Knowledge of the chemical composition of amyloid plaques and tau tangles at the earlier stages of Alzheimer’s disease (AD) pathology is sparse. This is due to limited access to human brain during life and at the earlier stages of AD pathophysiology and technical limitations in quantifying amyloid and tau species at a subcellular level. Understanding the chemical composition of plaques and tangles, how rapidly they grow and what factors drive growth is important for developing and refining therapeutics. We access in vivo cortical brain biopsy samples from individuals undergoing surgery, aiming to provide detailed characterisation of pathology with spatial and temporal resolution. We collected in vivo brain biopsies with matched ventricular and lumbar cerebrospinal fluid samples from individuals with suspected Normal Pressure Hydrocephalus (NPH) undergoing ventriculoperitoneal shunt surgery. All participants were labelled with intravenous 13 C 6 Leucine as per Stable Isotope Labelling Kinetics protocol. We used immunohistochemistry, immunoprecipitation-mass spectrometry (IP-MS) and Matrix Assisted Laser Desorption Ionization (MALDI) mass spectrometry-based imaging (MSI) to characterise amyloid and tau and their common post-translational modifications. We calculate the tracer-to-tracee ratio of labelled to unlabelled amyloid and tau to determine rate of pathological accumulation of these proteins. Using a 2-compartment model we establish the half-life of tau in brain tissue. We collected cortical brain biopsies from individuals with suspected NPH (n = 6), labelled between 4.25 hours to 133 days prior to surgery; 4 out of 6 individuals had amyloid plaques (range 1-25 plaques/mm2). These individuals had mild cognitive impairment. Cored plaques showed characteristic localization of Aβ1-40 and Aβ 3pE-40 in the core while x-42 species including 1-42, 4-42 and 3pE-42 showed a more homogenous distribution across both plaque core and diffuse/immature plaque periphery (Figure 1, 2). We did not detect incorporation of labelled amyloid in any subject using IP-MS or MALDI. We detected labelled tau in brain homogenate as early as 4.25 hours after label administration. The half-life of tau in human brain was calculated to be 26.85 days. Our study provides the first detailed chemical characterisation of AD pathology in living human brain giving insights into plaque composition, age and tau dynamics.

Cognitive disorders are a growing cause of morbidity and mortality worldwide. Diagnostic approaches to improve early diagnosis of cognitive disorders are constantly being sought. The pathogenesis of cognitive impairment is multifactorial and complex. It is believed that microglial activation and synaptic disturbance are crucial mechanisms leading to disease progression thus study of the interrelationships of the proteins involved in these processes appears to be important. Chemokine CX3CL1 seems to play a pivotal role in the central nervous system and it is involved in microglia-neuron communication, neuronal survival, synaptic plasticity, as well as neuronal excitability. Findings from preclinical studies on AD models have reported the crucial role of CX3CL1 in microglial activation, regulation of plaque load, and cognition. Neurogranin is considered, as a biomarker of early synaptic dysfunction in AD. Additionally, it may serve as a marker to predict disease progression. Therefore, we aimed to investigate and compare CX3CL1 and neurogranin (Ng) levels in CSF patients with mild cognitive decline (MCI) and cognitively normal subjects from the control group. We also assessed an association between CSF concentrations of CX3CL1, Ng, and neurochemical dementia biomarkers. The concentrations of CX3CL1, neurogranin as well as neurochemical dementia biomarkers, including amyloid beta 1-42 (Aß-42), amyloid beta 1-40, Tau, as well as pTau181 were measured in cerebrospinal fluid patients with mild cognitive impairment and individuals without cognitive decline by multiplexing and enzyme-linked immunosorbent techniques. Significantly higher CSF concentrations of CX3CL1 and neurogranin were found in MCI patients in comparison to subjects without cognitive decline. Furthermore, in the group of patients with MCI the CSF levels of CX3CL1 and Ng significantly correlated with Aβ-42, and pTau181 proteins. Similarly, a significant association between neurogranin and Tau protein was observed. Additionally, a positive correlation between CSF levels of Ng and CX3XL1 was noticed. Our findings indicate that both proteins CX3CL1, as well as neurogranin, could be applied as complementary early biomarkers for more accurate diagnosing and stratification of patients with cognitive decline.

