Cerebrospinal Fluid P-tau Research Articles

Clinical value of novel blood-based tau biomarkers in Creutzfeldt-Jakob disease.

The diagnostic and prognostic performance of the novel fluid biomarkers brain-derived tau (BD-tau) and phospho-tau217 (p-tau217) in Creutzfeldt-Jakob disease (CJD) is not defined. We measured cerebrospinal fluid (CSF) and plasma BD-tau, p-tau217, p-tau181, total tau (t-tau), neurofilament light (NfL), and 14-3-3 in 100 CJD patients, 100 with non-prion rapidly progressive dementia (np-RPD), 92 with mild cognitive impairment due to Alzheimer's disease (AD-MCI), and 55 healthy controls (HC). Plasma BD-tau performed comparably to plasma t-tau but had lower performance than CSF t-tau (p<0.001) and 14-3-3 (p=0.014) in CJD versus np-RPD differential diagnosis. Plasma BD-tau diagnostic accuracy increased when ratioed to plasma p-tau217, matching CSF 14-3-3. Plasma BD-tau levels were associated with survival (p<0.001), outperforming t-tau and NfL. Plasma BD-tau is a valuable marker for CJD prognostication. In the clinical setting, the plasma BD-tau/p-tau217 ratio provides an accurate, fast marker supporting the clinical diagnosis of CJD. The increase of plasma BD-tau levels parallels that of CSF t-tau in CJD. CSF p-tau217 levels are significantly increased in CJD, reflecting a prion-specific secondary tauopathy. Plasma p-tau217 shows a distinct profile than CSF p-tau217 in CJD. Plasma BD-tau/p-tau217 ratio is as accurate as CSF 14-3-3 in distinguishing CJD from np-RPDs, including AD. BD-tau represents a valuable blood-based biomarker for CJD prognostication.

Associations among healthy lifestyle characteristics, neuroinflammation, and cerebrospinal fluid core biomarkers of Alzheimer's disease in cognitively intact adults: The CABLE study.

The occurrence of Alzheimer's disease (AD) can be partially prevented through healthy lifestyles, but the mechanisms associated with AD pathology are unclear. To explore associations among healthy lifestyle characteristics (HLCs), cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), and AD biomarkers. From the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, 924 cognitively normal participants were enrolled in this cross-sectional analysis. We defined the following 11 HLCs: appropriate frequencies of coffee and tea consumption, sufficient frequencies of fish and fruit intake, non-social isolation, adequate sleep, regular physical activity, no depression, never smoking, non-hazardous drinking, and well-maintained blood pressure. We categorized participants according to the number of HLCs reported by participants into favorable, intermediate, and unfavorable lifestyle groups. Multiple linear regression was used to investigate the relationship among HLCs, CSF sTREM2, and AD biomarkers. Mediation effects were tested using a causal mediation analysis having 10,000 bootstrap iterations. Included subjects were with a mean age of 61.8 ± 10.2 years, of which 41.8% were female. Sufficient fish intake (β = -0.164, p = 0.017) and well-maintained blood pressure (β = -0.232, p = 0.006) were significantly correlated with lower CSF sTREM2 levels. A larger number of HLCs were associated with lower CSF T-tau (p = 0.001), P-tau (p = 0.012), and sTREM2 (p = 0.040) levels. CSF sTREM2 partially mediated the association between the number of HLCs and CSF tau pathology (mediating proportion T-tau: 22.4%; P-tau: 25.0%). HLCs might impact the pathological processes of AD by regulating neuroinflammation.

The association of the triglyceride-glucose index with Alzheimer's disease and its potential mechanisms.

