Utilization of an artificial intelligence-enhanced, web-based application to review bile duct brushing cytologic specimens: A pilot study.

BACKGROUND: The authors previously developed an artificial intelligence (AI) to assist cytologists in the evaluation of digital whole-slide images (WSIs) generated from bile duct brushing specimens. The aim of this trial was to assess the efficiency and accuracy of cytologists using a novel application with this AI tool. METHODS: Consecutive bile duct brushing WSIs from indeterminate strictures were obtained. A multidisciplinary panel reviewed all relevant information and provided a central interpretation for each WSI as being "positive," "negative," or "indeterminate." The WSIs were then uploaded to the AI application. The AI scored each WSI as positive or negative for malignancy (i.e., computer-aided diagnosis [CADx]). For each WSI, the AI prioritized cytologic tiles by the likelihood that malignant material was present in the tile. Via the AI, blinded cytologists reviewed all WSIs and provided interpretations (i.e., computer-aided detection [CADe]). The diagnostic accuracies of the WSI evaluation via CADx, CADe, and the original clinical cytologic interpretation (official cytologic interpretation [OCI]) were compared. RESULTS: Of the 84 WSIs, 15 were positive, 42 were negative, and 27 were indeterminate after central review. The WSIs generated on average 141,950 tiles each. Cytologists using the AI evaluated 10.5 tiles per WSI before making an interpretation. Additionally, cytologists required an average of 84.1 s of total WSI evaluation. WSI interpretation accuracies for CADx (0.754; 95% CI, 0.622-0.859), CADe (0.807; 95% CI, 0.750-0.856), and OCI (0.807; 95% CI, 0.671-0.900) were similar. CONCLUSIONS: This trial demonstrates that an AI application allows cytologists to perform a triaged review of WSIs while maintaining accuracy.

Cognitive Outcomes in Autosomal-Dominant Alzheimer's Disease: A Comprehensive Review from a Colombian Kindred with the Presenilin-1 E280A Mutation.

Background: The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer's disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30 s, with a median onset age of 49 years. Cognitive decline is a hallmark feature. Objective: This review synthesizes the existing literature on neuropsychological assessments in PSEN1 E280A mutation carriers throughout their lifespan. We provide a comprehensive overview of cognitive outcomes in this unique population. Methods: We reviewed and integrated the published research, analyzing studies on neuropsychological assessments in PSEN1 E280A carriers. Our focus was on measures of verbal, semantic, episodic, and spatial memory, and encompassed other cognitive domains such as language, attention, visuospatial memory, and executive functioning. Results: Verbal, semantic, episodic, and spatial memory emerged as the most sensitive indicators of preclinical changes in PSEN1 E280A carriers. Inconsistencies were noted in findings from tests assessing language, attention, visuospatial memory, and executive functioning, suggesting potential limitations in detecting early cognitive changes in PSEN1 mutation carriers. Specific cognitive tasks developed for this population proved effective but underutilized. Conclusions: The review underscores the importance of continued test development tailored to detect early cognitive changes in PSEN1 E280A carriers, potentially enhancing ADAD screening. Furthermore, investigating ADAD mutations in children may identify early changes in AD and enhance our understanding of neuropsychological functioning across the lifespan. This synthesis provides valuable insights for researchers, clinicians, and policymakers engaged in the study and management of ADAD.

Reduced visual context effects in global motion processing in depression.

Research supports abnormal inhibitory visual motion processing in adults with remitted and current depression, but all studies to date have used paradigms with simple grating stimuli. Global motion processing, where multiple motion signals must be integrated, has not been explored in depression, nor have inhibitory processes within that domain. Depressed participants (n = 46) and healthy controls (n = 28) completed a direction discrimination task featuring a random dot pattern stimulus. Various signal (rightward or leftward dots) to noise (dots with randomly assigned directions) ratios modulated task difficulty. Metrics of global center surround suppression and facilitation were calculated. Accuracy in the baseline condition (i.e., no surrounding annulus) was not significantly different between depressed and healthy participants. Global center surround suppression and facilitation were not significantly different between healthy and depressed participants overall. When limiting the sample to unmedicated individuals, depressed participants (n = 27) showed a reduced global center surround suppression effect compared to controls, and there was no difference in global center surround facilitation. While global motion processing is intact in depression, abnormal center surround suppression effects in depression do extend to global motion stimuli. These alterations may be mitigated by the psychotropic medications taken by some subjects in our depressed sample. Future studies should explore the mechanisms underlying these effects.