Understanding how amyloid beta (Aβ) plaques form and progress to neurotoxicity in Alzheimer’s disease remains a significant challenge. This study aims to elucidate the processes involved in Aβ plaque formation and maturation using a knock-in Aβ mouse model (AppNL- F/NL-F). By employing mass spectrometry imaging and stable isotope labeling, we timestamped Aβ plaques from their initial deposition, enabling the spatial tracking of plaque aging. Correlating single-plaque spatial transcriptomics with time since seeding, allowed us to track gene-expression changes specifically associated with plaque age, independent of chronological age of the mouse or disease severity. We found that plaque age, within sections from individual mice aged from 10 to 18 months, negatively correlates with synaptic gene expression. Further, correlation with hyperspectral confocal microscopy using structure-specific dyes revealed a positive link between plaque age and structural maturity, with older plaques identified as more compact and associated with significantly greater synapse loss and toxicity.

In the context of Alzheimer's disease (AD), blood-based biomarkers have become increasingly important for various clinical purposes, such as screening patients and tracking the progression of the disease. Tau is a protein that stabilizes microtubules in nerve cells. In AD, different isoforms of tau become hyperphosphorylated, leading to the formation of neurofibrillary tangles, which are a key pathological feature of the AD. Measuring levels of different phosphorylated tau in the blood can provide insights into the extent of tau pathology in the brain. Phosphorylated tau (pTau) serves as a blood biomarker signaling the existence of AD-related alterations, with pTau217, pTau181, and pTau231 proving to be significant indicators in this context. The primary goal of this study is to investigate the diagnostic utility of measuring plasma pTau217, pTau181 and pTau231 levels in identifying possible AD cases. This study intends to evaluate how effectively the concentrations of pTau217, pTau181 and pTau231 in the blood can differentiate individuals with CSF biomarker-confirmed AD in comparison to CSF biomarker-negative control group. Plasma concentrations of pTau217, pTau181 and pTau231 were measured by in-house Single molecule array (Simoa) assays developed at the University of Gothenburg (UGOT p-tau217, pTau181 and pTau231). The quantitative assessment of classical biomarkers (Aβ-42, Aβ-42/Aβ-40, tTau, and pTau181) in the CSF of patients with possible AD according to the Erlangen Score algorithm (ER 2 and 3) and controls (ER 0) were performed by Lumipulse. Significantly The levels of pTau217, pTau181 and pTau231 correlated positively with CSF tTau, pTau181 and negatively with CSF Aβ1-42 and Aβ ratio. The greatest effect size was observed for pTau217 (d=1.63), moderate for pTau181 (d=0.57) and pTau231 (d=0.3) respectively. The results of the present study indicate that plasma pTau217 could be the most valuable blood biomarker for AD diagnosis among the tested isoforms.

Alzheimer's disease (AD) is an uncurable, heterogeneous, and molecular complex neurodegenerative disease. Emerging evidence indicates that furin could play an essential role in the pathogenesis of neurodegenerative disorders. Furin participates in the proteolytic maturation and processing of large numbers of prohormones and proproteins, which among others play crucial roles in neuronal survival, axon growth, dendritic development, synaptogenesis, neurodegeneration, and inflammation. It is suggested that a stable activity of furin is crucial for maintaining of the central nervous system homeostasis. Some studies revealed reduced expression of mRNA of furin in the brains of Alzheimer's disease patients, which may suggest the implication of the protein in the pathophysiology of AD. However, little is known about changes of furin’s concentration in the cerebrospinal fluid (CSF) patients with AD. Therefore, we aimed to assess the usefulness of CSF furin’s measurement in patients with AD in relation to subjects without cognitive impairment. We also assessed associations between CSF concentrations of furin and neurochemical biomarkers of dementia. The study enrolled 39 participants, including patients with AD and subjects without cognitive decline. The concentrations of furin and classical biomarkers (amyloid beta 1-42, amyloid beta 1-40, Tau, as well as pTau181) were assessed in cerebrospinal fluid using a multiplexing method as well as enzyme-linked immunosorbent assay. A significantly higher CSF concentration of furin was noticed in AD patients as compared to subjects without cognitive impairment. Furthermore, in the whole study group of patients, the levels of furin correlated negatively with MMSE test and Aβ-1-42/ Aβ-1-40 ratio, as well as positively with total Tau and pTau181. Additionally, the CSF levels of furin significantly correlated with pTau181 protein in the AD group. Our preliminary study indicates the potential role of furin in the pathology of AD and its potential usefulness as a candidate biomarker. However, further investigations on an independent larger group of patients are necessary.

Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer’s disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts ( n = 388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.

In Alzheimer's disease (AD), amyloid-beta (Aβ) peptides are produced by proteolytic cleavage of the amyloid precursor protein (APP), which can occur during synaptic vesicle (SV) cycling at presynapses. Precisely how amyloidogenic APP processing may impair presynaptic proteostasis and how to therapeutically target this process remains poorly understood. Using App knock-in mouse models of early Aβ pathology, we found proteins with hampered degradation accumulate at presynaptic sites. At this mild pathological stage, amyloidogenic processing leads to accumulation of Aβ42 inside SVs. To explore if targeting SVs modulates Aβ accumulation, we investigated levetiracetam (Lev), a SV-binding small molecule drug that has shown promise in mitigating AD-related pathologies despite its mechanism of action being unclear. We discovered Lev reduces Aβ42 levels by decreasing amyloidogenic processing of APP in a SV2a-dependent manner. Lev corrects SV protein levels and cycling, which results in increased surface localization of APP, where it favors processing via the non-amyloidogenic pathway. Using metabolic stable isotopes and mass spectrometry we confirmed that Lev prevents the production of Aβ42 in vivo. In transgenic mice with aggressive pathology, electrophysiological and immunofluorescent microscopy analyses revealed that Lev treatment reduces SV cycling and minimizes synapse loss. Finally, we found that human Down syndrome brains with early Aβ pathology, have elevated levels of presynaptic proteins, confirming a comparable presynaptic deficit in human brains. Taken together, we report a mechanism that highlights the therapeutic potential of Lev to modify the early stages of AD and represent a promising strategy to prevent Aβ42 pathology before irreversible damage occurs.

It is of critical importance to our understanding of Alzheimer's disease (AD) pathology to determine how key pathological factors are interconnected and implicated in nerve cell death, clinical symptoms, and disease progression. The formation of extracellular beta-amyloid (Aβ) plaques is the major pathological hallmark of AD and Aβ has been suggested to be a critical inducer of AD, driving disease pathogenesis. Exactly how Aβ plaque formation begins and how ongoing plaque deposition proceeds and initiates subsequent neurotoxic mechanisms is not well understood. The primary aim of our research is to elucidate the biochemical processes underlying early Aβ plaque formation in brain tissue. We recently introduced a chemical imaging paradigm based on mass spectrometry imaging (MSI) and metabolic isotope labelling to follow stable isotope labelling kinetics (iSILK) in vivo to track the in vivo build-up and deposition of Aβ. Herein, knock-in Aβ mouse models (App NL-F ) that develop Aβ pathology gradually are metabolically labeled with stable isotopes. This chemical imaging approach timestamps amyloid plaques during the period of initial deposition allowing the fate of aggregating Aβ species from before and during the earliest events of plaque pathology through plaque maturation to be tracked. To identify the molecular and cellular response to plaque maturation, we integrated iSILK with single plaque transcriptomics performed on adjacent tissue sections. This enabled changes in gene expression to be tracked as a function of plaque age (as encoded in the Aβ peptide isotopologue pattern) distinct from changes due to the chronological age or pathological severity. This approach identified that plaque age correlates negatively with gene expression patterns associated with synaptic function as early as in 10-month-old animals but persists into 18 months. Finally, we integrated hyperspectral confocal microscopy into our multiomic approach to image amyloid structural isomers, revealing a positive correlation between plaque age and amyloid structural maturity. This analysis identified three categories of plaques, each with a distinct impact on the surrounding microenvironment. Here, we identified that older, more compact plaques were associated with the most significant synapse loss and toxicity. These data show how isotope-encoded MS imaging can be used to delineate Aβ toxicity dynamics in vivo. Moreover, we show for the first time a functional integration of dynamic MSI, structural plaque imaging and whole genome-wide spatial transcriptomics at the single plaque level. This multiomic approach offers an unprecedented combination of temporal and spatial resolution enabling a description of the earliest events of precipitating amyloid pathology and how Aβ modulates synaptotoxic mechanisms.