The correlation between Alzheimer's disease (AD) and the glucose-triglyceride (TyG) index remains undetermined. This study aimed to investigate the relationship between the TyG index and AD, as well as the relationship between the TyG index and cerebrospinal fluid (CSF) AD biomarkers and cognition. Six hundred twenty-eight non-dementia participants were included. The TyG index, pathological markers, and cognitive measures were studied using multiple linear regression. Also calculated using a multivariate Cox regression model were the hazard ratio (HR) and its 95% confidence interval (CI). Ten thousand bootstrap iterative causal mediation analyses were performed to investigate the potential mediating effect of AD pathology on cognition. The TyG index was linked to CSF AD biomarkers (βAβ42 = 0.880; βTau = -0.674; βpTau = -0.884; βAβ42/pTau = 1.764; βAβ42/Tau = 1.554; βpTau/Tau = -0.210) and cognitive measurements (βMEM = 0.570; βEF = 0.535; βADAS11 = -0.789). Mediation analysis revealed that the TyG index may influence cognition via CSF AD biomarkers, including Aβ42, tau, and pTau. Furthermore, each 1-unit increase in TyG index was associated with a 29.5% reduction in the risk of incident AD. A delayed rate of cognitive decline and a reduced risk of AD were found to be correlated with higher levels of the TyG index, but this does not mean increasing TyG index levels is beneficial for health. Through AD pathology, the TyG index may influence AD and cognitive changes.

Association of CSF α-synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer's Disease Neuroimaging Initiative study.

Cerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co-pathology in Alzheimer's disease. A total of 1637 cross-sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α-syn seeds, and phosphorylated tau181 (p-tau181), along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-. SAA+ individuals had faster cognitive decline than SAA-, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p-tau181 status. CSF Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline. These results highlight the interplay between amyloid and α-syn and their association with disease progression. Seed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset. Thirty-four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA- to SAA+, that is, ≈ 5% conversion. SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline. SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers. Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA. SAA kinetic parameters were associated with clinical features and progression.

Sex/gender effects of glial reactivity on preclinical Alzheimer's disease pathology.

Glial reactivity may contribute to sex/gender differences in Alzheimer's disease (AD) pathophysiology. Here, we investigated the differential effect of cerebrospinal fluid (CSF) glial markers on AD pathology and neurodegeneration by sex/gender among cognitively unimpaired older adults at increased risk of developing AD. We included 397 participants from the ALFA+ cohort with CSF Aβ42/40, p-tau181, sTREM2, YKL40, and GFAP, magnetic resonance imaging-based hippocampal volume (n = 299), and amyloid burden (centiloids) measured with [18F] flutemetamol positron emission tomography (n = 341). We ran multiple linear regression models to assess the association between glial markers, AD pathology and hippocampal volumes and their interaction with sex/gender, usingFalse Discovery Rateto correctfor multiple comparisons. Glial markers significantly contributed to explain amyloid burden, tau pathology, and hippocampal volumes, beyond age and/or primary AD pathology in a sex/gender-specific manner. Compared to men, women showed increased amyloid burden (centiloids) and CSF p-tau181 with increasing levels of sTREM2 and YKL40, and YKL40 and GFAP, respectively. Compared to women, men with greater tau burden showed lower hippocampal volumes as CSF YKL40 levels increased. Overall, our findings suggest that glial reactivity may contribute to sex/gender differences in AD progression, mostly, downstream amyloid. Further research identifying sex/gender-specific temporal dynamics in AD development is warranted to inform clinical trials.

Heparin-enriched plasma proteome is significantly altered in Alzheimer’s disease

IntroductionHeparin binding proteins (HBPs) with roles in extracellular matrix assembly are strongly correlated to β-amyloid (Aβ) and tau pathology in Alzheimer’s disease (AD) brain and cerebrospinal fluid (CSF). However, it remains challenging to detect these proteins in plasma using standard mass spectrometry-based proteomic approaches.MethodsWe employed heparin-affinity chromatography, followed by off-line fractionation and tandem mass tag mass spectrometry (TMT-MS), to enrich HBPs from plasma obtained from AD (n = 62) and control (n = 47) samples. These profiles were then correlated to Aβ, tau and phosphorylated tau (pTau) CSF biomarkers and plasma pTau181 from the same individuals, as well as a consensus brain proteome network to assess the overlap with AD brain pathophysiology.ResultsHeparin enrichment from plasma was highly reproducible, enriched well-known HBPs like APOE and thrombin, and depleted high-abundant proteins such as albumin. A total of 2865 proteins, spanning 10 orders of magnitude in abundance, were measured across 109 samples. Compared to the consensus AD brain protein co-expression network, we observed that specific plasma proteins exhibited consistent direction of change in both brain and plasma, whereas others displayed divergent changes, highlighting the complex interplay between the two compartments. Elevated proteins in AD plasma, when compared to controls, included members of the matrisome module in brain that accumulate with Aβ deposits, such as SMOC1, SMOC2, SPON1, MDK, OLFML3, FRZB, GPNMB, and the APOE4 proteoform. Additionally, heparin-enriched proteins in plasma demonstrated significant correlations with conventional AD CSF biomarkers, including Aβ, total tau, pTau, and plasma pTau181. A panel of five plasma proteins classified AD from control individuals with an area under the curve (AUC) of 0.85. When combined with plasma pTau181, the panel significantly improved the classification performance of pTau181 alone, increasing the AUC from 0.93 to 0.98. This suggests that the heparin-enriched plasma proteome captures additional variance in cognitive dementia beyond what is explained by pTau181.ConclusionThese findings support the utility of a heparin-affinity approach coupled with TMT-MS for enriching amyloid-associated proteins, as well as a wide spectrum of plasma biomarkers that reflect pathological changes in the AD brain.