Normal Face Detection Over a Range of Luminance Contrasts in Adolescents With Autism Spectrum Disorder.

Face recognition is impaired in autism spectrum disorders (ASDs), but the reason for this remains unclear. One possibility is that impairments in the ability to visually detect faces might be a factor. As a preliminary study in this vein, we measured face detection ability as a function of visual contrast level in 13 individuals with ASD, aged 13-18, and 18 neurotypical controls (NCs) in the same age range. We also measured contrast sensitivity, using sinusoidal grating stimuli, as a control task. Individuals with ASD did not differ from controls in face detection (p > 0.9) or contrast detection (p > 0.2) ability. Performance on contrast and face detection was significantly correlated in ASD but not in NC. Results suggest that the ability to visually detect faces is not altered in ASD overall, but that alterations in basic visual processing may affect face detection ability in some individuals with ASD.

Visual attention toward emotional stimuli: Anxiety symptoms correspond to distinct gaze patterns.

Decades of research have established a link between emotional disorders and attentional biases for emotional stimuli, but the relationship between symptom severity and visual attention is still not fully understood. Depression has been associated with increased attention towards dysphoric stimuli and decreased attention on positive stimuli ("negativity bias"), and some studies have also shown this trend in anxiety disorders. We examined eye fixation variables in 47 participants with emotional disorders completing an emotion recognition task. Results showed that depression severity was not associated with increased fixations on dysphoric stimuli, however, higher levels of generalized anxiety predicted increased fixations in the mouth region of sad and happy faces. Higher levels of social interaction anxiety predicted reduced fixations in the eye region of happy faces. While we did not replicate the negativity bias that has been shown in prior studies, our sample was highly comorbid, indicating the need to consider comorbidity, disorder severity, and the task itself when conducting research on visual attention in clinical samples. Additionally, more attention should be paid to the mouth region of emotional faces, as it may provide more specific information regarding the visual processing of emotions.

A discrete choice experiment exploring farmer preferences for insurance against extreme weather events.

Agriculture represents one of the most vulnerable sectors to extreme weather events that are projected to increase with climate change. Insurance has been advocated as a more efficient means to ensure financial security to farmers, than post-disaster aid for damages. A potential drawback of insurance however, is that unless carefully designed it could dis-incentivise farmers to engage in wider farm adaptation measures or lead to more risk-taking behaviour. This paper analyses the attractiveness of publicly-backed climate risk insurance offerings to farmers and explores their preferences for elements of insurance schemes that do not negatively affect incentives for wider farm adaptation. Specifically, a discrete choice experiment is used to reveal Irish farmers' preferences for multi-annual insurance contracts and weather-indexed versus traditional indemnity insurance and cost. Results indicate that a majority of farmers are willing to buy publicly-backed insurance for protection from extreme weather events. Younger farmers, farmers who currently have farm insurance, farmers from certain geographical locations and farmers who have been previously affected by extreme weather events are more likely to buy insurance. With respect to the design of insurance schemes, farmers prefer multi-annual coverage versus annual renewal. They also prefer indexed-insurance and have a strong preference for cheaper coverage. Despite the important role that insurance could play in protecting farms financially from damage caused by extreme weather events, few studies have examined preference for weather-indexed insurance within a European context. New evidence on farmer preferences and intended behaviours is therefore critical to inform policy in this area.

Visual short-term memory relates to tau and amyloid burdens in preclinical autosomal dominant Alzheimer's disease.

BACKGROUND: Over the past decade, visual short-term memory (VSTM) binding tests have been shown to be one of the most sensitive behavioral indicators of Alzheimer's disease (AD), especially when they require the binding of multiple features (e.g., color and shape). Recently, it has become possible to directly measure amyloid and tau levels in vivo via positron emission tomography (PET). To this point, these behavioral and neurochemical markers have not been compared in humans with AD or at risk for it. METHODS: In a cross-sectional study, we compared VSTM performance to tau and amyloid concentrations, measured by PET, in individuals certain to develop AD by virtue of their inheritance of the presenilin-1 E280A mutation. These included 21 clinically unimpaired subjects and 7 subjects with early mild cognitive impairment (MCI), as well as 30 family members who were not carriers of the mutation. RESULTS: We found that VSTM performance correlated strongly with tau in entorhinal cortex and inferior temporal lobe, and also with amyloid when examining asymptomatic carriers only. The condition requiring binding was not preferentially linked to tau-in fact, the non-binding "shape only" condition showed a stronger relationship. CONCLUSIONS: The results confirm VSTM's status as an early marker of AD pathology and raise interesting questions as to the course of binding-specific versus non-binding aspects of VSTM in early AD.

