Consensus Diagnosis Research Articles

Identifying gene expression signatures in individuals with minimal cognitive impairment in the presence of advanced Alzheimer's disease pathology

AbstractBackgroundThe pathological hallmarks of Alzheimer’s disease such as amyloid plaques and neurofibrillary tau tangles are usually associated with the primary clinical manifestation of cognitive decline. Recent studies implicate that a subset of “resistant” individuals have high burden of AD pathology, yet do not exhibit dementia (cognitive decline). Here, we compared the publicly available gene expression profiles of these resilient individuals and susceptible individuals (showing both AD pathology and cognitive decline) in dorsolateral prefrontal cortex (DLPFC) brain tissue obtained from individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP).MethodWe conducted bulk RNA‐Seq analysis on data from the DLPFC of 239 individuals with differing AD pathological findings and clinical consensus diagnosis. This data set is available through the Synapse portal (AMP‐AD consortium). The patients were subdivided into four groups of control, weakly resilient, strongly resilient, and susceptible, according to their degree of pathology (Braak stage) and clinical cognitive diagnosis. The control group included individuals with no cognitive impairment and initial braak stages; 0 and 1. The weakly and strongly resilient groups included individuals with no and mild cognitive impairment with advanced Braak stages respectively, while the susceptible group comprised individuals with AD‐dementia and advanced tauopathy (Braak stage>4). We used DESeq2 between these groups with a multiple factor approach that corrected for sex and age of death.ResultOur findings provide insight into genes that may be attributable to weak or strong resilience in the presence of relatively advanced AD pathology. Some of these candidate genes, such as SERPINA5 and GIPR, have previously been associated AD pathology and other neurodegenerative diseases, but we also identified a set of less well‐characterized genes that may be involved in cognition specific contributions to AD resilience.ConclusionOur study recapitulates genes with known associations with AD pathology, and also identifies new candidate genes and pathways worth pursuing further as potential therapeutic targets to mitigate cognitive decline associated with AD. As ongoing proteomics and snRNA‐seq data is generated, these candidates may be further refined through an integrative approach, yielding new insights into pathways involved in AD pathology‐mediated decline and cognitive resilience.

Geodesic path differences in neural networks in the Alzheimer's disease connectome project

AbstractBackgroundNeural networks derived from diffusion‐weighted MRI (DW‐MRI) may shed light on disease progression and pathology propagation in Alzheimer’s disease in vivo. In this work analysis of the path properties of such networks are presented. Geodesic or shortest paths are fundamental in understanding key network phenomenon such as the propagation rates of information, infection or pathology. For example, the ubiquitous small‐worldness property of natural occurring biological and social networks is based on having short paths between any pair of entities in the network.MethodConnectome protocol based DW‐MRI data acquired from n=68 participants (Table 1) were analyzed. Neural networks were extracted from the data using state‐of‐the‐art image processing and tractography algorithms available in MRtrix3 (overview panel in Figure‐1). The average geodesic path lengths between frontal, temporal, parietal, occipital, subcortical regions were computed using Dijkstra algorithm. The regions were identified based on the IIT‐Desikan gray matter atlas. The paths can be used to reason about the average efficiency of communication of electrical signals or propagation of pathology between brain lobes. Statistical analysis was performed to test the geodesic path length differences between the CU, MCI and the AD groups controlling for age and sex. The path lengths were normalized so that they were at unity for the AD group, and differences were considered significant at p<=0.05.ResultStatistical effects of consensus diagnosis on the relative geodesic path length (RGPL) differences between lobes are shown in Figure‐2. 80% of the connections showed statistically significant higher path lengths in AD compared to CU and 60% when compared to MCI. The distributions of the mean geodesic path lengths are shown in Figure‐3. For all the different pairs of lobes, the mean length was higher for the AD compared to the CU and MCI groups.ConclusionThe path lengths between all of the major lobes are higher for the AD group compared to both the CU and MCI groups. These findings suggest that network efficiency is reduced in AD and may explain cognitive dysfunction observed in the Alzheimer’s clinical syndrome. Future work entails incorporating better constraints on tractography using structural T1‐weighted images and separating disease groups by AD‐biomarker status.

