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At least 19 records

Large-scale deep learning for metastasis detection in pathology reports

Objectives No existing algorithm can reliably identify metastasis from pathology reports across multiple cancer types and the entire US population. In this study, we develop a deep learning model that automatically detects patients with metastatic cancer by using pathology reports from many laboratories and of multiple cancer types. Materials and Methods We use 60 471 unstructured pathology reports from 4 Surveillance, Epidemiology, and End Results (SEER) registries. The reports were coded into 1 of 3 labels: metastasis negative, metastases positive, or metastasis undetermined. We utilize a task-specific deep neural network trained from scratch and compare its performance with a widely used large language model (LLM). Results Our deep learning architecture trained on task-specific data outperforms a general-purpose LLM, with a recall of 0.894 compared to 0.824. We quantified model uncertainty and used it to defer reports for human review. We found that retaining 72.9% of reports increased recall from 0.894 to 0.969. Discussion A smaller deep learning architecture trained on task-specific data outperforms a general LLM. Equally critical to model performance is the incorporation of uncertainty quantification, achieved here through an abstention mechanism. Conclusions This study’s finding demonstrate the feasibility of developing algorithms to automatically identify metastatic cancer cases from unstructured pathology reports.

machine learning↗

Connectivity, Pathology, and ApoE4 Interactions Predict Longitudinal Tau Spatial Progression and Memory

ABSTRACT Tau pathology spread into neocortex indicates a transition from healthy aging to Alzheimer's disease (AD). Connectivity between tau epicenters and later accumulating regions of cortex has been proposed as a mechanism of tau spread, but how this relationship changes with greater AD pathology burden or genotype is not understood. We investigated tau accumulation in two key regions, precuneus and inferior temporal cortex, using resting state functional connectivity (rsFC) and longitudinal PET imaging from a multicohort sample of cognitively unimpaired older adults. We examined how baseline tau PET, Aβ PET, and ApoE4 genotype status interact with rsFC between hippocampus and these downstream regions to predict rate of tau accumulation in neocortex. We found that the 3‐way interaction between connectivity, baseline tau, and baseline Aβ or ApoE4 status was associated with neocortical tau accumulation in precuneus and inferior temporal cortex. In addition, baseline tau, Aβ, and ApoE4 status also moderated the association between connectivity and rate of memory decline. Together, these results suggest that the extent and distribution of future tau accumulation may be predicted by the interaction of baseline connectivity, AD pathology, and genetic risk.

Neurosciences & Neurology↗

Pathology and Therapeutic Significance of Fibroblast Growth Factors

The fibroblast growth factor (FGF) family includes 22 proteins in humans. Based on their mode of action, there are three families of FGFs: paracrine FGFs (FGF 1–10, 16, 17, 18, 20, and 22), intracrine FGFs (FGF 11–14), and endocrine FGFs (FGF 19, 21, and 23). FGF signaling plays critical roles in embryonic development, tissue repair, regeneration, angiogenesis, and metabolic regulation. They exert their cellular functions by binding, dimerization, and activation of transmembrane FGF receptors (FGFRs). Aberrant FGF signaling is associated with various human diseases. Thus, understanding the unique properties of FGF signaling will help to explore new therapeutic interventions against FGF-mediated pathological conditions. This review will discuss the differential expression and regulation of each FGF under normal human physiological and pathological conditions. Moreover, we will outline current therapeutics and treatment strategies that have been developed against FGF-related pathology.

Edirisinghe, Oshadi↗

Role of tau versus TDP-43 pathology on medial temporal lobe atrophy in aging and Alzheimer's disease

Hippocampal atrophy on magnetic resonance imaging is an important biomarker in Alzheimer's disease (AD). While hippocampal atrophy was thought to result from tau tangles in AD, different neuropathologies can lead to hippocampal atrophy, especially TAR DNA-binding protein 43 (TDP-43) pathology. In this narrative review, we evaluate existing studies on the relative contribution of tau and TDP-43 pathology to medial temporal lobe (MTL) atrophy. We report a clear association of both tau and TDP-43 neuropathology with MTL atrophy, even after correcting for other neuropathologies. Next, we discuss a potential synergism between tau and TDP-43 and the relative timing of the effects of both neuropathologies. Finally, avenues for future research will be discussed. A better understanding of the interplay between tau and TDP-43 neuropathologies and their effect on atrophy will help with the development of more specific biomarkers for limbic-predominant age-related TDP-43 encephalopathy and pinpointing of the optimal timing for testing anti-tau and anti-TDP-43 treatments in trials.

