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IntroductionWith emergence of disease-modifying therapies, efficient diagnostic pathways are critically needed to identify treatment candidates, evaluate disease severity, and support prognosis. A combination of plasma biomarkers and brief digital cognitive assessments could provide a scalable alternative to current diagnostic work-up.MethodsWe examined the accuracy of plasma biomarkers and a 10-minute supervised tablet-based cognitive assessment (Tablet-based Cognitive Assessment Tool Brain Health Assessment [TabCAT-BHA]) in predicting amyloid β positive (Aβ+) status on positron emission tomography (PET), concurrent disease severity, and functional decline in 309 older adults with subjective cognitive impairment (n = 49), mild cognitive impairment (n = 159), and dementia (n = 101).ResultsCombination of plasma pTau181, Aβ42/40, neurofilament light (NfL), and TabCAT-BHA was optimal for predicting Aβ-PET positivity (AUC = 0.962). Whereas NfL and TabCAT-BHA optimally predicted concurrent disease severity, combining these with pTau181 and glial fibrillary acidic protein was most accurate in predicting functional decline.DiscussionCombinations of plasma and digital cognitive markers show promise for scalable diagnosis and prognosis of ADRD.HighlightsThe need for cost-efficient diagnostic and prognostic markers of AD is urgent. Plasma and digital cognitive markers provide complementary diagnostic contributions. Combination of these markers holds promise for scalable diagnosis and prognosis. Future validation in community cohorts is needed to inform clinical implementation.

BackgroundPlasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations.MethodsWe examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61-73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter.ResultsAfter adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals.ConclusionsThese results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.

Alzheimer's disease (AD), the most prevalent form of dementia, is expected to rise dramatically in incidence due to the global population aging. Traditional diagnostic approaches, such as cerebrospinal fluid analysis and positron emission tomography, are expensive and invasive, limiting their routine clinical use. Recent advances in blood-based biomarkers, including amyloid-beta, phosphorylated tau, and neurofilament light, offer promising non-invasive alternatives for early AD detection and disease monitoring. This review synthesizes current research on these blood-based biomarkers, highlighting their potential to track AD pathology and enhance diagnostic accuracy. Furthermore, this review uniquely integrates recent findings on protein-protein interaction networks and microRNA pathways, exploring novel combinations of proteomic, genomic, and epigenomic biomarkers that provide new insights into AD's molecular mechanisms. Additionally, we discuss the integration of these biomarkers with advanced neuroimaging techniques, emphasizing their potential to revolutionize AD diagnostics. Although large-scale validation is still needed, these biomarkers represent a critical advancement toward more accessible, cost-effective, and early diagnostic tools for AD. [ABSTRACT FROM AUTHOR]

Background and objectives: This study evaluates the discriminative performance of the automated Lumipulse plasma pTau-217 compared to plasma pTau-181 and the Aβ42/Aβ40 ratio across cerebrospinal fluid (CSF) A/T classes and diagnostic groups within a memory-center-based population of cognitively impaired patients. Methods: This cross-sectional study in a Memory Center enrolled 98 patients along the AD continuum or affected by other neurodegenerative disorders, stratified by CSF A/T status and clinical syndrome. Plasma pTau-217, pTau-181, and Aβ42/Aβ40 were measured using Lumipulse. Relationships with CSF and glomerular filtration rate (GFR) were explored. ROC analysis was conducted to assess diagnostic performance. Results: The CSF A/T profiles included 49 A+/T+, 8 A+/T−, and 41 A−/T−. Clinical diagnoses at discharge were AD-dementia (AD-DEM), AD-MCI, NonAD-MCI, and NonAD-dementia (NonAD-DEM). Plasma pTau-217 and the pTau-217/Aβ42 ratio strongly correlated with CSF pTau-181 and total Tau (R = 0.80). GFR had minimal influence on plasma biomarker ratios. Plasma pTau-217 exhibited excellent AUC values (0.94–0.97) for distinguishing CSF A+/T+ and A+ status, showing higher discriminative accuracy than pTau-181 and Aβ42/Aβ40 (AUCs: 0.66–0.83). Optimal cutoff for plasma pTau-217 indicated excellent accuracy (93.3%), sensitivity (91.8%), and specificity (95.1%). AD-DEM patients displayed the highest pTau-217 levels, with significant differences across clinical groups. Discussion: The findings confirm that Lumipulse plasma pTau-217 offers superior diagnostic accuracy for reflecting CSF A/T status. Plasma pTau-217 emerged as an accurate standalone biomarker of AD neuropathology across MCI and dementia stages. The study underscores the utility of automated Lumipulse assays, promoting their integration into routine diagnostic workflows to facilitate early and accurate AD detection. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is frequently detected in late stages, which leads to limited therapeutic options and a dismal overall survival rate. To date, no robust method for the detection of early-stage PDAC that can be used for targeted screening approaches is available. Liquid biopsy allows the minimally invasive collection of body fluids (typically peripheral blood) and the subsequent analysis of circulating tumor cells or tumor-associated molecules such as nucleic acids, proteins, or metabolites that may be useful for the early diagnosis of PDAC. Single biomarkers may lack sensitivity and/or specificity to reliably detect PDAC, while combinations of these circulating biomarkers in multimarker panels may improve the sensitivity and specificity of blood test-based diagnosis. In this narrative review, we present an overview of different liquid biopsy biomarkers for the early diagnosis of PDAC and discuss the validity of multimarker panels. [ABSTRACT FROM AUTHOR]

To evaluate some confounding factors that influence the concentrations of S100 calcium binding protein B (S100B), glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L-1 (UCH-L1) in older individuals. Indeed, recent guidelines have proposed the combined use of S100B and the "GFAP-UCH-L1" mTBI test to rule out mild traumatic brain injuries (mTBI). As older adults are the most at risk of mTBI, it is particularly important to understand the confounding factors of those mTBI rule-out biomarkers in aging population. The protein S100B and the "GFAP and UCH-L1" mTBI test were measured using Liaison XL (Diasorin) and Alinity I (Abbott), respectively, in 330 and 341 individuals with non-suspected mTBI from the SarcoPhAge cohort. S100B, GFAP and UCH-L1 were all significantly correlated with renal function whereas alcohol consumption, Geriatric Depression Score (GDS), smoking habits and anticoagulant intake were not associated with any of these three biomarkers. Body mass index (BMI) and age were associated with GFAP and UCH-L1 expression while sex and mini-mental state examination (MMSE) were only associated with GFAP. According to the manufacturer's cut-offs for mTBI rule-out, only 5.5 % of participants were positive for S100B whereas 66.9 % were positive for the "GFAP-UCH-L1" mTBI test. All positive "GFAP-UCH-L1" mTBI tests were GFAP+/UCH-L1-. Among individuals with cystatin C>1.55 mg/L, 25 % were positive for S100B while 90 % were positive for the mTBI test. Our data show that confounding factors have different impacts on the positivity rate of the "GFAP-UCH-L1" mTBI test compared to S100B. [ABSTRACT FROM AUTHOR]

Abstract Pancreatic ductal adenocarcinoma (PDAC) is frequently detected in late stages, which leads to limited therapeutic options and a dismal overall survival rate. To date, no robust method for the detection of early-stage PDAC that can be used for targeted screening approaches is available. Liquid biopsy allows the minimally invasive collection of body fluids (typically peripheral blood) and the subsequent analysis of circulating tumor cells or tumor-associated molecules such as nucleic acids, proteins, or metabolites that may be useful for the early diagnosis of PDAC. Single biomarkers may lack sensitivity and/or specificity to reliably detect PDAC, while combinations of these circulating biomarkers in multimarker panels may improve the sensitivity and specificity of blood test-based diagnosis. In this narrative review, we present an overview of different liquid biopsy biomarkers for the early diagnosis of PDAC and discuss the validity of multimarker panels.