Diagnostic differentiation by NIH Toolbox‐Cognition (iPAD) for Alzheimer’s disease, mild cognitive impairment (MCI), and healthy control participants

AbstractBackgroundAge‐associated impairment among older adults is a significant public health concern. The NIH Toolbox for Assessment of Neurological and Behavioral Function® (NIHTB) was developed for use in studies for which standardized, computer‐based measurement of cognitive, motor, sensory, and behavioral processes is of importance. The NIH Toolbox–Cognition battery measures both crystallized and fluid cognitive functions. The goal of this study was to compare performance of the newly available tablet‐version of the Cognition battery across healthy and impaired older adults and to analyze if race and gender effects would be evident even when using NIHTB fully‐adjusted T‐scores.MethodA total of 104 individuals (28 men, 56 women; 45% African American) completed the NIH Toolbox–Cognition as part of a National Alzheimer’s Disease Coordinating Center (NACC) longitudinal study of memory and aging through the Michigan Alzheimer’s Disease Research Center (Michigan ADRC). All participants received the Unified Data Set (UDS) and consensus diagnosis of normal cognition (NL), amnestic mild cognitive impairment (aMCI), or Alzheimer’s dementia (AD). Univariate analyses of variance with post‐hoc comparisons were used to compare fully adjusted (age, gender, race/ethnicity, education) Toolbox T‐Score performance across the groups.ResultsUnivariate ANOVAs revealed significant findings for the Total and Fluid composites (both p<0.001) and Crystallized Composite (p<0.05). For Crystallized subtests, only Oral Reading demonstrated group differences, with NL>AD. Though NL and aMCI groups performed similarly, both groups outperformed AD on Dimensional Card Sort, Flanker, and Pattern Comparison Fluid subtests. NL>aMCI>AD on List Sorting Working Memory and Picture Sequence Memory. Main effects for race or gender were not seen for comparisons of NL to aMCI, but some group sizes were too small for adequate testing in the AD participants.ConclusionsAs expected, NL, aMCI, and AD demonstrated significant performance differences on NIH Toolbox—Cognition composite and scale scores. As expected, Crystallized tasks were least effective, traditionally representing cognitive areas least sensitive to neurologic dysfunction. Fluid tasks were noticeably more effective, with the working memory and learning measures showing a significant tiered difference, with NL highest and AD lowest. The fully adjusted scores were successful in accounting for demographic variables.

Correlation of anal cytology with follow-up histology and Human Papillomavirus genotyping: A 10-year experience from an academic medical center

BackgroundAnal cytology (AC) is accepted as a practical screening modality for anal cancer. However, studies suggest that AC and anal biopsy dysplasia correlation is less robust than in cervicovaginal specimens. The current study goals were to look at our institutional experience in a subset of ACs and correlate with surgical pathology (SP), as well as evaluate their Human Papillomavirus (HPV) status. Methods377 ACs from 169 patients (151 males and 18 females) from 2008 to 2017 were included. HPV genotyping (n = 47) and SP within one year of AC (n = 58) were reviewed. ResultsAC/SP was discrepant in 22 cases (37.9%), with a tendency towards AC underestimating the degree of dysplasia. Specifically, any abnormality on AC was 93.8% sensitive for detecting high-grade dysplasia (HGD). However, when requiring a high-grade AC diagnosis, the sensitivity decreases to 12.5%. “Other high-risk HPV” was the most common genotype (57.4%). When considered with all AC with a high-grade diagnosis, co-testing with HPV improved the sensitivity for HGD to 56.3%. Sensitivity improved further to 87.5% when only considering cases with both AC and HPV testing, and were high-risk HPV positive. Furthermore, following review and consensus diagnosis, 8 cases changed from “Discrepant” to “Agreed”, reducing the discrepancy rate to 24.1%. Remaining discrepancies were explained by sampling error. ConclusionGiven the enhanced sensitivity of AC and HPV testing together, and sampling error seen with AC leading to underestimating dysplasia, we recommend AC and HPV co-testing, as well as describing confounding factors in AC reports and obtaining consensus opinion in equivocal cases.

Prospective Consensus Reporting by Gynecologic Pathology and Dermatopathology Improves Diagnosis of Vulvar Biopsies.