60 APPLIED LIFE SCIENCES↗

Development of message passing-based graph convolutional networks for classifying cancer pathology reports

Abstract Background Applying graph convolutional networks (GCN) to the classification of free-form natural language texts leveraged by graph-of-words features (TextGCN) was studied and confirmed to be an effective means of describing complex natural language texts. However, the text classification models based on the TextGCN possess weaknesses in terms of memory consumption and model dissemination and distribution. In this paper, we present a fast message passing network (FastMPN), implementing a GCN with message passing architecture that provides versatility and flexibility by allowing trainable node embedding and edge weights, helping the GCN model find the better solution. We applied the FastMPN model to the task of clinical information extraction from cancer pathology reports, extracting the following six properties: main site, subsite, laterality, histology, behavior, and grade. Results We evaluated the clinical task performance of the FastMPN models in terms of micro- and macro-averaged F1 scores. A comparison was performed with the multi-task convolutional neural network (MT-CNN) model. Results show that the FastMPN model is equivalent to or better than the MT-CNN. Conclusions Our implementation revealed that our FastMPN model, which is based on the PyTorch platform, can train a large corpus (667,290 training samples) with 202,373 unique words in less than 3 minutes per epoch using one NVIDIA V100 hardware accelerator. Our experiments demonstrated that using this implementation, the clinical task performance scores of information extraction related to tumors from cancer pathology reports were highly competitive.

59 BASIC BIOLOGICAL SCIENCES↗

Brain phosphoproteomic analysis identifies diabetes‐related substrates in Alzheimer's disease pathology in older adults

INTRODUCTION: Type 2 diabetes increases the risk of Alzheimer's disease (AD) dementia. Insulin signaling dysfunction exacerbates tau protein phosphorylation, a hallmark of AD pathology. However, the comprehensive impact of diabetes on patterns of AD-related phosphoprotein in the human brain remains underexplored. METHODS: We performed tandem mass tag–based phosphoproteome profiling in post mortem human brain prefrontal cortex samples from 191 deceased older adults with and without diabetes and pathologic AD. RESULTS: Among 7874 quantified phosphosites, microtubule-associated protein tau (MAPT) phosphorylated at T529 and T534 (isoform 8 T212 and T217) were more abundant in AD and showed differential associations with diabetes. Network analysis of co-abundance patterns uncovered synergistic interactions between AD and diabetes, with one module exhibiting higher MAPT phosphorylation (15 MAPT phosphosites) and another displaying lower MAP1B phosphorylation (22 MAP1B phosphosites). DISCUSSION: This study offers phosphoproteomics insights into AD in diabetes, shedding light on mechanisms that can inform the development of therapeutics for dementia. Highlights: The risk of Alzheimer's disease (AD) dementia is increased among older adults living with diabetes. The patterns of AD-related phosphoprotein in the human brain in older adults are differential among older adults living with diabetes. Microtubule-associated protein tau phosphorylated at T529 and T534 (isoform 8 T212 and T217) showed differential associations with diabetes. Phosphosite co-abundance networks of synergistic interactions between AD and diabetes were identified.

60 APPLIED LIFE SCIENCES↗

Evaluating algorithmic bias on biomarker classification of breast cancer pathology reports

Objectives: This work evaluated algorithmic bias in biomarkers classification using electronic pathology reports from female breast cancer cases. Bias was assessed across 5 subgroups: cancer registry, race, Hispanic ethnicity, age at diagnosis, and socioeconomic status. Materials and Methods: We utilized 594 875 electronic pathology reports from 178 121 tumors diagnosed in Kentucky, Louisiana, New Jersey, New Mexico, Seattle, and Utah to train 2 deep-learning algorithms to classify breast cancer patients using their biomarkers test results. We used balanced error rate (BER), demographic parity (DP), equalized odds (EOD), and equal opportunity (EOP) to assess bias. Results: We found differences in predictive accuracy between registries, with the highest accuracy in the registry that contributed the most data (Seattle Registry, BER ratios for all registries >1.25). BER showed no significant algorithmic bias in extracting biomarkers (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) for race, Hispanic ethnicity, age at diagnosis, or socioeconomic subgroups (BER ratio <1.25). DP, EOD, and EOP all showed insignificant results. Discussion: We observed significant differences in BER by registry, but no significant bias using the DP, EOD, and EOP metrics for socio-demographic or racial categories. This highlights the importance of employing a diverse set of metrics for a comprehensive evaluation of model fairness. Conclusion: A thorough evaluation of algorithmic biases that may affect equality in clinical care is a critical step before deploying algorithms in the real world. We found little evidence of algorithmic bias in our biomarker classification tool. Artificial intelligence tools to expedite information extraction from clinical records could accelerate clinical trial matching and improve care.

