CSF and Plasma Biomarkers in Patients With Iatrogenic Cerebral Amyloid Angiopathy.

OBJECTIVES: Recently, a subset of patients affected by cerebral amyloid angiopathy (CAA) distinguished by atypical juvenile onset and a hypothesized iatrogenic origin (iatrogenic CAA, iCAA) has emerged. ß-Amyloid (Aß) accumulation evidenced by amyloid PET positivity or CSF Aß decrease was included in the iCAA diagnostic criteria. Conversely, diagnostic criteria for sporadic CAA (sCAA) do not involve biomarker analysis. The aim of this study was to assess CSF and plasma levels of Aß and tau in iCAA and sCAA cohorts. METHODS: Patients affected by probable or possible CAA according to established criteria (Boston 2.0) were prospectively recruited at Fondazione IRCCS Carlo Besta and San Gerardo dei Tintori from May 2021 to January 2024. Patients with probable and possible iCAA or sCAA with available plasma and/or CSF samples were included. Clinical and neurologic data were collected, and levels of Aß40, Aß42, total tau, and phospho-tau (p-tau) were assessed in CSF and plasma by SiMoA and Lumipulse. RESULTS: 21 patients with iCAA (72% male, mean age at symptom onset 50 years [36-74]) and 32 patients with sCAA (44% male, mean age at symptom onset 68 years [52-80]) were identified. Cognitive impairment and cardiovascular risk factors in the sCAA cohort were more common compared with the iCAA cohort. Patients with sCAA and iCAA showed similar CSF levels for Aß40 (p = 0.5 [sCAA, 95% CI 2,604-4,228; iCAA, 95% CI 1,958-3,736]), Aß42 (p = 0.7 [sCAA, 95% CI 88-157; iCAA, 95% CI 83-155]), and total tau (p = 0.08 [sCAA, 95% CI 80-134; iCAA, 95% CI 37-99]). Plasma levels of Aß40 (p = 0.08, 95% CI 181-222), Aß42 (p = 0.3, 95% CI 6-8), and total tau (p = 0.4, 95% CI 3-6) were not statistically different in patients with sCAA compared with iCAA ones (Aß40, 95% CI 153-193; Aß42, 95% CI 6-7 and total tau, 95% CI 2-4). DISCUSSION: Despite presenting with a younger age at onset, fewer cardiovascular risk factors, and lower cognitive impairment, patients with iCAA demonstrated Aß and tau levels comparable with elderly patients with sCAA, supporting a common molecular paradigm between the 2 CAA forms.

Phosphorylated Tau at T181 accumulates in the serum of hibernating Syrian hamsters and rapidly disappears after arousal.

The search for biomarkers for the early diagnosis of neurodegenerative diseases is a growing area. Numerous investigations are exploring minimally invasive and cost-effective biomarkers, with the detection of phosphorylated Tau (pTau) protein emerging as one of the most promising fields. pTau is the main component of the paired helical filaments found in the brains of Alzheimer's disease cases and serves as a precursor in the formation of neurofibrillary tangles (NFTs). Recent research has revealed that analysis of p-Tau181, p-Tau217 and p-Tau231 in blood may be an option for detecting the preclinical stage of Alzheimer's disease. In this study, we have analyzed the values of pTau 181 in the serum of Syrian hamsters during hibernation. Naturally, over the course of hibernation, these animals exhibit a reversible accumulation of pTau in the brain tissue, which rapidly disappears upon awakening. A biosensing system based on the interferometric optical detection method was used to measure the concentration of pTau181 protein in serum samples from Syrian hamsters. This method eliminates the matrix effect and amplifies the signal obtained by using silicon dioxide nanoparticles (SiO2 NPs) biofunctionalized with the αpTau181 antibody. Our results indicate a substantial increase in the serum concentration of pTau in threonine-181 during hibernation, which disappears completely 2-3 h after awakening. Investigating the mechanism by which pTau protein appears in the blood non-pathologically may enhance current diagnostic techniques. Furthermore, since this process is reversible, and no tangles are detected in the brains of hibernating hamsters, additional analysis may contribute to the discovery of improved biomarkers. Additionally, exploring drugs targeting pTau to prevent the formation of tangles or studying the outcomes of any pTau-targeted treatment could be valuable.