Vulvar biopsy interpretation and reporting, particularly of vulvar dermatoses, can be challenging in daily practice for both surgical pathologists (SPs) and dermatopathologists (DPs). To investigate whether prospective consensus reporting of vulvar biopsies by SPs and DPs would provide value and improve overall diagnostic concordance. Consecutive vulvar biopsies during a 6-month period were reviewed prospectively by both gynecologic SPs and DPs. Preliminary, independently generated diagnoses were recorded and then shared in consensus review (SPs+DPs). A third pathologist adjudicated cases without consensus. Multiple data elements were collected for each case: division (SP/DP), age, site, clinical history, diagnostic category, preliminary and final (consensus) diagnosis, need for adjudication, ancillary tests, and diagnostic discrepancy. Eighty-four biopsies (48 SP, 36 DP) from 70 patients were reviewed. Forty-two of 84 cases (50%) were neoplastic, 38 of 84 (45%) were reactive/inflammatory, with the remaining (5%) showing both or other features. Independent diagnoses were discrepant in 22 of 84 cases (26%), but consensus review resulted in an agreed-upon diagnosis in all cases, with adjudication required in 6 cases. Independent diagnostic agreement increased over time with a reduction in major and minor discrepancies between the first and second half of the study period. Prospective review of vulvar biopsies by both SPs and DPs can improve overall reporting. Consensus review allows pathologists to gain diagnostic confidence in interpretation of inflammatory (for SPs) and neoplastic (for DPs) vulvar biopsies; therefore, intradepartmental consultation is of value, particularly in select cases.

Atypical parkinsonian syndromes in a North African tertiary referral center.

IntroductionData on epidemiology of atypical parkinsonian syndromes (APS) in North African countries are limited. Our objective was to study the epidemiological features of APS in a Tunisian population.MethodsWe conducted a 17‐year retrospective cross‐sectional descriptive study in the Department of Neurology at Razi University Hospital. We included all patients responding to consensus diagnosis criteria of APS. We recorded demographic and clinical data. Group differences were assessed with a post hoc ANOVA with a Bonferroni error correction.ResultsWe included 464 APS patients. Hospital prevalence of APS among all parkinsonism cases was 20.6%. Mean annual increase of incidence defined as newly diagnosed APS cases per year reached 38.8%/year. APS were divided into 4 etiological subgroups: dementia with Lewy bodies (DLB; 56.7%); progressive supranuclear palsy(PSP; 16.2%); multiple system atrophy (MSA; 14.6%); and finally corticobasal syndrome (CBS; 12.5%). Sex‐ratio was 1.2. This male predominance was found in all subgroups except MSA (p = .013). Mean age at onset was 68.5 years, most belated in DLB (69.7 years; p < .001). Young‐onset parkinsonism (<40 years) was found only in MSA subgroup (p = .031). Parkinsonism was of late onset (>70 years) in 50.7% of patients and was significantly associated with DLB subgroup (p = .013). Inaugural parkinsonism was associated with CBS and MSA (p = .0497), and gait disorders at disease onset were associated with PSP and MSA (p = .0062). Cognitive and mood disorders were more marked in DLB and most preserved in MSA. Consanguinity was more marked in CBS (p = .037), and family history of dementia and psychiatric diseases was more common in DLB. Thirty‐seven families with similar cases of APS were identified.ConclusionsThis is the largest African epidemiological study on APS. In our population, APS were frequent and dominated by DLB. The age of onset of parkinsonism was the most decisive feature for differential diagnosis.

Association of Hypertension According to New American College of Cardiology/American Heart Association Blood Pressure Guidelines With Incident Dementia in the ARIC Study Cohort.

BackgroundThe impact of the new 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline on dementia risk at the population level has not been evaluated.Methods and ResultsWe studied dementia‐free participants in the ARIC (Atherosclerosis Risk in Communities) Study cohort in 1987 to 1989. Hypertension was defined by 2003 Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and 2017 ACC/AHA guidelines using blood pressure measured at baseline. Dementia was defined using adjudicated consensus diagnoses, informant telephone interviews, and discharge codes from hospitalizations and death certificates. Cox regression estimated hazard ratios (HRs) for dementia and 95% CIs by hypertension categories, adjusting for confounders. Population attributable fraction of dementia was calculated by hypertension categories. Among 13 971 participants followed up for a median of 23 years, 1381 dementia cases were identified. Prevalence of hypertension was 34% and 48%, according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and ACC/AHA criteria, respectively. HRs (95% CIs) compared with normal blood pressure, according to ACC/AHA categories, were 1.35 (1.12–1.61) for elevated blood pressure, 1.28 (1.07–1.52) for hypertension stage 1, and 1.36 (1.18–1.57) for hypertension stage 2. Population attributable fractions (95% CIs) of dementia from blood pressure categories were 3% (1%–5%), 3% (1%–5%), and 9% (4%–14%), respectively. Population attributable fractions (95% CIs) using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure categories were 6% (3%–9%) for prehypertension, 0% (−2% to 2%) for hypertension stage 1, and 9% (5%–13%) for hypertension stage 2.ConclusionsRisk of dementia increased across hypertension categories defined by ACC/AHA guidelines. The population impact on dementia incidence using ACC/AHA categories was similar to the impact of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Prevalence of dementia in the Torres Strait.