Abstract Background Alzheimer’s disease (AD) is a common, complex and multifactorial disease that may require screening across multiple routes of referral to enable early detection and subsequent future implementation of tailored interventions. Blood- and eye-based biomarkers show promise as low-cost, scalable and patient-friendly tools for early AD detection given their ability to provide information on AD pathophysiological changes and manifestations in the retina, respectively. Eye clinics provide an intriguing real-world proof-of-concept setting to evaluate the performance of these potential AD screening tools given the intricate connections between the eye and brain, presumed enrichment for AD pathology in the aging population with eye disorders, and the potential for an accelerated diagnostic pathway for under-recognized patient groups. Methods The BeyeOMARKER study is a prospective, observational, longitudinal cohort study aiming to include individuals visiting an eye-clinic. Inclusion criteria entail being ≥ 50 years old and having no prior dementia diagnosis. Excluded eye-conditions include traumatic insults, superficial inflammation, and conditions in surrounding structures of the eye that are not engaged in vision. The BeyeOMARKER cohort (n = 700) will undergo blood collection to assess plasma p-tau217 levels and a brief cognitive screening at the eye clinic. All participants will subsequently be invited for annual longitudinal follow-up including remotely administered cognitive screening and questionnaires. The BeyeOMARKER + cohort (n = 150), consisting of 100 plasma p-tau217 positive participants and 50 matched negative controls selected from the BeyeOMARKER cohort, will additionally undergo Aβ-PET and tau-PET, MRI, retinal imaging including hyperspectral imaging (primary), widefield imaging, optical coherence tomography (OCT) and OCT-Angiography (secondary), and cognitive and cortical vision assessments. Results We aim to implement the current protocol between April 2024 until March 2027. Primary outcomes include the performance of plasma p-tau217 and hyperspectral retinal imaging to detect AD pathology (using Aβ- and tau-PET visual read as reference standard) and to detect cognitive decline. Initial follow-up is ~ 2 years but may be extended with additional funding. Conclusions We envision that the BeyeOMARKER study will demonstrate the feasibility of early AD detection based on blood- and eye-based biomarkers in alternative screening settings, and will improve our understanding of the eye-brain connection. Trial registration The BeyeOMARKER study (Eudamed CIV ID: CIV-NL-23–09-044086; registration date: 19th of March 2024) is approved by the ethical review board of the Amsterdam UMC.

Abstract Alzheimer disease (AD) and Alzheimer Disease and Related Dementias (AD/ADRD) are growing public health challenges globally affecting millions of older adults, necessitating concerted efforts to advance our understanding and management of these conditions. AD is a progressive neurodegenerative disorder characterized pathologically by amyloid plaques and tau neurofibrillary tangles that are the primary cause of dementia in older individuals. Early and accurate diagnosis of AD dementia is crucial for effective intervention and treatment but has proven challenging to accomplish. Although testing for AD brain pathology with cerebrospinal fluid (CSF) or positron emission tomography (PET) has been available for over 2 decades, most patients never underwent this testing because of inaccessibility, high out‐of‐pocket costs, perceived risks, and the lack of AD‐specific treatments. However, in recent years, rapid progress has been made in developing blood biomarkers for AD/ADRD. Consequently, blood biomarkers have emerged as promising tools for non‐invasive and cost‐effective diagnosis, prognosis, and monitoring of AD progression. This review presents the evolving landscape of blood biomarkers in AD/ADRD and explores their potential applications in clinical practice for early detection, prognosis, and therapeutic interventions. It covers recent advances in blood biomarkers, including amyloid beta (Aβ) peptides, tau protein, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). It also discusses their diagnostic and prognostic utility while addressing associated challenges and limitations. Future research directions in this rapidly evolving field are also proposed.

Abstract Background Neuropsychiatric symptoms (NPS) are common in older people, may occur early in the development of dementia disorders, and have been associated with faster cognitive decline. Here, our objectives were to investigate whether plasma levels of neurofilament light chain (NfL), glial fibrillary acid protein (GFAP), and tau phosphorylated at threonine 181 (pTau181) are associated with current NPS and predict future NPS in non-demented older people. Furthermore, we tested whether the presence of NPS combined with plasma biomarkers are useful to predict Alzheimer’s disease (AD) pathology and cognitive decline. Methods One hundred and fifty-one participants with normal cognition (n = 76) or mild cognitive impairment (n = 75) were examined in a longitudinal brain aging study at the Memory Centers, University Hospital of Lausanne, Switzerland. Plasma levels of NfL, GFAP, and pTau181 along with CSF biomarkers of AD pathology were measured at baseline. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI-Q), along with the cognitive and functional performance at baseline and follow-up (mean: 20 months). Different regression and ROC analyses were used to address the associations of interest. Results None of the three plasma biomarker was associated with NPS at baseline. Higher GFAP levels were associated with the presence of NPS at follow-up (OR = 2.8, p = .002) and both, higher NfL and higher GFAP with an increase in the NPI-Q severity score over time (β = 0.25, p = .034 and β = 0.30, p = .013, respectively). Adding NPS and the plasma biomarkers to a reference model improved the prediction of future NPS (AUC 0.72 to 0.88, p = .002) and AD pathology (AUC 0.78 to 0.87, p = .010), but not of cognitive decline (AUC 0.79 to 0.85, p = .081). Conclusion Plasma NfL and GFAP are both associated with future NPS and NPS severity change. Considering the presence of NPS along with blood-based AD-biomarkers may improve the prediction of clinical progression of NPS over time and inform clinical decision-making in non-demented older people.

Abstract Background LRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinson’s disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological responses. The identification of factors that regulate LRRK2-mediated Rab10 phosphorylation in iPD, and whether phosphorylated-Rab10 levels change in different disease states, or with disease progression, may provide insights into the role of Rab10 phosphorylation in iPD and help guide therapeutic strategies targeting this pathway. Methods Capitalizing on past work demonstrating LRRK2 and phosphorylated-Rab10 interact on vesicles that can shed into biofluids, we developed and validated a high-throughput single-molecule array assay to measure extracellular pT73-Rab10. Ratios of pT73-Rab10 to total Rab10 measured in biobanked serum samples were compared between informative groups of transgenic mice, rats, and a deeply phenotyped cohort of iPD cases and controls. Multivariable and weighted correlation network analyses were used to identify genetic, transcriptomic, clinical, and demographic variables that predict the extracellular pT73-Rab10 to total Rab10 ratio. Results pT73-Rab10 is absent in serum from Lrrk2 knockout mice but elevated by LRRK2 and VPS35 mutations, as well as SNCA expression. Bone-marrow transplantation experiments in mice show that serum pT73-Rab10 levels derive primarily from circulating immune cells. The extracellular ratio of pT73-Rab10 to total Rab10 is dynamic, increasing with inflammation and rapidly decreasing with LRRK2 kinase inhibition. The ratio of pT73-Rab10 to total Rab10 is elevated in iPD patients with greater motor dysfunction, irrespective of disease duration, age, sex, or the usage of PD-related or anti-inflammatory medications. pT73-Rab10 to total Rab10 ratios are associated with neutrophil degranulation, antigenic responses, and suppressed platelet activation. Conclusions The extracellular serum ratio of pT73-Rab10 to total Rab10 is a novel pharmacodynamic biomarker for LRRK2-linked innate immune activation associated with disease severity in iPD. We propose that those iPD patients with higher serum pT73-Rab10 levels may benefit from LRRK2-targeting therapeutics that mitigate associated deleterious immunological responses.