Image acquisition and quality assurance in the Boston Adolescent Neuroimaging of Depression and Anxiety study.

The Connectomes Related to Human Diseases (CRHD) initiative was developed with the Human Connectome Project (HCP) to provide high-resolution, open-access, multi-modal MRI data to better understand the neural correlates of human disease. Here, we present an introduction to a CRHD project, the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study, which is collecting multimodal neuroimaging, clinical, and neuropsychological data from 225 adolescents (ages 14-17), 150 of whom are expected to have a diagnosis of depression and/or anxiety. Our transdiagnostic recruitment approach samples the full spectrum of depressed/anxious symptoms and their comorbidity, consistent with NIMH Research Domain Criteria (RDoC). We focused on an age range that is critical for brain development and for the onset of mental illness. This project sought to harmonize imaging sequences, hardware, and functional tasks with other HCP studies, although some changes were made to canonical HCP methods to accommodate our study population and questions. We present a thorough overview of our imaging sequences, hardware, and scanning protocol. We detail similarities and differences between this study and other HCP studies. We evaluate structural-, diffusion-, and functional-image-quality measures that may be influenced by clinical factors (e.g., disorder, symptomatology). Signal-to-noise and motion estimates from the first 140 adolescents suggest minimal influence of clinical factors on image quality. We anticipate enrollment of an additional 85 participants, most of whom are expected to have a diagnosis of anxiety and/or depression. Clinical and neuropsychological data from the first 140 participants are currently freely available through the National Institute of Mental Health Data Archive (NDA).

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.

A Double-Blind Placebo Controlled Study of Intranasal Oxytocin's Effect on Emotion Recognition and Visual Attention in Outpatients with Emotional Disorders.

The current study used double-blind, placebo-controlled design to examine the effect of intranasal oxytocin (OT) on emotion recognition (ER) and visual attention in 60 outpatients presenting for assessment and treatment of emotional disorders. Our primary hypothesis was that OT would improve recognition of happy faces in depressed participants. The main effect of OT on ER accuracy, speed, and proportion of fixations in the eye region was not significant. Diagnostic group (i.e., presence/absence of a depressive disorder) moderated the effect of OT on ER, but not as expected: OT significantly slowed ER speed for all emotions in participants with anxiety disorders, but did not affect performance in participants with depressive disorders. Depressed participants fixated significantly less in the eye region of sad faces than anxious participants. Before OT can be used to target ER biases, additional research is needed to explicate the differential impact of OT on ER speed in patients with anxiety versus mood disorders.

Striatal amyloid is associated with tauopathy and memory decline in familial Alzheimer's disease.

BACKGROUND: Autosomal dominant Alzheimer's disease (ADAD) is distinguished from late-onset AD by early striatal amyloid-ß deposition. To determine whether striatal Pittsburgh compound B (PiB)-PET measurements of amyloid-ß can help predict disease severity in ADAD, we compared relationships of striatal and neocortical PiB-PET to age, tau-PET, and memory performance in the Colombian Presenilin 1 E280A kindred. METHODS: Fourteen carriers (age = 28-42, Mini-Mental State Examination = 26-30) and 20 age-matched non-carriers were evaluated using PiB, flortaucipir (FTP; tau), and memory testing (CERAD Word List Learning). PiB-PET signal was measured in neocortical and striatal aggregates. FTP-PET signal was measured in entorhinal cortex. RESULTS: Compared to non-carriers, mutation carriers had age-related elevations in both neocortical and striatal PiB binding. The PiB elevation in carriers was significantly greater in the striatum than in the neocortex. In mutation carriers, PiB binding in both the neocortex and the striatum is related to entorhinal FTP; however, the association was stronger with the striatum. Only striatal PiB was associated with worse memory. Remarkably, PiB binding in the striatum, but not in the neocortex, predicted entorhinal FTP and lower memory scores after adjusting for age, indicating that striatal PiB identified the carriers with the most severe disease. CONCLUSIONS: Based on these preliminary cross-sectional findings, striatal PiB-PET measurements may offer particular value in the detection and tracking of preclinical ADAD, informing a mutation carrier's prognosis and evaluating amyloid-ß-modifying ADAD treatments.