To examine the prevalence of dementia and problems associated with ageing in the Torres Strait. The study was conducted across all 18 island and 5 mainland communities in the Torres Strait and Northern Peninsula Area of Far North Queensland. Participants underwent a comprehensive health assessment and a Geriatrician assessment, which were used to establish consensus diagnoses. A total of 276 Torres Strait residents aged between 45 and 93 participated in the study. The prevalence of dementia in the sample was 14.2%, which was 2.87 times higher than the wider Australian population. Torres Strait Islander peoples share the increased risk of dementia seen in Aboriginal Australians compared to the wider community. This highlights the need for interventions to address this increased dementia risk for Aboriginal and Torres Strait Islander communities.

Non-human papilloma virus associated adenocarcinomas of the cervix uteri. Cytologic features and diagnostic agreement using whole slide digital cytology imaging.

Non-Human Papilloma Virus associated adenocarcinomas (NHPVAs) are uncommon tumors of the cervix uteri which often show a deceptive morphology. Therefore, their diagnostic assessment may be challenging. Slide digital cytology imaging may be an useful tool to improve cytological diagnostic accuracy. However, this novel technology has not been applied to NHPVAs associated cytologies yet. The study included 31 whole slide digital cytology cases from 10 women with a proven histological diagnosis of NHPVA. As a control group, three further digital slides, from two women with a histological diagnosis of squamous intraepithelial lesion (SIL), were included. The digitally scanned cytological slides were revised to assess the concordance rate among three observers and to find out the most relevant NHPVA cytological criteria. Overall diagnostic agreement between observers was 67.60% (K = 0.50; P < 0.0001). At the consensus diagnosis 34 cases were re-classified as at least suspicious for glandular lesion (n = 24), SIL (n = 2) and negative (n = 8). The most relevant cytologic features for atypical glandular cells or adenocarcinoma at consensus were evident nucleoli, nuclear overlapping and atypical enlarged nuclei. The diagnosis of NHPVA in digital cytology is feasible using criteria which are also used in conventional microscopy. Our study shows a moderate agreement for the cytological diagnosis of NHPVAs using whole slide digital cytology approach. These results are discussed taking into account the most relevant differential diagnostic issues.

Leveraging Existing Institutional Resources to Maintain Quality Assurance Practices in Anatomic Pathology in the Era of Social Distancing

Introduction/ObjectiveDue to the COVID-19 pandemic, hospitals had to adapt practices to incorporate social distancing while maintaining quality assurance (QA) in anatomic pathology (AP). Prior to this, our general surgical pathology (SP) and cytopathology (CP) services held daily consensus conferences (CC) at a multi-headed microscope. Implementing social distancing meant only a few faculty were present onsite and avoidance of interactions at the multi-headed scope. In an effort to preserve QA through CC, faculty exploited the use of web conferencing through our HIPAA-compliant Zoom. We describe the utility of this new practice.MethodsFrom 3/25-4/30/20, all SP and CP cases selected for CC were presented by respective pathologists (n=8) in their own offices by using individual microscopes with cameras, image acquisition software, and screen-sharing through Zoom. One pathologist was responsible for sending out a new CC Zoom link daily and recording the consensus diagnosis. All onsite pathologists and those at home participated.ResultsWe presented 95 SP and 31 CP cases through Zoom compared to 300 SP and 60 CP cases presented at a similar timeframe prior to social distancing. This 68% and 48% decline could be attributed to elective procedure cancellation. We assigned a consensus diagnosis to all cases, with 77% overall being malignant diagnoses, and breast being the most common SP specimen type (22%). Additionally, all participating pathologists felt comfortable with the new format irrespective of being onsite or at home. Apart from minor audio issues, we did not notice significant lag time or visual disturbances that interfered with diagnostic abilities. Importantly, the transition did not involve investing in new technology.ConclusionThe new virtual CC allowed our department to maintain QA practices in AP without sacrificing quality and serves as a starting point to investigating the use of this technology to other applications in AP, such as overnight frozen sections.