Background: Alzheimer's disease (AD) is a common, complex and multifactorial disease that may require screening across multiple routes of referral to enable early detection and subsequent future implementation of tailored interventions. Blood- and eye-based biomarkers show promise as low-cost, scalable and patient-friendly tools for early AD detection given their ability to provide information on AD pathophysiological changes and manifestations in the retina, respectively. Eye clinics provide an intriguing real-world proof-of-concept setting to evaluate the performance of these potential AD screening tools given the intricate connections between the eye and brain, presumed enrichment for AD pathology in the aging population with eye disorders, and the potential for an accelerated diagnostic pathway for under-recognized patient groups. Methods: The BeyeOMARKER study is a prospective, observational, longitudinal cohort study aiming to include individuals visiting an eye-clinic. Inclusion criteria entail being ≥ 50 years old and having no prior dementia diagnosis. Excluded eye-conditions include traumatic insults, superficial inflammation, and conditions in surrounding structures of the eye that are not engaged in vision. The BeyeOMARKER cohort (n = 700) will undergo blood collection to assess plasma p-tau217 levels and a brief cognitive screening at the eye clinic. All participants will subsequently be invited for annual longitudinal follow-up including remotely administered cognitive screening and questionnaires. The BeyeOMARKER + cohort (n = 150), consisting of 100 plasma p-tau217 positive participants and 50 matched negative controls selected from the BeyeOMARKER cohort, will additionally undergo Aβ-PET and tau-PET, MRI, retinal imaging including hyperspectral imaging (primary), widefield imaging, optical coherence tomography (OCT) and OCT-Angiography (secondary), and cognitive and cortical vision assessments. Results: We aim to implement the current protocol between April 2024 until March 2027. Primary outcomes include the performance of plasma p-tau217 and hyperspectral retinal imaging to detect AD pathology (using Aβ- and tau-PET visual read as reference standard) and to detect cognitive decline. Initial follow-up is ~ 2 years but may be extended with additional funding. Conclusions: We envision that the BeyeOMARKER study will demonstrate the feasibility of early AD detection based on blood- and eye-based biomarkers in alternative screening settings, and will improve our understanding of the eye-brain connection. Trial registration: The BeyeOMARKER study (Eudamed CIV ID: CIV-NL-23–09-044086; registration date: 19th of March 2024) is approved by the ethical review board of the Amsterdam UMC. [ABSTRACT FROM AUTHOR]

BACKGROUND: This study investigated the potential of phosphorylated plasma Tau217 ratio (pTau217R) and plasma amyloid beta (Aβ) 42/Aβ40 in predicting brain amyloid levels measured by positron emission tomography (PET) Centiloid (CL) for Alzheimer's disease (AD) staging and screening. METHODS: Quantification of plasma pTau217R and Aβ42/Aβ40 employed immunoprecipitation‐mass spectrometry. CL prediction models were developed on a cohort of 904 cognitively unimpaired, preclinical and early AD subjects and validated on two independent cohorts. RESULTS: Models integrating pTau217R outperformed Aβ42/Aβ40 alone, predicting amyloid levels up to 89.1 CL. High area under the receiver operating characteristic curve (AUROC) values (89.3% to 94.7%) were observed across a broad CL range (15 to 90). Utilizing pTau217R‐based models for low amyloid levels reduced PET scans by 70.5% to 78.6%. DISCUSSION: pTau217R effectively predicts brain amyloid levels, surpassing cerebrospinal fluid Aβ42/Aβ40's range. Combining it with plasma Aβ42/Aβ40 enhances sensitivity for low amyloid detection, reducing unnecessary PET scans and expanding clinical utility. CLINICALTRIALS.GOV IDENTIFIERS: NCT02956486 (MissionAD1), NCT03036280 (MissionAD2), NCT04468659 (AHEAD3‐45), NCT03887455 (ClarityAD) Highlights: Phosphorylated plasma Tau217 ratio (pTau217R) effectively predicts amyloid‐PET Centiloid (CL) across a broad spectrum.Integrating pTau217R with Aβ42/Aβ40 extends the CL prediction upper limit to 89.1 CL.Combined model predicts amyloid status with high accuracy, especially in cognitively unimpaired individuals.This model identifies subjects above or below various CL thresholds with high accuracy.pTau217R‐based models significantly reduce PET scans by up to 78.6% for screening out individuals with no/low amyloid. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD) and Alzheimer Disease and Related Dementias (AD/ADRD) are growing public health challenges globally affecting millions of older adults, necessitating concerted efforts to advance our understanding and management of these conditions. AD is a progressive neurodegenerative disorder characterized pathologically by amyloid plaques and tau neurofibrillary tangles that are the primary cause of dementia in older individuals. Early and accurate diagnosis of AD dementia is crucial for effective intervention and treatment but has proven challenging to accomplish. Although testing for AD brain pathology with cerebrospinal fluid (CSF) or positron emission tomography (PET) has been available for over 2 decades, most patients never underwent this testing because of inaccessibility, high out‐of‐pocket costs, perceived risks, and the lack of AD‐specific treatments. However, in recent years, rapid progress has been made in developing blood biomarkers for AD/ADRD. Consequently, blood biomarkers have emerged as promising tools for non‐invasive and cost‐effective diagnosis, prognosis, and monitoring of AD progression. This review presents the evolving landscape of blood biomarkers in AD/ADRD and explores their potential applications in clinical practice for early detection, prognosis, and therapeutic interventions. It covers recent advances in blood biomarkers, including amyloid beta (Aβ) peptides, tau protein, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). It also discusses their diagnostic and prognostic utility while addressing associated challenges and limitations. Future research directions in this rapidly evolving field are also proposed. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) are common in older people, may occur early in the development of dementia disorders, and have been associated with faster cognitive decline. Here, our objectives were to investigate whether plasma levels of neurofilament light chain (NfL), glial fibrillary acid protein (GFAP), and tau phosphorylated at threonine 181 (pTau181) are associated with current NPS and predict future NPS in non-demented older people. Furthermore, we tested whether the presence of NPS combined with plasma biomarkers are useful to predict Alzheimer's disease (AD) pathology and cognitive decline. Methods: One hundred and fifty-one participants with normal cognition (n = 76) or mild cognitive impairment (n = 75) were examined in a longitudinal brain aging study at the Memory Centers, University Hospital of Lausanne, Switzerland. Plasma levels of NfL, GFAP, and pTau181 along with CSF biomarkers of AD pathology were measured at baseline. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI-Q), along with the cognitive and functional performance at baseline and follow-up (mean: 20 months). Different regression and ROC analyses were used to address the associations of interest. Results: None of the three plasma biomarker was associated with NPS at baseline. Higher GFAP levels were associated with the presence of NPS at follow-up (OR = 2.8, p =.002) and both, higher NfL and higher GFAP with an increase in the NPI-Q severity score over time (β = 0.25, p =.034 and β = 0.30, p =.013, respectively). Adding NPS and the plasma biomarkers to a reference model improved the prediction of future NPS (AUC 0.72 to 0.88, p =.002) and AD pathology (AUC 0.78 to 0.87, p =.010), but not of cognitive decline (AUC 0.79 to 0.85, p =.081). Conclusion: Plasma NfL and GFAP are both associated with future NPS and NPS severity change. Considering the presence of NPS along with blood-based AD-biomarkers may improve the prediction of clinical progression of NPS over time and inform clinical decision-making in non-demented older people. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck squamous cell carcinoma (HNSCC) remains a global health concern due to the lack of precise early diagnostic biomarkers and often-delayed diagnosis. This study employs machine learning, weighted gene co-expression network analysis, and network biology to identify transcriptomic markers for HNSCC detection. We identified nine genes with significantly differentially expressed activity in samples from HNSCC patients. These gene signatures could greatly improve early HNSCC identification and warrant further investigation to confirm their predictive and therapeutic significance. The transcriptional landscape of platelets in head and neck cancer patients revealed distinct gene expression profiles compared to healthy controls, underscoring the systemic impact of the tumor on blood platelets. Additionally, the study emphasizes the role of tumor-educated platelets (TEPs), which carry RNA signatures indicative of tumor-derived material, offering a non-invasive source for early-detection biomarkers. Although there has been a reduction in head and neck squamous cell carcinoma occurrence, it continues to be a serious global health concern. The lack of precise early diagnostic biomarkers and postponed diagnosis in the later stages are notable constraints that contribute to poor survival rates and emphasize the need for innovative diagnostic methods. In this study, we employed machine learning alongside weighted gene co-expression network analysis (WGCNA) and network biology to investigate the gene expression patterns of blood platelets, identifying transcriptomic markers for HNSCC diagnosis. Our comprehensive examination of publicly available gene expression datasets revealed nine genes with significantly elevated expression in samples from individuals diagnosed with HNSCC. These potential diagnostic markers were further assessed using TCGA and GTEx datasets, demonstrating high accuracy in distinguishing between HNSCC and non-cancerous samples. The findings indicate that these gene signatures could revolutionize early HNSCC identification. Additionally, the study highlights the significance of tumor-educated platelets (TEPs), which carry RNA signatures indicative of tumor-derived material, offering a non-invasive source for early-detection biomarkers. Despite using platelet and tumor samples from different individuals, our results suggest that TEPs reflect the transcriptomic and epigenetic landscape of tumors. Future research should aim to directly correlate tumor and platelet samples from the same patients to further elucidate this relationship. This study underscores the potential of these biomarkers in transforming early diagnosis and personalized treatment strategies for HNSCC, advocating for further research to validate their predictive and therapeutic potential. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Remote unsupervised cognitive assessments have the potential to complement and facilitate cognitive assessment in clinical and research settings. METHODS: Here, we evaluate the usability, validity, and reliability of unsupervised remote memory assessments via mobile devices in individuals without dementia from the Swedish BioFINDER‐2 study and explore their prognostic utility regarding future cognitive decline. RESULTS: Usability was rated positively; remote memory assessments showed good construct validity with traditional neuropsychological assessments and were significantly associated with tau‐positron emission tomography and downstream magnetic resonance imaging measures. Memory performance at baseline was associated with future cognitive decline and prediction of future cognitive decline was further improved by combining remote digital memory assessments with plasma p‐tau217. Finally, retest reliability was moderate for a single assessment and good for an aggregate of two sessions. DISCUSSION: Our results demonstrate that unsupervised digital memory assessments might be used for diagnosis and prognosis in Alzheimer's disease, potentially in combination with plasma biomarkers. Highlights: Remote and unsupervised digital memory assessments are feasible in older adults and individuals in early stages of Alzheimer's disease.Digital memory assessments are associated with neuropsychological in‐clinic assessments, tau‐positron emission tomography and magnetic resonance imaging measures.Combination of digital memory assessments with plasma p‐tau217 holds promise for prognosis of future cognitive decline.Future validation in further independent, larger, and more diverse cohorts is needed to inform clinical implementation. [ABSTRACT FROM AUTHOR]

