Tau Concentrations Research Articles

Internal-driven DNA nanowindmill: Multi-fulcrum mediated amplified rolling nanomachine for fast and ultrasensitive electrochemical detection of tau

Inspired by the wind driving windmill rolling to generate electrical energy, we have fabricated a multi-fulcrum mediated amplified rolling nanomachine (MFN) for Tau detection with the internal drive. The MFN backbone is DNA nanowindmill (DM) self-assembled from DNA, which is initially ineffective and finally activated into an effective DM through interaction with Tau followed by the magnetic separation. The DM is introduced to the electrode interface where it continues rolling under the drive of the multi-fulcrum and signal probe to achieve signal amplification. On one hand, the modular design and DM rolling feeds the impediment of signal transduction and amplification due to spatial hindrance during protein detection. On the other hand, it endows fast response and high sensitivity. The proposed MFN electrochemical biosensor is successfully applied to detect Tau ranging from 10 pg/mL to 2 μg/mL with low detection limit of 127 fg/mL, which is much lower than the pathological state concentration of Tau ∼400 pg/mL. Furthermore, our findings proves that MFN can successfully differentiate normal individuals from Alzheimer’s disease (AD) patients based on clinical samples analysis.

Real-time detection of Tau-381 protein using liquid crystal-based sensors for Alzheimer's disease diagnosis

Tau is a protein found in the central nervous system (CNS) and is involved in stabilizing microtubules in axons. Given the link between Tau levels in the body and Alzheimer's disease (AD), there is a demand for straightforward and precise strategies to detect Tau in body fluids. In this study, we report liquid crystal (LC)-based sensors for the real-time detection of Tau protein, a well-known AD biomarker. The sensor uses a detection method based on the orientation change of the LC because of the competitive biomolecular interaction between Tau and Tau aptamers with the cationic polymer poly-L-lysine (PLL). Tau and its aptamers form stable complexes through electrostatic interactions. Owing to the consumption of the aptamer, the positively charged PLL fails to interact with the aptamer but binds to the negatively charged 1.2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) sodium salt (DOPG). The PLL and DOPG complex alters the orientation of the LC to ensure a planar anchoring of the 4-cyano-4′-pentylbiphenyl (5CB)/aqueous interface; this anchoring intensifies with increasing Tau concentration, thus enabling the observation of a bright optical image. Our LC-based sensor demonstrated a low detection limit of 2.77 pg/mL in phosphate buffered saline (PBS) and 10.86 pg/mL and 19.31 pg/mL in human serum and plasma, respectively. Moreover, it is anticipated to be suitable for point-of-care diagnosis of AD because it does not require specialized analytical equipment and only requires microliters of sample.

Connectome-based predictive modeling of brain pathology and cognition in Autosomal Dominant Alzheimer's Disease.

Autosomal Dominant Alzheimer's Disease (ADAD) through genetic mutations can result in near complete expression of the disease. Tracking AD pathology development in an ADAD cohort of Presenilin-1 (PSEN1) E280A carriers' mutation has allowed us to observe incipient tau tangles accumulation as early as 6 years prior to symptom onset. Resting-state functional Magnetic Resonance Imaging (fMRI) and Positron-Emission Tomography (PET) scans were acquired in a group of PSEN1 carriers (n=32) and non-carrier family members (n=35). We applied Connectome-based Predictive Modeling (CPM) to examine the relationship between the participant's functional connectome and their respective tau/amyloid-β levels and cognitive scores (word list recall). CPM models strongly predicted tau concentrations and cognitive scores within the carrier group. The connectivity patterns between the temporal cortex, default mode network, and other memory networks were the most informative of tau burden. These results indicate that resting-state fMRI methods can complement PET methods in early detection and monitoring of disease progression in ADAD.

Genetic evidence for serum amyloid Pcomponent as a drug target in neurodegenerative disorders.

The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral Aβ amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis-Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10-3), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10-5) and plasma tau concentration (0.06 log2(ng l-1) 95%CI 0.03; 0.08, p = 4.55 × 10-6). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.

Interferon-Tau in Maternal Peripheral Blood and Its Relationship with Progesterone and Pregnancy-Associated Glycoproteins in the Early Phases of Gestation in Water Buffalo.

