthy controls. cfDNA extraction (&amp;gt;4ng) and sequencing (&amp;gt;1000x coverage on average, and absence of systematic high sequencing error rates on the 208bp) performed well on 431 (93%) PDAC cases, 138 (90%) chronic pancreatitis, and 388 (95%) controls. We fit a robust negative-binomial regression to estimate the distribution of the sequencing errors at each DNA bp position and identified outlying samples, which were considered as KRAS positive when q-value&amp;lt;10-3. We also estimated the detection threshold of our assay using serial dilutions of DNA from SW480 KRAS mutated cell-line (p.G12V) in wild-type DNA. Results: Sequencing of the serial dilutions of KRAS p.G12V mutated DNA indicated a detection threshold at a minor allele frequency of 0.2%. KRAS mutations in cfDNA were detected in 83 (19.3%) PDAC cases (73 on codon 12; 8 on codon 61; 1 on codon 13; and 1 multiple codons, i.e., similar in proportions as reported in tumor tissue from the International Cancer Genomic Consortium); 3 (2.2%) chronic pancreatitis (all on codon 12); and 8 (2.1%) healthy controls (4 on codon 12 and 4 on codon 61). Stage was significantly associated with the proportion of detected mutations in cancer cases (chi-squared p = 0.0005): the proportions of cases with detectable KRAS mutations in plasma were 7.9%, 14.9%, and 31.1% for local, regional, and advanced stages, respectively. Conclusions: The NGS-based KRAS mutation screening is a sensitive approach to detect low allelic fraction in plasma cfDNA, although its utility for early detection is still limited. However, it has the capacity to identify specific KRAS mutations, which could be useful in a panel of other non-invasive biomarkers. Citation Format: Florence Le Calvez-Kelm, Matthieu Foll, Magdalena B. Wozniak, Geoffroy Durand, Priscilia Chopard, Maroulio Pertesi, Tiffany Delhomme, Ivana Holcatova, Lenka Foretova, Vladimir Janout, Eleonora Fabianova, Maxime P. Vallée, Paul Brennan, James D. McKay, Graham Byrnes, Ghislaine Scélo. NGS-based detection of KRAS hotspot mutations in plasma cell-free DNA of pancreatic cancer cases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3137.

Cytomorphometric Analysis of Non-keratinized Malignant Squamous Cells in Exfoliated Cytosmears of Human Oral Neoplasm

Objectives: During the present investigation, a unique type of pleomorphic cytological atypia- named as nonkeratinized malignant squamous cell (NMSC) was frequently observed in the exfoliated cytosmears of the oral cancer patients. Details of these peculiar atypical, pleomorphic cells have not been reported earlier. Therefore, an attempt has been undertaken to find out the practical utility of NMSCs during difficult diagnoses and in early detection of oral squamous cell carcinoma (OSCC) cases through cytomorphometric analysis. Materials and Methods: In a hospital-based case-control study exfoliated scrape smears were collected from the clinically diagnosed 136 patients suffering from precancerous lesions and cancerous cases and a parallel set of 136 samples were also collected from the non-addicted and non-cancerous healthy individuals considered as control group. Wet fixed smears were stained by adopting Papanicolaou’s staining protocol and counter-stained with Giemsa’s solution. Out of one thousand screened cells, frequently observed NMSCs were scored. Cytomorphometry was done by using computer-assisted Cat Cam 1.30 (1.3 Mega Pixel) Microscope Camera® fitted with hund®-H500 research binocular microscope. The findings were statistically analyzed and interpreted by using software package PAleontological Statistics (PAST)® Version 2.17 with respect to age groups, degree of pathogenicity, oral sites and sexes. Results: Cytomorphometrically, the cellular parameters (mean length, breadth and area) of the NMSC were found to be in decreased state and nuclear parameters are in increased state. The quantitative parameters of the NMSCs were significantly (p ≤ 0.01) decreased with increasing age groups. Cytomorphometrically, the nuclearcytoplasmic (N/C) ratio of the NMSC was found to be 1:1 in both sexes. Conclusion: Extreme reduction of cellular diameter and increased nuclear diameter in each NMSC, lead to cellular non-keratinization, hyperchromasia and increased N/C ratios in both sexes indicate the state of malignancy. Thus, the present finding has a practical utility in early detection and diagnosis of the OSCC patients.