Plasma pTau181, a marker of amyloid and tau burden, was evaluated as a prognostic predictor of clinical decline and Alzheimer's disease (AD) progression of amyloid‐positive (Aβ+) patients with mild cognitive impairment (MCI). The training cohort for constructing the Bayesian prediction models comprised 135 Aβ+ MCI clinical trial placebo subjects. Performance was evaluated in two validation cohorts. An 18‐month ≥1 increase in the Clinical Dementia Rating Sum of Boxes was the clinical decline criterion. Baseline plasma pTau181 concentration matched clinical assessments' prediction performance. Adding pTau181 to clinical assessments significantly improved the prediction of an 18‐month clinical decline and the 36‐month progression from Aβ+ MCI to AD. The area under the receiver operating characteristic curve for the latter increased from 71.8% to 79%, and the hazard ratio for time‐to‐progression improved from 2.26 to 3.11 (p < 0.0001). Baseline plasma pTau181 has the potential for identifying Aβ+ MCI subjects with faster clinical decline over time. Highlights: This study assessed pTau181 as a prognostic predictor of 18‐month clinical decline and extended progression to Alzheimer's disease (AD) in amyloid‐positive patients with mild cognitive impairment (Aβ+ MCI).The research findings underscore the promise of baseline plasma pTau181 as a screening tool for identifying Aβ+ MCI individuals with accelerated clinical decline within a standard 18‐month clinical trial period. The predictive accuracy is notably enhanced when combined with clinical assessments.Similar positive outcomes were noted in forecasting the extended progression of Aβ+ MCI subjects to AD. [ABSTRACT FROM AUTHOR]

Prediabetes, a pivotal phase in glucose metabolism between normalcy and diabetes, exerts a profound influence on the aging process and the risk of age-related diseases. This comprehensive review delves into the intricate web of blood-based biomarkers that collectively expedite senescence, marking the transition from a state of health to age-related complications. Key findings underscore the significance of diverse biomarkers, such as telomere length, p16INK4a, senescence-associated secretory phenotype (SASP) factors, DNA methylation clocks, advanced glycation end products (AGEs), inflammatory and oxidative stress markers, circulating hormones, and additional factors such as folate, B12, and osteocalcin. Not only do these biomarkers serve as indicators of senescence but they also actively fuel chronic inflammation, oxidative stress, and metabolic dysregulation, all of which contribute to accelerated aging. The implications of this understanding are profound, as prediabetes emerges as a critical period in an individual's life, influencing various physiological systems, including the vascular and neural systems, metabolic functions, hormonal regulation, and bone health. Recognizing the profound influence of prediabetes on senescence provides a foundation for personalized intervention strategies to mitigate age-related complications and promote healthy aging. Future research directions call for a more diverse array of biomarkers, the in-depth exploration of their roles, and the development of tailored precision medicine strategies to ensure a holistic understanding and effective management of prediabetes-induced senescence and its implications for aging. This knowledge has far-reaching implications for public health and clinical practice, emphasizing the need for early detection and intervention in prediabetic individuals to enhance the quality of life in an aging population with diverse needs. [ABSTRACT FROM AUTHOR]