The aim of this study was to investigate the interferon tau (IFNt) concentration in the peripheral maternal blood during the early phase of pregnancy in buffalo cows and improve the knowledge on the physiological importance of circulating IFNt, evaluating the possible interaction with pregnancy-associated glycoproteins (PAGs) and progesterone (P4). Blood samples were taken from buffalo cows on day 0 (day of AI), 7, 14, 18, 28, and 40 post insemination for the IFNt, PAG, and P4 analysis and to determine the IFNt mRNA expression. The animals were categorized ex post into Pregnant, Non-pregnant and Embryo mortality groups. The interferon value was influenced by group (p = 0.003), being always higher in pregnant buffalo cows than in non-pregnant ones, while the embryo mortality group showed intermediate values between those for pregnant and non-pregnant animals. The mRNA expression of IFNt was not influenced by groups or any time points. The regression analysis that included IFNt as the independent variable showed that PAGs, from day 18 (p < 0.01), and P4, from day 28 (p < 0.05), were positively associated with IFNt values. The close associations among IFNt, PAGs and P4 demonstrate that all three molecules work together for fetal-placental well-being and pregnancy support. Unfortunately, the great individual variability in circulating IFNt makes this analysis unsuitable for early pregnancy diagnosis.

A Simple Sandwich Electrochemical Immunosensor for Rapid Detection of the Alzheimer's Disease Biomarker Tau Protein.

As a typical biomarker of Alzheimer's disease, rapid and specific detection of tau protein can help improve the early diagnosis and prognosis of the disease. In this study, a simple sandwich electrochemical immunosensor was developed for rapid detection of tau protein. Primary monoclonal antibodies (mAb1) against the middle domain of tau protein (amino acids 189-195) were immobilized on the gold electrode surface through a self-assembled monolayer (SAM) of 3,3'-dithiobis (sulfosuccinimidyl propionate) (DTSSP). Then the tau protein was captured through the specific adsorption between the antigen and the antibody, resulting in a change in the impedance. Secondary monoclonal antibodies (mAb2) against the N-terminal region of tau protein were used for further amplification of the binding reaction between mAb1 and tau protein. A linear correlation between the total change in impedance and the logarithm of tau concentration was found from 2 × 10-6 mg mL-1 to 2 × 10-3 mg mL-1, with a detection limit as low as 1 × 10-6 mg mL-1. No significant interference was observed from human serum albumin. Furthermore, the fabricated sandwich immunosensor successfully detected target tau protein in artificial cerebrospinal fluid (aCSF) samples, indicating good potential for clinical applications in the future.

P.102 Integration of Ultrasensitive electroluminescent immunoassay and cell-free DNA methylation analysis for the non-invasive discrimination of adult diffuse gliomas

Background: Gliomas are highly aggressive brain tumors with nearly universal recurrence rate. Despite this, the ability to accurately predict tumor recurrence relies solely on serial MRI imaging, highlighting the need for prognostic biomarkers. Due to the low accuracies of individual serum markers, we have proposed the use of an integrated, multi-platform approach to biomarker discovery. Methods: A cohort of 107 glioma plasma samples, including 30 pairs, underwent plasma proteomic, consisting of a panel of serum proteins (FABP4, GFAP, NFL, Tau and MMP3,4 &amp;7) quantified through ultrasensitive electrochemiluminescence multiplexed immunoassays, and plasma DNA methylation analysis, captured through cell-free methylated DNA immunoprecipitation and high-throughput sequencing. Results: Unsupervised hierarchal clustering revealed robust separation of primary and recurrent tumors through plasma proteomics, associated with a distinct plasma methylation signature. NFL, Tau and MMP3 levels differed between primary and recurrent samples; pair-wise analysis revealed increased in NFL and Tau concentrations upon recurrence. Tau levels predicted outcome independent of WHO Grade and IDH status. A predictive model created through the integration of the proteomic and methylation signatures revealed an AUC of 0.83. Conclusions: The combination of DNA methylation and plasma proteomics showcases that an integrative approach may improve the ability of these techniques for the serial monitoring of gliomas patients.

Assessment of Preanalytical Cerebrospinal Fluid Handling and Storage Factors on Measurement of Aβ1-42, Aβ1-40, and pTau181 Using an Automated Chemiluminescent Platform.