In-situ nanozyme catalytic amplification coupled with a universal antibody orientation strategy based electrochemical immunosensor for AD-related biomarker.

An in-situ nanozyme signal tag combined with a DNA-mediated universal antibody-oriented strategy was proposed to establish a high-performance immunosensing platform for Alzheimer's disease (AD)-related biomarker detection. Briefly, a Zr-based metal-organic framework (MOF) with peroxidase (POD)-like activity was synthesized to encapsulating the electroactive molecule methylene blue (MB), and subsequently modified with a layer of gold nanoparticles on its surface. This led to the creation of double POD-like activity nanozymes surrounding the MB molecule to form a nanozyme signal tag. A large number of hydroxyl radicals were generated by the nanozyme signal tag with the help of H2O2, which catalyzed MB molecules in situ to achieve efficient signal amplification. Subsequently, a DNA-aptamer-mediated universal antibody-oriented strategy was proposed to enhance the binding efficiency for the antigen (target). Meanwhile, a poly adenine was incorporated at the end of the aptamer, facilitating binding to the gold electrode and providing anti-fouling properties due to the hydrophilicity of the phosphate group. Under optimal conditions, this platform was successfully employed for highly sensitive detection of AD-associated tau protein and BACE1, achieving limits of detection with concentrations of 3.34 fg/mL and 1.67 fg/mL, respectively. It is worth mentioning that in the tau immunosensing mode, 20 clinical samples from volunteers of varying ages were analyzed, revealing significantly higher tau expression levels in the blood samples of elderly volunteers compared to young volunteers. This suggests that the developed strategy holds great promise for early AD diagnosis.

Plasma markers of neurodegeneration, latent cognitive abilities and physical activity in healthy aging.

Blood-based biomarkers of neurodegeneration demonstrate great promise for the diagnosis and prognosis of Alzheimer's disease. Ultra-sensitive plasma assays now allow for quantification of the lower concentrations in cognitively unimpaired older adults, making it possible to investigate whether these markers can provide insight also into the early neurodegenerative processes that affect cognitive function and whether the markers are influenced by modifiable risk factors. Adopting an exploratory approach in 93 healthy older adults (65-75 years), we used structural equation modelling to investigate cross-sectional associations between multiple latent cognitive abilities (working memory, episodic memory, spatial and verbal reasoning) and plasma amyloid beta (Aß42/Aß40 ratio), phosphorylated-tau 181 (ptau-181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL), as well as the influence of device-measured habitual physical activity on these associations. The results showed that NfL was negatively associated with working memory, and that NfL interacted with moderate-to-vigorous physical activity in its association with episodic memory. The study has thereby demonstrated the potential of neurodegenerative plasma markers for improving understanding of normative cognitive aging and encourages future research to test the hypothesis that high levels of NfL, indicative of white matter pathology, limit the beneficial effect of physical activity on episodic memory in healthy aging.

A prediction model of dementia conversion for mild cognitive impairment by combining plasma pTau181 and structural imaging features.