Early Detection of Mild Cognitive Impairment, Dementia and Alzheimer’s Using Qeeg

This article reports the biomarkers of the Mild Cognitive Impairment (MCI) among the elderly group aged around 60 -75 years old by analyzing the EEG signals recorded by using the quantitative electroencephalograph (qEEG). There is growing evidence that EEG analysis in resting state condition are useful in early detection of neural signatures of Alzheimer’s and dementia. EEG findings and analysis shows potential of discriminating MCI, Alzheimer’s and dementia. In this research, the purpose is to 1) develop the indexes for each of the EEG bands and sub-bands such as delta (1.5 – 3.5 Hz), theta (3.3 – 7.5 Hz), alpha ( 8 – 12 Hz), beta 1 (15 – 18 Hz) and beta 2 (22 – 30 Hz); 2) provide reference for early diagnosis; 3) extract and analyze the brainwave pattern of MCI and cognitively healthy group. This study involved 19 channel resting state EEG from a total of 30 subjects, 18 diagnosed as having MCI and 12 cognitively healthy elderly with criteria for inclusion if the mini mental state examination (MMSE) score is more than or equal to 28, based on the age and educational level. Development of qEEG index started by decomposition of EEG by performing Fourier analysis, averaging and normalizing the value from the 19 channels to obtain the z-score. Findings showed promise of utility in early detection of Alzheimer’s. Notably, 1) Increases in delta/ theta posterior temporal and prefrontal area i.e., H(6.64) vs. MCI(26.29); beta temporal region, 2) Decreases in alpha at sensory motor region i.e., H(0.27) vs. MCI(0.23).

CpG island methylation profile in non-invasive oral rinse samples is predictive of oral and pharyngeal carcinoma

BackgroundThere are currently no screening tests in routine use for oral and pharyngeal cancer beyond visual inspection and palpation, which are provided on an opportunistic basis, indicating a need for development of novel methods for early detection, particularly in high-risk populations. We sought to address this need through comprehensive interrogation of CpG island methylation in oral rinse samples.MethodsWe used the Infinium HumanMethylation450 BeadArray to interrogate DNA methylation in oral rinse samples collected from 154 patients with incident oral or pharyngeal carcinoma prior to treatment and 72 cancer-free control subjects. Subjects were randomly allocated to either a training or a testing set. For each subject, average methylation was calculated for each CpG island represented on the array. We applied a semi-supervised recursively partitioned mixture model to the CpG island methylation data to identify a classifier for prediction of case status in the training set. We then applied the resultant classifier to the testing set for validation and to assess the predictive accuracy.ResultsWe identified a methylation classifier comprised of 22 CpG islands, which predicted oral and pharyngeal carcinoma with a high degree of accuracy (AUC = 0.92, 95 % CI 0.86, 0.98).ConclusionsThis novel methylation panel is a strong predictor of oral and pharyngeal carcinoma case status in oral rinse samples and may have utility in early detection and post-treatment follow-up.

Colour influences perception of facial emotions but this effect is impaired in healthy ageing and schizophrenia

Introduction. Social cognition is commonly assessed by identification of emotions in facial expressions. Presence of colour, a salient feature of stimuli, might influence emotional face perception.Methods. We administered 2 tests of facial emotion recognition, the Emotion Recognition Test (ER40) using colour pictures and the Penn Emotional Acuity Test using monochromatic pictures, to 37 young healthy, 39 old healthy and 37 schizophrenic men.Results. Among young healthy individuals recognition of emotions was more accurate and faster in colour than in monochromatic pictures. Compared to the younger group, older healthy individuals revealed impairment in identification of sad expressions in colour but not monochromatic pictures. Schizophrenia patients showed greater impairment in colour than monochromatic pictures of neutral and sad expressions and overall total score compared to both healthy groups. Patients showed significant correlations between cognitive impairment and perception of emotion in colour but not monochromatic pictures.Conclusions. Colour enhances perception of general emotional clues and this contextual effect is impaired in healthy ageing and schizophrenia. The effects of colour need to be considered in interpreting and comparing studies of emotion perception. Coloured face stimuli may be more sensitive to emotion processing impairments but less selective for emotion-specific information than monochromatic stimuli. This may impact on their utility in early detection of impairments and investigations of underlying mechanisms.