Novel targets for the treatment and prevention of Alzheimer's disease in the European population, inspiration from amyloid beta and tau protein

Alzheimer's disease (AD) is a gradual neurodegenerative ailment that lacks any disease-modifying intervention. Our objective was to pinpoint pharmacological targets with a focus on amyloid beta (Aβ) and tau to treat and prevent AD in the European population. A proteome-wide Mendelian randomization (MR) analysis was carried out to estimate the associations between proteins and cerebrospinal fluid (CSF) Aβ-42 and phosphorylated Tau (p-Tau). We utilized colocalization and MR analysis to investigate whether the identified proteins were associated with the risk of AD. Additionally, we expanded our investigation to include non-AD phenotypes by conducting a phenome-wide MR analysis of 1646 disease traits based on the FinnGen and UK Biobank databases to explore potential side effects. We identified 11 proteins that were genetically associated with both CSF Aβ-42 and p-Tau levels. The genetically predicted levels of three proteins, GAL3ST2, POLR1C, and BIN1, were found to be associated with an increased risk of AD with high colocalization. In the phenome-wide MR analysis, two out of the three biomarkers were associated with at least one disease, except for GAL3ST2, which was not associated with any disease under the threshold of FDR <0.1. POLR1C was found to be associated with the most disease traits, and all disease associations with genetically inhibited BIN1 were protective. The proteome-wide MR investigation revealed 11 proteins that were associated with the level of CSF Aβ-42 and p-Tau. Among them, GAL3ST2, POLR1C, and BIN1 were identified as potential therapeutic targets for AD and warrant further investigation.

Diagnostic accuracy of automated Lumipulse plasma pTau-217 in Alzheimer's disease: a real-world study.

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. 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. 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. 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.

Alzheimer's Disease-Related Cerebrospinal Fluid Biomarkers in Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is the most common four-repeat tauopathy. PSP cases are typically characterized by vertical gaze palsy and postural instability; however, various phenotypes have been reported, making antemortem diagnosis based on clinical symptoms challenging. The development of biomarkers reflecting brain pathology and the ability to diagnose patients based on these biomarkers are essential for developing future intervention strategies, including disease-modifying therapies. However, despite many dedicated efforts, no highly specific fluid biomarker for PSP has yet been established. Conversely, several cerebrospinal fluid (CSF) biomarkers of Alzheimer's Disease (AD) have been established, and an AT(N) classification system has been proposed. Typically, among patients with AD, CSF amyloid β42 (Aβ42), but not Aβ40, is decreased, resulting in a reduction in the Aβ42/Aβ40 ratio, while tau phosphorylated at threonine 181 (p-tau181) and total tau (t-tau) are increased. Interestingly, the core CSF AD biomarkers show unique patterns in patients with PSP. Furthermore, reports have indicated that the CSF levels of both Aβ42 and Aβ40 are decreased independently of Aβ accumulation in PSP. Therefore, the Aβ42/Aβ40 ratio could potentially be used to differentiate PSP from AD. Additionally, studies have reported that CSF p-tau and t-tau are reduced in PSP, and that the neurofilament light chain is remarkably increased compared to healthy controls and patients with AD, even though PSP is a neurodegenerative disease associated with tau accumulation. These PSP-specific changes in AD-related core biomarkers may reflect the pathology of PSP and contribute to its diagnosis. As such, elucidating the mechanisms underlying the observed decreases in Aβ and tau levels could facilitate a better understanding of the pathogenesis of PSP.