A Three-Factor Structure of Cognitive Functioning Among Unimpaired Carriers and Non-Carriers of Autosomal-Dominant Alzheimer's Disease.

BACKGROUND: There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline. OBJECTIVE: We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. METHODS: 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). RESULTS: The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset. CONCLUSIONS: The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease.

Importance: It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms. Objective: To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation. Design, Setting, and Participants: In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals' proximity to the expected onset of dementia. Cross-sectional measures of carbon 11-labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24 PSEN1 E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpaired and 3 of whom had mild cognitive impairment, and 12 cognitively unimpaired noncarriers. Main Outcomes and Measures: We compared carbon 11-labeled Pittsburgh Compound B PET cerebral with cerebellar distribution volume ratios as well as flortaucipir F 18 PET cerebral with cerebellar standardized uptake value ratios in mutation carriers and noncarriers. Spearman correlations characterized the associations between age and mean cortical Pittsburgh Compound B distribution volume ratio levels or regional flortaucipir standardized uptake value ratio levels in both groups. Results: Of the 24 individuals, the mean (SD) age was 38.0 (7.4) years, or approximately 6 years younger than the expected onset of clinical symptoms in carriers. Compared with noncarriers, cognitively unimpaired mutation carriers had elevated mean cortical Pittsburgh Compound B distribution volume ratio levels in their late 20s, and 7 of 9 carriers older than 30 years reached the threshold for amyloidosis (distribution volume ratio level > 1.2). Elevated levels of tau deposition were seen within medial temporal lobe regions in amyloid-positive mutation carriers 6 years before clinical onset of AD in this kindred. Substantial tau deposition in the neocortex was only observed in 1 unimpaired carrier and in those with mild cognitive impairment. ß-Amyloid uptake levels were diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment. In carriers, higher levels of tau deposition were associated with worse performance on the Mini-Mental State Examination (entorhinal cortex: r = -0.60; P = .04; inferior temporal lobe: r = -0.54; P = .06) and the Consortium to Establish a Registry for Alzheimer Disease Word List Delayed Recall (entorhinal cortex: r = -0.86; P < .001; inferior temporal lobe: r = -0.70; P = .01). Conclusions and Relevance: The present findings add to the growing evidence that molecular markers can characterize biological changes associated with AD in individuals who are still cognitively unimpaired. The findings also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptoms of AD and to track disease progression.

Subjective memory complaints in preclinical autosomal dominant Alzheimer disease.

OBJECTIVE: To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). METHODS: We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. RESULTS: Self-reported SMC were greater in carriers than noncarriers (p = 0.02). Study partner-based SMC did not differ between groups (p = 0.21), but in carriers increased with age (r = 0.66, p < 0.001) and decreased with hippocampal volume (r = -0.35, p = 0.08). CONCLUSIONS: Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset.

Synthesis and pre-clinical studies of new amino-acid ester thiazolide prodrugs.

Thiazolides are polypharmacology agents with at least three mechanisms of action against a broad spectrum of parasites, bacteria and viruses. In respiratory viruses they inhibit the replication of orthomyxoviridae and paramyxoviridae at a post-translational level. Nitazoxanide 1a, the prototype thiazolide, was originally developed as an antiparasitic agent and later repurposed for the treatment of viral respiratory infections. The second generation thiazolides following nitazoxanide, such as the 5-chloro analogue RM-5038 2a, are also broad-spectrum antiviral agents as we have reported. Both 1a and its effective circulating metabolite, tizoxanide 1b, are 5-nitrothiazole derivatives, while RM-5038 2a and its de-acetyl derivative RM-4848 2b are the corresponding 5-chloro derivatives. Recently 1a has completed phase II-III clinical trials in the United States, Canada, Australia and New Zealand in a total of 2865 adults and adolescents of at least 12 months of age with viral acute respiratory illness. Since its biodisposition is primarily seen in the gastro-intestinal tract, its efficacy in systemic viral diseases requires relatively high oral doses. The chemical synthesis of new derivatives with a better systemic absorption was therefore urgently needed. In order to improve their systemic absorption, new amino-ester prodrug derivatives of 1b and RM4848 2b were prepared and tested for their animal pharmacology, pharmacokinetics and toxicology. RM-5061 8a in rats showed 7-fold higher blood concentration compared to 1a: absolute bioavailability increased from 3 to 20%, with a good safety profile in animal safety pharmacology and toxicology.