Background: Mechanisms underlying neurodegeneration in multiple sclerosis (MS) remain poorly understood but mostly implicate molecular pathways that are not unique to MS. Recently detected tau seeding activity in MS brain tissues corroborates previous neuropathological reports of hyperphosphorylated tau (p-tau) accumulation in secondary and primary progressive MS (PPMS). We aimed to investigate whether aberrant tau phosphorylation can be detected in the cerebrospinal fluid (CSF) of MS patients by using novel ultrasensitive immunoassays for different p-tau biomarkers. Methods: CSF samples of patients with MS (n = 55) and non-inflammatory neurological disorders (NIND, n = 31) were analysed with in-house Single molecule array (Simoa) assays targeting different tau phosphorylation sites (p-tau181, p-tau212, p-tau217 and p-tau231). Additionally, neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were measured with a multiplexed Simoa assay. Patients were diagnosed with clinically isolated syndrome (CIS, n = 10), relapsing-remitting MS (RRMS, n = 21) and PPMS (n = 24) according to the 2017 McDonald criteria and had MRI, EDSS and basic CSF analysis performed at the time of diagnosis. Results: Patients with progressive disease course had between 1.4-fold (p-tau217) and 2.2-fold (p-tau212) higher p-tau levels than relapsing MS patients (PPMS compared with CIS + RRMS, p < 0.001 for p-tau181, p-tau212, p-tau231 and p = 0.042 for p-tau217). P-tau biomarkers were associated with disease duration (rho=0.466-0.622, p < 0.0001), age (rho=0.318-0.485, p < 0.02, all but p-tau217) and EDSS at diagnosis and follow-up (rho=0.309-0.440, p < 0.02). In addition, p-tau biomarkers correlated with GFAP (rho=0.517-0.719, p <= 0.0001) but not with the albumin quotient, CSF cell count or NFL. Patients with higher MRI lesion load also had higher p-tau levels p <= 0.01 (<10 vs. >= 10 lesions, all p <= 0.01). Conclusion: CSF concentrations of novel p-tau biomarkers point to a higher degree of tau phosphorylation in PPMS than in RRMS. Associations with age, disease duration and EDSS suggest this process increases with disease severity; however, replication of these results in larger cohorts is needed to further clarify the relevance of altered tau phosphorylation throughout the disease course in MS.