The Alzheimer's Association Global Biomarker Standardization Consortium (GBSC) plasma phospho-tau Round Robin study.

Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer's disease (AD) pathology. Multiple p-tau biomarkers on several analytical platforms are poised for clinical use. The Alzheimer's Association Global Biomarker Standardisation Consortium plasma phospho-tau Round Robin study engaged assay developers in a blinded case-control study on plasma p-tau, aiming to learn which assays provide the largest fold-changes in AD compared to non-AD, have the strongest relationship between plasma and cerebrospinal fluid (CSF), and show the most consistent relationships between methods (commutability) in measuring both patient samples and candidate reference materials (CRM). Thirty-three different p-tau biomarker assays, built on eight different analytical platforms, were used to quantify paired plasma and CSF samples from 40 participants. AD biomarker status was categorised as "AD pathology" (n=25) and "non-AD pathology" (n=15) by CSF Aβ42/Aβ40 (US-FDA; CE-IVDR) and p-tau181 (CE-IVDR) methods. The commutability of four CRM, at three concentrations, was assessed across assays. Plasma p-tau217 consistently demonstrated higher fold-changes between AD and non-AD pathology groups, compared to other p-tau epitopes. Fujirebio LUMIPULSE G, UGOT IPMS, and Lilly MSD p-tau217 assays provided the highest median fold-changes. In CSF, p-tau217 assays also performed best, and exhibited substantially larger fold-changes than their plasma counterparts, despite similar diagnostic performance. P-tau217 showed the strongest correlations between plasma assays (rho=0.81 to 0.97). Plasma p-tau levels were weakly-to-moderately correlated with CSF p-tau, and correlations were non-significant within the AD group alone. The evaluated CRM were not commutable across assays. Plasma p-tau217 measures had larger fold-changes and discriminative accuracies for detecting AD pathology, and better agreement across platforms than other plasma p-tau variants. Plasma and CSF markers of p-tau, measured by immunoassays, are not substantially correlated, questioning the interchangeability of their continuous relationship. Further work is warranted to understand the pathophysiology underlying this dissociation, and to develop suitable reference materials facilitating cross-assay standardisation. Alzheimer's Association (#ADSF-24-1284328-C).

In Vivo Prevalence of Beta-Amyloid Pathology and Alzheimer's Disease Co-Pathology in Idiopathic Normal-Pressure Hydrocephalus-Association with Neuropsychological Features.

Idiopathic normal-pressure hydrocephalus (iNPH) is a clinic-radiological neurological syndrome presenting with cognitive deficits, gait disturbances and urinary incontinence. It often coexists with Alzheimer's disease (AD). Due to the reversible nature of iNPH when promptly treated, a lot of studies have focused on possible biomarkers, among which are cerebrospinal fluid (CSF) biomarkers. The aim of the present study was to determine the rate of beta-amyloid pathology and AD co-pathology by measuring AD CSF biomarkers, namely, amyloid beta with 42 and 40 amino acids (Aβ42), the Aβ42/Aβ40 ratio, total Tau protein (t-Tau) and phosphorylated Tau protein at threonine 181 (p-Tau), in a cohort of iNPH patients, as well as to investigate the possible associations among CSF biomarkers and iNPH neuropsychological profiles. Fifty-three patients with iNPH were included in the present study. CSF Aβ42, Aβ40, t-Tau and p-Tau were measured in duplicate with double-sandwich ELISA assays. The neuropsychological evaluation consisted of the Mini-Mental State Examination, Frontal Assessment Battery, Five-Word Test and CLOX drawing tests 1 and 2. After statistical analysis, we found that amyloid pathology and AD co-pathology are rather common in iNPH patients and that higher values of t-Tau and p-Tau CSF levels, as well as the existence of the AD CSF profile, are associated with more severe memory impairment in the study patients. In conclusion, our study has confirmed that amyloid pathology and AD-co-pathology are rather common in iNPH patients and that CSF markers of AD pathology and t-Tau are associated with a worse memory decline in these patients.