AIMS: The early stages of Alzheimer's disease (AD) are no longer insurmountable. Therefore, identifying at-risk individuals is of great importance for precise treatment. We developed a model to predict cognitive deterioration in patients with mild cognitive impairment (MCI). METHODS: Based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we constructed models in a derivation cohort of 761 participants with MCI (138 of whom developed dementia at the 36th month) and verified them in a validation cohort of 353 cognitively normal controls (54 developed MCI and 19 developed dementia at the 36th month). In addition, 1303 participants with available AD cerebrospinal fluid core biomarkers were selected to clarify the ability of the model to predict AD core features. We assessed 32 parameters as candidate predictors, including clinical information, blood biomarkers, and structural imaging features, and used multivariable logistic regression analysis to develop our prediction model. RESULTS: Six independent variables of MCI deterioration were identified: apolipoprotein E ε4 allele status, lower Mini-Mental State Examination scores, higher levels of plasma pTau181, smaller volumes of the left hippocampus and right amygdala, and a thinner right inferior temporal cortex. We established an easy-to-use risk heat map and risk score based on these risk factors. The area under the curve (AUC) for both internal and external validations was close to 0.850. Furthermore, the AUC was above 0.800 in identifying participants with high brain amyloid-ß loads. Calibration plots demonstrated good agreement between the predicted probability and actual observations in the internal and external validations. CONCLUSION: We developed and validated an accurate prediction model for dementia conversion in patients with MCI. Simultaneously, the model predicts AD-specific pathological changes. We hope that this model will contribute to more precise clinical treatment and better healthcare resource allocation.

[Blood Biomarkers for Alzheimer's Disease: Current Status and Prospects].

Blood biomarkers are minimally invasive, are available at a relatively low cost, and are easily accessible; therefore, they are expected to play a pivotal role in the diagnosis of dementia. Measurement of the amyloid-ß ratio and phosphorylated tau in plasma has shown high potential for accurate detection of brain pathology in patients with Alzheimer's disease. Studies have investigated blood biomarkers that reflect neurodegeneration and neuroinflammation in patients with dementia. Challenges associated with blood biomarker use include the lack of robustness of the test and the role of confounders that potentially prevent their immediate clinical application. Further real-world studies are warranted to validate the usefulness of blood biomarkers in dementia management. Appropriate recommendations for the use of blood biomarkers for dementia have been published for physicians and investigators, both in Japan and overseas. Considering the versatility of blood biomarkers, they should be cautiously introduced for clinical use.

P-tau217 and other blood biomarkers of dementia: variation with time of day.

Plasma biomarkers of dementia, including phosphorylated tau (p-tau217), offer promise as tools for diagnosis, stratification for clinical trials, monitoring disease progression, and assessing the success of interventions in those living with Alzheimer's disease. However, currently, it is unknown whether these dementia biomarker levels vary with the time of day, which could have implications for their clinical value. In two protocols, we studied 38 participants (70.8 ± 7.6 years; mean ± SD) in a 27-h laboratory protocol with either two samples taken 12 h apart or 3-hourly blood sampling for 24 h in the presence of a sleep-wake cycle. The study population comprised people living with mild Alzheimer's disease (PLWA, n = 8), partners/caregivers of PLWA (n = 6) and cognitively intact older adults (n = 24). Single-molecule array technology was used to measure phosphorylated tau (p-tau217) (ALZpath), amyloid-beta 40 (Aß40), amyloid-beta 42 (Aß42), glial fibrillary acidic protein, and neurofilament light (NfL) (Neuro 4-Plex E). Analysis with a linear mixed model (SAS, PROC MIXED) revealed a significant effect of time of day for p-tau217, Aß40, Aß42, and NfL, and a significant effect of participant group for p-tau217. For p-tau217, the lowest levels were observed in the morning upon waking and the highest values in the afternoon/early evening. The magnitude of the diurnal variation for p-tau217 was similar to the reported increase in p-tau217 over one year in amyloid-ß-positive mild cognitively impaired people. Currently, the factors driving this diurnal variation are unknown and could be related to sleep, circadian mechanisms, activity, posture, or meals. Overall, this work implies that the time of day of sample collection may be relevant in the implementation and interpretation of plasma biomarkers in dementia research and care.

Plasma Biomarkers of Traumatic Brain Injury in Adolescents With Sport-Related Concussion.