Standardizing cerebrospinal fluid (CSF) laboratory protocols will improve the reliability and availability of clinical biomarker testing required for prescription of novel Alzheimer disease (AD) therapies. This study evaluated several preanalytical handling and storage factors common to β-amyloid1-42 (Aβ1-42), β-amyloid1-40 (Aβ1-40), and phosphorylated tau (pTau181) concentrations including storage at different temperatures, extended cap contact, various mixing methods, and multiple freeze-thaw cycles. Aβ1-42, Aβ1-40, and pTau181 concentrations were measured using LUMIPULSE G1200 automated assays. Samples were collected in polypropylene tubes of various volumes. Sample cap-contact was evaluated by storing samples in upright and inverted positions at either 4°C for 1 week or -80°C for 1 month. To assess mixing methods, samples were freeze-thawed and mixed by inversion, vortex, horizontal roller, or unmixed prior to assay sampling. The impact of successive freeze-thaw cycles was assessed through freezing, thawing, and analyzing CSF samples. Short-term storage at 4°C did not affect Aβ1-42, Aβ1-40, or pTau181 measurements in any tube type. Tube cap contact affected Aβ1-42 in 2.5 mL tubes and pTau181 levels in 10 mL tubes. No difference was observed between mixing methods. After 4 freeze-thaw cycles, Aβ1-42 significantly decreased but Aβ1-40 remained unchanged. Utilizing the Aβ1-42/Aβ1-40 ratio, Aβ1-42 values normalized, maintaining ratio values within ±5% of baseline measurements. Storage of CSF at 4°C for 1 week or -80°C for 1 month did not significantly affect Aβ1-42, Aβ1-40, pTau181, or associated ratio measurements. Tube cap-contact impacted pTau181 and pTau181/Aβ1-42 values in larger tubes. Mixing methods are equivalent. The Aβ1-42/Aβ1-40 ratio compensates for freeze-thaw variability up to 4 cycles.

Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study

In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease. In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid. We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease. Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. None.

Lipocalin-type prostaglandin D synthase: a glymphopathy marker in idiopathic hydrocephalus.

Idiopathic normal pressure hydrocephalus in elderly people is considered a form of glymphopathy caused by malfunction of the waste clearance pathway, called the glymphatic system. Tau is a representative waste material similar to amyloid-β. During neurodegeneration, lipocalin-type prostaglandin D synthase (L-PGDS), a major cerebrospinal fluid (CSF) protein, is reported to act as a chaperone that prevents the neurotoxic aggregation of amyloid-β. L-PGDS is also a CSF biomarker in idiopathic normal pressure hydrocephalus and significantly correlates with tau concentration, age, and age-related brain white matter changes detected by magnetic resonance imaging. To investigate this glymphopathy, we aimed to analyze white matter changes and contributing factors in vivo and their interactions ex vivo. Cerebrospinal tap tests were performed in 60 patients referred for symptomatic ventriculomegaly. Patients were evaluated using an idiopathic normal pressure hydrocephalus grading scale, mini-mental state examination, frontal assessment battery, and timed up-and-go test. The typical morphological features of high convexity tightness and ventriculomegaly were measured using the callosal angle and Evans index, and parenchymal white matter properties were evaluated with diffusion tensor imaging followed by tract-based spatial statistics. Levels of CSF biomarkers, including tau, amyloid-β, and L-PGDS, were determined by ELISA, and their interaction, and localization were determined using immunoprecipitation and immunohistochemical analyses. Tract-based spatial statistics for fractional anisotropy revealed clusters that positively correlated with mini-mental state examination, frontal assessment battery, and callosal angle, and clusters that negatively correlated with age, disease duration, idiopathic normal pressure hydrocephalus grading scale, Evans index, and L-PGDS. Other parameters also indicated clusters that correlated with symptoms, microstructural white matter changes, and L-PGDS. Tau co-precipitated with L-PGDS, and colocalization was confirmed in postmortem specimens of neurodegenerative disease obtained from the human Brain Bank. Our study supports the diagnostic value of L-PGDS as a surrogate marker for white matter integrity in idiopathic normal pressure hydrocephalus. These results increase our understanding of the molecular players in the glymphatic system. Moreover, this study indicates the potential utility of enhancing endogenous protective factors to maintain brain homeostasis.