60 APPLIED LIFE SCIENCES↗

Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology

Abstract INTRODUCTION Factors responsible for the deposition of pathological tau in the brain are incompletely understood. This study links macroscale tau deposition in the human brain to cerebrospinal fluid (CSF) flow dynamics using resting‐state functional magnetic resonance imaging (rsfMRI). METHODS Low‐frequency (< 0.1 Hz) resting‐state global brain activity is coupled with CSF flow and potentially reflects CSF dynamics‐related clearance. We examined the correlation between rsfMRI measures of CSF inflow and global activity (gBOLD–CSF coupling) as a predictor, interacting with amyloid beta (Aβ), of tau and cortical thickness (dependent variables) across Alzheimer's Disease Neuroimaging Initiative (ADNI) participants from cognitively unimpaired through mild cognitive impairment (MCI) and Alzheimer's disease (AD). RESULTS Tau deposition in Aβ+ participants, accompanied by cortical thinning and cognitive decline, is associated with decreased gBOLD–CSF coupling. Tau mediates the relationship between coupling and thickness. DISCUSSION Findings suggest that resting‐state global brain activity and CSF movements comodulate Alzheimer's tau deposition, presumably related to CSF clearance. Highlights A non‐invasive functional magnetic resonance imaging (fMRI) assessment of a CSF clearance‐related process is carried out. Global brain activity is coupled with CSF inflow in human fMRI during resting state. Global fMRI–CSF coupling is correlated with tau in Alzheimer's disease (AD). This coupling measure is also associated with cortical thickness, mediated by tau.

Neurosciences & Neurology↗

Cognitive aging outcomes are related to both tau pathology and maintenance of cingulate cortex structure

Abstract INTRODUCTION Successful cognitive aging is related to both maintaining brain structure and avoiding Alzheimer's disease (AD) pathology, but how these factors interplay is unclear. METHODS A total of 109 cognitively normal older adults (70+ years old) underwent amyloid beta (Aβ) and tau positron emission tomography (PET) imaging, structural magnetic resonance imaging (MRI), and cognitive testing. Cognitive aging was quantified using the cognitive age gap (CAG), subtracting chronological age from predicted cognitive age. RESULTS Lower CAG (younger cognitive age) was related to slower decline in episodic memory, multi‐domain cognition, and atrophy of the midcingulate cortex (MCC). Lower entorhinal cortical tau was linked to slower decline in episodic memory, multi‐domain cognition, and hippocampal atrophy. DISCUSSION These results suggest that aging outcomes may be influenced by two independent pathways: one associated with tau accumulation, affecting primarily memory and hippocampal atrophy, and another involving tau‐independent structural preservation of the MCC, benefiting multi‐domain cognition over time. Highlights Younger cognitive age (lower cognitive age gap [CAG]) is related to slower cognitive decline. Lower CAG is linked to slower midcingulate cortex (MCC) atrophy. Reduced tau in the entorhinal cortex is related to less hippocampal atrophy and cognitive decline. Structural preservation of the MCC benefits multi‐domain cognition over time. Two independent pathways influence cognitive aging: tau accumulation and MCC preservation.

Neurosciences & Neurology↗

Global Explainability of A Deep Abstaining Classifier for Cancer Pathology Reports

We present a global explainability method to characterize sources of errors in a real-world multitask deep abstaining classifier (DAC), in the context of cancer histology prediction. Our multitask classifier, currently deployed for automated annotation of cancer pathology reports from NCI-SEER registries, was trained and evaluated on 1.04 million hand-annotated samples and makes simultaneous predictions of cancer site, subsite, histology, laterality, and behavior for each report. The DAC framework enables the model to abstain on ambiguous reports and confusing classes to achieve the target accuracy on the retained (non-abstained) samples, but at the cost of decreased coverage. Requiring 97% accuracy on the histology task caused our model to retain only 22% of all samples, mostly the less ambiguous and common classes. Local explainability with the GradInp technique provided a computationally efficient way of obtaining contextual reasoning for hundreds of thousands of individual predictions. Our method, involving dimensionality reduction of approximately 13000 aggregated local explanations (ALE), offers a tractable path to true global explainability. It enabled identification of sources of errors in histology classification, globally, as hierarchical complexity among classes, label noise, insufficient information, and conflicting evidence. This suggests several strategies for iterative improvement of our DAC, including well-designed exclusion criteria, focused annotation, and reduced penalties for errors involving hierarchically related classes.