Wilms tumor (WT) is a pediatric kidney cancer associated with poor outcomes in patients with unfavorable histological features such as anaplasia. Small non-coding RNAs, such as miRNAs, are known to be involved in WT pathogenesis. However, research on the clinical potential of blood-based miRNAs is limited. This study aimed to profile aberrantly expressed miRNAs in WT serum samples, evaluate their potential to differentiate standard-risk patients with favorable histology from those with anaplastic WTs, and assess their clinical value as minimally invasive biomarkers for WT detection. The study used next-generation sequencing (NGS) to analyze miRNA expressions in serum samples from 37 Egyptian children, including 10 healthy individuals, 14 with non-anaplastic WTs (favorable histology FH-WTs), and 13 with anaplastic WTs (unfavorable histology UnFH-WTs). Functional enrichment analysis was conducted to identify critical pathways and biological processes affected by dysregulated miRNAs, and a network was created for the most promising miRNA-target interactions linked to WT. The study identified a distinct miRNA expression signature of 45 miRNAs (3 upregulated and 42 downregulated) in WT serum samples compared to healthy controls, with 29 miRNAs exclusively dysregulated in FH-WTs and 6 miRNAs dysregulated solely in UnFH-WTs. These dysregulated miRNAs displayed significant enrichment in cancer-related pathways, such as PI3K/AKT, FOXO, and MAPK signaling. In relation to WT clinicopathological features, decreased levels of hsa-miR-2355-3p showed a significant positive correlation with clinical stage (r = 0.6597, p = 0.0006) and WT metastasis (r = 0.439, p = 0.021). The ROC curve analysis revealed that multiple dysregulated miRNAs in WT, specifically hsa-miR-7-5p, hsa-miR-146a-5p, hsa-miR-378a-3p, and hsa-miR-483-5p, exhibited high diagnostic potential for WT, with AUC values exceeding 0.86. Among WT histopathology types, the hsa-miR-1180-3p showed a 2.3 log2fold difference in expression between UnFH-WTs and FH-WTs, indicating its potential as a biomarker with 92% sensitivity and 85% specificity for identifying UnFH-WTs. Its target genes were enriched in pathways related to cell division and cell cycle regulation. In conclusion, hsa-miR-1180-3p could be a reliable blood-based biomarker for distinguishing WT histopathological types, and further research is needed to validate its clinical value.

Prediabetes, a pivotal phase in glucose metabolism between normalcy and diabetes, exerts a profound influence on the aging process and the risk of age-related diseases. This comprehensive review delves into the intricate web of blood-based biomarkers that collectively expedite senescence, marking the transition from a state of health to age-related complications. Key findings underscore the significance of diverse biomarkers, such as telomere length, p16INK4a, senescence-associated secretory phenotype (SASP) factors, DNA methylation clocks, advanced glycation end products (AGEs), inflammatory and oxidative stress markers, circulating hormones, and additional factors such as folate, B12, and osteocalcin. Not only do these biomarkers serve as indicators of senescence but they also actively fuel chronic inflammation, oxidative stress, and metabolic dysregulation, all of which contribute to accelerated aging. The implications of this understanding are profound, as prediabetes emerges as a critical period in an individual’s life, influencing various physiological systems, including the vascular and neural systems, metabolic functions, hormonal regulation, and bone health. Recognizing the profound influence of prediabetes on senescence provides a foundation for personalized intervention strategies to mitigate age-related complications and promote healthy aging. Future research directions call for a more diverse array of biomarkers, the in-depth exploration of their roles, and the development of tailored precision medicine strategies to ensure a holistic understanding and effective management of prediabetes-induced senescence and its implications for aging. This knowledge has far-reaching implications for public health and clinical practice, emphasizing the need for early detection and intervention in prediabetic individuals to enhance the quality of life in an aging population with diverse needs.

Abstract Background Plasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations. Methods We examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61–73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter. Results After adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals. Conclusions These results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.

Abstract Background Epigenetic Scores (EpiScores) for blood protein levels have been associated with disease outcomes and measures of brain health, highlighting their potential usefulness as clinical biomarkers. They are typically derived via penalised regression, whereby a linear weighted sum of DNA methylation (DNAm) levels at CpG sites are predictive of protein levels. Here, we examine 84 previously published protein EpiScores as possible biomarkers of cross-sectional and longitudinal measures of general cognitive function and brain health, and incident dementia across three independent cohorts. Results Using 84 protein EpiScores as candidate biomarkers, associations with general cognitive function (both cross-sectionally and longitudinally) were tested in three independent cohorts: Generation Scotland (GS), and the Lothian Birth Cohorts of 1921 and 1936 (LBC1921 and LBC1936, respectively). A meta-analysis of general cognitive functioning results in all three cohorts identified 18 EpiScore associations (absolute meta-analytic standardised estimates ranged from 0.03 to 0.14, median of 0.04, P FDR

Blood-based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work-up of Alzheimer's disease (AD), as well as to improve the design of interventional trials. Here we discuss in detail further research needed to be performed before widespread use of BBMs. We already now recommend use of BBMs as (pre-)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease-modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work-up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand-alone diagnostic AD markers, or before considering use in primary care.

Recent technological advances have improved the sensitivity and specificity of blood-based biomarkers for Alzheimer's disease and related dementias. Accurate quantification of amyloid-ß peptide, phosphorylated tau (pTau) isoforms, as well as markers of neurodegeneration (neurofilament light chain [NfL]) and neuro-immune activation (glial fibrillary acidic protein [GFAP] and chitinase-3-like protein 1 [YKL-40]) in blood has allowed researchers to characterize neurobiological processes at scale in a cost-effective and minimally invasive manner. Although currently used primarily for research purposes, these blood-based biomarkers have the potential to be highly impactful in the clinical setting – aiding in diagnosis, predicting disease risk, and monitoring disease progression. Whereas plasma NfL has shown promise as a non-specific marker of neuronal injury, plasma pTau181, pTau217, pTau231, and GFAP have demonstrated desirable levels of sensitivity and specificity for identification of individuals with Alzheimer's disease pathology and Alzheimer's dementia. In this forward looking review, we (i) provide an overview of the most commonly used blood-based biomarkers for Alzheimer's disease and related dementias, (ii) discuss how comorbid medical conditions, demographic, and genetic factors can inform the interpretation of these biomarkers, (iii) describe ongoing efforts to move blood-based biomarkers into the clinic, and (iv) highlight the central role that clinical neuropsychologists may play in contextualizing and communicating blood-based biomarker results for patients. [ABSTRACT FROM AUTHOR]

Background: Amyloid-β (Aβ) plaques play a pivotal role in Alzheimer's disease. The current positron emission tomography (PET) is expensive and limited in availability. In contrast, blood-based biomarkers (BBBMs) show potential for characterizing Aβ plaques more affordably. We have previously proposed an MRI-based hippocampal morphometry measure to be an indicator of Aβ plaques. Objective: To develop and validate an integrated model to predict brain amyloid PET positivity combining MRI feature and plasma Aβ42/40 ratio. Methods: We extracted hippocampal multivariate morphometry statistics from MR images and together with plasma Aβ42/40 trained a random forest classifier to perform a binary classification of participant brain amyloid PET positivity. We evaluated the model performance using two distinct cohorts, one from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the other from the Banner Alzheimer's Institute (BAI), including prediction accuracy, precision, recall rate, F1 score, and AUC score. Results: Results from ADNI (mean age 72.6, Aβ+ rate 49.5%) and BAI (mean age 66.2, Aβ+ rate 36.9%) datasets revealed the integrated multimodal (IMM) model's superior performance over unimodal models. The IMM model achieved prediction accuracies of 0.86 in ADNI and 0.92 in BAI, surpassing unimodal models based solely on structural MRI (0.81 and 0.87) or plasma Aβ42/40 (0.73 and 0.81) predictors. CONCLUSIONS: Our IMM model, combining MRI and BBBM data, offers a highly accurate approach to predict brain amyloid PET positivity. This innovative multiplex biomarker strategy presents an accessible and cost-effective avenue for advancing Alzheimer's disease diagnostics, leveraging diverse pathologic features related to Aβ plaques and structural MRI. [ABSTRACT FROM AUTHOR]