Importance: Blood-based biomarkers may clarify underlying neuropathology and potentially assist in clinical management of adolescents with sport-related concussion (SRC). Objective: To investigate the association between SRC and plasma biomarkers in adolescents. Design, Setting, and Participants: Prospective cohort study in Canadian sport and clinic settings (Surveillance in High Schools and Community Sport to Reduce Concussions and Their Consequences study; September 2019 to November 2022). Participants were a convenience sample of 849 adolescent (ages 10-18 years) sport participants with blood samples. Data were analyzed from February to September 2023. Exposures: Blood collection and clinical testing preseason (uninjured) and post-SRC follow-ups (ie, ≤72 hours, 1 week, and biweekly until medical clearance to return to play [RTP]). Main Outcomes and Measures: Plasma glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase-L1 (UCH-L1), neurofilament light (NfL), and total tau (t-tau) were assayed. Group-level comparisons of biomarker levels were conducted between uninjured and post-SRC intervals (postinjury day [PID] 0-3, 4-10, 11-28, and >28) considering age and sex as modifiers. Secondary analyses explored associations between biomarker concentrations and clinical outcomes (Sport Concussion Assessment Tool, Fifth Edition [SCAT5] symptom scores and time to RTP). Results: This study included 1023 plasma specimens from 695 uninjured participants (467 male participants [67.2%]; median [IQR] age, 15.90 [15.13-16.84] years) and 154 participants with concussion (78 male participants [51.0%]; median [IQR] age, 16.12 [15.31-17.11] years). Acute (PID 0-3) differences relative to uninjured levels were found for GFAP (female participants: 17.8% increase; ß = 0.164; 95% CI, 0.064 to 0.263; P = .001; male participants: 17.1% increase; ß = 0.157; 95% CI, 0.086 to 0.229; P < .001), UCH-L1 (female participants: 43.4% increase; ß = 0.361; 95% CI, 0.125 to 0.596; P = .003), NfL (male participants: 19.0% increase; ß = 0.174; 95% CI, 0.087 to 0.261; P < .001), and t-tau (female participants: -22.9%; ß = -0.260; 95% CI, -0.391 to -0.130; P < .001; male participants: -18.4%; ß = -0.203; 95% CI, -0.300 to -0.106; P < .001). Differences were observed for all biomarkers at PID 4 to 10, 11 to 28, and greater than 28 compared with uninjured groups. GFAP, NfL, and t-tau were associated with SCAT5 symptom scores across several PID intervals. Higher GFAP after 28 days post-SRC was associated with earlier clearance to RTP (hazard ratio, 4.78; 95% CI, 1.59 to 14.31; P = .01). Male participants exhibited lower GFAP (-9.7%), but higher UCH-L1 (21.3%) compared with female participants. Age was associated with lower GFAP (-5.4% per year) and t-tau (-5.3% per year). Conclusions and Relevance: In this cohort study of 849 adolescents, plasma biomarkers differed between uninjured participants and those with concussions, supporting their continued use to understand concussion neuropathology. Age and sex are critical considerations as these biomarkers progress toward clinical validation.

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

BACKGROUND: Plasma 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). METHODS: Paired plasma and cerebrospinal fluid (CSF) samples were analysed from the TIMC-BRAiN cohort. Amyloid (Aß) and Tau (T) pathology were classified based on established cut-offs for CSF Aß42 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. RESULTS: Of 108 participants (age: 69 ± 6.5 years; 54.6% female) with paired samples obtained at time of LP, 64.8% (n = 70/108) had Aß pathology detected (35 with Mild Cognitive Impairment and 35 with mild dementia). Plasma p-tau217 was over three-fold higher in Aß + (12.4 pg/mL; 7.3-19.2 pg/mL) vs. Aß- 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 Aß 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 Aß pathology (z = 3.24, p < 0.001). Of the other BBMs, only plasma GFAP significantly differed by Aß status which significantly correlated with plasma p-tau217 in Aß + (but not in Aß-) 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. CONCLUSIONS: Plasma p-tau217 measured using a high-sensitivity ECL immunoassay demonstrated excellent performance for detection of Aß 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.

Rationale and design of the BeyeOMARKER study: prospective evaluation of blood- and eye-based biomarkers for early detection of Alzheimer's disease pathology in the eye clinic.

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

The associations between common neuroimaging parameters of Progressive Supranuclear Palsy in magnetic resonance imaging and non-specific inflammatory factors - pilot study.