Performance of plasma p-tau217 for the detection of amyloid-β positivity in a memory clinic cohort using an electrochemiluminescence immunoassay

BackgroundPlasma p-tau217 has emerged as the most promising blood-based marker (BBM) for the detection of Alzheimer Disease (AD) pathology, yet few studies have evaluated plasma p-tau217 performance in memory clinic settings. We examined the performance of plasma p-tau217 for the detection of AD using a high-sensitivity immunoassay in individuals undergoing diagnostic lumbar puncture (LP).MethodsPaired plasma and cerebrospinal fluid (CSF) samples were analysed from the TIMC-BRAiN cohort. Amyloid (Aβ) and Tau (T) pathology were classified based on established cut-offs for CSF Aβ42 and CSF p-tau181 respectively. High-sensitivity electrochemiluminescence (ECL) immunoassays were performed on paired plasma/CSF samples for p-tau217, p-tau181, Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light (NfL) and total tau (t-tau). Biomarker performance was evaluated using Receiver-Operating Curve (ROC) and Area-Under-the-Curve (AUC) analysis.ResultsOf 108 participants (age: 69 ± 6.5 years; 54.6% female) with paired samples obtained at time of LP, 64.8% (n = 70/108) had Aβ pathology detected (35 with Mild Cognitive Impairment and 35 with mild dementia). Plasma p-tau217 was over three-fold higher in Aβ + (12.4 pg/mL; 7.3—19.2 pg/mL) vs. Aβ- participants (3.7 pg/mL; 2.8—4.1 pg/mL; Mann–Whitney U = 230, p < 0.001). Plasma p-tau217 exhibited excellent performance for the detection of Aβ pathology (AUC: 0.91; 95% Confidence Interval [95% CI]: 0.86–0.97)—greater than for T pathology (AUC: 0.83; 95% CI: 0.75–0.90; z = 1.75, p = 0.04). Plasma p-tau217 outperformed plasma p-tau181 for the detection of Aβ pathology (z = 3.24, p < 0.001). Of the other BBMs, only plasma GFAP significantly differed by Aβ status which significantly correlated with plasma p-tau217 in Aβ + (but not in Aβ-) individuals. Application of a two-point threshold at 95% and 97.5% sensitivities & specificities may have enabled avoidance of LP in 58–68% of cases.ConclusionsPlasma p-tau217 measured using a high-sensitivity ECL immunoassay demonstrated excellent performance for detection of Aβ pathology in a real-world memory clinic cohort. Moving forward, clinical use of plasma p-tau217 to detect AD pathology may substantially reduce need for confirmatory diagnostic testing for AD pathology with diagnostic LP in specialist memory services.

Myo-inositol and total NAA in the hippocampus are linked to CSF tau pathology in cognitively normal older adults.

Understanding relationships between in vivo neurometabolic changes and Alzheimer's disease (AD) pathology in the hippocampus, a region vulnerable to early changes in AD, will support early diagnosis. Two studies using 1 H-MRS examined concentrations of myo-inositol (MI), total creatine (tCr) and total NAA (tNAA) in the hippocampus. The first study compared hippocampal metabolite concentrations in healthy young and older adults and the second study assessed relationships between hippocampal metabolites and cerebrospinal fluid (CSF) measurements of Aβ42, phosphotau 181 (pTau181), and total tau (t-Tau) while adjusting for demographic covariates and spectral characteristics (linewidth, signal- to-noise ratio) in a separate group of older adults ranging from cognitively normal (CN) to AD-dementia. Hippocampal MI, but not tCr or tNAA, was increased in cognitively normal older versus young adults. Within the second older adult group, MI and tNAA, but not tCr, were linked to increases in CSF pTau181 and t-Tau, but not Aβ42. Tau deposition in cognitively normal individuals is associated with biochemical changes related to glial reactivity and neural integrity in the hippocampus.

Associations Between Free and Cued Selective Reminding Test and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment.