THE INFLUENCE OF ANTI-SSA-52 KDA (ASSA52) ANTIBODIES ON THE CLINICAL PRESENTATION OF INTERSTITIAL LUNG DISEASE

SESSION TITLE: Diffuse Lung Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Interstitial lung disease (ILD) is a common manifestation of idiopathic inflammatory myopathies (IIM) and is responsible for nearly 80% of the mortality from IIM. Seropositivity for myositis specific antibodies (MSA) has been strongly associated with this complication. Less is known about the correlation between myositis associated antibodies (MAA) and ILD. The anti-SSA-52 kDa (aSSA52) antibody has been of particular interest, although whether it plays a prognostic role in patients with ILD is unknown. We aimed to investigate the impact of aSSA52 on the clinical characteristics of patients with ILD. METHODS: This retrospective cohort study included patients followed by the ILD clinic at the University of Chicago who tested positive for at least one antibody in the MyoMarker Panel 3. Patients were grouped according to their serology for aSSA52 (positive or negative). Data on clinical status, serologies, pulmonary function tests (PFT), and chest computed tomography (CT) were collected. RESULTS: A total of 125 patients were included, 63% of whom were positive for aSSA52. Most patients who were positive for aSSA52 did not test positive for other MAA (P < 0.001) or MSA (P = 0.005). Other immune serologies were similar between the two groups, with the exception of anti-dsDNA and total SSA, which were more common in aSSA52 positive patients (P = 0.004). Rheumatologic diagnoses did not differ between the groups, nor did multidisciplinary consensus diagnosis of ILD. Notably, aSSA52 positive patients were more likely to have hypomyopathic myositis (P = 0.04) with a trend towards higher levels of aldolase (P = 0.07). Pulmonary function and outcomes (death or lung transplantation) were comparable. Modeling did not support aSSA52 as an independent predictor of forced vocal capacity (FVC) or diffusing capacity (DLCO) upon diagnosis, although the latter was close to statistical significance (P = 0.06). CONCLUSIONS: Our study identified that patients with aSSA52 and ILD were more likely to have laboratory evidence of skeletal muscle inflammation without associated muscle weakness at diagnosis, and most of these patients did not have other accompanying MSA or MAA. These patients had similar ILD diagnoses compared to the aSSA52 negative cohort. Surprisingly, the presence of aSSA52 across all subtypes of ILD did not impact severity of ILD at diagnosis nor was it associated with short-term outcomes. CLINICAL IMPLICATIONS: Our study supports a correlation between autoimmune-mediated hypomyopathic myositis and ILD, which although common in IIM remains excluded from diagnostic criteria. Further long-term analysis will be needed to understand whether aSSA52 is associated with accelerated loss of pulmonary function or other complications over time, particularly in the subset of patients with connective tissue disease-associated ILD. DISCLOSURES: Speaker/Speaker's Bureau relationship with Boehringer Ingelheim Please note: $20001 - $100000 Added 03/30/2020 by Ayodeji Adegunsoye, source=Web Response, value=Honoraria Removed 03/30/2020 by Ayodeji Adegunsoye, source=Web Response Speaker/Speaker's Bureau relationship with Boehringer Ingelheim Please note: $20001 - $100000 Added 03/30/2020 by Ayodeji Adegunsoye, source=Web Response, value=Grant/Research Support Removed 03/30/2020 by Ayodeji Adegunsoye, source=Web Response Advisory Committee Member relationship with Genentech Please note: $1-$1000 Added 03/30/2020 by Ayodeji Adegunsoye, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Boehringer Ingelheim Please note: $20001 - $100000 Added 03/30/2020 by Ayodeji Adegunsoye, source=Web Response, value=Honoraria No relevant relationships by Iazsmin Bauer Ventura, source=Web Response No relevant relationships by Renea Jablonski, source=Web Response No relevant relationships by Cathryn Lee, source=Web Response No relevant relationships by Eleanor Phillips, source=Web Response PI relationship with Boehringer-Ingelheim Please note: >$100000 by Mary Strek, source=Web Response, value=Grant/Research Support PI relationship with Galapagos Please note: $5001 - $20000 by Mary Strek, source=Web Response, value=Grant/Research Support PI relationship with Novartis Please note: $5001 - $20000 by Mary Strek, source=Web Response, value=Grant/Research Support

A new 7-point method facilitates accurate diagnosis of high-grade urothelial carcinoma in routine urinary cytology practice