Progressive Supranuclear Palsy is an atypical parkinsonism based on tauopathic pathology. Growing interest is associated with the pathomechanism of this disease. Among theories analyzing this issue can be mentioned the one highlighting the significance of inflammation. In this study authors examined 14 patients with PSP-Richardson syndrome (PSP-RS) and 13 healthy volunteers using laboratory testing based on the analysis of interleukins 1 and 6 (IL-1 and IL-6), tau in the cerebrospinal fluid (CSF) and non-specific parameters of peripheral inflammation in the serum (IL-1, IL-6, neutrophils, lymphocytes, monocytes, platelets and the ratios based on the factors). All of the patients underwent neuroimaging using magnetic resonance imaging using 3 Tesla. The serum levels of IL-1 were positively correlated with the area of the mesencephalon, suggesting that higher levels of IL-1 are not linked with atrophic changes in this region, whereas serum levels IL-6 was positively correlated with frontal horn width and negatively correlated with superior cerebellar area. Additionally IL-6 in the serum was found to be correlated with neutrophil-to-high density lipoprotein ratio. The observations were not confirmed in the analysis of the levels of interleukins in the CSF. To the best of our knowledge this work is one of the first analyzing this issue. The outcome of the work shows that the role of interleukins associated with microglial activation may possibly differ in the context of neurodegenerative changes, moreover the role of peripheral inflammation in PSP requires further analysis.

Blood biomarkers for neuroaxonal injury and astrocytic activation in chemotherapy-induced peripheral neuropathy.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome side effect in patients exposed to taxanes in the treatment of cancer and may affect quality of life dramatically. Here we assessed whether serum levels of neurofilament light (NfL) and tau (two neuroaxonal injury biomarkers) and glial fibrillary acidic protein (GFAP, a biomarker for astrocytic activation) correlate with the development of CIPN in the adjuvant setting of early breast cancer. MATERIALS AND METHODS: Using ultrasensitive single molecule array technology, serum levels of NfL, GFAP, and tau were measured before and every 3 weeks in 10 women receiving adjuvant EC (epirubicin 90 mg/m² and cyclophosphamide 600 mg/m²) every 3 weeks × 3, followed by weekly paclitaxel 80 mg/m² × 9-12 weeks after surgery due to early breast cancer. CIPN was graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) and the questionnaire EORTC QLQ CIPN-20. RESULTS: Serum levels of GFAP increased successively during cycles of EC. NfL increased instead in response to the treatment of paclitaxel. NfL and GFAP continued to rise throughout exposure of cumulatively higher doses of paclitaxel and were reduced 3 months after the end of chemotherapy. Serums levels of tau were marginally affected by exposure to chemotherapy. Women with worse symptoms of CIPN had higher concentrations of NfL than women with mild symptoms of CIPN. INTERPRETATION: NfL and GFAP are promising biomarkers to identify women at risk of developing CIPN. Larger prospective studies are now needed.

Differential neuropsychiatric associations of plasma biomarkers in older adults with major depression and subjective cognitive decline.

Older adults with major depressive disorder (MDD) or early cognitive decline during the subjective cognitive decline (SCD) stage may exhibit neuropsychiatric symptoms such as anxiety, depression, and subtle cognitive impairment. The clinicopathological features and biological mechanisms of MDD differ from those of SCD among older adults; these conditions thus require different treatment strategies. This study enrolled 82 participants above 50 years old with normal cognitive levels from the communities to examine biomarker-behavior correlations between MDD (n = 23) and SCD (n = 23) relative to a normal control (NC) group (n = 36). Multidomain assessments were performed for all participants, including immunomagnetic reduction tests to detect plasma beta-amyloid (Aß), total tau (Tau), phosphorylated tau-181 (p-Tau181), neurofilament light chain, and glial fibrillary acidic protein (GFAP). This study observed that depressive symptoms in MDD were associated with amyloid pathology (plasma Aß40 vs. HADS-D: R = 0.45, p = 0.031; Aß42/Aß40 vs. HADS-D: R = -0.47, p = 0.024), which was not observed in the NC (group difference p < 0.05). Moreover, cognitive decline in MDD was distinguished by a mixed neurodegenerative process involving amyloid (plasma Aß42 vs. facial memory test: R = 0.48, p = 0.025), tau (Tau/Aß42 vs. digit symbol substitution test (DSST): R = -0.53, p = 0.01), and astrocytic injury (plasma GFAP vs. Montreal cognitive assessment score: R = -0.44, p = 0.038; plasma GFAP vs. DSST: R = -0.52, p = 0.014), findings that did not apply to the NC (group difference p < 0.05). Moreover, this study revealed different biomarker-behavior correlations between individuals with SCD and the NC. Compared with the NC, cognitive decline in the SCD group might be unrelated to amyloid pathology and instead might be early manifestations of tau pathology. This study underscores the difference in clinicopathological features between MDD and SCD among older adults, which differ from those of the NC. These findings enhance our understanding of the mechanisms underlying MDD and SCD in older individuals.