Plasma concentrations of glial fibrillary acidic protein, neurofilament light, and tau in Alexander disease

IntroductionAlexander disease (AxD) is a rare leukodystrophy caused by dominant gain-of-function mutations in the gene encoding the astrocyte intermediate filament, glial fibrillary acidic protein (GFAP). However, there is an urgent need for biomarkers to assist in monitoring not only the progression of disease but also the response to treatment. GFAP is the obvious candidate for such a biomarker, as it is measurable in body fluids that are readily accessible for biopsy, namely cerebrospinal fluid and blood. However, in the case of ASOs, the treatment that is furthest in development, GFAP is the target of therapy and presumably would go down independent of disease status. Hence, there is a critical need for biomarkers that are not directly affected by the treatment strategy.MethodsWe explored the potential utility of biomarkers currently being studied in other neurodegenerative diseases and injuries, specifically neurofilament light protein (NfL), phosphorylated forms of tau, and amyloid-β peptides (Aβ42/40).Results and ConclusionsHere, we report that GFAP is elevated in plasma of all age groups afflicted by AxD, including those with adult onset. NfL and p-tau are also elevated, but to a much lesser extent than GFAP. In contrast, the levels of Aß40 and Aß42 are not altered in AxD.

Comprehensive analysis of brain injury parameters in a preclinical porcine model of acute liver failure.

Acute liver failure (ALF) is defined as acute loss of liver function leading to hepatic encephalopathy associated with a high risk of patient death. Brain injury markers in serum and tissue can help detect and monitor ALF-associated brain injury. This study compares different brain injury parameters in plasma and tissue along with the progression of ALF. ALF was induced by performing an 85% liver resection. Following the resection, animals were recovered and monitored for up to 48 h or until reaching the predefined endpoint of receiving standard medical therapy (SMT). Blood and serum samples were taken at Tbaseline, T24, and upon reaching the endpoint (Tend). Control animals were euthanized by exsanguination following plasma sampling. Postmortem brain tissue samples were collected from the frontal cortex (FCTx) and cerebellum (Cb) of all animals. Glial fibrillary acidic protein (GFAP) and tau protein and mRNA levels were quantified using ELISA and qRT-PCR in all plasma and brain samples. Plasma neurofilament light (NFL) was also measured using ELISA. All ALF animals (n = 4) were euthanized upon showing signs of brain herniation. Evaluation of brain injury biomarkers revealed that GFAP was elevated in ALF animals at T24h and Tend, while Tau and NFL concentrations were unchanged. Moreover, plasma glial fibrillary acidic protein (GFAP) levels were negatively correlated with total protein and positively correlated with both aspartate transaminase (AST) and alkaline phosphatase (AP). Additionally, lower GFAP and tau RNA expressions were observed in the FCTx of the ALF group but not in the CB tissue. The current large animal study has identified a strong correlation between GFAP concentration in the blood and markers of ALF. Additionally, the protein and gene expression analyses in the FCTx revealed that this area appears to be susceptible, while the CB is protected from the detrimental impacts of ALF-associated brain swelling. These results warrant further studies to investigate the mechanisms behind this process.

Higher levels of brain injury biomarker tau are associated with unfavorable outcomes in patients supported with ECMO following cardiac arrest

AimWe sought to determine if higher plasma levels of brain injury biomarkers neurofilament light (NfL), phosphorylated tau 181 (pT181), tau, and ubiquitin C-terminal hydrolase L1 (UCHL1) were associated with unfavorable outcomes in children supported on extracorporeal membrane oxygenation (ECMO) with and without preceding cardiac arrest. MethodsWe conducted a secondary analysis of a two-center prospective observational study of ECMO patients 0-<18 years. Plasma concentrations of NfL, pT181, tau, and UCHL1 were measured on ECMO days 1, 2 and 3. Unfavorable outcome was defined as in-hospital mortality or discharge Pediatric Cerebral Performance Category (PCPC) >2 with decline from baseline PCPC among survivors. ResultsAmong 88 children on ECMO, mean tau levels were significantly higher on each of the first three ECMO days in children who underwent extracorporeal cardiopulmonary resuscitation (ECPR) compared to those with non-ECPR cardiac arrest or with no cardiac arrest preceding ECMO. Higher ECMO day 1 tau levels were significantly associated with increased hazard of unfavorable outcome in unadjusted (HR, 1.35, 95% CI 1.09–1.66) and adjusted (HR, 1.42; 95% CI 1.13–1.79) models. Higher levels of NfL or pT181 were not associated with increased hazard for unfavorable outcome in multivariable models.UCHL1 values were outside of detectable limits and thus deferred from analysis. ConclusionsLevels of tau were significantly associated with increased hazard of death or unfavorable neurologic outcome in unadjusted and adjusted models. Biomarkers of brain injury, particularly tau, may aid in detection of neurologic injury and neuroprognostication in patients on ECMO with and without preceding cardiac arrest.