This study was designed to identify the minimal and necessary cell morphologies to be considered for high-precision diagnosis of high-grade urothelial carcinoma (HGUC) in a routine urinary cytology practice. We included 338 urine cytology specimens from 11 medical facilities in Japan. Six experts evaluated these Papanicolaou-stained specimens using their own diagnostic criteria to categorize them within an initial 4-tiered classification system. Of the 338 cases, 70 HGUC and 32 benign cases (with a complete consensus diagnosis of 6 experts) were included for the analysis. Two of the cytologists evaluated the specimens for 20 specific cellular features. The results were analyzed using a contingency table and by discriminant analysis. Of the original 338 cases, 165 were originally diagnosed as HGUC, but only 70 (42.4%) were scored as malignant by all participating cytologists; of the 101 benign cases, only 32 (31.7%) were classified as such in all examinations. These specimens were re-evaluated by 6 experts using a panel of 20 specific cellular features used to distinguish between HGUC and benign diseases; tests of significance and discriminant analyses identified 7 critical features that were most useful for cytological diagnosis. Statistical analysis revealed that a focus on these 7 features led to a diagnosis of HGUC with a probability of over 95%. The accuracy of our presently used method to evaluate urinary cytology is not consistently high. This novel classification system, which focuses on 7 critical features, facilitates the high accurate diagnosis of HGUC in routine cytology practice.

RNA in situ hybridization for human papillomavirus testing in oropharyngeal squamous cell carcinoma on a routine clinical diagnostic platform.

The current diagnostic standard for detection of high-risk human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma is via a two-stage algorithm, namely p16 immunohistochemistry followed by HPV DNA in situ hybridization in p16 positive cases. This study evaluated the feasibility of automated RNA in situ hybridization on a clinical platform as a single-step alternative to the two-stage algorithm within a routine diagnostic histopathology setting. Thirty-eight cases positive for both p16 and DNA in situ hybridization, 42 p16 negative cases and 20 cases positive for p16 but negative for DNA in situ hybridization were randomly selected. High-risk HPV RNA in situ hybridization was undertaken on all cases on an automated clinical platform. Manufacturer-recommended and on-slide additional p16/HPV positive and negative controls were used. Test quality assurance and diagnostic RNA in situ hybridization were independently assessed by two observers. A consensus diagnosis was reached in the presence of a third observer on discordant cases. All RNA in situ hybridization results were then correlated against p16 and DNA ISH status. Inter-slide RNA in situ hybridization staining variation was observed in control sections. RNA in situ hybridization demonstrated a high inter-observer agreement rate (κ=.897, P<.001). Following consensus review, there was full concordance between RNA in situ hybridization and the current standard. Human papillomavirus testing by standalone automated RNA in situ hybridization on a clinical diagnostic platform currently available in routine diagnostic histopathology laboratories is a feasible alternative to the two-step algorithm of p16 and DNA in situ hybridization. Control tissue staining procedures need to be adapted to achieve the most accurate results.

A-02 A Novel Tool for the Differential Diagnosis of Clinical Alzheimer’s Disease, Mild Cognitive Impairment, and Normal Cognition: Development and Validation

Abstract Objective To create a clinician-friendly diagnostic tool based on neuropsychological and demographic data to assist classification of Alzheimer’s Disease (AD), Mild Cognitive Impairment (MCI), and normal cognition (NC). Methods Neuropsychological and demographic data from 652 (256 NC,122 MCI,274 AD) subjects were selected from a regional Alzheimer’s Disease Research Center. Utilizing half the sample, two binary logistic regressions compared NC to (MCI + AD) and AD to (NC + MCI) groups. Initial models were reduced in a step-wise manner to determine significant predictors. Raw scores for these variables were multiplied by weights derived from the final regression models and combined to create weighted-sum scores. Cut-points between diagnoses were established using ROC curves based on weighted-sum scores. The tool was validated in the remaining subjects through ROC analyses and sensitivity/specificity calculations for each diagnosis. Results Age, education, sex, Trails A&amp;B, Logical Memory, Animals, and CVLT were all diagnostic predictors. ROC curves comparing weighted sum scores and consensus diagnoses in the validation set showed good discriminability (NC vs MCI + AD: AUC = .95; AD vs NC + MCI: AUC = .98). Scores of 305.75 predicted AD, MCI, and NC respectively, with good sensitivity/specificity in the validation sample (NC = .857/.913, MCI = .711/.883, AD = .914/.951), with 83% of all subjects correctly classified. Conclusions We created a user-friendly diagnostic tool based on demographic and neuropsychological test scores which distinguished between AD, MCI, and NC in an initial validation sample with relatively good accuracy. Results merit replication in other samples, but suggest that this approach may be useful to aid clinical diagnosis, particularly when biomarker data are not available in clinical settings.

Predictive Value of Odor Identification for Incident Dementia: The Shanghai Aging Study.