Clinical significance of plasma candidate biomarkers of Alzheimer's Disease.

The number of patients with Alzheimer's Disease (AD) has increased rapidly in recent decades. AD is a complex progressive neurodegenerative disease affecting c.14 million patients in Europe and the United States. The hallmarks of this disease are neurotic plaques composed of the amyloid-ß (Aß) peptide and neurofibrillary tangles formed of hyperphosphorylated tau protein (pTau). To date, four CSF biomarkers: amyloid beta 42 (Aß42), Aß42/40 ratio, Tau protein, and Tau phosphorylated at threonine 181 (pTau181) have been validated as core neurochemical AD biomarkers. Imaging biomarkers are valuable for AD diagnosis, although they suffer from limitations in their cost and accessibility, while CSF biomarkers require lumbar puncture. Thus, there is an urgent need for alternative, less invasive and more cost-effective biomarkers capable of diagnosing and monitoring AD progression in a clinical context, as well as expediting the development of new therapeutic strategies. This review assesses the potential clinical significance of plasma candidate biomarkers in AD diagnosis. We conclude that these proteins might hold great promise in identifying the pathological features of AD. However, the future implementation process, and validation of the assays' accuracy using predefined cut-offs across more diverse patient populations, are crucial in establishing their utility in daily practice.

Neurodegenerative biomarkers in different chambers of the eye relative to plasma: an agreement validation study.

BACKGROUND: Protein biomarkers have been broadly investigated in cerebrospinal fluid and blood for the detection of neurodegenerative diseases, yet a clinically useful diagnostic test to detect early, pre-symptomatic Alzheimer's disease (AD) remains elusive. We conducted this study to quantify Aß40, Aß42, total Tau (t-Tau), hyperphosphorylated Tau (ptau181), glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) in eye fluids relative to blood. METHODS: In this cross-sectional study we collected vitreous humor, aqueous humor, tear fluid and plasma in patients undergoing surgery for eye disease. All six biomarkers were quantitatively measured by digital immunoassay. Spearman and Bland-Altman correlation analyses were performed to assess the agreement of levels between ocular fluids and plasma. RESULTS: Seventy-nine adults underwent pars-plana vitrectomy in at least one eye. Of the 79, there were 77 vitreous, 67 blood, 56 tear fluid, and 51 aqueous samples. All six biomarkers were quantified in each bio-sample, except GFAP and NfL in tear fluid due to low sample volume. All six biomarkers were elevated in vitreous humor compared to plasma samples. T-Tau, ptau181, GFAP and NfL were higher in aqueous than in plasma, and t-Tau and ptau181 concentrations were higher in tear fluid than in plasma. Significant correlations were found between Aß40 in plasma and tears (r = 0.5; p = 0.019), t-Tau in plasma and vitreous (r = 0.4; p = 0.004), NfL in plasma and vitreous (r = 0.3; p = 0.006) and plasma and aqueous (r = 0.5; p = 0.004). No significant associations were found for Aß42, ptau181 and GFAP among ocular fluids relative to plasma. Bland-Altman analysis showed aqueous humor had the closest agreement to plasma across all biomarkers. Biomarker levels in ocular fluids revealed statistically significant associations between vitreous and aqueous for t-Tau (r = 0.5; p = 0.001), GFAP (r = 0.6; p < 0.001) and NfL (r = 0.7; p < 0.001). CONCLUSION: AD biomarkers are detectable in greater quantities in eye fluids than in plasma and show correlations with levels in plasma. Future studies are needed to assess the utility of ocular fluid biomarkers as diagnostic and prognostic markers for AD, especially in those at risk with eye disease.