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Background: Epigenetic Scores (EpiScores) for blood protein levels have been associated with disease outcomes and measures of brain health, highlighting their potential usefulness as clinical biomarkers. They are typically derived via penalised regression, whereby a linear weighted sum of DNA methylation (DNAm) levels at CpG sites are predictive of protein levels. Here, we examine 84 previously published protein EpiScores as possible biomarkers of cross-sectional and longitudinal measures of general cognitive function and brain health, and incident dementia across three independent cohorts. Results: Using 84 protein EpiScores as candidate biomarkers, associations with general cognitive function (both cross-sectionally and longitudinally) were tested in three independent cohorts: Generation Scotland (GS), and the Lothian Birth Cohorts of 1921 and 1936 (LBC1921 and LBC1936, respectively). A meta-analysis of general cognitive functioning results in all three cohorts identified 18 EpiScore associations (absolute meta-analytic standardised estimates ranged from 0.03 to 0.14, median of 0.04, PFDR < 0.05). Several associations were also observed between EpiScores and global brain volumetric measures in the LBC1936. An EpiScore for the S100A9 protein (a known Alzheimer disease biomarker) was associated with general cognitive functioning (meta-analytic standardised beta: − 0.06, P = 1.3 × 10−9), and with time-to-dementia in GS (Hazard ratio 1.24, 95% confidence interval 1.08–1.44, P = 0.003), but not in LBC1936 (Hazard ratio 1.11, P = 0.32). Conclusions: EpiScores might make a contribution to the risk profile of poor general cognitive function and global brain health, and risk of dementia, however these scores require replication in further studies. [ABSTRACT FROM AUTHOR]

Abstract Plasma pTau181, a marker of amyloid and tau burden, was evaluated as a prognostic predictor of clinical decline and Alzheimer's disease (AD) progression of amyloid‐positive (Aβ+) patients with mild cognitive impairment (MCI). The training cohort for constructing the Bayesian prediction models comprised 135 Aβ+ MCI clinical trial placebo subjects. Performance was evaluated in two validation cohorts. An 18‐month ≥1 increase in the Clinical Dementia Rating Sum of Boxes was the clinical decline criterion. Baseline plasma pTau181 concentration matched clinical assessments’ prediction performance. Adding pTau181 to clinical assessments significantly improved the prediction of an 18‐month clinical decline and the 36‐month progression from Aβ+ MCI to AD. The area under the receiver operating characteristic curve for the latter increased from 71.8% to 79%, and the hazard ratio for time‐to‐progression improved from 2.26 to 3.11 (p

Molecular biomarkers require the reproducible capture of disease-associated changes and are ideally sensitive, specific and accessible with minimal invasiveness to patients. Exosomes are a subtype of extracellular vesicles that have gained attention as potential biomarkers. They are released by all cell types and carry molecular cargo that reflects the functional state of the cells of origin. These characteristics make them an attractive means of measuring disease-related processes within the central nervous system (CNS), as they cross the blood–brain barrier (BBB) and can be captured in peripheral blood. In this review, we discuss recent progress made toward identifying blood-based protein and RNA biomarkers of several neurodegenerative diseases from circulating, CNS cell-derived exosomes. Given the lack of standardized methodology for exosome isolation and characterization, we discuss the challenges of capturing and quantifying the molecular content of exosome populations from blood for translation to clinical use.

Abstract Introduction Pre-analytical factors can cause substantial variability in the measurements of cerebrospinal fluid (CSF) and plasma biomarkers of Alzheimer’s disease (AD). However, their effects on the performance of one of the most promising plasma AD biomarkers, phosphorylated tau (p-tau)217, are not known. Methods We included 50 amyloid-β positive (Aβ+) and 50 Aβ− participants from the Swedish BioFINDER-1 study. Plasma and CSF p-tau217 were measured using an immunoassay developed by Lilly Research Laboratories. We examined the effect of four plasma handling conditions, i.e., (1) thawing at room temperature (RT) with no centrifugation, (2) thawing at RT followed by centrifugation, (3) thawing on ice with no centrifugation, and (4) thawing on ice followed by centrifugation. In addition, we also tested the effects of up to 3 freeze–thaw cycles on the associations of plasma p-tau217 with AD-related pathologies measured with CSF p-tau217 and CSF Aβ42/Aβ40. Results In the whole cohort (combining Aβ+ and Aβ− participants), we found significant correlations between plasma p-tau217 and both CSF p-tau217 (R range, 0.614–0.717, p 0.11). P-tau217 concentration was consistently higher in non-centrifuged samples than in centrifuged samples (p ≤ 0.021). There were no differences between samples freeze-thawed once, twice, or three times. Conclusion Centrifugation improved the performance of plasma p-tau217, but thawing temperatures and up to three freeze–thaw cycles did not have a significant impact. These results may inform the future development of standardized sample-handling protocols for AD biomarkers.

Introduction: Pre-analytical factors can cause substantial variability in the measurements of cerebrospinal fluid (CSF) and plasma biomarkers of Alzheimer's disease (AD). However, their effects on the performance of one of the most promising plasma AD biomarkers, phosphorylated tau (p-tau)217, are not known. Methods: We included 50 amyloid-β positive (Aβ+) and 50 Aβ− participants from the Swedish BioFINDER-1 study. Plasma and CSF p-tau217 were measured using an immunoassay developed by Lilly Research Laboratories. We examined the effect of four plasma handling conditions, i.e., (1) thawing at room temperature (RT) with no centrifugation, (2) thawing at RT followed by centrifugation, (3) thawing on ice with no centrifugation, and (4) thawing on ice followed by centrifugation. In addition, we also tested the effects of up to 3 freeze–thaw cycles on the associations of plasma p-tau217 with AD-related pathologies measured with CSF p-tau217 and CSF Aβ42/Aβ40. Results: In the whole cohort (combining Aβ+ and Aβ− participants), we found significant correlations between plasma p-tau217 and both CSF p-tau217 (Rrange, 0.614–0.717, p < 0.001) and CSF Aβ42/Aβ40 (Spearman Rrange, − 0.515 to − 0.652, p < 0.001) for each of the four tested conditions. Correlations between plasma and CSF p-tau217 were also significant for all conditions in the Aβ+ group (Rrange, 0.506–0.579, p < 0.001). However, in this Aβ+ subgroup, correlations with CSF Aβ42/Aβ40 were only significant for centrifuged samples (thawed at RT, R = − 0.394, p = 0.010; thawed on ice, R = − 0.406; p = 0.007). In Aβ− participants, correlations between plasma and CSF p-tau217 were again significant only for centrifuged samples (thawed at RT, R = 0.394, p = 0.007; thawed on ice, R = 0.334; p = 0.022), with no correlations seen between plasma p-tau217 and CSF Aβ42/Aβ40 for any of the conditions. While the accuracy of plasma p-tau217 to identify individuals with abnormal CSF Aβ42/Aβ40 or CSF p-tau217 status was high, the AUCs for samples thawed at RT and analyzed without centrifugation were numerically lower than the AUCs of other conditions (CSF Aβ42/Aβ40 = 0.845 vs 0.872–0.884; CSF p-tau217 = 0.866 vs 0.908–0.924, pdiff > 0.11). P-tau217 concentration was consistently higher in non-centrifuged samples than in centrifuged samples (p ≤ 0.021). There were no differences between samples freeze-thawed once, twice, or three times. Conclusion: Centrifugation improved the performance of plasma p-tau217, but thawing temperatures and up to three freeze–thaw cycles did not have a significant impact. These results may inform the future development of standardized sample-handling protocols for AD biomarkers. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD), the most common cause of dementia, poses a significant global burden. Diagnosis typically involves invasive and costly methods like neuroimaging or cerebrospinal fluid (CSF) biomarker testing of phosphorylated tau (p-tau) and amyloid-β42/40 (Aβ42/40). Such procedures are especially impractical in resource-constrained regions, such as the Democratic Republic of Congo (DRC). Blood-based biomarker testing may provide a more accessible screening opportunity. Objective: This study aims to examine if AD-related blood-based biomarkers are associated with cognitive test performance in the Congolese population, where limited research has been conducted. Methods: In this cross-sectional study of 81 Congolese individuals, cognitive assessments (Alzheimer's Questionnaire (AQ) and Community Screening Interview for Dementia (CSID)) distinguished dementia cases from controls. Blood draws were taken to assess p-tau 181 and Aβ42/40 biomarkers. Relationships between the biomarkers and cognitive performance were analyzed using multiple linear regression models. Results: Lower plasma Aβ42/40 was significantly associated with lower CSID scores and higher AQ scores, indicative of AD (p < 0.001). These relationships were observed in healthy controls (CSID p = 0.01, AQ p = 0.03), but not in dementia cases. However, p-tau 181 did not exhibit significant associations with either measure. Factors such as age, sex, education, presence of APOEɛ4 allele, did not alter these relationships. Conclusions: Understanding relationships between AD-related screening tests and blood biomarkers is a step towards utilization of blood-based biomarker tests as a screening tool for AD, especially in resource-limited regions. Further research should be conducted to evaluate blood biomarker test efficacy in larger samples and other populations. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Incorporating blood‐based Alzheimer's disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve screening efficiency. METHODS: Plasma Aβ, phosphorylated tau (p‐tau)181, and p‐tau217 concentration levels from AHEAD 3–45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter‐individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. RESULTS: The area under the receiver operating curve (AUC) was 0.87 for Aβ42/Aβ40, 0.74 for phosphorylated variant p‐tau181 ratio (p‐tau181/np‐tau181), and 0.92 for phosphorylated variant p‐tau217 ratio (p‐tau217/np‐tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p‐tau217/np‐tau217, Aβ42/Aβ40, age, and apolipoprotein E improved AUC to 0.95. DISCUSSION: Including plasma p‐tau217/np‐tau217 along with Aβ42/Aβ40 in predictive algorithms may streamline screening preclinical individuals into anti‐amyloid clinical trials. ClinicalTrials.gov Identifier: NCT04468659 Highlights: The addition of plasma phosphorylated variant p‐tau217 ratio (p‐tau217/np‐tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity.Prediction performance at higher NAV Centiloid levels was improved with p‐tau217/np‐tau217.All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use. [ABSTRACT FROM AUTHOR]