ObjectiveThis study aimed to evaluate the value of odors in the olfactory identification (OI) test and other known risk factors for predicting incident dementia in the prospective Shanghai Aging Study.MethodsAt baseline, OI was assessed using the Sniffin’ Sticks Screening Test 12, which contains 12 different odors. Cognition assessment and consensus diagnosis were conducted at both baseline and follow-up to identify incident dementia. Four different multivariable logistic regression (MLR) models were used for predicting incident dementia. In the no-odor model, only demographics, lifestyle, and medical history variables were included. In the single-odor model, we further added one single odor to the first model. In the full model, all 12 odors were included. In the stepwise model, the variables were selected using a bidirectional stepwise selection method. The predictive abilities of these models were evaluated by the area under the receiver operating characteristic curve (AUC). The permutation importance method was used to evaluate the relative importance of different odors and other known risk factors.ResultsSeventy-five (8%) incident dementia cases were diagnosed during 4.9 years of follow-up among 947 participants. The full and the stepwise MLR model (AUC = 0.916 and 0.914, respectively) have better predictive abilities compared with those of the no- or single-odor models. The five most important variables are Mini-Mental State Examination (MMSE) score, age, peppermint detection, coronary artery disease, and height in the full model, and MMSE, age, peppermint detection, stroke, and education in the stepwise model. The combination of only the top five variables in the stepwise model (AUC = 0.901 and sensitivity = 0.880) has as a good a predictive ability as other models.ConclusionThe ability to smell peppermint might be one of the useful indicators for predicting dementia. Combining peppermint detection with MMSE, age, education, and history of stroke may have sensitive and robust predictive value for dementia in older adults.

Reynolds Intellectual Screening Instrument 1st versus 2nd Edition in a Memory Disorder Sample.

The Reynolds Intellectual Screening Instrument (RIST) and its second edition (RIST-2) are brief intelligence screening instruments that potentially have value in older populations as their norms extend over age 90. This study examined performance on these two instruments in a sample of individuals presenting for evaluation in a memory disorder clinic. A sample of 1,145 subjects over the age of 50 was chosen from 1,761 consecutive referrals. Individuals who obtained a consensus diagnosis of Mild Cognitive Impairment (MCI; n=536), possible dementia of the Alzheimer Type (DAT; n=400), or those with subjective cognitive complaints (SCC; n=209) and who completed a neuropsychological battery that included either the RIST (n=747) or the RIST-2 (n=398) were included in the sample. No clinically significant demographic or neuropsychological performance differences were found for those taking either version of the RIST. Unlike the original version, RIST-2 Total and subtest scores were well below the mean for the DAT group and over 1 SD mean difference was seen for the DAT group when comparing the RIST and RIST-2 Totals. Diagnostic accuracy calculations suggested that the RIST-2 showed greater discrimination between the three groups although both versions achieved greater sensitivity than specificity. Performance differences were evident when comparing the RIST and RIST-2, particularly for the DAT group. Although the RIST-2 evidenced greater diagnostic accuracy than its predecessor it should not be utilized in isolation for the clinical determination of DAT or MCI.

Discrepancies in digital hematopathology diagnoses for consultation and expert panel analysis

Digital pathology with whole-slide imaging (WSI) has a large potential to make the process of expert consultation and expert panel diagnosis more rapid and more efficient. However, comparison with the current methods is necessary for validation of the technique. In this study, we determined if digital assessment of whole-slide images of hematopathology specimens with a focus on the assessment of lymphoma can be used for consultation and panel diagnostics. Ninety-three histological specimens with a suspicion for lymphoma were assessed both with conventional microscopy and digital microscopy with a wash out period between assessments. A consensus diagnosis was based on full concordance between the pathologists or, in case of discordances, was reached at a joint session at a multi-headed microscope. In 81% of the cases, there was a full concordance between digital and light microscopical assessment for all three pathologists. Discordances between conventional microscopy and digital pathology were present in 3% of assessments. In comparison with the consensus diagnosis, discordant diagnoses were made in 5 cases with digital microscopy and in 3 cases with light microscopy. The reported level of confidence and need for additional investigations were similar between assessment by conventional and by digital microscopy. In conclusion, the performance of assessment by digital pathology is in general comparable with that of conventional light microscopy and pathologists feel confident using digital pathology for this subspecialty.

Multiplatform molecular test performance in indeterminate thyroid nodules.