Dysregulation of visual motion inhibition in major depression.

Individuals with depression show depleted concentrations of the inhibitory neurotransmitter GABA in occipital (visual) cortex, predicting weakened inhibition within their visual systems. Yet, visual inhibition in depression remains largely unexplored. To fill this gap, we examined the inhibitory process of center-surround suppression (CSS) of visual motion in depressed individuals. Perceptual performance in discriminating the direction of motion was measured as a function of stimulus presentation time and contrast in depressed individuals (n=27) and controls (n=22). CSS was operationalized as the accuracy difference between conditions using large (7.5°) and small (1.5°) grating stimuli. Both depressed and control participants displayed the expected advantage in accuracy for small stimuli at high contrast. A significant interaction emerged between subject group, contrast level and presentation time, indicating that alterations of CSS in depression were modulated by stimulus conditions. At high contrast, depressed individuals showed significantly greater CSS than controls at the 66ms presentation time (where the effect peaked in both groups). The results' specificity and dependence on stimulus features such as contrast, size and presentation time suggest that they arise from changes in early visual processing, and are not the results of a generalized deficit or cognitive bias.

Visuospatial Attention to Single and Multiple Objects Is Independently Impaired in Parkinson's Disease.

Parkinson's disease (PD) is associated with deficits in visuospatial attention. It is as yet unknown whether these attentional deficits begin at a perceptual level or instead reflect disruptions in oculomotor or higher-order processes. In the present study, non-demented individuals with PD and matched normal control adults (NC) participated in two tasks requiring sustained visuospatial attention, both based on a multiple object tracking paradigm. Eye tracking was used to ensure central fixation. In Experiment 1 (26 PD, 21 NC), a pair of identical red dots (one target, one distractor) rotated randomly for three seconds at varied speeds. The task was to maintain the identity of the sole target, which was labeled prior to each trial. PD were less accurate than NC overall (p = .049). When considering only trials where fixation was maintained, however, there was no significant group difference, suggesting that the deficit's origin is closely related to oculomotor processing. To determine whether PD had additional impairment in multifocal attention, in Experiment 2 (25 PD, 15 NC), two targets were presented along with distractors at a moderate speed, along with a control condition in which dots remained stationary. PD were less accurate than NC for moving (p = 0.02) but not stationary targets. This group difference remained significant when considering only trials where fixation was maintained, suggesting the source of the PD deficit was independent from oculomotor processing. Taken together, the results implicate separate mechanisms for single vs. multiple object tracking deficits in PD.

Perceptual, cognitive, and personality rigidity in Parkinson's disease.

Parkinson's disease (PD) is associated with motor and non-motor rigidity symptoms (e.g., cognitive and personality). The question is raised as to whether rigidity in PD also extends to perception, and if so, whether perceptual, cognitive, and personality rigidities are correlated. Bistable stimuli were presented to 28 non-demented individuals with PD and 26 normal control adults (NC). Necker cube perception and binocular rivalry were examined during passive viewing, and the Necker cube was additionally used for two volitional-control conditions: Hold one percept in front, and Switch between the two percepts. Relative to passive viewing, PD were significantly less able than NC to reduce dominance durations in the Switch condition, indicating perceptual rigidity. Tests of cognitive flexibility and a personality questionnaire were administered to explore the association with perceptual rigidity. Cognitive flexibility was not correlated with perceptual rigidity for either group. Personality (novelty seeking) correlated with dominance durations on Necker passive viewing for PD but not NC. The results indicate the presence in mild-moderate PD of perceptual rigidity and suggest shared neural substrates with novelty seeking, but functional divergence from those supporting cognitive flexibility. The possibility is raised that perceptual rigidity may be a harbinger of cognitive inflexibility later in the disease course.