59 BASIC BIOLOGICAL SCIENCES↗

Diagnosis of Alzheimer’s disease using plasma biomarkers adjusted to clinical probability

Abstract Recently approved anti-amyloid immunotherapies for Alzheimer’s disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of disease prevalence in relation to clinical presentation (clinical pretest probability). Here, in a study of 6,896 individuals evaluated from 11 cohort studies from six countries, we determined the positive and negative predictive value of five plasma biomarkers for amyloid-β pathology in cognitively impaired individuals in relation to clinical pretest probability. We observed that p-tau217 could rule in amyloid-β pathology in individuals with probable AD dementia (positive predictive value above 95%). In mild cognitive impairment, p-tau217 interpretation depended on patient age. Negative p-tau217 results could rule out amyloid-β pathology in individuals with non-AD dementia syndromes (negative predictive value between 90% and 99%). Our findings provide a framework for the individual-level interpretation of plasma biomarkers, suggesting that p-tau217 combined with clinical phenotyping can identify patients where amyloid-β pathology can be ruled in or out without the need for PET or CSF confirmatory testing.

Cell Biology↗

A multilayer network analysis of Alzheimer's disease pathogenesis: Roles for p‐tau, synaptic peptides, and physical activity

INTRODUCTION: In the aging brain, cognitive abilities emerge from the coordination of complex pathways arising from a balance between protective lifestyle and environmental factors and accumulation of neuropathologies. METHODS: As part of the Rush Memory and Aging Project (n = 440), we measured accelerometer-based actigraphy, cognitive performance, and after brain autopsy, selected reaction monitoring mass spectrometry. Multilevel network analysis was used to examine the relationships among the molecular machinery of vesicular neurotransmission, Alzheimer's disease (AD) neuropathology, cognition, and late-life physical activity. RESULTS: Synaptic peptides involved in neuronal secretory function were the most influential contributors to the multilayer network, reflecting the complex interdependencies among AD pathology, synaptic processes, and late-life cognition. Older adults with lower physical activity evidenced stronger adverse relationships among phosphorylated tau peptides, markers of synaptic integrity, and tangle pathology. DISCUSSION: Network-based approaches simultaneously model interdependent biological processes and advance understanding of the role of physical activity in age-associated cognitive impairment. Highlights: Network-based approaches simultaneously model interdependent biological processes. Secretory synaptic peptides were influential contributors to the multilayer network. Older adults with lower physical activity had adverse relationships among pathology. There was interdependence among phosphorylated tau, synaptic integrity, and tangles. Network methods elucidate the role of physical activity in cognitive impairment.

60 APPLIED LIFE SCIENCES↗

Biofluid-based staging of Alzheimer’s disease

Recently, conceptual systems for the in vivo staging of Alzheimer’s disease (AD) using fluid biomarkers have been suggested. Thus, it is important to assess whether available fluid biomarkers can successfully stage AD into clinically and biologically relevant categories. In the TRIAD cohort, we explored whether p-tau217, p-tau205 and NTA-tau (biomarkers of early, intermediate and late AD pathology, respectively) have potential for biofluid-based staging in cerebrospinal fluid (CSF; n = 219) and plasma (n = 150), and compared them in a paired CSF and plasma subset (n = 76). Our findings suggest a good concordance between biofluid staging and underlying pathology when classifying amyloid-positivity into three categories based on neurofibrillary pathology: minimal/non-existent (p-tau217 positive), early-to-intermediate (p-tau217 and p-tau205 positivity), and advanced tau tangle deposition (p-tau217, p-tau205 and NTA-tau positive), as indexed by tau-PET. Discordant cases accounted for 4.6% and 13.3% of all CSF and plasma measurements respectively (9.2% and 11.8% in paired samples). Notably, CSF- and plasma-based staging matched one another in 61.7% of the cases, while approximately 32% of the remaining participants were one to three biofluid stages higher in CSF as compared to plasma. Overall, these exploratory results suggest that biofluid staging of AD holds potential for offering valuable insights into underlying AD hallmarks and disease severity. However, its applicability beyond molecular characterization at research settings has yet to be demonstrated.