Biomarker-based staging of Alzheimer disease: rationale and clinical applications.

Disease staging, whereby the spatial extent and load of brain pathology are used to estimate the severity ofAlzheimer disease (AD), is pivotal to the gold-standard neuropathological diagnosis of AD. Current in vivo diagnostic frameworks for AD are based on abnormal concentrations of amyloid-β and tau in the cerebrospinal fluid or on PET scans, and breakthroughs in molecular imaging have opened up the possibility of in vivo staging of AD. Focusing on the key principles of disease staging shared across several areas of medicine, this Review highlights the potential for in vivo staging of AD to transform our understanding of preclinical AD, refine enrolment criteria for trials of disease-modifying therapies and aid clinical decision-making in the era of anti-amyloid therapeutics. We provide a state-of-the-art review of recent biomarker-based AD staging systems and highlight their contributions to the understanding of the natural history of AD. Furthermore, we outline hypothetical frameworks to stage AD severity using more accessible fluid biomarkers. In addition, by applying amyloid PET-based staging to recently published anti-amyloid therapeutic trials, we highlight how biomarker-based disease staging frameworks could illustrate the numerous pathological changes that have already taken place in individuals with mildly symptomatic AD. Finally, we discuss challenges related to the validation and standardization of disease staging and provide a forward-looking perspective on potential clinical applications.

Phosphorylation regulates tau’s phase separation behavior and interactions with chromatin

Tau is a microtubule-associated protein often found in neurofibrillary tangles (NFTs) in the brains of patients with Alzheimer’s disease. Beyond this context, mounting evidence suggests that tau localizes into the nucleus, where it may play a role in DNA protection and heterochromatin regulation. The molecular mechanisms behind these observations are currently unclear. Using in vitro biophysical experiments, here we demonstrate that tau can undergo liquid-liquid phase separation (LLPS) with DNA, mononucleosomes, and reconstituted nucleosome arrays under low salt conditions. Low concentrations of tau promote chromatin compaction and protect DNA from digestion. While the material state of samples at physiological salt is dominated by chromatin oligomerization, tau can still associate strongly and reversibly with nucleosome arrays. These properties are driven by tau’s strong interactions with linker and nucleosomal DNA. In addition, tau co-localizes into droplets formed by nucleosome arrays and phosphorylated HP1α, a key heterochromatin constituent thought to function through an LLPS mechanism. Importantly, LLPS and chromatin interactions are disrupted by aberrant tau hyperphosphorylation. These biophysical properties suggest that tau may directly impact DNA and chromatin accessibility and that loss of these interactions could contribute to the aberrant nuclear effects seen in tau pathology.

Pilot Study of the Total and Phosphorylated Tau Proteins in Early-Stage Multiple Sclerosis.