Plasma p-tau181 and amyloid markers in Alzheimer's disease: A comparison between Lumipulse and SIMOA.

Aim of the project was to evaluate the technical and clinical validity of plasma Lumipulse p-tau, Aß42 and Aß40 species and their correlation with CSF core Alzheimer's Disease (AD) markers; a method comparison with SIMOA was also performed. One-hundred-thirthy-three participants, namely 55 A+T+N+ AD, 28 Neurodegenerative disorders (NDD) and 50 controls were enrolled for the study. Lumipulse technical validity showed high stability for p-tau181, Aß42, and Aß40, with higher stability of p-tau to repeated freezing thaw cycles. p-tau181 levels detected by both techniques were higher in AD compared to both NDD/controls and exhibited a similar correlation with CSF p-tau levels, whereas Aß42 levels were slightly lower in AD with both methods. In the comparison between SIMOA and Lumipulse plasma markers, both techniques exhibited similar diagnostic accuracy for AD for p-tau181 (0.87; 95 %CI 0.81-0.94, vs 0.85; 95 %CI 0.78-0.93), whereas the best performance was reached by p-tau181/ Aß42 Lumipulse ratio (ROC AUC 0.915, 95 %CI 0.86-0.97). The study thus confirmed the construct validity of both Lumipulse and SIMOA techniques for the identification of CSF AD pattern in clinical settings.

Tau pathology mediated the plasma biomarkers and cognitive function in patients with mild cognitive impairment.

Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are putative non-amyloid biomarkers indicative of ongoing inflammatory and neurodegenerative disease processes. Hence, this study aimed to demonstrate the relationship between plasma biomarkers (GFAP and NfL) and 18F-AV-1451 tau PET images, and to explore their effects on cognitive function. Ninety-one participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and 20 participants from the Shanghai Action of Prevention Dementia for the Elderly (SHAPE) cohort underwent plasma biomarker testing, 18F-AV-1451 tau PET scans and cognitive function assessments. Within the ADNI, there were 42 cognitively normal (CN) individuals and 49 with mild cognitive impairment (MCI). Similarly, in the SHAPE, we had 10 CN and 10 MCI participants. We calculated the standardized uptake value ratios (SUVRs) for the regions of interest (ROIs) in the 18F-AV-1451 PET scans. Using plasma biomarkers and regional SUVRs, we trained machine learning models to differentiate between MCI and CN subjects with ADNI database and validated in SHAPE. Results showed that eight selected variables (including left amygdala SUVR, right amygdala SUVR, left entorhinal cortex SUVR, age, education, plasma NfL, plasma GFAP, plasma GFAP/ NfL) identified by LASSO could differentiate between the MCI and CN individuals, with AUC ranging from 0.783 to 0.926. Additionally, cognitive function was negatively associated with the plasma biomarkers and tau deposition in amygdala and left entorhinal cortex. Increased tau deposition in amygdala and left entorhinal cortex were related to increased plasma biomarkers. Moreover, tau pathology mediated the effect of plasma biomarkers level on the cognitive decline. The present study provides valuable insights into the association among plasma markers (GFAP and NfL), regional tau deposition and cognitive function. This study reports the mediation effect of brain regions tau deposition on the plasma biomarkers level and cognitive function, indicating the significance of tau pathology in the MCI patients.

Inflammatory plasma profile in genetic symptomatic and presymptomatic Frontotemporal Dementia - A GENFI study.