Objective: To evaluate blood‐based biomarkers to detect endometriosis and/or adenomyosis across nine European centers (June 2014–April 2018). Methods: This prospective, non‐interventional study assessed the diagnostic accuracy of 54 blood‐based biomarker immunoassays in samples from 919 women (aged 18–45 years) with suspicion of endometriosis and/or adenomyosis versus symptomatic controls. Endometriosis was stratified by revised American Society for Reproductive Medicine stage. Symptomatic controls were "pathologic symptomatic controls" or "pathology‐free symptomatic controls". The main outcome measure was receiver operating characteristic‐area under the curve (ROC‐AUC) and Wilcoxon P values corrected for multiple testing (q values). Results: CA‐125 performed best in "all endometriosis cases" versus "all symptomatic controls" (AUC 0.645, 95% confidence interval [CI] 0.600–0.690, q < 0.001) and increased (P < 0.001) with disease stage. In "all endometriosis cases" versus "pathology‐free symptomatic controls", S100‐A12 performed best (AUC 0.692, 95% CI 0.614–0.769, q = 0.001) followed by CA‐125 (AUC 0.649, 95% CI 0.569–0.729, q = 0.021). In "adenomyosis only cases" versus "symptomatic controls" or "pathology‐free symptomatic controls", respectively, the top‐performing biomarkers were sFRP‐4 (AUC 0.615, 95% CI 0.551–0.678, q = 0.045) and S100‐A12 (AUC 0.701, 95% CI 0.611–0.792, q = 0.004). Conclusion: This study concluded that no biomarkers tested could diagnose or rule out endometriosis/adenomyosis with high certainty. Synopsis: None of the biomarkers or biomarker combinations studied could diagnose or rule out endometriosis/adenomyosis with a high level of certainty. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We aimed to evaluate informal caregivers' attitudes toward undergoing and future implementation of blood‐based biomarkers (BBBM) testing for Alzheimer's disease (AD). METHODS: We explored caregivers' perspectives, by combining an online survey (n = 107) with a subsequent focus group (n = 7). We used descriptive statistics and thematic content analysis to identify common themes in answers to open‐ended survey questions and focus group data. RESULTS: Most caregivers (72.0%) favored BBBM for AD diagnosis. Provided with hypothetical scenarios, confidence in a normal result decreased significantly if experienced symptoms were more severe (mild: 78.5% vs. severe: 48.6%). Caregivers' attitudes toward BBBM for screening purposes significantly improved with prospect of treatment (53.3% vs. 92.5%). Concerns toward BBBM testing included treatment unavailability, increased/prolonged distress, and AD‐related stigma. Potential benefits were actionability, explanation for symptoms, and opportunities for better care and future treatment. DISCUSSION: Emerging AD treatment and reduction of AD‐related stigma could profoundly increase public interest in BBBM testing for AD. Highlights: Most informal caregivers would want blood‐based biomarker (BBBM) testing for Alzheimer's disease (AD) diagnosis.Perceived (dis)advantages were related to diagnosing AD early.With severe symptoms, there was less confidence in normal BBBM results.Treatment availability would significantly increase interest in BBBM testing for AD.Informal caregivers showed uncertainty regarding the meaning of the term "AD." [ABSTRACT FROM AUTHOR]

INTRODUCTION: Circulating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia‐specific mortality, have not been investigated. METHODS: We associated serum NfL, GFAP, total tau ,and ubiquitin carboxyl‐terminal hydrolase‐L1, measured in 1712 dementia‐free adults, with 19‐year incident dementia and dementia‐specific mortality risk, and with 3‐year cognitive decline. RESULTS: In adjusted models, being in the highest versus lowest tertile of NfL or GFAP associated with a hazard ratio (HR) of 1.49 (1.20–1.84) and 1.38 (1.15–1.66) for incident dementia, and 2.87 (1.79–4.61) and 2.76 (1.73–4.40) for dementia‐specific mortality. Joint third versus first tertile exposure further increased risk; HR = 2.06 (1.60–2.67) and 9.22 (4.48–18.9). NfL was independently associated with accelerated cognitive decline. DISCUSSION: Circulating NfL and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease (AD) blood tests are likely to become increasingly important in clinical practice, but they need to be evaluated in diverse groups before use in the general population. METHODS: This study enrolled a community‐based sample of older adults in the St. Louis, Missouri, USA area. Participants completed a blood draw, Eight‐Item Informant Interview to Differentiate Aging and Dementia (AD8®), Montreal Cognitive Assessment (MoCA), and survey about their perceptions of the blood test. A subset of participants completed additional blood collection, amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), and Clinical Dementia Rating (CDR®). RESULTS: Of the 859 participants enrolled in this ongoing study, 20.6% self‐identified as Black or African American. The AD8 and MoCA correlated moderately with the CDR. The blood test was well accepted by the cohort, but it was perceived more positively by White and highly educated individuals. DISCUSSION: Studying an AD blood test in a diverse population is feasible and may accelerate accurate diagnosis and implementation of effective treatments. Highlights: A diverse group of older adults was recruited to evaluate a blood amyloid test.The enrollment rate was high and the blood test was well accepted by participants.Cognitive impairment screens have moderate performance in a diverse population.Alzheimer's disease blood tests are likely to be feasible for use in real‐world settings. [ABSTRACT FROM AUTHOR]