Background and Objectives: Recent findings suggest that neurodegeneration starts early in the course of multiple sclerosis (MS) and significantly contributes to the progression of patients' disability. Tau is a microtubule-binding protein that is known to play a role in the pathophysiology of many neurodegenerative disorders. Newly emerging data on tau protein-induced neurodegenerative processes and its possible involvement in MS suggest that it may be involved in the pathology of early-stage MS. Therefore, this study aimed to test this hypothesis in patients with newly diagnosed MS. Materials and Methods: Cerebrospinal fluid (CSF) was collected from 19 patients with newly diagnosed MS and 19 control subjects. All MS patients underwent neurological examination, lumbar punction, and brain magnetic resonance imaging (MRI). CSF concentrations of total and phosphorylated tau (phospho-tau-181) protein were measured using commercial enzyme-linked immunosorbent assay kits. Results: The total tau concentration was significantly higher in the CSF of MS patients compared to controls (141.67 pg/mL, IQR 77.79-189.17 and 68.77 pg/mL, IQR 31.24-109.17, p = 0.025). In MS patients, the total tau protein positively correlated with total CSF protein (r = 0.471, p = 0.048). Significantly higher total tau concentration was measured in MS patients with higher lesion load in brain MRI (≥9 versus <9 lesions; 168.33 pg/mL, IQR 111.67-222.32 and 73.33 pg/mL, IQR -32.13-139.29-, p = 0.021). The CSF concentration of phospho-tau-181 protein was below the detection limit in both MS and control subjects. Conclusions: The concentration of total tau protein level is elevated, whereas phospho-tau-181 is undetectable in the CSF of patients with early-stage MS.

Abstract WMP14: Cerebrospinal Fluid Beta-Amyloid Concentration and MRI Manifestations of Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is associated with reduced cerebrospinal fluid (CSF) levels of the beta-amyloid (Aβ) 40- and 42-amino acid species, thought to reflect the burden of vascular Aβ deposition in the brain. Little is known regarding the association of CSF Aβ reduction with specific MRI manifestations of CAA. Methods: We identified 31 patients with CAA per Boston criteria v2.0 (1 definite, 27 probable, and 3 possible), who underwent CSF sampling for measurement of Aβ42, total tau (t-tau), and phospho-tau (p-tau) as part of their evaluation with ADmark (Athena Diagnostics). We assessed the following MRI manifestations of CAA while blinded to CSF biomarkers: the presence of cortical superficial siderosis (cSS), number of lobar cerebral microbleeds (CMBs), pattern and severity of white matter hyperintensities (WMH), and number of enlarged perivascular spaces in centrum semiovale (CSO-EPVS). Results: Median age of presentation was 69 years (range 56-89). Out of 31 patients, 19 were female (61.3%), 20 (64.5%) presented with cognitive impairment, 9 (29%) with intracerebral hemorrhage, and 2 (6.5%) with transient focal neurologic events. Mean (±SD) CSF Aβ42 concentration in our cohort was 359.3±126.7 pg/ml, substantially reduced relative to that reported in healthy controls. MRI manifestations associated with reduced Aβ42 without altered tau were presence of cSS (310±136 vs. 406±101, p=0.03) and higher burden of CSO-EPVS (307±101 vs. 431±127, p=0.005). Patients presented with cognitive impairment had higher tau levels (t-tau: 551±320 vs. 317±141, p=0.03; p-tau: 75.7±39.8 vs. 49.2±22.4, p=0.05) without altered Aβ42. Similar results were obtained when patients with possible CAA were excluded. Discussion: Our results suggest that presence of cSS and higher burden of CSO-EPVS are associated with lower Aβ42 concentration in CSF, potentially reflecting higher overall burden of vascular Aβ deposition in the brain. We found that higher tau concentrations in CSF are associated with cognitive impairment, presumably reflecting concomitant Alzheimer’s disease pathology. These results help inform interpretation of this clinically accessible test in practice and suggest potential mechanisms for specific CAA-related pathologies.

Uptake of 18F-AV45 in the Putamen Provides Additional Insights into Alzheimer's Disease beyond the Cortex.

Cortical uptake in brain amyloid positron emission tomography (PET) is increasingly used for the biological diagnosis of Alzheimer's disease (AD); however, the clinical and biological relevance of the striatum beyond the cortex in amyloid PET scans remains unclear. A total of 513 amyloid-positive participants having 18F-AV45 amyloid PET scans available were included in the analysis. The associations between cognitive scores and striatal uptake were analyzed. The participants were categorized into three groups based on the residual from the linear fitting between 18F-AV45 uptake in the putamen and the cortex in the order of HighP > MidP > LowP group. We then examined the differences between these three groups in terms of clinical diagnosis, APOE genotype, CSF phosphorylated tau (ptau) concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate to evaluate the additional insights provided by the putamen beyond the cortex. The 18F-AV45 uptake in the putamen was more strongly associated with ADAS-cog13 and MoCA scores (p < 0.001) compared to the uptake in the caudate nucleus. Despite comparable cortical uptakes, the HighP group had a two-fold higher risk of being ε4-homozygous or diagnosed with AD dementia compared to the LowP group. These three groups had significantly different CSF ptau concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate. These findings suggest that the assessment of 18F-AV45 uptake in the putamen is of unique value for evaluating disease severity and predicting disease progression.