BackgroundApproximately 25% of thyroid nodule fine‐needle aspirates (FNAs) have cytology that is indeterminate for malignant disease. Accurate risk stratification of these FNAs with ancillary testing would reduce unnecessary thyroid surgery.MethodsWe evaluated the performance of an ancillary multiplatform test (MPTX) that has three diagnostic categories (negative, moderate, and positive). MPTX includes the combination of a mutation panel (ThyGeNEXT®) and a microRNA risk classifier (ThyraMIR®). A blinded, multicenter study was performed using consensus histopathology diagnosis among three pathologists to validate test performance.ResultsUnanimous consensus diagnosis was reached in 197 subjects with indeterminate thyroid nodules; 36% had disease. MPTX had 95% sensitivity (95% CI,86%‐99%) and 90% specificity (95% CI,84%‐95%) for disease in prevalence adjusted nodules with Bethesda III and IV cytology. Negative MPTX results ruledout disease with 97% negative predictive value (NPV; 95% CI,91%‐99%) at a 30% disease prevalence, while positive MPTX results ruledin high risk disease with 75% positive predictive value (PPV; 95% CI,60%‐86%). Such results are expected in four out of five Bethesda III and IV nodules tested, including RAS positive nodules in which the microRNA classifier was useful in rulingin disease. 90% of mutation panel false positives were due to analytically verified RAS mutations detected in benign adenomas. Moderate MPTX results had a moderate rate of disease (39%, 95% CI,23%‐54%), primarily due to RAS mutations, wherein the possibility of disease could not be excluded.ConclusionsOur results emphasize that decisions for surgery should not solely be based on RAS or RAS‐like mutations. MPTX informs management decisions while accounting for these challenges.

Cholesterol profiles and incident cognitive decline among older adults: the Shanghai Aging Study.

the association between cholesterol profiles and risk of cognitive decline among older adults was inconclusive. to examine the association between cholesterol profiles and risk of cognitive decline in older adults with or without vascular risk factors (VRFs) in the prospective phase of the Shanghai Aging Study. a prospective community-based cohort study. Shanghai, China. we prospectively followed 1,556 dementia-free participants aged ≥60years with a baseline cholesterol profile for 5.2years on average. Participants with at least one of obesity, diabetes, hypertension, stroke, and coronary artery disease were categorised to the VRFs group, and those free of any VRFs were categorised to the non-VRFs group. total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol in serum were measured at baseline. At follow-up, consensus diagnosis of incident dementia and Alzheimer's disease (AD) were established based on medical, neurological, and neuropsychological examinations. Cox regression was used to assess the association between cholesterol and incident dementia/AD; multivariate linear regression was used to examine the relationship between cholesterol and an annual rate of Mini Mental State Examination (MMSE) score decline in participants with or without VRFs. among VRFs-free participants, TC (HR 0.62, 95%CI 0.40-0.95) and LDL-C (HR 0.47, 95%CI 0.28-0.80) were inversely associated with incident dementia, LDL-C was inversely associated with incident AD (HR 0.50, 95%CI 0.28-0.90). A significant correlation was found between incremental TC (β = 0.08), LDL-C (β = 0.09), and a slower annual decline of MMSE score. effect of cholesterol on cognitive decline may be modified by VRFs.

Online Clinical Consensus Diagnosis of Dementia: Development and Validation.

To introduce cost-effective expert clinical diagnoses of dementia into population-based research using an online platform and to demonstrate their validity against in-person clinical assessment and diagnosis. The online platform provides standardized data necessary for clinicians to rate participants on the Clinical Dementia Rating (CDR® ). Using this platform, clinicians diagnosed 60 patients at a range of CDR levels at two clinical sites. The online consensus diagnosis was compared with in-person clinical consensus diagnosis. All India Institute of Medical Sciences (AIIMS), Delhi, and National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India. Thirty patients each at AIIMS and NIMHANS with equal numbers of patients previously independently rated in person by experts as CDR is 0 (cognitively normal), CDR is 0.5 (mild cognitive impairment), and CDR is 1 or greater (dementia). Multiple clinicians independently rate each participant on each CDR domain using standardized data and expert clinical judgment. The overall summary CDR is calculated by algorithm. When there are discrepancies among clinician ratings, clinicians discuss the case through a virtual consensus conference and arrive at a consensus overall rating. Online clinical consensus diagnosis based on standardized interview data provides consistent clinical diagnosis with in-person clinical assessment and consensus diagnosis (κ coefficient = 0.76). A web-based clinical consensus platform built on the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India interview data is a cost-effective way to obtain reliable expert clinical judgments. A similar approach can be used for other epidemiological studies of dementia. J Am Geriatr Soc 68:S54-S59, 2020.