60 APPLIED LIFE SCIENCES↗

Lipid and lipoprotein metabolism in microglia: Alzheimer’s disease mechanisms and interventions

Alzheimer's disease (AD) presents a significant challenge owing to its widespread prevalence and complex neuropathogenesis, affecting millions worldwide. Current therapeutic strategies that predominantly target amyloid-beta accumulation are insufficient, particularly for ApoE4 carriers. Alterations in lipid composition are well documented in AD, characterized by reductions in phospholipids and sulfatides, along with increases in cholesterol, cholesteryl esters, and triglycerides (TGs). Microglia, the brain's resident immune cells, link dysfunctional lipid processing to AD neuropathogenesis. For example, genetic studies have pointed to microglial lipid and lipoprotein processing gene variants as some of the strongest risk factors for AD. In addition, microglial dysfunction, characterized by lipid droplet accumulation, increased cholesterol and TG levels, and altered lipid transport, may exacerbate the pathological hallmarks of AD, such as amyloid-beta and tau accumulation. Conversely, emerging studies have shown that strategies aimed at inhibiting lipid droplet accumulation in microglia, reducing TG synthesis, and promoting the activity of lipoprotein receptors expressed by microglia can improve cell functions and markers of AD pathology. This review dissects the interplay between microglial lipid metabolism and AD, highlighting the significance of lipid transport and trafficking within the CNS. Given the intrinsic link between microglial metabolism and AD progression, emerging and potential therapeutic strategies aimed at restoring lipid handling and improving microglial function are explored. This review provides a comprehensive examination of the emerging literature, detailing the current state of knowledge on microglial lipid metabolism, its genetic underpinnings, and the potential for novel interventions targeting these mechanisms to ameliorate AD pathology.

Alzheimer's disease↗

Discovery of Proteoforms Associated With Alzheimer's Disease Through Quantitative Top-Down Proteomics

The complex nature of Alzheimer's disease (AD) and its heterogenous clinical presentation has prompted numerous large-scale - omic analyses aimed at providing a global understanding of the pathophysiological processes involved. AD involves isoforms, proteolytic products, and posttranslationally modified proteins such as amyloid beta (Aβ) and microtubule-associated protein tau. Top-down proteomics directly measures these species and thus, offers a comprehensive view of pathologically relevant proteoforms that are difficult to analyze using traditional proteomic techniques. Here, we broadly explored associations between proteoforms and clinicopathological traits of AD by deploying a quantitative top-down proteomics approach across frontal cortex of 103 subjects selected from the ROS and MAP cohorts. The approach identified 1213 proteins and 11,782 proteoforms, of which 154 proteoforms had at least one significant association with a clinicopathological phenotype. One important finding included identifying Aβ C-terminal truncation state as the key property for differential association between amyloid plaques and cerebral amyloid angiopathy. Furthermore, various N-terminally truncated forms of Aβ had noticeably stronger association with amyloid plaques and global cognitive function. Additionally, we discovered six VGF neuropeptides that were positively associated with cognitive function independent of pathological burden. The database of brain cortex proteoforms provides a valuable context for functional characterization of the proteins involved in AD and other late-onset brain pathologies.

60 APPLIED LIFE SCIENCES↗

Associations between regional blood-brain barrier permeability, aging, and Alzheimer’s disease biomarkers in cognitively normal older adults

Background Increased blood-brain barrier permeability (BBBp) has been hypothesized as a feature of aging that may lead to the development of Alzheimer’s disease (AD). We sought to identify the brain regions most vulnerable to greater BBBp during aging and examine their regional relationship with neuroimaging biomarkers of AD. Methods We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify K trans values, as a measure of BBBp, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBp than YA. In OA, K trans values were compared based on sex, Aβ positivity status, and APOE4carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between K trans and AD biomarkers. Results OA showed greater BBBp than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in K trans values based on sex or Aβ positivity, but OA who were APOE4carriers had significantly higher K trans values. There was no direct relationship between averaged K trans and global Aβ pathology, but there was a trend for an Ab status by tau interaction on K trans in this region. SCCA showed increased K trans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between K trans and FTP SUVR. Discussion Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBp in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aβ.

Science & Technology - Other Topics↗

In-vivo neuronal dysfunction by Aβ and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer’s disease

The molecular mechanisms underlying neuronal dysfunction in Alzheimer’s disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aβ and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant’s real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aβ-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aβ and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aβ and tau’s synergistic impact on neuronal activity (q < 0.001). These results further support the central role of the immune system and neuroinflammatory pathways in AD pathogenesis. Neuronal dysregulation by AD pathologies also associated with neurotypical synaptic and developmental processes. In addition, we identified drug candidates from the vast LINCS library to halt or reduce the observed Aβ-tau effects on neuronal activity. Top-ranked pharmacological interventions target inflammatory, cancer and cardiovascular pathways, including specific medications undergoing clinical evaluation in AD. Our findings, based on the examination of molecular-pathological-functional interactions in humans, may accelerate the process of bringing effective therapies into clinical practice.

60 APPLIED LIFE SCIENCES↗