Serum GFAP, NfL, and tau concentrations are associated with worse neurobehavioral functioning following mild, moderate, and severe TBI: a cross-sectional multiple-cohort study.

The purpose of this study was to examine whether blood-based biomarkers associate with neurobehavioral functioning at three time points following traumatic brain injury (TBI). Participants were 328 United States service members and veterans (SMVs) prospectively enrolled in the Defense and Veterans Brain Injury Center-Traumatic Brain Injury Center of Excellence (DVBIC-TBICoE) 15-Year Longitudinal TBI Study, recruited into three groups: uncomplicated mild TBI (MTBI, n = 155); complicated mild, moderate, severe TBI combined (STBI, n = 97); non-injured controls (NIC, n = 76). Participants were further divided into three cohorts based on time since injury (≤12 months, 3-5 years, and 8-10 years). Participants completed the Minnesota Multiphasic Personality Inventory-2-Restructured Format (MMPI-2-RF) and underwent blood draw to measure serum concentrations of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau. A total of 11 MMPI-2-RF scales were examined (e.g., depression, anxiety, anger, somatic, cognitive symptoms). Stepwise hierarchical regression models were conducted within each group. Significant associations were found between biomarkers and MMPI-2-RF scales (all p < 0.05; R2Δ > 0.10). GFAP was inversely related to (a) neurological complaints in the MTBI group at ≤12 months, (b) demoralization, anger proneness in the STBI group at ≤12 months, and (c) head pain complaints in the STBI group at 8-10 years. NfL was (a) related to low positive emotions in the NIC group; and inversely related to (b) demoralization, somatic complaints, neurological complaints, cognitive complaints in the MTBI group at ≤12 months, (c) demoralization in the STBI group at ≤12 months, and (d) demoralization, head pain complaints, stress/worry in the STBI group at 3-5 years. In the STBI group, there were meaningful findings (R2Δ > 0.10) for tau, NFL, and GFAP that did not reach statistical significance. Results indicate worse scores on some MMPI-2-RF scales (e.g., depression, stress/worry, neurological and head pain complaints) were associated with lower concentrations of serum GFAP, NfL, and tau in the sub-acute and chronic phase of the recovery trajectory up to 5 years post-injury, with a reverse trend observed at 8-10 years. Longitudinal studies are needed to help elucidate any patterns of association between blood-based biomarkers and neurobehavioral outcome over the recovery trajectory following TBI.

Chemical components and against alzheimer's disease effects of the calyxes of Physalis alkekengi L. var. franchetii (Mast.) Makino

Physalis alkekengi L. var. franchetii (Mast.) Makino (PA), a traditional Chinese medicine, is utilised for treating dermatitis, sore throat, dysuria, and cough. This research aimed to identify the main constituents in the four extracted portions from the calyces of PA (PAC) utilising ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The Alzheimer's disease (AD) mice model was induced by D-galactose (D-gal) combined with aluminium chloride (AlCl3). Subsequent investigation into the underlying mechanisms involved behavioural and histopathological observations. The results demonstrated that four extracted portions of PAC (PACE) significantly enhanced memory and learning abilities in the Morris water maze. The concentrations of Aβ, tau and p-tau in brain tissue exhibited a significant decrease relative to the model group. Moreover, the four PACE treatment groups increased the glutathione (GSH) and superoxide dismutase (SOD) levels, while concurrently reducing malondialdehyde (MDA), interleukin-1β (IL-1β) and interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) levels. In summary, the current study demonstrates that the four PACE formulations exhibit beneficial anti-AD properties, with the most pronounced efficacy observed in the EA group. Additionally, PAC shows potential in mitigating neuroinflammation and oxidative damage by inhibiting the TLR4/NF-κB signalling pathway. This research lays a theoretical groundwork for the future clinical development and utilisation of PAC in treating AD.