INTRODUCTION:The established cerebrospinal fluid (CSF) phosphorylated tau181 (p-tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age-related tauopathy (PART) found in Creutzfeldt-Jakob disease (CJD) at autopsy. METHODS:We investigated CSF N-terminal p-tau181, p-tau217, and p-tau231 with in-house Simoa assays in definite CJD (n = 29), AD dementia (n = 75), mild cognitive impairment (MCI) due to AD (n = 65), and subjective cognitive decline (SCD, n = 28). Post-mortem examination performed in patients with CJD 1.3 (0.3-14.3) months after CSF collection revealed no co-pathology in 10, concomitant AD in 8, PART in 8, and other co-pathologies in 3 patients. RESULTS:N-terminal p-tau was increased in CJD versus SCD (p < 0.0001) and correlated with total tau (t-tau) in the presence of AD and PART co-pathology (rho = 0.758-0.952, p ≤ 001). Concentrations in CJD+AD were indistinguishable from AD dementia, with the largest fold-change in p-tau217 (11.6), followed by p-tau231 and p-tau181 (3.2-4.5). DISCUSSION:Variable fold-changes and correlation with t-tau suggest that p-tau closely associates with neurodegeneration and concomitant AD in CJD. HIGHLIGHTS:N-terminal phosphorylated tau (p-tau) biomarkers are increased in Creutzfeldt-Jakob disease (CJD) with and without concomitant AD. P-tau217, p-tau231, and p-tau181 correlate with total tau (t-tau) and increase in the presence of amyloid beta (Aβ) co-pathology. N-terminal p-tau181 and p-tau231 in Aβ-negative CJD show variation among PRNP genotypes. Compared to mid-region-targeting p-tau181, cerebrospinal fluid (CSF) N-terminal p-tau has greater potential to reflect post-mortem neuropathology in the CJD brain.

ABSTRACT Amyloid plaque deposition is recognized as the primary pathological hallmark of Alzheimer’s disease(AD) that precedes other pathological events and cognitive symptoms. Plaque pathology represents itself with an immense polymorphic variety comprising plaques with different stages of amyloid fibrillization ranging from diffuse to fibrillar, mature plaques. The association of polymorphic Aβ plaque pathology with AD pathogenesis, clinical symptoms and disease progression remains unclear. Advanced chemical imaging tools, such as functional amyloid microscopy combined with MALDI mass spectrometry imaging (MSI), are now enhanced by deep learning algorithms. This integration allows for precise delineation of polymorphic plaque structures and detailed identification of their associated Aβ compositions. We here set out to make use of these tools to interrogate heterogenic plaque types and their associated biochemical architecture. Our findings reveal distinct Aβ signatures that differentiate diffuse plaques from fibrilized ones, with the latter showing substantially higher levels of Aβx-40. Notably, within the fibrilized category, we identified a distinct subtype known as coarse-grain plaques. Both in sAD and fAD brain tissue, coarse grain plaques contained more Aβx-40 and less Aβx-42 compared with cored plaques. The coarse grain plaques in both sAD and fAD also showed higher levels of neuritic content including paired helical filaments (PHF-1)/phosphorylated phospho Tau-immunopositive neurites. Finally, the Aβ peptide content in coarse grain plaques resembled that of vascular Aβ deposits (CAA) though with relatively higher levels of Aβ1-42 and pyroglutamated Aβx-40 and Aβx-42 species in coarse grain plaques. This is the first of its kind study on spatial in situ biochemical characterization of different plaque morphotypes demonstrating the potential of the correlative imaging techniques used that further increase the understanding of heterogeneous AD pathology. Linking the biochemical characteristics of amyloid plaque polymorphisms with various AD etiologies and toxicity mechanisms is crucial. Understanding the connection between plaque structure and disease pathogenesis can enhance our insights. This knowledge is particularly valuable for developing and advancing novel, amyloid-targeting therapeutics.

Recent investigations implicate neuroinflammatory changes, including astrocyte and microglia activation, as crucial in the progression of Alzheimer’s disease (AD) Thus, we compared selected proteins reflecting neuroinflammatory processes to establish their connection to AD pathologies. Our study, encompassing 80 subjects with (n = 42) AD, (n = 18) mild cognitive impairment (MCI) and (n = 20) non-demented controls compares the clinical potential of tested molecules. Using antibody-based methods, we assessed concentrations of NGAL, CXCL-11, sTREM1, and sTREM2 in cerebrospinal fluid (CSF). Proinflammatory proteins, NGAL, and CXCL-11 reached a peak in the early stage of the disease and allowed for the identification of patients with MCI. Furthermore, the concentration of the anti-inflammatory molecule sTREM2 was highest in the more advanced stage of the disease and permitted differentiation between AD and non-demented controls. Additionally, sTREM2 was biochemically linked to tau and pTau in the AD group. Notably, NGAL demonstrated superior diagnostic performance compared to classical AD biomarkers in discriminating MCI patients from controls. These findings suggest that proteins secreted mainly through microglia dysfunction might play not only a detrimental but also a protective role in the development of AD pathology.