The Free and Cued Selective Reminding Test (FCSRT), assessing verbal episodic memory with controlled learning and semantic cueing, has been recommended for detecting the genuine encoding and storage deficits characterizing AD-related memory disorders. The present study aims at investigating the ability of FCSRT in predicting cerebrospinal fluid (CSF) evidence of amyloid-β positivity in subjects with amnestic mild cognitive impairment (aMCI) and exploring its associations with amyloidopathy, tauopathy and neurodegeneration biomarkers. 120 aMCI subjects underwent comprehensive neurological and neuropsychological examinations, including the FCSRT assessment, and CSF collection; CSF Aβ42/40 ratio, p-tau181, and total-tau quantification were conducted by an automated CLEIA method on Lumipulse G1200. Based on the Aβ42/40 ratio value, subjects were classified as either A+ or A-. All FCSRT subitem scores were significantly lower in A+ group and significantly predicted the amyloid-β status, with Immediate Total Recall (ITR) being the best predictor. No significant correlations were found between FCSRT and CSF biomarkers in the A- aMCI group, while in the A+ aMCI group, all FCSRT subitem scores were negatively correlated with CSF p-tau181 and total-tau, but not with the Aβ42/40 ratio. FCSRT confirms its validity as a tool for the diagnosis of AD, being able to predict the presence of amyloid-β deposition with high specificity. The associations between FCSRT subitem scores and CSF p-tau-181 and total-tau levels in aMCI due to AD could further encourage the clinical use of this simple and cost-effective test in the evaluation of individuals with aMCI.

Plasma Insulin Predicts Early Amyloid-β Pathology Changes in Alzheimer's Disease.

Evidence suggests that type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD), sharing similar pathophysiological traits like impaired insulin signaling. To test the association between plasma insulin and cerebrospinal fluid (CSF) AD pathology. A total of 304 participants were included in the Alzheimer's Disease Neuroimaging Initiative, assessing plasma insulin and CSF AD pathology. We explored the cross-sectional and longitudinal associations between plasma insulin and AD pathology and compared their associations across different AD clinical and pathological stages. In the non-demented group, amyloid-β (Aβ)+ participants (e.g., as reflected by CSF Aβ42) exhibited significantly lower plasma insulin levels compared to non-demented Aβ-participants (p < 0.001). This reduction in plasma insulin was more evident in the A+T+ group (as shown by CSF Aβ42 and pTau181 levels) when compared to the A-T- group within the non-dementia group (p = 0.002). Additionally, higher plasma insulin levels were consistently associated with more normal CSF Aβ42 levels (p < 0.001) across all participants. This association was particularly significant in the Aβ-group (p = 0.002) and among non-demented individuals (p < 0.001). Notably, baseline plasma insulin was significantly correlated with longitudinal changes in CSF Aβ42 (p = 0.006), whereas baseline CSF Aβ42 did not show a similar correlation with changes in plasma insulin over time. These findings suggest an association between plasma insulin and early Aβ pathology in the early stages of AD, indicating that plasma insulin may be a potential predictor of changes in early Aβ pathology.

Cerebrospinal fluid p-tau181, 217, and 231 in definite Creutzfeldt-Jakob disease with and without concomitant pathologies.

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. 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. 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). Variable fold-changes and correlation with t-tau suggest that p-tau closely associates with neurodegeneration and concomitant AD in CJD. 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.

Effects of time of the day at sampling on CSF and plasma levels of Alzheimer’ disease biomarkers