BACKGROUND: Inflammation has been proposed as a crucial player in neurodegeneration, including Frontotemporal Dementia (FTD). A few studies on sporadic FTD lead to inconclusive results, whereas large studies on genetic FTD are lacking. The aim of this study is to determine cytokine and chemokine plasma circulating levels in a large cohort of genetic FTD, collected within the GENetic Frontotemporal dementia Initiative (GENFI). METHODS: Mesoscale technology was used to analyse levels of 30 inflammatory factors in 434 plasma samples, including 94 Symptomatic Mutation carriers [(SMC); 15 with mutations in Microtubule Associated Protein Tau (MAPT) 34 in Progranulin (GRN) and 45 in Chromosome 9 Open Reading Frame (C9ORF)72], 168 Presymptomatic Mutation Carriers (PMC; 34 MAPT, 70 GRN and 64 C9ORF72) and 173 Non-carrier Controls (NC)]. RESULTS: The following cytokines were significantly upregulated (P<0.05) in MAPT and GRN SMC versus NC: Tumor Necrosis Factor (TNF)α, Interleukin (IL)-7, IL-15, IL-16, IL-17A. Moreover, only in GRN SMC, additional factors were upregulated, including: IL-1ß, IL-6, IL-10, IL-12/IL-23p40, eotaxin, eotaxin-3, Interferon γ-induced Protein (IP-10), Monocyte Chemotactic Protein (MCP)4. On the contrary, IL-1α levels were decreased in SMC compared with NC. Significantly decreased levels of this cytokine were also found in PMC, independent of the type of mutation. In SMC, no correlations between disease duration and cytokine and chemokine levels were found. Considering NfL and GFAP levels, as expected, significant increases were observed in SMC as compared to NC. These differences in mean values remain significant even when stratifying symptomatic patients by the mutated gene (P<0.0001). Considering instead the levels of NfL, GFAP, and the altered inflammatory molecules, no significant correlations emerged. CONCLUSION: We showed that inflammatory proteins are upregulated in MAPT and GRN SMC, with some specific factors altered in GRN only, whereas no changes were seen in C9ORF72 carriers. Notably, only IL-1α levels were decreased in both SMC and PMC, independent of the type of causal mutation, suggesting common modifications occurring in the preclinical phase of the disease.

Elevated plasma neurofilament light was associated with multi-modal neuroimaging features in Alzheimer's disease signature regions and predicted future tau deposition.

BACKGROUND: Neurofilament Light (NfL) is a biomarker for early neurodegeneration in Alzheimer's disease (AD). This study aims to examine the association between plasma NfL and multi-modal neuroimaging features across the AD spectrum and whether NfL predicts future tau deposition. METHODS: The present study recruited 517 participants comprising Aß negative cognitively normal (CN-) participants (n = 135), Aß positive cognitively normal (CN +) participants (n = 64), individuals with amnestic mild cognitive impairment (aMCI) (n = 212), and those diagnosed with AD dementia (n = 106). All the participants underwent multi-modal neuroimaging examinations. Cross-sectional and longitudinal associations between plasma NfL and multi-modal neuro-imaging features were evaluated using partial correlation analysis and linear mixed effects models. We also used linear regression analysis to investigate the association of baseline plasma NfL with future PET tau load. Mediation analysis was used to explore whether the effect of NfL on cognition was mediated by these imaging biomarkers. RESULTS: The results showed that baseline NfL levels and the rate of change were associated with Aß deposition, brain atrophy, brain connectome, glucose metabolism, and brain perfusion in AD signature regions (P<0.05). In both Aß positive CN and MCI participants, baseline NfL showed a significant predictive value of elevating tau burden in the left medial orbitofrontal cortex and para-hippocampus (ß = 0.336, P = 0.032; ß = 0.313, P = 0.047). Lastly, the multi-modal neuroimaging features mediated the association between plasma NfL and cognitive performance. CONCLUSIONS: The study supports the association between plasma NfL and multi-modal neuroimaging features in AD-vulnerable regions and its predictive value for future tau deposition.