Background: Many epigenetic factors, including microRNAs, are involved in the process of changing gene expressions. Small non-coding RNA molecules, called miRNAs, are responsible for regulating gene translation by silencing or degrading target mRNAs. It is acknowledged that for many diseases, they may be novel diagnostic and prognostic biomarkers. Patients with autoimmune thyroid diseases are more likely to develop nodules in the thyroid tissue, and Hashimoto’s thyroiditis and Graves’ disease predispose patients to thyroid cancer. We evaluated the concentrations of microRNA molecules (miR-15a-5p, miR-126-3p, miR-142-5p, miR-21-5p, miR-150-5p) in the blood of children with thyroid disorders. In addition, we wished to identify molecules whose change in concentration predisposes to the development of thyroid cancer. Aim: The aim of this study is to evaluate selected epigenetic elements by analyzing the levels of miR-15a-5p, miR-126-3p, miR-142-5p, miR-150-5p and miR-21-5p in the blood of pediatric patients with Graves’ disease (n = 25), Hashimoto’s thyroiditis (n = 26) and thyroid nodular disease (n = 20) compared to a control group of healthy children (n = 17). Materials and Methods: The study consists of groups of children and adolescents aged 10–18 years with autoimmune thyroid disease, with thyroid nodular disease compared to a control group. The miR-15a-5p, miR-126-3p, miR-142-5p, miR-21-5p and miR-150-5p molecules were determined through an immunoenzymatic assay using BioVendor reagents. Results: There is a statistically significant decrease in the expression of the miR-15a-5p in children with Graves’ disease (21.61 vs. 50.22 amol/μL, p = 0.03) and in patients with thyroid nodular disease compared to controls (20.23 vs. 50.22 amol/μL, p = 0.04). Higher levels of the miR-142-5p molecule are found in patients with thyroid disease (with GD-3.8 vs. 3.14 amol/μL, p = 0.01; with HT-3.7 vs. 3.14 amol/μL, p = NS, with thyroid nodular disease-4.16 vs. 3.14 amol/μL, p = 0.04). Lower levels of miR-126-3p were noted in the GD group compared to the control group (7.09 vs. 7.24 amol/μL, p = 0.02). No statistically significant changes in the expressions of miR-150-5p and miR-21-5p molecules were observed in the study groups. Conclusions: 1. The overexpression of the miR-142-5p molecule occurs in children and adolescents with thyroid diseases. 2. Decreased blood levels of miR-15a-5p predispose patients to the formation of focal lesions in the thyroid gland. 3. Identifying a lower expression of the miR-126-3p molecule in the blood of children with GD requires careful follow-up for the development of focal lesions in the thyroid gland and evaluation for their potential malignancy.

Early deficits of cognitive symptoms have molecular background closely related to Alzheimer’s Disease (AD). Before developing full-blown AD, mild cognitive impairment (MCI) develops. It has been suggested that synaptic pathology is closely associated with memory impairment in the early phase of the disease and may be monitored by assessment of the synaptic proteins in cerebrospinal fluid (CSF), like neuronal pentraxin receptor (NPTXR). The highest expression of NPTXR and involvement in neuronal processes have been observed in the hippocampus and cortex. This candidate biomarker of synaptic dysfunction may have a crucial role in synaptic transmission and modulation of memory processes with other synaptic proteins. The purpose of the our investigation was to assessed the neuronal pentraxin receptor (NPTXR) level in cerebrospinal fluid (CSF) in MCI patients. The study included 17 patients with MCI and 17 non-demented controls. The CSF levels of NPTXR and classical AD biomarkers, such as Aβ-42, Aβ-42/Aβ-40, Tau, and pTau181, were assessed by commercially available immunoenzyme assays. The CSF concentration of NPTXR was significantly lower in MCI patients compared to non-demented controls. Moreover, NPTXR level was positively correlated with Tau181, Aβ-42, and total Tau proteins in MCI patients. Our results suggest that Neuronal Pentraxin Receptor may be one of the biomarker reflecting synaptic dysfunction in MCI patients. These preliminary results seem very promising, particularly for the early diagnosis of Alzheimer’s disease. Future research concerning NPTXR is necessary to understand better the role of the protein in early pathological processes of the disease.