Abstract Background Development of in vivo biomarkers has shifted the diagnosis of Alzheimer’s disease (AD) from the later dementia stages of disease towards the earlier stages and has introduced the potential for pre-symptomatic diagnosis. The International Working Group recommends that AD diagnosis is restricted in the clinical setting to people with specific AD phenotypes and supportive biomarker findings. Main body In this review, we discuss the phenotypic presentation and use of biomarkers for the early diagnosis of typical and atypical AD and describe how this can support clinical decision making, benefit patient communication, and improve the patient journey. Early diagnosis is essential to optimize the benefits of available and emerging treatments. As atypical presentations of AD often mimic other dementias, differential diagnosis can be challenging and can be facilitated using AD biomarkers. However, AD biomarkers alone are not sufficient to confidently diagnose AD or predict disease progression and should be supplementary to clinical assessment to help inform the diagnosis of AD. Conclusions Use of AD biomarkers with incorporation of atypical AD phenotypes into diagnostic criteria will allow earlier diagnosis of patients with atypical clinical presentations that otherwise would have been misdiagnosed and treated inappropriately. Early diagnosis is essential to guide informed discussion, appropriate care and support, and individualized treatment. It is hoped that disease-modifying treatments will impact the underlying AD pathology; thus, determining the patient’s AD phenotype will be a critical factor in guiding the therapeutic approach and the assessment of the effects of interventions.

Many tools of clinical medicine, such as clinical chemistry and diagnostic imaging, are prioritized for clinical diagnosis over post mortem diagnosis. Indeed, it is reasonable that the assessment of a patient’s functional status should take priority over the post mortem, cross-sectional use of diagnostic tests and laboratory equipment. In addition, these tools are sometimes expensive, and their use does not always have a reasonable cost–benefit ratio. However, some post mortem observations, such as inflammation, pulmonary edema, or infiltration and cerebral swelling, cannot be explained without using immunohistochemical markers for post mortem diagnosis. Introducing blood-based biomarkers into post mortem care could significantly reduce the rates of inconclusive post mortems and discrepancies in autopsy findings and clinical diagnoses. This is particularly relevant in relation to vascular pathology, considering the significant burden that vascular diseases represent for overall mortality. Expanding traditional autopsies with blood-based (circulating) biomarkers to avoid invasive post mortem examination would have cultural, religious, and potentially economic advantages. All of the target molecules were discussed in the context of the processes they up-regulate or down-regulate, which turned out to be the final cause of death. Ultimately, it is evident that further studies are needed to provide concrete validation for using a combination of markers for each case to reach a post mortem diagnosis with or without clinical records.

Objective: Stroke and transient ischemic attack may have long-term negative effects on the blood-brain barrier (BBB) and promote endothelial inflammation, both of which could increase neurodegeneration and dementia risk beyond the cell death associated with the index event. Methods: Serum from 88 postmortem subjects in the Arizona Study of Aging and Neurodegenerative Disorders were analyzed by sandwich ELISA for specific biomarkers to investigate the effects of cerebrovascular accidents (CVAs) on BBB integrity and endothelial activation. Statistical analyses were performed using the Mann-Whitney U Test, Spearman rank correlation, and linear/logistic regressions adjusted for potential confounders; a P-value < .05 was considered significant for all analyses. Results: Serum PDGFRẞ, a putative biomarker of BBB injury, was significantly increased in subjects with vs without a history of CVA who had similar cardiovascular risk factors (P < .01). This difference was stable after adjusting for age, hypertension, and other potential confounders in regression analysis (odds ratio, 27.02; 95% confidence interval, 2.61-411.7; P < .01). In addition, PDGFRẞ was positively associated with VCAM-1, a biomarker of endothelial inflammation (ρ = 0.42; P < .01). Conclusions: Our data suggest that patients with stroke or transient ischemic attack have lasting changes in the BBB. Still more, this demonstrates the utility of PDGFRẞ as a serum-based biomarker of BBB physiology, a potentially powerful tool in studying the role of the BBB in various neurodegenerative diseases and COVID infection sequelae. Clinical Relevance: Our data demonstrate the utility of serum PDGFRẞ, a putative biomarker of BBB integrity in the setting of stroke and TIA (CVA). A serum biomarker of BBB integrity could be a useful tool to detect early BBB damage and allow prospective work to study how such damage affects long-term neurodegenerative risk. Since BBB disruption occurs early in ADRD development, it could be monitored to help better understand disease progression and involvement of vascular pathways in ADRD.

Abstract INTRODUCTION We aimed to evaluate informal caregivers’ attitudes toward undergoing and future implementation of blood‐based biomarkers (BBBM) testing for Alzheimer's disease (AD). METHODS We explored caregivers’ perspectives, by combining an online survey (n = 107) with a subsequent focus group (n = 7). We used descriptive statistics and thematic content analysis to identify common themes in answers to open‐ended survey questions and focus group data. RESULTS Most caregivers (72.0%) favored BBBM for AD diagnosis. Provided with hypothetical scenarios, confidence in a normal result decreased significantly if experienced symptoms were more severe (mild: 78.5% vs. severe: 48.6%). Caregivers’ attitudes toward BBBM for screening purposes significantly improved with prospect of treatment (53.3% vs. 92.5%). Concerns toward BBBM testing included treatment unavailability, increased/prolonged distress, and AD‐related stigma. Potential benefits were actionability, explanation for symptoms, and opportunities for better care and future treatment. DISCUSSION Emerging AD treatment and reduction of AD‐related stigma could profoundly increase public interest in BBBM testing for AD. Highlights Most informal caregivers would want blood‐based biomarker (BBBM) testing for Alzheimer's disease (AD) diagnosis. Perceived (dis)advantages were related to diagnosing AD early. With severe symptoms, there was less confidence in normal BBBM results. Treatment availability would significantly increase interest in BBBM testing for AD. Informal caregivers showed uncertainty regarding the meaning of the term “AD.”

Background: Development of in vivo biomarkers has shifted the diagnosis of Alzheimer's disease (AD) from the later dementia stages of disease towards the earlier stages and has introduced the potential for pre-symptomatic diagnosis. The International Working Group recommends that AD diagnosis is restricted in the clinical setting to people with specific AD phenotypes and supportive biomarker findings. Main body: In this review, we discuss the phenotypic presentation and use of biomarkers for the early diagnosis of typical and atypical AD and describe how this can support clinical decision making, benefit patient communication, and improve the patient journey. Early diagnosis is essential to optimize the benefits of available and emerging treatments. As atypical presentations of AD often mimic other dementias, differential diagnosis can be challenging and can be facilitated using AD biomarkers. However, AD biomarkers alone are not sufficient to confidently diagnose AD or predict disease progression and should be supplementary to clinical assessment to help inform the diagnosis of AD. Conclusions: Use of AD biomarkers with incorporation of atypical AD phenotypes into diagnostic criteria will allow earlier diagnosis of patients with atypical clinical presentations that otherwise would have been misdiagnosed and treated inappropriately. Early diagnosis is essential to guide informed discussion, appropriate care and support, and individualized treatment. It is hoped that disease-modifying treatments will impact the underlying AD pathology; thus, determining the patient's AD phenotype will be a critical factor in guiding the therapeutic approach and the assessment of the effects of interventions. [ABSTRACT FROM AUTHOR]