BackgroundStudies suggest that cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)42 and Aβ40 present a circadian rhythm. However sustained sampling of large volumes of CSF with indwelling intrathecal catheters used in most of these studies might have affected CSF dynamics and thereby confounded the observed fluctuations in the biomarker levels.MethodsWe included 38 individuals with either normal (N = 20) or abnormal (N = 18) CSF Aβ42/Aβ40 levels at baseline. CSF and plasma were collected at two visits separated by an average of 53 days with lumbar punctures and venipunctures performed either in the morning or evening. At the first visit, sample collection was performed in the morning for 17 participants and the order was reversed for the remaining 21 participants. CSF and plasma samples were analyzed for Alzheimer’ disease (AD) biomarkers, including Aβ42, Aβ40, GFAP, NfL p-tau181, p-tau217, p-tau231 and t-tau. CSF samples were also tested using mass spectrometry for 22 synaptic and endo-lysosomal proteins.ResultsCSF Aβ42 (mean difference [MD], 0.21 ng/mL; p = 0.038), CSF Aβ40 (MD, 1.85 ng/mL; p < 0.001), plasma Aβ42 (MD, 1.65 pg/mL; p = 0.002) and plasma Aβ40 (MD, 0.01 ng/mL, p = 0.002) were increased by 4.2-17.0% in evening compared with morning samples. Further, CSF levels of 14 synaptic and endo-lysosomal proteins, including neurogranin and neuronal pentraxin-1, were increased by 4.5-13.3% in the evening samples (MDrange, 0.02-0.56 fmol/µl; p < 0.042). However, no significant differences were found between morning and evening levels for the Aβ42/Aβ40 ratio, different p-tau variants, GFAP and NfL. There were no significant interaction between sampling time and Aβ status for any of the biomarkers, except that CSF t-tau was increased (by 5.74%) in the evening samples compared to the morning samples in Aβ-positive (MD, 16.46 ng/ml; p = 0.009) but not Aβ-negative participants (MD, 1.89 ng/ml; p = 0.47). There were no significant interactions between sampling time and order in which samples were obtained.DiscussionOur findings provide evidence for diurnal fluctuations in Aβ peptide levels, both in CSF and plasma, while CSF and plasma p-tau, GFAP and NfL were unaffected. Importantly, Aβ42/Aβ40 ratio remained unaltered, suggesting that it is more suitable for implementation in clinical workup than individual Aβ peptides. Additionally, we show that CSF levels of many synaptic and endo-lysosomal proteins presented a diurnal rhythm, implying a build-up of neuronal activity markers during the day. These results will guide the development of unified sample collection procedures to avoid effects of diurnal variation for future implementation of AD biomarkers in clinical practice and drug trials.

CSF and plasma biomarkers in cerebral amyloid angiopathy: A single-center study and a systematic review/meta-analysis.

There are limited data regarding cerebrospinal fluid (CSF) and plasma biomarkers among patients with Cerebral Amyloid Angiopathy (CAA). We sought to investigate the levels of four biomarkers [β-amyloids (Aβ42 and Aβ40), total tau (tau) and phosphorylated tau (p-tau)] in CAA patients compared to healthy controls (HC) and patients with Alzheimer Disease (AD). A systematic review and meta-analysis of published studies, including also a 5 year single-center cohort study, with available data on CSF and plasma biomarkers in symptomatic sporadic CAA versus HC and AD was conducted. Biomarkers' comparisons were investigated using random-effects models based on the ratio of mean (RoM) biomarker concentrations. RoM < 1 and RoM > 1 indicate lower and higher biomarker concentration in CAA compared to another population, respectively. We identified nine cohorts, comprising 327 CAA patients (mean age: 71 ± 5 years; women: 45%) versus 336 HC (mean age: 65 ± 5 years; women: 45%) and 384 AD patients (mean age: 68 ± 3 years; women: 53%) with available data on CSF biomarkers. CSF Aβ42 levels [RoM: 0.47; 95% CI: 0.36-0.62; p < 0.0001], Aβ40 levels [RoM: 0.70; 95% CI: 0.63-0.79; p < 0.0001] and the ratio Aβ42/Aβ40 [RoM: 0.62; 95% CI: 0.39-0.98; p = 0.0438] differentiated CAA from HC. CSF Aβ40 levels [RoM: 0.73; 95% CI: 0.64-0.83; p = 0.0003] differentiated CAA from AD. CSF tau and p-tau levels differentiated CAA from HC [RoM: 1.71; 95% CI: 1.41-2.09; p = 0.0002 and RoM: 1.44; 95% CI: 1.20-1.73; p = 0.0014, respectively] and from AD [RoM: 0.65; 95% CI: 0.58-0.72; p < 0.0001 and RoM: 0.64; 95% CI: 0.57-0.71; p < 0.0001, respectively]. Plasma Aβ42 [RoM: 1.14; 95% CI: 0.89-1.45; p = 0.2079] and Aβ40 [RoM: 1.07; 95% CI: 0.91-1.25; p = 0.3306] levels were comparable between CAA and HC. CAA is characterized by a distinct CSF biomarker pattern compared to HC and AD. CSF Aβ40 levels are lower in CAA compared to HC and AD, while tau and p-tau levels are higher in CAA compared to HC, but lower in comparison to AD patients.