Accumulation of tau aggregates is a pathological hallmark of Alzheimer’s disease (AD) that is closely related to the emergence of neurodegeneration and manifestation of clinical symptoms. Currently, CSF and plasma biomarkers of tau pathology, which would improve the diagnostic process in everyday clinical practice and facilitate the classification of patients for clinical trials, are the focus of research. Biomarkers of tau pathology correlate with post-mortem AD pathology. Furthermore, they allow for differentiation of AD from other types of dementia, and prediction of future progression from normal cognition and mild cognitive impairment to AD. The availability of The clinical utility of novel assays for the detection of several isoforms of tau pathophysiology in the blood, which are currently available, requires verification. Therefore, the aim of the present study was evaluation of tau proteins in the blood of AD patients and non-demented controls, and assessment of their diagnostic utility. Plasma concentrations of pTau181 and pTau231 were assessed using a Single molecule array (Simoa). CSF biomarkers, including Aβ-42, Aβ-42/Aβ-40, tau and pTau181 were evaluated in 20 AD patients and 18 elderly subjects without cognitive deficits by ELISA technique. Statistically significantly higher blood levels of pTau181 and pTau231 were observed in AD patients in comparison to cognitively normal individuals. Increased concentration of pTau231 correlated with age and MMSE. Furthermore, the associations between the levels of plasma pTau231 and plasma pTau181, CSF Tau and pTau181, as well as Aβ-42 were observed in the whole study group. The results indicate that plasma P-tau181 and P-tau231 may be diagnostic biomarkers that can help to predict cognitive decline and that they hold promise for use in routine clinical practice.

Experts emphasize that colorectal cancer (CRC) incidence and mortality are increasing. That is why its early detection is of the utmost importance. Patients with cancer diagnosed in earlier stages have a better prognosis and a chance for faster implementation of treatment. Consequently, it is vital to search for new parameters that could be useful in its diagnosis. Therefore, we evaluated the usefulness of CXCL5, CXCL14 and CXCL16 in serum of 115 participants (75 CRC patients and 40 healthy volunteers). Concentrations of all parameters were measured using Luminex. CRP (C-reactive protein) levels were determined by immunoturbidimetry, while levels of classical tumor markers were measured using CMIA (Chemiluminescence Microparticle Immunoassay). Concentrations of CXCL5 were statistically higher in the CRC group when compared to healthy controls. The diagnostic sensitivity, specificity, positive and negative predictive value, and area under the ROC curve (AUC) of CXCL5 and CXCL14 were higher than those of CA 19–9. Obtained results suggest the usefulness of CXCL5 and CXCL16 in the determination of distant metastases and differentiation between TNM (Tumor-Node-Metastasis) stages, as well as the usefulness of CXCL14 and CRP combination in CRC detection (primary or recurrence). However, further studies concerning their role in CRC progression are crucial to confirm and explain their diagnostic utility and clinical application as biomarkers.

Beta-amyloid (Aβ) plaque pathology is one of the most prominent histopathological feature of Alzheimer's disease (AD). The exact pathogenic mechanisms linking Aβ to AD pathogenesis remain however not fully understood. Recent advances in amyloid-targeting pharmacotherapies highlight the critical relevance of Aβ aggregation for understanding the molecular basis of AD pathogenesis. We developed a novel, integrated, tetramodal chemical imaging paradigm for acquisition of trimodal mass spectrometry imaging (MSI) and interlaced fluorescent microscopy from a single tissue section. We used this approach to comprehensively investigate lipid–Aβ correlates at single plaques in two different mouse models of AD (tgAPPSwe and tgAPPArcSwe) with varying degrees of intrinsic properties affecting amyloid aggregation. Integration of the multimodal imaging data and multivariate data analysis identified characteristic patterns of plaque-associated lipid- and peptide localizations across both mouse models. Correlative fluorescence microscopy using structure-sensitive amyloid probes identified intra-plaque structure-specific lipid- and Aβ patterns, including Aβ 1–40 and Aβ 1–42 along with gangliosides (GM), phosphoinositols (PI), conjugated ceramides (CerP and PE-Cer), and lysophospholipids (LPC, LPA, and LPI). Single plaque correlation analysis across all modalities further revealed how these distinct lipid species were associated with Aβ peptide deposition across plaque heterogeneity, indicating different roles for those lipids in plaque growth and amyloid fibrillation, respectively. Here, conjugated ceramide species correlated with Aβ core formation indicating their involvement in initial plaque seeding or amyloid maturation. In contrast, LPI and PI were solely correlated with general plaque growth. In addition, GM1 and LPC correlated with continuous Aβ deposition and maturation. The results highlight the potential of this comprehensive multimodal imaging approach and implement distinct lipids in amyloidogenic proteinopathy.

The most prevalent form of dementia in the world is Alzheimer Disease (AD), a common neurodegenerative condition. Amyloid peptides, phosphorylated tau proteins, and neuroinflammation are the disease’s hallmarks. Finding new biomarkers that can assist in early AD detection is crucial due to the late appearance of the disease symptoms. Triggering receptor expressed on myeloid cell 1 (TREM-1) is hypothesized that may contribute to the development of AD by causing neuroinflammation. Due of its significance in inflammatory responses, it has been regarded as a promising biomarker. Literature data indicate that TREM-1 could be potential biomarker of AD severity. Therefore the purpose of our research was to measure the concentration of soluble TREM-1 in cerebrospinal fluid of AD and MCI patients and non-demented controls and compare it with classical AD biomarkers. The concentrations of TREM-1 were measured in cerebrospinal fluid (CSF) of 20 AD patients and 15 MCI patients as well as 11 non-demented controls using multiplexing method. Classical biomarkers, such as Aβ-42, Aβ-42/Aβ-40, tau and pTau181 were assessed by immunoenzyme assays. TREM-1 concentrations were significantly higher in AD and MCI patients in comparison to non-demented controls. Moreover, in MCI patients, the levels of this protein were significantly higher than in AD patients. Additionally, increased CSF levels of TREM-1 correlated positively with Tau, pTau181 in the whole study group. Findings of our research suggest that TREM-1 could be early indicator of AD pathology. However, follow-up studies on larger study group are needed.

In addition to amyloid and tau pathology in the central nervous system (CNS), inflammatory processes and synaptic dysfunction are highly important mechanisms involved in the development and progression of dementia diseases. In the present study, we conducted a comparative analysis of selected pro-inflammatory proteins in the CNS with proteins reflecting synaptic damage and core biomarkers in mild cognitive impairment (MCI) and early Alzheimer’s disease (AD). To our knowledge, no studies have yet compared CXCL12 and CX3CL1 with markers of synaptic disturbance in cerebrospinal fluid (CSF) in the early stages of dementia. The quantitative assessment of selected proteins in the CSF of patients with MCI, AD, and non-demented controls (CTRL) was performed using immunoassays (single- and multiplex techniques). In this study, increased CSF concentration of CX3CL1 in MCI and AD patients correlated positively with neurogranin (r = 0.74; p < 0.001, and r = 0.40; p = 0.020, respectively), ptau181 (r = 0.49; p = 0.040), and YKL-40 (r = 0.47; p = 0.050) in MCI subjects. In addition, elevated CSF levels of CXCL12 in the AD group were significantly associated with mini-mental state examination score (r = −0.32; p = 0.040). We found significant evidence to support an association between CX3CL1 and neurogranin, already in the early stages of cognitive decline. Furthermore, our findings indicate that CXCL12 might be a useful marker for tract severity of cognitive impairment.