Blood Cathepsins on the Risk of Alzheimer’s Disease and Related Pathological Biomarkers: Results from Observational Cohort and Mendelian Randomization Study

BackgroundAlzheimer’s disease (AD), the main type of dementia, involves in complex pathophysiological processes, including abnormal lysosomes function. Cathepsins are the predominant proteases responsible for the degradation of diverse substrates in the endo-lysosomal system. However, there was still a lack of systematic study on the causal association between cathepsins and AD.MethodsThis study utilized Mendelian randomization (MR) to investigate the association between blood cathepsins and the risk of AD, as well as the level of amyloid-β (Aβ) and p-Tau in cerebrospinal fluid. Furthermore, an independent dataset was employed to corroborate the above result. Importantly, this study incorporated the Alzheimer’s disease Immunization and Microbiota Initiative study Cohort to further validate the alteration of blood cathepsins expression level and examine its correlation with cognitive level and plasma AD-related pathological markers.ResultsUsing MR method, we observed that high level of cathepsin L (CTSL) was associated with a lower risk of AD in both training and validation data. In observational cohort, we found there was decreased blood CTSL expression level in Aβ+ cognitive impaired (CI) group, compared with Aβ− cognitive unimpaired (CU) group. Correlation analysis revealed that blood CTSL expression level was negatively correlated with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) score, plasma Aβ42 and Aβ42/40 level in Aβ+ CI group. Mediation analysis showed that plasma Aβ42/40 level was the key mediator in the association between blood CTSL and MMSE score in Aβ+ CI participants.ConclusionThis study revealed that blood CTSL was an important factor affecting the risk of AD, and it affected the cognitive level of AD patients through plasma Aβ42/40 level.

Awareness of episodic memory and meta-cognitive profiles: associations with cerebrospinal fluid biomarkers at the preclinical stage of the Alzheimer's continuum.

The lack of cognitive awareness, anosognosia, is a clinical deficit in Alzheimer's disease (AD) dementia. However, an increased awareness of cognitive function, hypernosognosia, may serve as a marker in the preclinical stage. Subjective cognitive decline (SCD) might correspond to the initial symptom in the dynamic trajectory of awareness, but SCD might be absent along with low awareness of actual cognitive performance in the preclinical stage. We hypothesized that distinct meta-cognitive profiles, both hypernosognosia and anosognosia, might be identified in preclinical-AD. This research evaluated the association between cerebrospinal fluid (CSF) AD biomarkers and the awareness of episodic memory, further exploring dyadic (participant-partner) SCD reports, in the preclinical Alzheimer's continuum. We analyzed 314 cognitively unimpaired (CU) middle-aged individuals (mean age: 60, SD: 4) from the ALFA+ cohort study. Episodic memory was evaluated with the delayed recall from the Memory Binding Test (MBT). Awareness of episodic memory, meta-memory, was defined as the normalized discrepancy between objective and subjective performance. SCD was defined using self-report, and dyadic SCD profiles incorporated the study partner's report using parallel SCD-Questionnaires. The relationship between CSF Aβ42/40 and CSF p-tau181 with meta-memory was evaluated with multivariable regression models. The role of SCD and the dyadic contingency was explored with the corresponding stratified analysis. CSF Aβ42/40 was non-linearly associated with meta-memory, showing an increased awareness up to Aβ-positivity and a decreased awareness beyond this threshold. In the non-SCD subset, the non-linear association between CSF Aβ42/40 and meta-memory persisted. In the SCD subset, higher Aβ-pathology was linearly associated with increased awareness. Individuals presenting only study partner's SCD, defined as unaware decliners, exhibited higher levels of CSF p-tau181 correlated with lower meta-memory performance. These results suggested that distinct meta-cognitive profiles can be identified in preclinical-AD. While most individuals might experience an increased awareness associated with the entrance in the AD continuum, hypernosognosia, some might be already losing insight and stepping into the anosognosic trajectory. This research reinforced that an early anosognosic profile, although at increased risk of AD-related decline, might be currently overlooked considering actual diagnostic criteria, and therefore its medical attention delayed.